3795 - Scrip

Transcription

3795 - Scrip

March 25th 2016 No 3795
scripintelligence.com
Witty Succumbs: GSK’s Search For New CEO Begins
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GlaxoSmithKline PLC’s beleaguered CEO Sir
Andrew Witty is to retire from the company
in March 2017. Chair Philip Hampton said the
UK pharma major would now start a formal
search for a successor and would consider
“internal and external candidates for the role.”
The news has not come as a big surprise.
When Hampton, a former chair of the Royal
Bank of Scotland, took on the role at GSK
last year finding a new CEO was widely
speculated to be one of his priorities.
Witty joined GSK in 1985 as a graduate
trainee. By the time he accepted the top job
in 2007, many would argue that he inherited
a bad hand. Supporters say he has played it
as well as he could, and that the UK’s biggest
drug maker is much better off as a result.
GSK was formed in 2000 by the merger of
GlaxoWellcome PLC and SmithKline Beecham
PLC, creating an unwieldy combination and the
world’s biggest drug maker at the time, and
its share price languished as a result. When he
started as CEO in 2008, Witty took an axe to
the edifice, launching a painful restructuring
process that cut costs and unnecessary
HIGH HOPES: Some investors want eventual
successor to enforce radical changes at GSK
infrastructure, diversifying the group’s product
mix and jettisoning non-core activities.
But he also came to the job just as several
US criminal and civil investigations into the
company under previous management were
drawing to an end. In 2012, Glaxo pleaded
guilty to charges of illegally marketing
drugs and agreed to pay a $3bn fine tied
to lawsuits over diabetes drug Avandia and
a variety of other legal disputes involving
its antidepressant Paxil. His tenure has also
Turn to page 8
Amgen’s PCSK9 Patent Win: A Long-Term Value Shift?
Amgen Inc. may have won a battle in its
lawsuit involving two patents on its proprotein
convertase subtilisin/kexin 9 (PCSK9) inhibitor
Repatha (evolocumab) against Sanofi SA and
Regeneron Pharmaceuticals Inc., which market
a competing drug, Praluent (alirocumab), but
the California biotech giant is far from winning
the war – that is, making the prophesied
blockbuster profits on its medicine.
In fact, both companies have struggled
to gain wide acceptance in the prescriber
community and nab the previously predicted
pots of gold for their PCSK9 inhibitors, which
are indicated in the US to treat certain
conditions that cause unusually high levels of
low density lipoprotein cholesterol.
But a March 16 jury verdict, and what
follows, stands to impact the profitability of
Let’s get
Social
both US-approved PCSK9s, obviously, more
positively for Amgen if it prevails in obtaining
royalties – shifting value in its favor.
In siding with Amgen, the jury in Delaware
determined the company’s rivals had failed
to prove the Repatha patents invalid on the
grounds of inadequate written description
and enablement.
Turn to page 10
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contents/editor’s letter
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Witty Succumbs: GSK’s Search
For New CEO Begins
Amgen’s PCSK9 Patent Win:
A Long-Term Value Shift?
Lilly’s Leap Tests Investors’
Faith In Solanezumab
Roche Commits Up To $1bn For
Blueprint’s Immunokinase Inhibitors
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Mega Pixel/shutterstock.com
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12Celator Claims Phase III Vyxeos
Victory In AML
13Biogen Loses Four Years Of EU
Tecfidera Exclusivity
14Allergan’s UK Generics Business
Up For Sale
14Rumor Has It: Express Scripts’
Miller Responds To Diabetes Buzz
Drug Price Competition:
An ‘Eye-Of-The-Beholder’ Debate
15Business Bulletin
16Orexigen Insists It Can Grow
India Avastin Off-Label Use:
Roche Defines Responsibility
18Fauci: Zika Funds Risks Branding
Did FDA Just Snatch Control
Of The Drug Price Debate?
18Beware The ‘Pitchforks,’ Pharma
19Policy & Regulation Briefs
20Expert View: Behind The Scenes:
CRUK Boasts 11-Day Breast Cancer
Therapy
Witty’s Successor: The Shortlist
Sanofi Throws Dice Molecules
A Multi-Billion Dollar Deal
10Clouds Darken Over Gilead’s
Zydelig In EU
11R&D Bites
Contrave After Takeda Exit
NIH ‘Unreliable’
How The Pfizergan Deal Got Done
21Stockwatch: Lilly And GW Move
Goalposts
22Pipeline Watch
23Appointments
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ISSN 0143 7690.
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March 25th 2016
@scripnews
Eleanor Malone,
Editor,
Scrip Intelligence
We hear a lot about big data and how it is a
resource just waiting to be properly tapped
by the big pharma industry.
People everywhere – patients, pharma
companies, technology firms, healthcare
providers – need to face up to its
vulnerabilities, though. A cybersecurity survey
from KPMG last year revealed that 81% of
healthcare organizations had been hacked
in the previous two years and only half of
healthcare execs felt they were adequately
prepared to prevent attacks. Meanwhile,
Arxan, a firm that makes software protection
technology, in its latest annual report into
the state of application security, exposes a
shocking level of vulnerability in healthcare
and finance apps. The organization tested
126 popular mobile health and finance
apps and found 90% had at least two of
the top 10 security risk features as outlined
by a recognised independent authority on
application security (OWASP). Even health apps
approved by the US FDA and the UK NHS were
no more secure than unapproved apps.
These findings suggest a catastrophic data
breach involving a healthcare organization
and/or healthcare app will happen sooner
or later. It will no doubt be a shock and an
outrage to affected individuals, who might
have thought a high level of security was a
given. New levels of anxiety and suspicion
about what happens to private data will not
be beneficial to organizations that collect
and use such data.
At the moment there is fragile public
support for pharma firms to have access to
health data: just over half of people responding
to a newly published survey commissioned
by the UK’s Wellcome Trust said they would
be happy for commercial organizations to use
their NHS data for research.
The Wellcome Trust report highlighted that
improved understanding about how data can
be used specifically in health research does
lead to greater acceptance of data sharing.
Pharma should take note and work on
effectively telling the good stories about
how data sharing can lead to new and better
treatments. But it should also remember that
data is a fragile gift from individual patients,
and get serious about striving for better data
security and tough sanctions against data
breaches and misuse.
© Informa UK Ltd 2016
headline news
Lilly’s Leap Tests Investors’ Faith In Solanezumab
Eli Lilly & Co. concedes that its revised primary
endpoint for the ongoing Phase III clinical
trial testing solanezumab in mild Alzheimer’s
patients goes against US FDA and European
Medicines Agency (EMA) requirements, but
the company is “hopeful” the change still will
support regulatory approvals.
Lilly’s stock fell 3.6% to $71.24 per share
on March 15 – the company’s lowest closing
price so far this year – after the big pharma
said the EXPEDITION3 primary endpoint
will be based solely on cognitive gains, not
cognitive and functional improvements,
despite prior FDA and EMA guidance that
both measures would be required for
approval of therapies to treat mild Alzheimer’s
disease. The FDA has shown some willingness
to consider cognitive data alone, but the EMA
has not, so Lilly’s hope that cognitive gains
alone will be enough to sway regulators could
be a big leap of faith.
Company spokesperson Nicole Hebert told
Scrip that Lilly is “hopeful that the efficacy and
safety data for solanezumab will support both
acceptance of our submission for review, as
well as approval.”
Could the FDA or EMA reject a biologic
license application (BLA) or marketing
authorization application (MAA) for
solanezumab if Lilly’s primary endpoint
analysis excludes functional improvements
for mild Alzheimer’s disease patients and
relegates functional gains to secondary
endpoint status? Maybe, maybe not. It may
depend on the strength of the cognitive
improvement results in EXPEDITION3, but
that’s a big bet to make in a disease that’s
seen many clinical trial failures.
Credit Suisse analyst Vamil Divan said in a
March 15 research note that “we think today’s
news does add greater uncertainty and risk to
what was already a high-risk program,” but the
analyst believes that solanezumab still has a
chance for clinical and regulatory success.
Trading Statistical Risk
For Regulatory Risk?
“Though it is unclear if improvement
on cognition only as a clinical endpoint
is sufficient for a trial examining mild
Alzheimer’s disease, [Lilly] may have decided
to take that risk while ensuring a statistical
effect is reached,” Datamonitor Healthcare
analyst Maha Elsayed said.
Datamonitor’s lead central nervous system
(CNS) analyst Daniel Chancellor said Lilly’s
decision does seem to suggest that the
company expects less than stellar functional
gains, which could drag down positive
cognitive results.
“I’m reading this as Lilly having less
confidence in the drug and it is shifting the
goalposts in order to give it the best shot
at the trial meeting its primary endpoint.
Lilly must be worried that a weak effect on
function would drag down the overall result,
and is hoping that the demand for a diseasemodifying drug would mean that regulators
would approve it, even with little or no
measurable effect on function,” Chancellor said.
Lilly made the decision to focus on
cognitive improvements, as measured by
the Alzheimer’s Disease Assessment Scale
– Cognitive subscale (ADAS-Cog14), for its
EXPEDITION3 primary endpoint after a review
of “emerging scientific evidence.”
Is Lilly shifting the goalposts
in order to give the drug its
best shot at meeting primary
endpoints in Phase III?
The new data, which include more detailed
analyses of the company’s prior EXPEDITION1
and EXPEDITION2 Phase III clinical trials and the
trials’ extension study EXPEDITION-EXT, show
cognitive declines generally precede and predict
functional declines experienced by patients
with mild Alzheimer’s disease. EXPEDITION-EXT
showed that solanezumab’s impact on cognitive
decline slowed disease progression by 34%.
While the company has new internal and
external data that support a cognition-only
primary endpoint analysis in EXPEDITION3,
it’s still unclear why Lilly waited until now
to move the analysis of functional gains
to secondary status. The company knew
back in 2012 that a 34% gain in cognition
for mild Alzheimer’s patients treated
with solanezumab in EXPEDITION1 and
EXPEDITION2 was statistically significant
versus placebo, but the 17% gain in function
was not significant.
Even so, Lilly emphasized that functional
gains still will be measured in EXPEDITION3
by the Alzheimer’s Disease Cooperative
Study-Instrumental Activities of Daily Living
(ADCS-iADL) and the Functional Assessment
Questionnaire (FAQ).
“For regulators in any geography interested
in the effect of solanezumab on function in
EXPEDITION3, those data will be available for
their review and consideration,” Hebert said.
Regulatory Guidance In Limbo
The FDA and EMA do not have to approve
Lilly’s decision to change the primary
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endpoint from a dual to a single data point,
because the revision amends only the data
analysis plan, not the way in which the
company will conduct the study. Lilly has
been in contact with the regulators regarding
the new EXPEDITION3 primary endpoint, but
the company has not received confirmation
that the change will not affect potential
solanezumab approval.
As it stands now, FDA guidance issued in
2013 regarding the development of drugs
for early-stage Alzheimer’s disease says that
primary endpoints should assess cognitive
and functional benefits or a composite that
takes both into consideration.
However, the guidance also acknowledges
that “milder functional and/or global
impairments become more challenging to
assess accurately, especially for patients early
in the spectrum of the illness,” which means
that “clear evidence of an effect on delaying
cognitive impairment may provide sufficient
evidence of effectiveness.”
The agency suggested that accelerated
approval may be possible for therapies
that show a cognitive benefit, if the
developer can show in additional trials or
extension studies that the drug provides
functional benefits.
EMA draft guidance on the clinical
investigation of Alzheimer’s and dementia
therapies, which was released in December,
was less forgiving: “In earlier disease stages,
assessment tools need to be more sensitive
and it is recognized that the requirement
of two co-primary endpoints addressing
cognition and functional activities of daily
living (ADL) might be difficult. However, it
is still necessary to demonstrate the clinical
relevance of the results.”
Bernstein analyst Tim Anderson pointed
out in a March 15 research note about the
revised EXPEDITION3 primary endpoint
that Lilly admits cognitive and functional
data are required for drug approvals in mild
Alzheimer’s disease, “so on its surface this
move by the company is concerning.”
On the positive side, Anderson wrote,
focusing on one primary endpoint ups
the chances of EXPEDITION3’s success.
On the negative side, he said, Lilly is
“signaling concern that functional changes
in the trial have a higher risk of not being
accomplished.”
Lilly completed patient enrollment in
EXPEDITION3 in 2015 and the last patient visit
is likely to take place in October 2016. The
company is expected to report top-line results
before the end of this year.
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March 25th 2016
3
headline news
Roche Commits Up To $1bn For Blueprint’s
Immunokinase Inhibitors
Right Partner, Right Economics
For Immuno-Oncology
Immunokinases are intracellular targets
involved in the regulation of immune
response. Blueprint and Roche will develop
small molecules that target immunokinases
with the goal of boosting the tumor immune
response. The companies will investigate
immunokinase inhibitors as monotherapies
and as part of combination regimens to boost
the efficacy of other immunotherapies.
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March 25th 2016
There are not a lot of large pharmas that
would be as flexible.”
Haviland noted that it was important for
Blueprint to retain US rights for two of the five
programs “as an opportunity to commercialize
and build out our company in a way that
complements our efforts. It was a big reason
why Roche was willing to consider the deal
and why we ended up doing the partnership
with them.”
Mega Pixel/shutterstock.com
When Blueprint Medicines Corp. sought a
partner to help advance its kinase inhibitors
with the potential to boost immune
responses to cancer, the company came
up with a short list of ideal big pharma
collaborators and Roche rose to the top.
Cambridge, Massachusetts-based Blueprint
will receive $45m from Roche up front
and up to $965m in option and milestone
fees under an agreement to develop
immunokinase inhibitors for as many as five
unnamed targets. Blueprint may keep the
US rights for up to two of the five programs,
which could help the biotechnology
company build commercial operations to
support its wholly-owned kinase inhibitors
for rare cancer indications.
Blueprint is developing small molecule
kinase inhibitors for genetically defined
patient populations. The company plans to
report Phase I data before the end of 2016
for its two lead programs in three different
indications: BLU-554, which targets fibroblast
growth factor receptor 4 (FGFR4), in the
treatment of hepatocellular carcinoma (HCC),
and BLU-285, which targets PDGFRa D842V
and KIT Exon 7 mutants, for the treatment of
gastrointestinal stromal tumors (GIST) and
systemic mastocytosis (SM).
Blueprint also has a year-old partnership
agreement with Alexion Pharmaceuticals Inc.
for the development of small molecule drugs
against a kinase associated with a rare genetic
disease. Last year’s Alexion agreement gave
Blueprint $15m up front with the promise of
up to $250m in milestone fees plus royalties
on future product sales, but Alexion will take
over development after an investigational
new drug (IND) application is submitted to
the US FDA.
The Roche agreement is a step up from
the Alexion deal on multiple levels. It keeps
Blueprint focused on cancer drugs, keeps the
company involved in development after the
IND is filed, and it gives Blueprint a greater
share of the financial upside.
Targeted Therapies,
Immuno-Oncology Combos
Blueprint chief scientific officer Christoph
Lengauer said the company knew when it
began looking at immunokinases that the
development of small molecule inhibitors
would require a partner with immunooncology combination study expertise, longstanding experience in immunology, and
access to tumor samples.
Both companies will earn
royalties ranging from the midsingle digits to the low double
digits in their partner’s territories
“With those parameters you have a small
list of partners. There was less than a handful
of companies and we approached all of
those,” Lengauer told Scrip. “Roche shared that
vision with us in the most desirable way.”
Blueprint will lead development of all
five programs under the Roche agreement
through preclinical and Phase I proof-ofconcept studies. For each asset, if Roche
exercises its option, the Swiss pharma will take
over clinical development after the proofof-concept studies and retain worldwide
rights, owing Blueprint royalties that range
from a low-double-digit to high-double-digit
percentage of sales.
If Blueprint retains US development rights
to two of the partnered programs in the US, it
will share post-Phase I clinical trial costs with
Roche. Both companies will earn royalties
ranging from the mid-single digits to the low
double digits in their partner’s territories.
“The whole deal, as it’s structured, has
different elements of balance to it,” Blueprint
chief business officer Kate Haviland told Scrip.
“We looked at how we balance the early
milestones with the back-end milestones.
@scripnews
Without disclosing the exact immunokinases
that the partners will focus on, Lengauer
said the targets were chosen based on
compounds in Blueprint’s library and targets
identified by the company’s genomics
efforts. Drug candidates that enter the
clinic under the collaboration will be tested
as monotherapies and in combination
with other immuno-oncology therapies,
including Roche assets and immunotherapies
developed by other companies.
“There is no restriction to using only Roche
compounds in the combinations. We are not
restricted in any way,” Haviland said. “We tried
to build in as much flexibility as possible,
because the deal is at such an early stage.”
Blueprint chief medical officer Anthony
Boral noted that “our goal is to find out what
are the best combinations for patients.”
Blueprint is not in a rush to sign additional
collaboration agreements and at the moment
the company does not plan to seek partners
for BLU-554 or BLU-285. Lengauer said the
company has reached the limits of its existing
capacity between its three clinical trials, a
couple of preclinical programs, the Alexion
partnership and now the Roche collaboration.
“We have our work cut out for us with this
collaboration, I think,” he said. “It’s up to five
targets and that’s huge if you look at Blueprint’s
programs and see that we have only six.”
Between its partnerships and its $147m
initial public offering in April, the company
appears to be well-positioned from a cash
standpoint to run early-stage studies for its
existing pipeline. Blueprint priced its IPO at $18
per share, which was above a preliminary range
of $15 to $17, but the company’s valuation has
slipped since then as have other biotech stocks
during the past six or seven months.
Blueprint traded as high as $20 on March 15
after the Roche deal was announced, but the
stock closed down 4.3% versus the prior day at
$17.03. The company’s market cap is $461.5m.
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headline news
Drug Price Competition: An ‘Eye-Of-The-Beholder’ Debate
It was like the Pharmaceutical Research and
Manufacturers of America (PhRMA) took a
page straight out of the payer groups’ and
generic lobbyists’ playbooks – declaring
competition is the best way to drive down the
prices of expensive medicines.
Indeed, in comments from more than
60 individuals, companies and stakeholder
groups submitted to Sens. Ron Wyden (D-OR)
and Charles Grassley (R-IA), there was wide
agreement competition was key to reducing
prescription drug prices in the US.
But from there, the perspectives about how
competition should work were in the eyes of
the beholders.
The comments came in response to a
December 2015 report in which Wyden
and Grassley accused Gilead Sciences Inc.
of putting profits before patient access to
the firm’s hepatitis C virus (HCV) medicines
Sovaldi (sofosbuvir) and Harvoni (ledipasvirsofosbuvir).
While it was Gilead’s HCV drug pricing
that prompted Wyden’s and Grassley’s
investigation, which spurred the report, the
lawmakers’ greater concerns were over the
fear the company’s $1,000-per pill strategy
would be more widely adopted and go viral.
In a March 14 statement, Wyden and
Grassley said they were reviewing the
63 comments they received and were
considering how to address policy issues
related to drug prices.
PhRMA argued that while the price of a
medicine may increase or decrease over its
lifetime, costs of drugs fall dramatically as
competition occurs among brand-name
therapies – dropping even further, up to 80%,
with the introduction of generics.
The big pharma industry group asserted
that prescription medicines “face some of the
most stringent cost controls in healthcare,”
due to the “concentration of purchasing
power” and extensive use of “aggressive
tactics,” like tiered formularies, by payers – cost
containment tools that “go to work quickly”
when new products arrive on the market.
PhRMA, whose new chief, Stephen Ubl, last
week said it’s time the industry went on the
offensive and drove the conversation about
drug prices, and the insurer and pharmacy
benefit manager (PBM) lobbying groups
– America’s Health Insurance Plans (AHIP)
and the Pharmaceutical Care Management
Association, respectively – all pointed to HCV
medicines as illustrative of how market forces
can work to contain costs, at least, for payers.
How they told their stories in their
comments to the lawmakers, however, differed.
Competition Fails MS
But while there’s been some cost reductions
in the HCV market, the same hasn’t been true
for multiple sclerosis (MS) medicines, AHIP
and some of the other stakeholders argued in
their comments.
When the first disease modifying therapy
(DMT) for MS came onto the US market in
1993, it was priced at $11,532 per year. But
today, that drug costs over $70,000 annually,
the National MS Society (NMSS) said.
“It is not uncommon to see multiple price
increases in a single year” for MS drugs, NMSS
told Wyden and Grassley.
The group pointed to a study published
last year in the peer-reviewed medical journal
Neurology, in which an analysis of the prices
of MS drugs from 1993-2003 by researchers
at Oregon State University and the Oregon
Health and Science University found that
the annual costs of DMTs grew from $8,000$11,000 to an average of $60,000, including
for the older drugs.
“While we would expect that legitimate
advances, such as the development of
oral DMTs, might garner higher prices, the
escalation in costs for first-generation agents
that have been available for up to two
@scripnews
decades is puzzling,” the authors of the April
2015 Neurology study wrote.
Updated information from the article’s
authors showed the prices of DMTs for MS have
continued to increase – some now costing
higher than $75,000 per year, NMSS said.
The pricing trends in MS, AHIP said, “seem
to defy basic economics.”
NMSS noted that patients have been
awaiting the first potential therapy for primary
progressive MS, Roche AG’s ocrelizumab,
an investigational humanized monoclonal
antibody designed to selectively target CD20positive B cells, which has been designated by
the FDA as a breakthrough therapy.
But NMSS said there’s concern about what
price Roche will set for the medicine once
it’s approved.
Government Control
Some of those who commented said the only
solution was for the US government to step in
and take control – PhRMA’s greatest fear.
“Until our government asserts a degree of
control over prices for medical goods and
services, Americans will continue to pay the
highest prices in the world for drugs,” said
Abbey Meyers, the founder of the National
Organization for Rare Disorders, who played
a key role in the Orphan Drugs Act getting
enacted in 1983.
But PhRMA would have none of that and
preferred the “forceful bargaining” of the PBMs
in containing costs over government controls.
Restrictions imposed by the UK’s National
Institute for Health and Care Excellence (NICE),
the drug industry group said, have created
“substantial barriers between patients and lifesaving treatments” – arguing that almost 80%
of caner medicines reviewed in the last seven
years by the agency have had some sort of
access limitation imposed on them.
NICE’s centralized value judgments also
have created delays to accessing new
medicines, PhRMA contended.
“There should be no mistake that
government assessments of value would
dramatically expand government’s role in
deciding which treatments patients do and do
not receive,” the drug industry group declared.
Notwithstanding the unsettled debate over
the development and use of value assessment
tools by private payers and other groups in
healthcare, “the competitive market is far
better positioned than government to drive
value in ways that are responsive to continued
innovation and individual differences,” PhRMA
argued, adding that methods of and approaches
to value assessment “must continue to evolve.”
[email protected]
March 25th 2016
5
headline news
India Avastin Off-Label Use: Roche Defines Responsibility
He explained that even a medical query
reply though scientifically sound, may be
“picked up” to be “promotional” if the safety
aspect wasn’t highlighted enough.
“A company can claim indemnity because it
can prove it has always promoted on label and
has gone to great lengths to tell doctors during
promotion and medical information replies
where not to prescribe the product. But courts
may not always agree,” the expert added.
David Smart/shutterstock.com
Swiss multinational Roche says that
it “respects” the Indian regulator’s
recommendations to permit off label use of
its anticancer, Avastin (bevacizumab), but has
made it clear that it can’t be held responsible
for risks associated with prescriptions for
indications other than the one the product is
approved for.
Roche said while physicians have the right
to choose which treatment is clinically best
for their patients, it is also important that
they understand, and explain to patients, the
risks associated with using Avastin off-label
in the eye.
“Once a medicine is used in a way other
than that for which it is approved for, the
responsibility lies with the person prescribing,”
Roche told Scrip when asked if the firm can be
held accountable for complications from offlabel use of Avastin.
Roche added that to ensure that physicians
are able to make these decisions with a “full
awareness” of the evidence, it will continue
to make them aware of the known risks
associated with the off-label use of Avastin in
the eye including that the product has neither
been developed nor manufactured according
to the quality standards for drugs to be
injected into the eye.
An industry expert, though, appeared to
suggest that defining accountability in offlabel use may have its own complexities.
“If the company can prove that it had
not promoted off label use then it is the
prescribing physician who gets questioned.
So liability passes to the healthcare
professional (HCP). However, in such a case
even medical to medical communication may
be examined. So any communication from an
employee, even informal, can be held against
it,” the expert said.
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March 25th 2016
Off-Label Use
Last week, India withdrew a previous notice
dated Jan. 21 that specified that bevacizumab
is not used in “ophthalmology” and that state
regulatory authorities alert their inspectorate
staff to monitor the “movement” of the drug
and its use in ophthalmology.
The alert followed reports that Avastin used
in the treatment of “eye ailments through
the intra-vitreal route” had led to the loss of
vision in certain patients in the CH Nagri Eye
Hospital in the state of Gujarat.
Roche, however, clarified that it had
completed an assessment of the available
information on the batch reported to have
been used at CH Nagri Eye Hospital and said
that based on the information available, there
is “no reason to believe” there were quality
problems with the Avastin vials in this batch.
“The batch was released for sale for the
approved indications in oncology across
global markets only after it was confirmed
to have met the safety and quality criteria
defined in the Good Manufacturing Practices
(GMP),” the company told Scrip.
On March 11, Dr GN Singh, Drugs
Controller General of India, said that it is now
proposed, based on the recommendations
of an expert committee, that the All India
Ophthalmological Society and the Vitreo
Retinal Society of India will formulate
guidelines for safe and effective use of
bevacizumab injection for ophthalmic
purpose, based on “written informed consent”
as is practiced globally for off-label use under
“appropriate environmental conditions” by
skilled ophthalmic surgeons based on riskbenefit analysis.
“They will further ensure that appropriate
training and awareness may be imparted to its
members,” Singh said in the March 11 notice.
The notice also refers to the expert
committee’s observations that bevacizumab
injection is not approved by global regulatory
authorities for intravitreal use due to
“non-application by the innovator” for this
purpose. It, though, notes that the WHO has
recommended the product by including it
in the list of essential medicines prepared
@scripnews
as anti-vascular endothelial growth factor
in the ophthalmic section based on the
recommendation of the International Council
of Ophthalmology. France and Italy have
permitted off label use as a temporary use
recommendation, it added.
The committee also noted that the safety
and efficacy of the product is said to be
proven in various independent studies done
globally - more than 2,500 studies have
been published.
Significantly, a leading Indian
ophthalmologist indicated to Scrip that he
had not had a single case of infection in
several years of having used Avastin and
attributed any safety concerns to potential
contamination during syringe preparation,
storage after part use or then possible
spurious products.
“Patients are willing to use the drug if the
doctor is confident about the product’s safety
and effectiveness,” he said, adding that price
was also an important consideration.
Cost factor
Significantly, the March 11 notice also refers to
the cost factor, wherein the committee noted
that bevacizumab is 40 times cheaper than
the other available drug, ranibizumab, “for
same use and equally effective” in India.
“This would put less financial burden on
patients and prevent blindness of many,” the
committee added.
Roche, however, told Scrip that it was
opposed to any efforts that would “override
informed clinical decision-making” by approving
or encouraging off-label use of compounded
bevacizumab for “economic purposes.”
“We firmly support a physician’s right to
make an informed choice of medication for
their patients, based on the available scientific
evidence,” it underscored.
Novartis’ ranibizumab (Lucentis/Accentrix)
and a version from the Indian firm Intas
Pharmaceuticals are available in India. Lucentis
was developed by Genentech (now part of
the Roche group), which retains commercial
rights in the US and Novartis has exclusive
commercial rights for the rest of the world.
Asked whether it expects the Indian decision
to buttress efforts internationally for off label
use and reimbursement decisions as seen in
France, Roche said: “We will not speculate.”
Last year a judge at France’s top
administrative court, the Conseil d’Etat,
turned down Roche’s request to suspend the
government’s decision to reimburse Avastin
for the off-label indication of wet age-related
macular degeneration (AMD).
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headline news
Did FDA Just Snatch Control
Of The Drug Price Debate?
The head of the Pharmaceutical Research
and Manufacturers of America, Stephen Ubl,
told industry to stop playing defense and go
on the offense to drive the discussion about
drug prices. The FDA, however, may have just
beaten drug makers to the punch.
By instituting a new policy to expedite the
reviews for applications of generic versions
of medicines that are the sole source on the
market, the FDA may have taken a big step in
changing the conversation about prescription
drug pricing – at least in situations involving
older marketed products whose prices have
recently skyrocketed.
Under the FDA’s new policy, companies
like Turing Pharmaceuticals Inc. and Valeant
Pharmaceuticals International Inc. that
buy up older sole-source drugs and take
advantage of that status by jacking up the
medicines’ prices will have less incentive to
follow that pattern.
The FDA unveiled its new expedited
action for abbreviated new drug applications
(ANDAs) in a manual of policies and
procedures, a public document used to
outline federal directives and changes to
internal guidelines and processes.
FDA spokesperson Stephen King told Scrip
the public debate over sole-source drugs
“prompted us to review our policies on point.”
“We identified a gap and were able to
identify a path forward to address it by
revising our review prioritization policy,”
King said.
He said the FDA has estimated the change
in its policy could potentially expedite up to
125 more ANDAs than before the revision.
King emphasized that while all ANDAs that
qualify are eligible for an expedited review,
“high quality submissions are easier to act
upon than low quality submissions.”
Lawmakers have been pressing the
FDA for months to make such a change
for fast-tracking applications for generic
versions of sole-source medicines. At a
Senate hearing in January, Sen. Susan
Collins (R-ME) suggested the FDA ought to
be able to use an “express lane” for those
products – especially when the owners of
the sole-source branded medicines have
substantially increased their prices.
She called on Janet Woodcock, director
of the FDA’s Center for Drug Evaluation and
Research, to work with lawmakers to set a
timeline for expediting approvals of generics
with the intent to “discourage a company
from buying up a decades-old drug and
increasing its costs.”
Collins insisted that if that expedited
pathway was “short enough,” the “hedgefund pharmaceutical companies” – meaning
Turing – would be discouraged from buying
sole-source drugs with the aim of hiking
their prices.
The lawmaker, who chairs the Senate
Aging Committee, had joined Sen. Claire
McCaskill (D-MO), the ranking member, earlier
this month in introducing a bill that seeks
to require the FDA to fast-track the review
of ANDAs for generics in which there is a
shortage of the medicines or there’s only
one supplier of a product and act on the
application within 150 calendar days.
The legislation also calls for the FDA to
establish a new generic priority review
voucher, which would be awarded to
manufacturers with successful ANDAs
involving a medicine that was on the agency’s
drug shortage list or provided competition
against sole-source products. The vouchers
would be used to expedite the review of
another ANDA.
Collins and McCaskill have been
investigating companies that have
significantly raised the prices of their drugs,
like Turing and Valeant, and are holding a
series of hearings on the matter – the first of
which was in December, with a second set for
March 17.
What’s been most frustrating for hospitals
in trying to obtain drugs like Valeant’s
Nitropress (sodium nitroprusside) and Isuprel
(isoprenaline), Erin Fox, director of the
Drug Information Service at the University
of Utah Health Care in Salt Lake City, told
Scrip before testifying at the December
Senate hearing, is knowing the company
isn’t using the extra cash it’s making off its
dramatic price increases to improve the way
those products are manufactured, because,
after all, the firm doesn’t actually make the
medicines – Pfizer Inc. subsidiary Hospira
Inc. does under a contract.
After being the subject of investigations by
prosecutors in Massachusetts and New York,
the Securities and Exchange Commission and
Congress, Valeant officials pledged to employ
“more modest” pricing of their medicines
from now on and to seek fewer transactions
focused on what it called “mispriced”
products – with CEO Michael Pearson, who
recently returned to his post after being
severely ill with pneumonia, reiterating that
point during a March 15 conference call with
investors and analysts.
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@scripnews
CRUK Boasts
11-Day Breast
Cancer Therapy
A Cancer Research UK-funded study
has shown that combination treatment
of Tykerb (lapatinib; Novartis AG) and
Herceptin (trastuzumab; Roche Holding
AG), given before surgery, is able to shrink
and “destroy” tumors in women with HER2positive breast cancer within 11 days.
The combination of Herceptin and
Tykerb is already approved for use in
HER2-positive breast cancer patients in
the UK but only after surgery. However,
Tykerb is not currently approved for use
on the National Health System (NHS)
in England and Wales, nor is the drug
available on the Cancer Drugs Fund.
The charity-sponsored EPHOS B trial,
led by researchers at The Institute of
Cancer Research, London, the University
of Manchester and University Hospital of
South Manchester NHS Foundation Trust,
studied 257 women with HER2-positive
breast cancer in the short gap between
initial diagnosis and surgery to remove
their tumors.
The trial planned to study the drug
combination by measuring biological
markers of cellular proliferation after 11
days of therapy. When trying to measure
this, researchers discovered that in roughly
a quarter of the 66 women who received
both drugs the remaining tumor was too
small for the second measurement of cell
proliferation. 17% of the women receiving
both drugs had only minimal residual
disease – defined as an invasive tumor
smaller than 5mm in size – and 11% had a
pathological complete response.
While current treatments are effective
in early stage HER2-breast cancer, and
complete response is common after
three to four months, researchers said
observing a disease response after 11
days was “very surprising.”
CRUK said that though the data
(presented at the 10th European Breast
Cancer Conference on March 10) are
early, they could result in some HER2positive breast cancer patients no longer
needing chemotherapy as a part of their
treatment. The charity hopes that once
the trial is completed, the data could
lead to a new, more personalized way to
treat certain HER2-positive breast cancer
patients whose cancers are sensitive to
[email protected]
the treatment.
March 25th 2016
7
headline news
Witty Succumbs: GSK’s Search For New CEO Begins
coincided with a wave of cheap competition
to some of GSK’s biggest-selling drugs, the
downturn in the global economy and the rise
of austerity.
Despite his efforts to revamp the company,
Witty’s job has often looked vulnerable in
recent years: weak sales, disappointing new
drug launches, profit warnings and bribery
allegations coincided with a damaging
corruption scandal in China. Top-selling drug
Seretide Evohaler (salmeterol xinafoate +
fluticasone propionate) - known in the US as
Advair Diskus - has seen its sales slump since
the start of 2015, underscoring the increasing
urgency for GSK to build up its overall
respiratory portfolio. But launches of new
drugs Breo Ellipta and Anoro Ellipta, expected
to take up the slack as sales of older products
decline, were slow to pick up.
Still, away from the well-documented
troubles in China and expensive legal
settlements, Witty has won praise for his
deal-making.
Highlights
Witty’s tenure has been notable for some
novel R&D partnerships as he sought to steer
the company through the generic erosion of
its mature brands.
After the formation of the HIV company
ViiV Healthcare with Pfizer in 2009 to position
it as a leading HIV player, the most striking of
these was the 2014 asset swap agreement
with Novartis. With this, GSK offloaded its
marketed oncology portfolio, related research,
and development activities and rights to
its AKT inhibitor afuresertib, in return for
Novartis’s global vaccines business (excluding
influenza vaccines). GSK will also grant
commercialization partner rights for future
oncology products to Novartis. In addition
the two firms created a new world-leading
consumer healthcare business, in which
GlaxoSmithKline will have majority control.
“Witty will leave the company primed for
growth,” said Datamonitor Healthcare lead
analyst Ali Al-Bazergan. “He will hope his
legacy will stem from his turnaround strategy
and his bold $20bn asset swap with Novartis
- moving away from riskier high-margin
pharmaceuticals in favor of consumer health
and vaccines.”
Citi analysts agree GSK is in better shape
than at the start of Witty’s tenure. “Sir Andrew
will leave as CEO in considerably stronger
position that when he inherited it from his
predecessor in 2008. However, as the relative
share price performance over the last six
years has indicated, there is still much work
to be done.”
8
March 25th 2016
(Continued from page 1)
What Happened Last Time
Sir Andrew Witty
GlaxoSmithKline’s respiratory and
infectious diseases portfolios will remain
the cornerstones of its prescription
pharmaceutical offering during 2014–24,
thanks to the contribution of blockbuster
asthma and chronic obstructive pulmonary
disease (COPD) therapy franchises (Breo and
Anoro) and a broad vaccines and HIV portfolio
(Tivicay), respectively.
Growth of the respiratory and infectious
disease portfolios, combined with smaller gains
in the immunology and inflammation, and
endocrine, metabolic, and genetic disorders
areas, will more than offset the impact of
the divestment of the oncology portfolio to
Novartis and large declines in cardiovascular
drug sales due to generic incursion.
However, it will face competition from
Boehringer Ingelheim in the respiratory sector
and Gilead in HIV.
Improved Outlook
The company’s outlook has improved in
recent months, with earnings forecast to grow
by a double-digit percentage this year. That
might help explain the unhurried timeline of
the transition, along with the board’s apparent
reluctance to disrupt the business at a critical
juncture for GSK, as the business shifts away
from pharmaceuticals and toward consumer
healthcare and vaccines.
But some investors want Witty’s eventual
successor to bring in radical change at GSK.
One, Neil Woodford, has been urging the
company to consider spinning off some of its
units to boost payoffs to investors. According
to Woodford GSK should be split in four parts
– with consumer health, vaccines, prescription
drug brands and HIV-focused ViiV Healthcare
all going their own way. Other investors
have suggested GSK buy out Pfizer Inc and
Shionogi & Company Inc.’s interest in ViiV
Healthcare Ltd, as well as Novartis’ interest in
their consumer joint venture.
Witty had considered an IPO of its stake in
ViiV, but the plan was scrapped last year.
@scripnews
Last time around GSK had the pick of three
exceptional internal candidates for the
top job, Witty, who was then president of
its European pharmaceuticals business,
David Stout, president of pharmaceuticals,
and Chris Viehbacher, president of its US
pharmaceuticals division, with Witty being
appointed in the autumn of 2007 and
succeeding J P Garnier when that executive
retired as CEO in May 2008.
The company will probably want to
avoid this time around what happened
then, irrespective of whether an internal
or external candidate is picked: both Stout
and Viehbacher left GSK in the months after
the Witty appointment, despite apparently
being offered various incentives to stay, with
Viehbacher most notably leaving to head the
European big pharma competitor, SanofiAventis, now called Sanofi.
Witty was, and still is, an engaging public
speaker, and had a formidable grasp of the
issues facing the industry back in 2007.
He was said to be highly experienced in
European pricing and value issues, and it may
be disappointing that significant progress
has not been made in value-based pricing,
with payers remaining focused on pricing and
costs to this day.
In some of his first utterances on strategy,
Witty highlighted increased investment in
consumer healthcare, vaccines, emerging
markets and the increased diversification of
it pharmaceuticals business, which in 2008
was dominated by 10 high-selling products;
it’s interesting to note such areas remain
prominent in GSK’s thinking today. But Witty’s
initial concerns back in the day were a high
patent cliff, improving the efficiency of R&D
and reducing the late-stage, Phase III, attrition
of promising therapeutic compounds.
On announcing his retirement, Witty said:
“GSK is a very special company with an inspiring
mission and many dedicated people. By next
year, I will have been CEO for nearly 10 years
and I believe this will be the right time for a
new leader to take over. In making this decision
it has been important to me that the Board
have the time to conduct a full and proper
process and that we sustain the momentum of
our current business performance, capitalizing
on the very significant progress we made last
year to strengthen the group. By doing so
we will strongly position GSK to achieve the
medium-term outlook set out to investors
last year and deliver a return to core earnings
growth in 2016.”
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headline news
Witty’s Successor: The Shortlist
“The board will now start a formal search
for a successor and will consider internal
and external candidates for the role,” said
GlaxoSmithKline PLC’s chair Sir Philip
Hampton, and the games begin.
GSK won’t want a repeat of the 2007/2008
fiasco, when the two of the three unsuccessful
internal candidates for the job – David Stout
and Christopher Viehbacher – left within
months of Sir Andrew Witty being appointed.
This time around, the roster of internal
candidates also features three strong runners:
Abbas Hussain, Emma Walmsley and Simon
Dingemans. The three have quite different
experiences and skill sets. The outcome will
depend on where the board, and also Witty,
see the future of GSK.
“We believe the CEO and board’s decision
[on divesting its consumer health business] in
likely late 2017/ 2018 will be determined by
interim margin improvement in the consumer
business, competitive environment and
Novartis (based on its decision on the put
option). Historic shareholder value creation
across industries argues for the sale/ spin,”
noted Citi analysts. However, splitting up GSK
is definitely not a forgone conclusion.
At GSK’s fourth quarter and annual results
presentation on Feb. 3, 2016 Witty said there
was an “extraordinarily low” likelihood of
GSK spinning off its consumer healthcare
business within the next three years. He was
also cautious of making the split after the
three year timeframe, espousing a “balanced
and Novartis. Prior to this Walmsley was
president of GlaxoSmithKline Consumer
Healthcare. She joined GSK in 2010, with
responsibility for Consumer Healthcare,
Europe. Prior to joining GSK, Walmsley
worked with L’Oreal for 17 years where she
held a variety of marketing and general
management roles.
Simon Dingemans
Dingemans has been CFO of GSK since April
2011. Simon joined GSK from Goldman Sachs
International where he was a managing
director and partner.
External Candidates
Could this be big pharma’s
first female CEO?
set of businesses” rather than aiming for one
key vertical.
Internal Candidates
Abbas Hussain
Hussain is president of global
pharmaceuticals, a position he has held since
October 2014. He joined the company as
president of emerging markets & Asia Pacific
in June 2008. He was previously president of
Europe at Eli Lilly.
Emma Walmsley
Walmsley is the CEO of GSK Consumer
Healthcare, the joint venture between GSK
Fund manager and GSK investor Neil
Woodford has been vocal in his preference
for an external candidate with a “fresh
pair of eyes” to replace Witty. The only
candidate that observers have put forward
thus far is David Epstein, head of Novartis
Pharmaceuticals since 2010. Prior to this he
was head of Novartis Oncology.
Left field
When Viehbacher left Sanofi in 2014,
rumor has it that another ex-GSK man
was approached about the job but turned
it down. Could Christophe Weber, Takeda’s
first non-Japanese CEO, be tempted back
to Europe for the top job at his former
employer?
[email protected]
Sanofi Throws Dice Molecules A Multi-Billion Dollar Deal
A more efficient way of tagging small molecules
in compound libraries and identifying those
that could affect protein-protein interactions
and be used therapeutically instead of
monoclonal antibodies, are some of the aims
of a potentially multi-billion dollar collaboration
announced Mar. 16 between Sanofi and DiCE
Molecules, a San Francisco-based biotech
founded in 2013.
Dysfunctional protein-protein interactions are
some of the most difficult processes to influence
therapeutically with oral small molecules, but
DiCE’s technology is “uniquely positioned to
overcome these historical challenges,” said
president and CEO Kevin Judice.
The technology was developed
by company founder Pehr Harbury, a
biochemistry professor at Stanford University,
and other founders include entrepreneur
John Bedbrook, who is founder and chair and
Phil Patten, a directed evolution expert, who is
founder and chief scientific officer.
DiCE’s technology allows the full range of
chemical compounds that act as ligands to
protein-protein interactions to be identified
and amplified, through tagging each of
them with a DNA template that directs
the synthesis of that ligand. This means
the ligand can be amplified for testing
and enhanced for drug-like properties in
proprietary assays in an efficient and rapid
manner, the company says.
The five-year, 12-target deal between Sanofi
and privately held DiCE will include the big
pharma providing more than $50m for equity,
upfront, target exclusivity, technology access
fees and research services, along with up to
$184m in research, clinical and regulatory
milestone payments per target, and royalty
payments based on any future annual net
sales, adding up to a potential value of $2.25
billion for the agreement.
The 12 targets represent disease areas of
strategic interest to Sanofi, and a joint steering
@scripnews
committee comprised of Sanofi and DiCE
representatives will oversee the initiative.
The company is increasingly turning
to external sources of innovation. The
DiCE deal is the fourth in the French
multinational’s “Sunrise” open innovation
initiative that is searching for and backing
potentially disruptive platform technologies
that could leapfrog the company’s
development pipeline to the nextgeneration of therapeutic products.
Previous “Sunrise” deals include one with US
biotech Warp Drive Bio which was refocused
on intractable oncogene and antibiotic
targets at the start of this year, a second
2014 deal with South San Francisco-based
MyoKardia, involving the identification of
targeted therapies for genetic heart diseases,
and a third with Cambridge, Mass.-based
Portal Instruments, Inc. that is developing a
needle-free drug delivery system.
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March 25th 2016
9
headline news
Clouds Darken
Over Gilead’s
Zydelig In EU
A fresh obstacle to Gilead Sciences Inc.’s
blood cancer therapy Zydelig (idelalisib)
is looming amid news the European
Medicines Agency is reviewing the PI3K
inhibitor’s safety profile after a jump in
serious adverse events, including deaths,
mostly due to infections, observed in
three clinical studies.
As part of the agency’s investigation,
done at the behest of the EU’s executive
European Commission, Europe’s top
drugs regulator will assess data from the
studies to see whether the findings have
any impact on currently the authorized
uses of Zydelig in Europe - chronic
lymphocytic leukemia (CLL) and follicular
lymphoma (FL).
London-based EMA in a statement
March 11 said the high adverse events
were seen in trials studying Zydelig in
combination with other cancer medicines.
Those clinical trials involved patients
with CLL and indolent non-Hodgkin
lymphoma. “The study in chronic
lymphocytic leukemia investigated
combinations of medicines that are
currently not approved, and the studies in
non-Hodgkin lymphoma included patients
with disease characteristics different from
those covered by the currently approved
indication,” the agency added.
“Patients who are receiving or starting
treatment with the PI3K delta inhibitor
should be carefully monitored for signs
of infection,” EMA said. It is considering
whether any other immediate steps are
needed while the review is ongoing.
Gilead acknowledged that a review of
ongoing Zydelig Phase III studies found
an increased risk of serious adverse events
and death, generally due to infections, in
patients receiving the therapy for first line
treatment of (CLL) and relapsed indolent
NHL (iNHL).
“We are proactively terminating several
ongoing studies in first line CLL and
iNHL and relapsed iNHL and conducting
a comprehensive review of all ongoing
studies,” the company said. It did not
elaborate. Zydelig received its marketing
approval in Europe 2014, along with
Johnson & Johnson/ AbbVie Inc.‘s BTK
inhibitor Imbruvica (ibrutinib).
Read full story at: http://bit.ly/1Zku7zt
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10 March 25th 2016
Amgen’s PCSK9 Patent Win: A Long-Term Value Shift?
The judge earlier dismissed Sanofi’s and
Regeneron’s claims of obviousness, Jefferies
analyst Biren Amin noted.
Amgen’s competitors immediately said they
would appeal – proclaiming they “strongly”
disagreed with the verdict.
“This is a complex area of law and science,
and we believe the facts and controlling law
support our position,” insisted Joseph LaRosa,
Regeneron’s general counsel, who said the
firm and its partner Sanofi were looking
forward to taking the case to the US Court of
Appeals for the Federal Circuit.
LaRosa asserted Praluent was developed
with Regeneron’s “proprietary science and
technology.”
‘In the end we have a hard time
believing that permanently
barring Praluent from the market
would be the final outcome’
The next step in the litigation, which
was filed by Amgen in October 2014, is
a March 23-24 hearing, in which District
Judge Sue Robinson of the US District Court
for the District of Delaware is expected to
decide damages and whether to impose a
permanent injunction that would block Sanofi
and Regeneron from marketing Praluent.
Analysts, however, predicted an injunction
was unlikely.
“In the end, we have a hard time believing
that permanently barring Praluent from the
market would be the final outcome,” said JP
Morgan analyst Cory Kasimov.
But Kasimov and other Wall Street analysts
expected either a settlement or a ruling,
under which Sanofi and Regeneron would be
required to pay royalties to Amgen.
With the jury verdict, the likelihood of a
settlement “has now increased substantially,”
declared Deutsche Bank analyst Tim Race.
But with the lack of available information,
“it is impossible to place a finger on exact
numbers,” said JPM’s Kasimov, who estimated
that figure could land in the mid-single digits,
“if not more.”
“But that’s only a preliminary guess,” he
emphasized, adding that the March 16 ruling
and the upcoming determination of damages
would have an impact on the size of the
royalty the firms may ultimately be required to
pay to Amgen.
Given the breadth of Amgen’s patents,
however, “it remains difficult” to determine the
likely extent of the royalties, DB’s Race added.
@scripnews
(Continued from page 1)
But he said a settlement with “modest
financial impact” seemed most likely.
If the royalties are set at 5%, Evercore ISI
analyst Mark Schoenebaum estimated that
would take a bite of about $106m out of
Regeneron’s 2020 forecasted sales.
Jefferies’ Amin pointed out that triple
damages were off the table, since Judge
Robinson said Amgen had failed to establish
sufficient evidence of “willful infringement.”
Value Impact
When Praluent, whose list price was set at
$14,600 per year, and Repatha, which was
priced slightly lower at $14,100, were both
approved last summer – and even before –
payers were frantic the PCSK9 class would
break the US healthcare system’s bank.
So they took advantage of the closely
timed launches of the medicines to instigate a
rebate and discount war between the rivals.
Pharmacy benefit manager (PBM) giant
Express Scripts Holding Co. ended up sealing
deals for both Repatha and Praluent.
CVS Health Corp, however, made an
exclusive deal with Amgen for its drug over
Sanofi’s and Regeneron’s PCSK9 inhibitor,
while health insurer giant UnitedHealth
Group Inc.’s PBM unit OptumRx in December
2015 added Praluent to its preferred access
formulary – snubbing Repatha.
Nonetheless, sales of both PCSK9s have been
slow out of the gate, analysts pointed out.
The companies are counting on their
cardiovascular outcomes trials to take them to
broader approvals for Repatha and Praluent,
which they hope will spark wider use –
garnering greater revenues.
Clearly, said JP Morgan’s Kasimov, an
injunction or royalty on net sales would
impact the value the companies ultimately
realize from their respective PCSK9 inhibitors –
favorably for Amgen, but not so for Sanofi and
Regeneron.
And, he said, royalties on net sales or an
injunction imposed on Praluent could in fact
impact the long-term value distribution of the
PCSK9 class.
Shares of Amgen gained $3.79 on March 16,
or 2.6%, before closing at $143.98, up 77 cents.
Trading in Regeneron’s shares was halted
from mid-morning just before the ruling
was revealed until early afternoon, but on
resuming, the stock tumbled $7.22, or 2%.
The shares, however, regained some ground,
closing at $368.46, up $1.24.
Shares of Sanofi also took a 2% hit, before
ending the day at $40.76, down 39 cents, or
about 1%.
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R&D bites
R&D Bites
Argenx, Bird Rock Bio:
Anti-IL6 RA Drug
Belgian biotech Argenx N.V. is looking to
low and infrequent dosing to carve out
a place for its novel anti-inflammatory in
rheumatoid arthritis. Its partner Bird Rock
Bio (formerly RuiYi) has announced that
their investigational product gerilimzumab,
a novel antibody that neutralizes IL-6, has
shown a safety and pharmacokinetics profile
that supports these attributes and therefor
has the “potential for favorable pricing”,
argenx says. The subcutaneous product
was tested in two clinical trials in a total of
50 healthy adult volunteers. IL-6 is a new
target in inflammation, and the only product
already approved in rheumatoid arthritis is
Roche’s Actemra (tocilizumab) that targets
the IL-6 receptor. Its two closest competitors
- Regeneron/Sanofi’s IL-6 receptor targeting
sarilumab, which has been filed for approval
in the US, and Johnson & Johnson’s
sirukumab, which targets the cytokine have so far failed to differentiate themselves
at Phase III. Product differentiation is
critical for new therapies attempting to
enter the already crowded rheumatoid
arthritis space, and one which is braced for
further competition from biosimilars of the
mainstay anti-TNF therapies. What experts
in the field want are novel biologics that
are associated with fewer treatment failures
and inadequate responders. Datamonitor
Healthcare says that between 30% and 40%
of patients fail on anti-TNF therapy, hence
the continued strong investment by the
industry in this disease. Argenx and Bird
Rock Bio’s product has a bit of catching up
to do, though, as it appears at the moment
to be the furthest back of the IL-6 targeted
MAbs in development. Slightly further ahead
of it in Phase II are Alder Biopharmaceuticals
and Bristol-Myers Squibb’s clazakizumab
and R-Pharm’s olokizumab, which is due to
enter Phase III this half. However, Bird Rock
Bio says it plans to complete submission
for a pivotal trial for rheumatoid arthritis
by the first half of 2016. Gerilimzumab
was originally discovered using argenx’s
SIMPLE Antibody platform and was further
differentiated with its proprietary NHance
technology that prolongs the circulation
time and improves the tissue distribution
of antibodies. Other IL-6 receptor targeted
MAbs in development for rheumatoid
arthritis include Roche’s humanized
tocilizmab follow-on product of SA-237 and
Ablynx’s IL6 receptor targeted nanobody
and a biobetter, ALX-0061.
Circassia Uses Adaptive Design For
Phase III
The Phase III study of Circassia PLC’s second
leading allergy product, Grass-SPIRE, will use
an adaptive design, an approach that senior
vice-president of R&D Rod Hafner believes has
not previously been used in the allergy sector.
The company plans to “repower” Grass-SPIRES’s
proposed pivotal Phase III study halfway through
its course, adjusting the number of subjects
recruited to make sure the study will achieve
a robust result at the end. The adaptive design
has been accepted by regulatory authorities,
Hafner noted. Initially Circassia will recruit 400
subjects during the 2016 grass pollen season and
confirm they have allergy symptoms, and will
then treat them with a single course of therapy,
eight administrations of 6nmol of antigens or
placebo, during the 2017 season, Hafner said
in an interview. Then based on results in the
these subjects, up to 1,100 more subjects will be
recruited into the study in 2017 for evaluation in
the 2018 grass pollen season. First results should
be available in the second half of 2018. The
conduct of clinical trials of potential new allergy
therapies can be problematic, with results made
uncertain by subjects being exposed to variable
amounts of other pollens that they may also be
allergic to, at different times, and to environmental
factors like temperature and humidity that can
affect treatment outcomes. The use of adaptive
design might allow results to be obtained quicker
and at a lower cost than more traditional designs.
But studies can fail for different reasons. A Phase
IIb study of one of Circassia’s other pipeline
products, Ragweed-SPIRE, failed to show a
statistically significant effect on symptoms when
compared with placebo in a study conducted
in 2014, said by the company to be due to the
optimal dose not being used; further clinical
studies are planned.
Janssen Seeks New Niche For Stelara
Doctors who treat Crohn’s disease are prescribing
biologics more frequently than in the past to
quickly reduce inflammation, but they’re searching
for alternatives to tumor necrosis factor (TNF)
inhibitors to cut the side effect risks, and that is
where the Johnson & Johnson subsidiary Janssen
Biotech Inc. may find its best niche for Stelara
(ustekinumab).The Interleukin-12 (IL-12) and IL-23
antagonist is approved in 87 countries to treat
psoriasis and in 71 countries to treat psoriatic
arthritis, including the US and EU where Janssen
is seeking approvals to treat Crohn’s disease.
The proportion of patients who were treated
with Stelara and had a clinical response, and the
number who entered remission, was statistically
significant versus placebo group response rates in
the Phase III UNITI-1 clinical trial from which results
were presented on March 18 during the Congress
of the European Crohn’s and Colitis Organisation
(ECCO). “We have a lot of expertise here at Janssen,
having developed [the TNF inhibitor] Remicade
(infliximab) in Crohn’s disease years ago. It’s a great
drug in inflammatory bowel disease (IBD), but there
@scripnews
are several patients who failed, or they responded
then failed, or they couldn’t tolerate anti-TNFs,”
Janssen Research & Development LLC vice
president of dermatology and gastroenterology
Philippe Szapary said in an interview with Scrip.
“The UNITI-1 trial enrolled patients who had failed
or were intolerant to TNF blockers, which is the
population with the highest unmet medical need,”
Szapary said.
GW Pharmaceuticals High
On Epilepsy Data
GW Pharmaceuticals PLC is preparing to file a new
drug application with FDA after its marijuanabased medicine showed an ability to reduce
seizures in children with a severe form of epilepsy.
Investors saw this as a good sign and believe
the drug can be approved despite the stigma
associated with cannabinoids. The company’s
stock more than doubled on March 14, jumping
125% to trade above $85 per share, well above
its 52-week low of $35.83. Investors and analysts
were both pleased with the company’s topline
results and believe epidiolex could have peak
sales over $1bn. The biotech announced results
from a Phase III trial of epidiolex compared with
a placebo in children with Dravet Syndrome, a
rare form of epilepsy that begins during infancy
and is highly treatment-resistant. The trial
showed that those patients taking the 20mg
dose of epidiolex had a 39% reduction in seizures
compared with only a 13% reduction in those
being given placebo, a statistically significant
improvement. The company conducted nine
different sensitivity analyses on the data. “I would
emphasize that the primary outcome measure,
the primary endpoint that we’ve presented to
you is the most conservative interpretation of the
data, which adds to our level of comfort,” said GW
Pharmaceuticals’ R&D director Stephen Wright on
a call with analysts on March 14.
Verona Makes Strides With COPD
Treatment
Verona Pharma’s dual-acting novel therapy for
chronic obstructive pulmonary disease (COPD)
RPL554 has matched the bronchodilatory effects
of salbutamol with fewer side-effects in a Phase
IIa study, top-line data show. Combined with
the molecule’s anti-inflammatory action, Verona
says the product could provide a meaningful
and much-needed new treatment option in
COPD both, alone or in combination. The data
appear to provide some early vindication for the
company’s decision to go it alone and concentrate
on a niche setting for the product, financed by
a £14m fundraising two years ago. RPL554 is a
novel inhaled PDE3/PDE4 inhibitor with both
bronchodilator and anti-inflammatory properties,
in development as a nebulised treatment for
acute exacerbations in COPD patients in a hospital
or homecare setting. Such patients typically
require additional bronchodilation as well as
anti-inflammatory treatment despite being on
maximum doses of approved COPD medications
(which often contain salbutamol), Verona says.
March 25th 2016
11
headline news
Celator Claims Phase III Vyxeos Victory In AML
sondem/shutterstock.com
AIMING HIGH: Vyxeos may hit
the market before competitors
Celator Pharmaceuticals Inc. more than
quadrupled in after-hours trading on March
14 after the company reported Phase III
overall survival (OS) data for Vyxeos (CPX-351)
that could support US and EU approvals for
the first new acute myeloid leukemia (AML)
therapy in almost 40 years.
Median OS for high-risk (secondary)
AML patients treated with Vyxeos, which
is a lyposomal formulation of a 5:1 ratio of
the chemotherapy agents cytarabine and
daunorubicin, was 9.56 months compared
with 5.95 months for patients treated
with the standard of care – a 7:3 ratio of
cytarabine and daunorubicin (HR=0.69;
p=0.005). Vyxeos also improved long-term
survival among the study’s 309 patients, who
represent a population with five-year survival
rates below 10%.
Ewing, New Jersey-based Celator plans to
submit a new drug application (NDA) to the
US FDA later this year, which will be followed
by submission of a marketing authorization
application (MAA) to the European Medicines
Agency (EMA) in the first quarter of 2017.
The Vyxeos data sent Celator’s stock up
367.9% to $7.86 per share after the stock
market closed, but the Phase III win also was a
victory for the Leukemia & Lymphoma Society
(LLS), which invested $9.1m via the nonprofit
group’s Therapy Acceleration Program (TAP)
to fund the company’s Phase II and III studies.
The LLS noted in a statement about the
Vyxeos results on March 14 that more than
25% of its budget is dedicated to research in
AML – one of the deadliest blood cancers.
TAP is a nine-year-old venture philanthropy
initiative that was designed to accelerate
research discoveries into the clinic with the
goal of reducing the time it takes to get new
therapies to patients. Vyxeos could be the
12 March 25th 2016
first TAP-funded program – and the LLS’s first
direct investment in a biotech company – to
win FDA approval.
“From the start, LLS recognized the
potential of [Vyxeos], so we are very gratified
with the results of this clinical trial, and we are
hopeful that this positive news brings us a
step closer to delivering better outcomes for
patients with high-risk (secondary) AML,” LLS
president and CEO Louis DeGennaro said in a
statement from the organization.
Phase III Data Show
Extended Efficacy
Celator executives were not available to
speak with Scrip immediate following the
Phase III Vyxeos announcement, but the
company planned to host a conference call
at 8 a.m. Eastern on March 15 to discuss
the results. Celator was not likely to provide
any data beyond its press release, since the
company intends to submit the results for
presentation during the American Society
of Clinical Oncology (ASCO) annual meeting
from June 3 to 7 in Chicago.
Beyond the OS data, Celator reported that
the percentage of patients who were alive 12
months after starting treatment was 41.5%
in the Vyxeos arm of the Phase III trial and
27.6% for patients treated with the traditional
cytarabine and daunorubicin regimen, which
is known as 7+3. Survival at 24 months was
31.1% for Vyxeos and 12.3% for 7+3.
The LLS also noted that 34% of patients
in the Vyxeos arm of the study were able to
follow their clinical trial participation with a
stem cell transplant compared with 25% in
the standard-of-care group.
Celator provided few safety details for Vyxeos,
but said 60-day, all-cause mortality was 13.7% in
the Vyxeos group and 21.2% for patients treated
@scripnews
with 7+3. There was no substantial difference
in the number of Grade 3 or higher adverse
events between the study’s two arms.
“The overall survival advantage seen with
[Vyxeos] compared to 7+3, along with a
superior response rate and no increase in
serious toxicity indicates that we’ll likely have
a new standard of care for treating older
patients with secondary AML,” the study’s
principal investigator Jeffrey Lancet said in
a statement from Celator. The doctor is a
senior member and chief of the Leukemia/
Myelodysplasia Program at Moffitt Cancer
Center in Tampa, Florida.
Patients enrolled in Celator’s Phase III study
were between the ages of 60 and 75, all of
whom had secondary AML – newly diagnosed
AML that occurred as a result of treatment for or
following a history of myelodysplastic syndrome
(MDS) or other rate myeloid malignancies. The
LLS notes that up to 80% of AML patients die
within five years of diagnosis, but the prognosis
is worse for secondary AML patients.
No Other AML Drugs
Awaiting Approval
Celator previously reported complete remission
rates (CRRs) in its Phase III study of 47.7% for
Vyxeos-treated patients and 33.3% for those
treated with 7+3. Based on the preliminary
Phase III data and prior Phase IIb results, Sagient
Research’s BioMedTracker analyst service gave
the drug a 39% likelihood of FDA approval
(LOA), which was 4% above average for cancer
therapies in similar stages of development.
Vyxeos has the second-highest highest LOA
out of the 12 Phase III AML therapies listed in
the BioMedTracker database. The highest LOA
of 42% was given to AG-221 from Celgene
Corp. and Agios Pharmaceuticals Inc. based
on high response rates, long-term stable
disease rates and good tolerability for the
IDH2 inhibitor in a Phase I clinical trial.
However, Vyxeos may hit the market well
before AG-221, assuming the Celator therapy
wins US and EU approvals, because Celgene
and Agios just started their first Phase III trial
in AML in October. There are no AML drugs
currently under consideration for approval in
the US, according to BioMedTracker.
The LLS is entitled to a return of up to
3.55 times its $9.1m investment in Celator,
according to the company’s quarterly
earnings statement filed with the US
Securities and Exchange Commission in (SEC)
November, or up to $32.3m. The return on
the LLS investment may come from cash
payments under licensing agreements for
Vyxeos or royalties from product sales.
[email protected]
headline news
Biogen Loses Four Years Of EU Tecfidera Exclusivity
The European Patent Office has revoked
one of the few remaining patents covering
Tecfidera (dimethyl fumarate) in Europe. The
method of use patent (EP2137537) covers the
use of 480mg of Tecfidera for the treatment
of multiple sclerosis, which is the labeled
dose of Tecfidera.
Though Biogen Inc. says it will appeal the
decision, and analysts expect this process
to take another couple of years, there is
now a real possibility that Tecfidera will lose
exclusivity in Europe in 2024, rather than 2028.
“We believe the probability of winning an
appeal is relatively low,” stated Baird Equity
Research analysts.
Denmark’s Forward Pharma A/S received
an intention-to-grant status from the EPO
on its competing EU patent (EP2801355)
around a year ago, which could be the reason
behind the latest decision. However, until the
EPO provides its written explanation of its
revocation decision, which could take some
weeks, the full picture is unclear.
Forward Pharma’s ‘355 patent covers a
composition of dimethyl fumarate that
includes a total daily dose of 480mg to treat
multiple sclerosis. Unsurprisingly, Biogen
and a number of generic companies are
opposing Forward Pharma’s ‘355 patent in
other proceedings.
In Europe, patent interference cases are
governed on a first-file basis, whereas in the
US it is on a first-to-invent basis. In Europe,
‘355 was filed in 2005, whereas Biogen’s ‘537
was filed in 2008.
Forward Pharma is also challenging the
US equivalent patent, but owing to the
variation in how patents are awarded, it
is difficult to assess how the US situation
might play out.
According to Baird, the latest decision
only leaves one active European patent
protecting Tecfidera and it is set to expire
in 2019. The patent covers formulations of
dialkyl fumarates and their use for treating
autoimmune diseases. However, the
company was granted ‘new active substance’
designation in Europe in late 2013, which
means it has 10 years of exclusivity in
Europe from the date of launch. “Thus, if the
company loses the appeal, Tecfidera sales in
Europe will be protected until 2024, despite
expiry of the formulation patent,” explained
the analysts.
Leerink analysts believe the US decision will
also go Forward Pharma’s way. “We continue
to favor Forward Pharma in both the US and
EU patent disputes and expect the parties to
reach a settlement sometime in the next 8-12
months,” they said.
“The granted ‘355 patent is infringed by
Biogen’s marketing of Tecfidera at the 480mg
dose,” said Forward Pharma in a company
update on March 11.
Forward Pharma is in Phase II development
with a slow release formulation of dimethyl
fumarate for the treatment of multiple
sclerosis and psoriasis. The company raised
$235m in an IPO in 2014.
Tecfidera is an immediate release
formulation of dimethyl fumarate. The product
was launched by Biogen in the US and Europe
in 2013, and 2014 revenue was $3.6bn, about
a third of the company’s total of $10.8bn.
“We currently forecast Tecfidera to make
$1.1bn in annual sales in the 5EU in 2023,
so any earlier loss of exclusivity – even in
the smaller EU market – would have a large
effect on Biogen,” Datamonitor Healthcare
analyst Daniel Chancellor told Scrip.
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PPD’S PHARMA COMPANY
OF THE YEAR
WINNER:
GILEAD SCIENCES
CATEGORY SPONSORED BY
The winner of this special award was chosen by Scrip Intelligence’s senior editorial team, based on a variety of key
metrics. Gilead Sciences enjoyed a phenomenal year, reaping the financial rewards of its transformational new
treatments for hepatitis C, which have propelled it into the top ten pharma companies worldwide. Following the launch
of its ground-breaking drug Sovaldi, Gilead’s 2014 pharma sales more than doubled to nearly $25bn dollars, and its
net profits nearly quadrupled. And this momentum continued with the arrival of its combination treatment, Harvoni.
Mike Ward, Global Director of Content for IBI Pharma News & Datamonitor Healthcare, said: “As the first big biotech to
break into the Scrip100 top 10, the choice of Gilead as PPD’s Pharma Company of the Year was not a difficult one.”
@scripnews
March 25th 2016
13
headline news
Allergan’s UK
Generics Business
Up For Sale
The European Commission has approved
the proposed $40.5bn acquisition of
the generics business of Allergan (the
company formerly known as Actavis) by
Teva, subject to a number of significant
conditions, including the divestment
of the majority of Allergan Generics’
business in the UK and Ireland.
The Commission had concerns that
the merged entity would have faced
insufficient competition from the
remaining players in the generics space.
Commissioner Margrethe Vestager,
in charge of competition policy,
commented: “Effective competition
between generic pharmaceutical
manufacturers is essential to drive down
prices for patients and healthcare systems.”
Teva and Allergan are currently the two of
the largest generics retailers in the UK, with
Mylan and Sandoz making up the top four.
The Commission found that Iceland,
Ireland and the UK, where the merging
parties are the two largest generics
suppliers, the remaining players would have
been unable to compete effectively with
the merged entity due to the prevalent
distribution models and the structure of the
national generics market.In particular:
• In Iceland, Allergan Generics has
historically been the dominant generics
supplier, a position that was being
challenged by Teva’s offering, sold by its
wholesaler Lyfis.
• In Ireland, Teva and Allergan
Generics are recent entrants that
shortly afterwards became market
leaders, successfully challenging
the established generics players, in
particular through aggressive pricing.
• In the UK, Teva and Allergan
Generics are the only two generics
manufacturers with a portfolio of
generics broad enough to be able to
sell directly to pharmacies (without
going through a wholesaler), offering
competitive discount schemes and a
level of service valued by customers.
In view of these market features,
the Commission concluded that the
elimination of one of the merging parties
would harm competition for the sale of
generics in these countries.
Read full story at: http://bit.ly/1UwVnvg
[email protected]
14 March 25th 2016
Rumor Has It: Express Scripts’
Miller Responds To Diabetes Buzz
You’ve probably heard the recent chatter
about Express Scripts not being interested in
making Novo Nordisk’s newest insulin offering
a preferred option, despite recent studies
showing that Tresiba was differentiated from
Sanofi’s market-leading insulin Lantus. Express
Scripts’ CMO Steve Miller clarified comments
he recently made in the press and the
pharmacy benefit manager’s thinking behind
pricing in the diabetes market.
Miller created quite a buzz when he told
Bloomberg that the recently released Tresiba
(insulin degludec) data would have little
impact on a formulary coverage decision.
The pharmacy benefit manager’s rationale for
this was that the differentiation – that Tresiba
helped patients control incidents of low blood
sugar better than Lantus (insulin glargine) – was
just not enough. Miller even went as far as to
say that they’ve given patients better options
for controlling these hypoglycemic events.
Miller’s comments put a kink in Novo
Nordisk’s strategy (which has been trying
to push Tresiba in an effort to shore up its
franchise) and added a new dynamic to the
hot issue of pricing. Yet, the chatter left the
market wondering where this leaves the
major diabetes drug makers.
In hopes of shedding a little more light on
the subject, Scrip caught up with Miller and
got some clarification on the decision.
Miller explained that Express Scripts has a
self-governing, independent body of physicians
and experts – who are not allowed to consider
price – to review all of the clinical decisions
based on data provided by the pharmaceutical
company, as well as publicly available data, data
used for FDA submissions and even real-world
experience. He also noted that the PBM looks
at assessments from other groups like the nonprofit Institute for Clinical and Economic Review
(ICER) to inform its decisions.
In regard to the SWITCH-1 and SWITCH-2
trials, which pitted Tresiba against Lantus,
Miller said, “ICER, like our people, found that
the difference, while statically significant,
was insufficient to justify a premium in the
marketplace.”
“There is not just one way to get to
a clinical outcome,” he said, explaining
that drugs aren’t the only way to control
hypoglycemic events in diabetes patients.
Sanofi has tried to make similar claims about
hypoglycemia for its own Lantus-update Toujeo
(insulin glargine) – also to no avail. While clinical
trials results show the benefits, there has been
no label change and payers have not been
interested in the slight difference. Sanofi, unlike
@scripnews
Novo Nordisk, has been willing to compromise
greatly on price just to get Toujeo on formulary.
Toujeo, a more concentrated form of Lantus, is
priced on par with its predecessor at about 25
cents per insulin unit.
Meanwhile, Express Scripts lists Tresiba as
a non-preferred option – meaning it requires
a higher co-pay than other insulins on the
market. This isn’t the first time that Novo
Nordisk has been thwarted by the PBM: its
market-leading GLP-1 Victoza has just entered
its third year as a non-preferred option on the
Express Scripts formulary and has been losing
market share to better priced options.
‘There is not just one way to
get to a clinical outcome,’ and
drugs aren’t the only way to
control hypoglycemia
Miller noted that taking Victoza off the
formulary was an instance where the PBM got
to be opportunistic. “We had real world data
[about the GLP-1s] that the pharmaceutical
manufacturers didn’t have. Our data showed
us that patients didn’t stay on [Victoza] very
long and that when they moved off the GLP-1s
they often moved to different classes of drugs,”
said Miller. After looking at clinical equivalency
data, Express Scripts made the decision to stop
covering the market leader in favor of lower
cost GLP-1s from other manufacturers.
Yet, the PBM doesn’t look at insulin the same
way as GLP-1s. “Insulins are different,” explained
Miller. “When I get a diabetic that is wellcontrolled on a medication, I am not excited to
move them to some other medication. So we
are much more careful not to make frequent
changes and risk patients being uncontrolled.”
It is decisions like these that have analysts
and investors closely watching the market for
any indication on how pricing could affect
market share – especially since biosimilars
are expected to enter the market by the end
of the year.
“We are seeing more and more products
coming to the market place and we can take
advantage of the competition. We expect to see
our first biosimilar this year and we think that’s
going to be a great opportunity,” said Miller.
Novo Nordisk is going to be forced to take
a page out of Sanofi’s book and compromise
on price or watch as market share dwindles in
the face of increased competition.
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business bulletin
Business Bulletin
Valeant Investors Bail
As Credibility Plunges
Just when it seemed like Valeant
Pharmaceuticals International Inc.’s luster
on Wall Street couldn’t fade further, it has.
The company revealed March 15 that sales
and earnings for 2016 will be substantially
lower than previously forecast in December,
even as it has yet to file finalized 2015
financials – at the risk of defaulting on its
credit agreements. CEO J. Michael Pearson
was there to walk investors through the
numbers during a conference call, his first
public statements since returning from
an extended medical leave of absence
amid the company’s crisis. But the return
of Valeant’s outspoken leader did little to
soften the blow from the news, and investors
hit back. The company’s stock plunged
51% on the news, hitting a 52-week low
of $33.01 before closing the day at $33.51.
The company’s fall from a 52-week high
of $263.81 in August has been staggering.
Investors hoping Pearson would come to
the preliminary fourth quarter sales and
earnings report with a plan that would begin
to restore the company’s credibility were left
wanting. Instead, the unexpected change
in the financial forecast only added to the
uncertainty surrounding the firm and what
has been a steady stream of disappointing
news over the last six months, including a
legal probe into Valeant’s pricing tactics,
accounting fraud charges and management
issues amidst the controversy. Valeant has
not yet released finalized 2015 financial
results while it sorts out the accounting
issues related to its controversial relationship
with the specialty pharmacy Philidor Rx
Services that came to light in October.
J&J Innovation Launches JLINX
Johnson & Johnson Innovation LLC is expanding
its innovation strategy to include a new initiative
in Europe that combines venture investment
and company incubation. The initiative is called
JLINX and it is hoped that it will catalyze scientific
innovation and successful company formation
by offering start-ups flexible ways to grow and
collaborate across the European life science
ecosystem. JLINX will be located in a dedicated
facility on the Janssen campus in Beerse, Belgium,
and will be managed through a collaboration with
Bioqube Ventures, which will provide independent
oversight for venture funding and company
selection. “JLINX will provide innovators and
entrepreneurs with opportunities to share ideas
and collaborate with each other while accessing
the global resources of J&J including investment,
infrastructure, and access to relevant internal and
external scientific, technical and business expertise,”
Richard Mason, head of Johnson & Johnson’s
London Innovation Centre, told Scrip. The new
initiative is accepting applications immediately and
will be fully operational by this summer, he added.
Mason also outlined the criteria for selection to
the JLINX facility. “We’re looking for transformative
innovation ideas that will go forward and have
the potential to make significant contributions
to human healthcare in pharma, medical devices
or consumer health.” JLINX will be looking for
opportunities that are “loosely tied” to areas of
interest to J&J, but owing to the “broad nature” of
the company’s interests Mason expects the majority
of opportunities would be considered. However,
JLINX will have a particular interest in human
microbiome research, in line with the recent launch
of the Janssen Human Microbiome Institute.” It is
very likely that some of the companies that come
into JLINX will be very nascent,” said Mason. “Some
might be small, but want access to the capabilities
on offer. For others this may even be the catalyst
for their creation.” Johnson & Johnson Innovation
will work closely with Bioqube Ventures, which will
provide a management team to run the day-today operations of JLINX, including managing the
investment portfolio and relationships with external
venture investors, involvement in identifying and
securing new companies, and supporting the
overall scale-up of the new initiative.
India To Weed Out Over 300 FixedDose Combos
India has clamped down on the country’s
burgeoning market for irrational fixed-dose
combinations (FDCs), weeding out more than
300 such products – a move that is seen as
denting the industry sharply but being welcomed
by physicians given the lack of therapeutic
rationale for most of these medicines and the
growing challenge of drug resistance in the
case of anti-infectives. Pfizer and Abbott, whose
top cough syrup brands have been covered
under the ban, have, however, already moved
court against the government’s action. Pfizer
has secured interim relief from the Delhi High
Court on March 14. India’s ministry of health
and family welfare has already prohibited the
manufacture, sale and distribution for human
use 344 FDCs deemed likely to involve “risk to
human beings” and where safer alternatives are
available. The matter was examined by an expert
committee appointed by the central government
and the panel recommended that these FDCs
have “no therapeutic justification”, government
notifications, dated March 10 and now publicly
available, said. It is, however, not immediately
clear how pipeline stocks will have to be dealt
with. The ban covers products across segments
such as respiratory, pain, diabetes and cardiology
and is expected to impact over INR38bn ($572m)
of the Indian market in value terms, according
to early estimates from AIOCD AWACS, a market
research agency that tracks retail sales. The
respiratory, anti-diabetics, pain/analgesics and
anti-infectives segments are among those badly
@scripnews
hit, the agency’s data suggested. Pfizer and
Abbott are among those staring at big dents, with
their cough syrup brands Corex and Phensedyl
respectively to be pulled off the market, though
both firms have sought legal relief. Among
the Indian firms, Macleods, Mankind, Alkem,
Ipca and Glenmark are some of those affected.
Early on March 14, Pfizer informed the Bombay
Stock Exchange that it had “discontinued” the
manufacture and sale of Corex with immediate
effect, following the government prohibition
concerning the chlopheniramine maleate +
codeine syrup. The US firm, though, maintained
that Corex has a “well-established” efficacy and
safety profile in India for more than 30 years.
Corex reported sales of INR1.76bn for the nine
months ended December 2015.
Biocon-PiSA Gear To Mount
US Insulin Challenge
Biocon and Laboratorios PiSA SA de CV of
Mexico have cemented their ties further and
will now co-develop and commercialize generic
recombinant human insulin for the US market. The
duo have a long-running relationship in Mexico,
where they command a dominant position in the
insulins space - an estimated market share of over
50% for rh-insulin and a significant hold in the
insulin glargine space as well - according to the
Indian firm. Biocon now expects the alliance to
address the large demand for generic rh-insulin
in the US, which accounts for over 40% of the
global sales of $5bn and believes that the US
market offers a “very attractive price point” for
the product. More than 1.4 million people are
diagnosed with diabetes every year in the US.
“We believe it is a very lucrative opportunity
for Biocon to target. We have a significant
opportunity to play in this market through a
judicious discounting mechanism,” Biocon chair
and managing director Kiran Mazumdar-Shaw
said at media call on March 17. The US market
for the product, she noted, is largely an OTC
and institutional business and “plays well” to
Biocon’s strengths. Under the cost and profit
sharing agreement, Biocon will be responsible for
clinical development, regulatory approvals, and
commercialization of the product in the US. PiSA
with apply its sterile injectable and biotechnology
development and manufacturing capabilities to
contract manufacture Biocon’s generic rh-insulin
products. The alliance also expects to benefit from
PiSA’s proximity to the US market and Mexico’s
NAFTA membership that will ensure an efficient
and optimal supply chain to address the needs
of the US market, a company statement added.
Asked whether the FDA’s plans to move products
like insulin to the biologics license application
(BLA) process will have an impact on the alliance’s
plans, Biocon’s CEO, Dr Arun Chandavarkar, told
Scrip that there is a grand fathering of the 505
pathway that the firm is using for insulin and
glargine for 10 years. “The 10 years continue to be
in place till roughly the end of 2020. We don’t see
this to be a challenge since we expect to have our
filings well before that,” he said.
March 25th 2016
15
headline news
Orexigen Insists It Can Grow Contrave After Takeda Exit
Beware the Ides of March, especially if you’re
an investor in the obesity drug market.
Orexigen added further evidence that the
market is crumbling as it hitched its wagon to
a partner that is even worse off.
Orexigen did its best to put a positive
spin on its big pharma partner Takeda
Pharmaceutical Co. Ltd. exiting the alliance
for Contrave, and announced a smaller
partnership in hopes of distracting from the
news. Yet, investors remain unenthused by
the biotech’s new strategy for its obesity drug.
The La Jolla, Calif. biotech announced March
15 that its Japanese pharma partner Takeda
would be returning the rights to its obesity
drug Contrave (naltrexone/bupropion), ending
a five-plus year partnership. Orexigen called
it an acquisition that positions the firm for
growth, while Takeda claimed the exit is part of
its strategy to refocus its resources.
“We have long desired to take more active
role in the US commercialization of Contrave.
We are pleased that we have the opportunity
to acquire the asset which was in part made
possible because of Takeda’s desire to increase
its investments and focus on its recently
announced strategic therapeutic areas,”
Orexigen CEO Michael Narachi told a March
15 call with analysts.
“Orexigen now has the control and the
capital strength to implement a focused,
creative US commercialization plan designed
for near-term profitability while still building
and retaining value for the longer-term
potential of Contrave/Mysimba,” he added.
Orexigen investors weren’t buying the
positive spin: shares dropped 8.76% to close
well below $1 apiece. The stock is far from its
52-week high of $8.24.
The deal will close at the end of the month
and Takeda will transition Contrave back to
Orexigen over the next six months. During
that time, Takeda will continue to live up to
its commitment to commercialize the drug in
the US and Orexigen will continue to receive
royalties on the product.
Takeda isn’t merely giving the drug back
though; Orexigen will pay $60m upon closing
of the deal plus another $15m in the first
quarter of 2017. The biotech has also agreed
to pay out another $10m, $20m, $30m, $40m
and $50m in milestone payments should
Contrave exceed $200m, $300m, $400m or
$500m in sales, respectively, in any given year
(an unlikely occurrence since the drug just
broke $50m in sales annually).
The Slow Goodbye
Takeda’s departure shouldn’t come as a
surprise. The partnership was not a happy
16 March 25th 2016
match. The original deal was struck in
September 2010 when Takeda paid $50m
upfront and agreed to more than $1bn in
milestone payments. The partnership started
to get rocky when Contrave went from being
the frontrunner in the race to get a new
obesity drug to market to third-to-market
after several rounds with regulators.
Contrave finally garnered approval in
September 2014 and Takeda began the US
launch, but Orexigen was quick to accuse its
partner of neglecting its commercialization
responsibilities and insisted slow sales were due
to a poor ramp up by the Japanese pharma.
‘Orexigen now has control and
capital strength to implement
a focused, creative US
commercialization plan for the
Contrave/Mysimba’
The relationship deteriorated further
when Orexigen released early data from its
then-ongoing cardiovascular outcomes trial.
The move widened the rift between the
pair and brought criticism from FDA, which
then required the companies to conduct a
costly new CV outcomes trial. Orexigen said
the matter with Takeda had been resolved
in August 2015 when it took back Contrave
rights for Mexico and Canada, as well as
amending the deal agreement.
Another Bad Match?
In conjunction with the announcement about
Takeda, Orexigen also announced March 15
that it has struck a deal with beleaguered
Valeant Pharmaceuticals International Inc.
The specialty pharma has agreed to market
Contrave, known as Mysimba in Europe, in
19 Central and Eastern European countries.
The pair is expected to split proceeds 50/50.
Valeant is expected to launch the drug in
the second half of 2016 in the 12 European
countries that have already approved
Mysimba, including Greece, Slovenia, Slovakia,
Czech Republic, Hungary, Croatia, Lithuania,
Estonia, Poland, Latvia, Bulgaria and Romania.
“Our strategy outside of the US is to secure
partnerships with companies that have a
strong desire to commercialize our product.
Valeant has very strong capabilities in these
19 countries and we believe will make an
ideal partner for the region,” said Narachi.
Yet, a deal with Valeant is unlikely to quell
investor concerns. The specialty pharma
has been a regular in the headlines over the
@scripnews
last several months as it came to light that
Valeant had an unethical relationship with a
specialty pharmacy and has faced unrelated
accusations about price gouging.
We Can Do It Better
Orexigen is taking Takeda’s departure as an
opportunity to tell investors that it has a
plan in place to increase sales of Contrave.
The obesity drug is currently the market
leader in the space, at least amongst the
branded drugs, with a 41% share of branded
prescriptions. That statistic is misleading
though, because the obesity market is much
smaller than analysts once hoped it would
be and is currently dominated by low-cost
generic amphetamines – phentermine has a
75% share of the market.
But Orexigen believes that there will be
5% to 10% growth each year for the next
three years in the obesity market (despite
trends pointing to the contrary) and that
Contrave can capture a lot of that growth. The
company also believes that marketing to the
right prescribers will allow it to capture some
of those phentermine prescriptions, as well as
keep marketing costs down.
Orexigen is basing these assumptions on
surveys it has conducted amongst physicians.
“So physicians report that they would switch
approximately 34% of phentermine patients
to another medicine. And when asked what
agent they would switch to, they reported
Contrave 35% of the time, which is roughly
double the intent to prescribe of any other
agent in the market,” chief commercial officer
Thomas Cannell said. “It certainly speaks to the
huge potential that exists in the market and
the willingness of phentermine prescribers to
consider other agents.”
Cannell explained that Orexigen’s 160 sales
reps in 15 regions will call on approximately
18,000 targeted physicians. Up until this point,
Takeda has handled all US commercialization
activities and provided approximately 900
sales reps to launch the drug.
“We estimate that the frequency of
interactions with the right 18,000 targets will
increase roughly 7%. More importantly, because
our specialty organization will be dedicated
only to Contrave and we estimate that there
will be a roughly three-fold increase then the
time spent with each target,” said Cannell, who
expects costs for commercialization to run
between $80m to $100m annually, including
$25m set aside for DTC advertising. The
company admits it won’t be making any Super
Bowl commercials, but expects to use outlets
like Facebook and Pinterest to its advantage.
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headline news
Fauci: Zika Funds
Risks Branding NIH
‘Unreliable’
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18 March 25th 2016
ivo-soier/shutterstock.com
Congress’ failure to approve President
Barack Obama’s 1.9bn emergency funding
request to address the Zika virus risks
branding the National Institutes of Health
(NIH) an “unreliable partner,” complained
Anthony Fauci, director of the agency’s
National Institute of Allergy and Infectious
Diseases (NIAID).
While the NIAID has been “gratified”
by the interest it’s received from
biopharmaceutical companies in
partnering with the agency in pursuing a
Zika vaccine and other countermeasures
against the virus, “when it looks like the
funding on our part is somewhat tenuous,
that we may or may not get it or we
don’t know where we’re going to get it,
we’re looked upon a bit as kind of a nonreliable partner,” – a negative perception
the agency wants to avoid, Fauci told
reporters during a March 10 press briefing.
“You want to seek to have a collaboration,
but you want to know you’re a reliable
partner,” he said.
But, Fauci said, “uncertainty about
funding and how much we’re going to
put in and how much we’ll be able to do
really brands us a little bit, if not a lot, like
an unreliable partner.”
Fauci said it’s been his experience that
when the NIH has developed relationships
with industry and thought the agency
had funding coming, only to have
Congress not approve it, the companies
quickly backed away and eventually lost
interest altogether. He’s hoping that won’t
happen with the Zika efforts.
While Fauci said he was “cautiously
optimistic” about eventually having
Zika vaccine available – expressing
optimism about the number candidates
in the works – without the approval
of Obama’s request for the emergency
funds, which initially was for $1.8bn, but
he upped it to about $1.9bn, he said he
was worried about being able to keep
up the NIH’s efforts on the dollars that
essentially have been borrowed from
other programs.
If the NIH doesn’t get the emergency
funds, it might find itself halfway through
a Phase I trial and not being able to finish
it or being able to move on to the larger
Phase II and III studies, Fauci said.
Beware The ‘Pitchforks,’ Pharma
While lawmakers on March 17 spent another
day on Capitol Hill beating up on Turing
Pharmaceuticals Inc., it was the model that
company and other firms like Retrophin Inc.
and Valeant Pharmaceuticals International
Inc. base their businesses on – buying up
sole-source medicines and significantly
raising their prices, rather than engaging in
research and development activities – that
was under scrutiny at the Senate Special
Committee on Aging.
And the pitchforks are out, declared Sen.
Claire McCaskill (D-MO), the ranking member
on the committee, meaning Americans are at
the boiling point over skyrocketing drug prices.
“This nonsense is why people are furious,
and they’re mad at us, because we’re letting”
drug companies do it, she asserted.
But Sen. Elizabeth Warren (D-MA) made it
clear the pitchforks aren’t just aimed at the
Turings and the Valeants of the world, but also
at the big pharmas whose prices also have
shot up.
For instance, Warren said, the price of
Novartis AG’s lifesaving leukemia medicine
Gleevec (imatinib) has gone from $26,400 in
2001 to more than $120,000 today.
She pointed out that Biogen Inc. has raised
the price of its multiple sclerosis drug Avonex
(interferon beta-1a) an average of 16% per
year over the last decade.
The cost for Amgen Inc.’s tumor necrosis
factor alpha inhibitor Enbrel (etanercept) has
risen 88% over the last five years, Warren said.
And, she said, at the beginning of this year,
Pfizer Inc. raised its list prices by an average of
11% for more than 60 branded products.
“This happens again and again,” Warren
charged – insisting it was time for Congress to
take action to ensure the markets aren’t just
working for the biopharmaceutical firms, but
also “functions for patients.”
“If the market has actually failed, there is a
role for Congress to step in and put in price
limits,” said Sen. Sheldon Whitehouse (D-RI).
The pressure from Washington over drug
@scripnews
pricing is likely to continue for some time to
be a dark cloud hanging over the industry
– whose vulnerability was demonstrated
by the single tweet sent out last fall by
presidential candidate Hillary Clinton in which
she threatened to take on the price gougers,
which led to a $132bn drop in market cap.
Wall Street On The Hook
McCaskill also took aim at Wall Street –
charging that hedge funds and other investors
have “turned their eyes” to companies like
Turing, Valeant and Retrophin, because they’ve
realized those firms have a “commodity” with a
“stubbornly inelastic demand.”
The senator made her point by reading
an email exchange – part of a large group
of subpoenaed documents – between Dan
Wichman, a partner and analyst at Broadfin
Capital, who testified at the hearing, and former
Turing and Retrophin CEO Martin Shkreli, who
wasn’t on Capitol Hill on March 17, but had
appeared under a subpoena at a House hearing
last month, although he invoked his Fifth
Amendment Rights under the US Constitution
to remain silent when questioned.
“Funny that these small companies still
haven’t realized you can raise price aggressively
and nobody gets too upset,” Wichman told
Shkreli in a May 3, 2014 email, in which the two
were discussing Retrophin’s acquisition of the
orphan disease drug Thiola (tiopronin).
“I figure this dynamic may not last forever,
you need to maximize opportunities while
you can,” Wichman said.
He compared the differences between
Depomed Inc.’s more passive approach to
pricing versus Horizon Pharma PLC’s more
aggressive strategy – declaring that “It’s not
like people are giving companies gold stars
for charging slightly lower prices.”
It’s “ironic” how it took Jazz Pharmaceuticals
Inc. and Horizon to get to “the brink of
insolvency to decide they should aggressively
play the price card,” Wichman told Shkreli,
who is under indictment for fraud and
misappropriating its assets.
And while Questcor Pharmaceuticals Inc.,
which was acquired in 2014 by Mallinckrodt
Pharmaceuticals PLC, was the “poster child” and
took the “heat and bad PR” for its high pricing,
that approach “didn’t work out so badly in the
end, did it,” Wichman said in the email.
In closing the hearing – the second in
a series – McCaskill had one final warning
for pharmaceutical firms who’ve recently
raised their prices: “We’re not done. So better
grab while the grabbing’s good, because
something going to happen.”
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policy & regulation briefs
Policy & Regulationfailure
Briefs
to sign a free movement agreement with
Scrip Poll Result: Brexit
Would Be Bad For UK
Life Science Industry
It’s official. The vast majority of you think the
UK life sciences industry would hit stormy
seas should the country decide to leave the
relatively safe haven of the European Union.
Of the 128 people who had voted in Scrip’s
poll as of March 9, a total of 110 (85.94%) said
a Brexit would be bad for the industry, while
just six (4.69%) thought it would be a good
thing. 12 (9.38%) of those who voted expected
the effects to be “neutral”. Admittedly this is a
small and not necessarily representative sample
of our readers worldwide, and it gives no
indication as to the reasons why respondents
judge that a Brexit would be good, bad or
indifferent for UK life sciences. But the strong
showing against a Brexit is broadly in line
with the position taken by industry bodies in
Europe, which have expressed concern over
the likely regulatory, research, commercial and
other implications of a UK departure. The UK
BioIndustry Association said recently that a
UK departure would “negatively impact the
life sciences sector and lead to disruption,
expense and significant regulatory burdens for
a new authorization system.” For the European
R&D-based industry association EFPIA, the UK’s
continued membership of the EU is “in the best
interests of the pharmaceutical industry in the
UK and across Europe.” As might be expected,
the largest single block of votes in our poll – 53,
or 41.1% of the total – originated from the UK.
Perhaps surprisingly – or perhaps not, given
its strong presence in the EU pharma sector –
the US was next in line, with Scrip subscribers
there offering 22 votes (17.19%), followed
by Germany with 20 (15.63%). 10 people in
Switzerland expressed a preference, but in
France, the EU’s second-largest pharmaceutical
market after Germany, just five did so. The
remainder of the votes were spread across
Hungary, Australia, Belgium, Denmark, Chile,
India and Singapore. Of the 53 people who
voted in the UK, the overwhelming majority
(45 or 81.82%) felt a Brexit would be bad for
the life science industry, while just two (3.64%)
thought it would be a positive move. Six
people (10.01%) pressed the “neutral” button.
Interestingly, a greater proportion of US and
German respondents to the poll saw Brexit as a
bad thing (86.36% and 85% respectively). None
of the 10 voters based in Switzerland saw any
positives for industry in a Brexit (nine “bad”, one
“neutral”). Could this be linked to Switzerland’s
loss of access to the EU’s Horizon 2020 and
Erasmus research programs as a result of its
the newest EU member state, Croatia, in 2014?
Possibly, but we will never know. Our poll
does not of course reflect general UK attitudes
towards the EU, and as a subscriber-based
survey it will bear little or no resemblance to
the actual result of the referendum come June
23. But it does at least give a flavour of how
our readers throughout the world view the
consequences of a possible UK departure from
the EU after 43 years of membership.
Vectura, Skyepharma To Form
Respiratory Leader
A UK-based global leader in respiratory therapies
will be created by Vectura Group PLC’s planned
purchase of SkyePharma PLC in a friendly, all-stock
deal to forge a combined group with estimated
market capitalization of just over £1bn, joint sales
of £153.9m and profits of around £50.5m. Vectura is
offering SkyePharma shareholders 2.7977 new shares
for each share held, valuing SkyePharma at £441.3m
($621.9m). SkyePharma shareholders can alternatively
choose to receive a part of the offer in cash. An allstock deal would result in SkyePharma shareholders
owning about 41.75% of the combined company. If
the £70m available under the cash alternative is paid
in full, Skyepharma shareholders would own about
37.62% of the combined company. The planned
marriage, announced March 16, will tie together
two British biotechs which develop treatments for
asthma and other respiratory conditions. Vectura
has expertise in respiratory devices, formulation and
inhaled product development, while Skyepharma
offers inhalation and oral product development
capabilities and technologies. Skyepharma’s metered
dose inhalers, or MDI capabilities, open up the 38%
of the respiratory market that Vectura did not target
previously, bringing in growing revenues from its
best-selling asthma Flutiform (fluticasone/formoterol)
MDI product along with and near-term potential of
the novel flutiform-based inhalation product SKP2076 which is in preclinical feasibility studies, and a
promising Phase II respiratory asset SKP-2075 which
combines previously approved monotherapies
composed of low-dose theophylline and an inhaled
corticosteroid.
Analysis Provides Insight Into FDA’s
Biosimilars Workload
A final analysis of the first three years of the first
round of the Biosimilar User Fee Act (BsUFA) found
the FDA spent $81.7m on biosimilars-related work.
The analysis, conducted by Eastern Research Group
Inc. (ERG) of Lexington, MA, provides some insight
into the FDA’s ability to handle the workload and
costs associated with biosimilar activities, although
the research firm only reviewed the activities
surrounding seven applications – a number that is
expected to substantially increase over the coming
years. The FDA received two of those applications
in fiscal year 2014 and the others in FY 2015. But so
far, the agency only has approved one biosimilar
for the US market – Sandoz Inc.’s Zarxio (filgrastimsndz), which is a version of Amgen Inc.’s Neupogen.
@scripnews
Sandoz also is awaiting the FDA’s decisions on its
biosimilars of Amgen’s Neulasta (pegfilgrastim) and
Enbrel (etanercept). Apotex Inc. also has 351(k)s for
its pegfilgrastim and filgrastim biosimilars under
review at the FDA – applications whose user fee
action dates have already come and gone. The FDA
is expected to soon make a decision on Celltrion
Inc.’s 351(k) for CTP13, a version of Janssen Biotech
Inc.’s tumor necrosis factor blocker Remicade
(infliximab), which got a thumbs up last month
from the agency’s Arthritis Advisory Committee. But
the FDA has rejected at least one 351(k) – Hospira
Inc.’s biosimilar of Amgen’s Epogen (epoetin alfa).
Pfizer Moves To Block Unichem Over
Xeljanz Patent
Pfizer has moved court against Unichem
Laboratories seeking to block the Indian firm from
allegedly infringing its patents concerning the
rheumatoid arthritis therapy, tofacitinib (Xeljanz).
The case is significant given that in September last
year India rejected, for the second time, certain
patents concerning tofacitinib, though it is not
immediately clear if Pfizer has already appealed
against the decision. Unichem’s counsel is said
to have clarified to the Delhi High Court that the
company was not manufacturing or selling the
drugs/compounds that are a subject matter of
Pfizer’s Indian patent No.s 241773 and 218212.
Details in the court documents also indicated that
should Unichem want to commercially manufacture
and sell the drugs covered under Pfizer’s patent,
then the Indian firm would either “take a license
from the plaintiffs [Pfizer] or actions of the
defendants would be such which will not amount
to infringement of the patents of the plaintiffs.”
Unichem appears to have been working on an
“improved and efficient process” for the preparation
of tofacitinib citrate, though the current position on
this could not be ascertained by Scrip.
Bayer Protests ‘Incomprehensible’
German Decision on Stivarga In mCRC
A decision by the German health technology
assessment agency IQWiG that new analysis
provided by Bayer of Stivarga (regorafenib) in
metastatic colorectal cancer (mCRC) result in the
product’s disadvantages outweighing its benefits
“is essentially incomprehensible to Bayer,” the
German pharma told Scrip. Stivarga has been
approved in Europe since 2013 for adults with
mCRC for whom previous treatments are no
longer effective or where alternatives are not an
option. Bayer says it is “assessing all its options”
with regards to the latest news. In two previous
benefit assessments conducted in early 2014 and
in early 2016, IQWiG found a “hint of a minor added
benefit” of the drug over the comparator therapy.
This means survival benefit was accompanied by
frequent severe side events, said IQWiG. In these
assessments, IQWiG had also criticized Bayer for not
adequately analyzing the data on patient-reported
outcomes (symptoms and quality of life). In the
commenting procedure after the second dossier
assessment, Bayer presented changed analyses on
health-related quality of life and symptoms.
March 25th 2016
19
expert view
Behind The Scenes: How The Pfizergan Deal Got Done
The deal to combine Pfizer Inc. and Allergan
PLC was the culmination of 16 months of
careful negotiations, beginning with a dinner
between Ian Read and Brent Saunders in
July 2014, well before the company that was
then Actavis had even disclosed its interest
in merging with Allergan. The tortuous
process highlights just how challenging it is
to establish a solid union between two big
pharmas, not to mention finalize a megadeal. Pfizer approached Allergan and its
predecessor company Actavis two times and
walked away before a deal was finally signed.
The background behind the combination of
the two companies is outlined in a registration
statement filed by Allergan with the Securities
& Exchange Commission March 7. The process
started with dinner in July 2014, involved
advances and cold shoulders, and ended
in the $160bn mega-merger announced in
November 2015, the industry’s largest ever.
The initial dinner involved Pfizer CEO Ian
Read and chief financial officer Frank D’Amelio
and two leaders from the company that
was at the time Actavis, CEO Brent Saunders
and chair Paul Bisaro. The Pfizer executives
wanted to discuss a potential combination
with Actavis, a hybrid generics company
and specialty pharma built out of sequential
mergers between Watson Laboratories Inc.,
Actavis and Forest Laboratories Inc.
The dinner came just months after Pfizer
had been publicly spurned by AstraZeneca
PLC, which it had been looking to buy in part
for the company’s advantageous tax domicile
in the UK. Actavis, based in Ireland, also
offered tax benefits, and after the AstraZeneca
opportunity dissolved, reports surfaced
suggesting that Pfizer might pursue a merger
with another ex-US company, with Actavis
named as a potential target.
Pfizer In The Dark On
Actavis/Allergan
Actavis, on the other hand, was also pursuing
its own business development strategy. The
company had approached Allergan, best
known at the time as the maker of Botox,
regarding a potential merger, unbeknownst to
Pfizer. Following that initial dinner, Pfizer and
Actavis moved forward with their negotiations
via telephone and various in-person meetings,
according to the SEC filing. They outlined
the key terms of a potential transaction,
including the premium to be paid to Actavis
shareholders and the mix of cash and Pfizer
common stock. The implied value offered by
Pfizer was $307 per Actavis share.
Action progressed with the companies
going as far as conducting preliminary due
20 March 25th 2016
diligence, but it suddenly fell apart. At a
meeting of Pfizer’s board of directors on Sept.
23, 2014, the board decided against moving
forward. The deal was scuttled, with Pfizer
never having known about Actavis’ earlier
interest in Allergan, the filing says.
Meanwhile, as Pfizer and Actavis were
negotiating, Allergan was fending off Valeant
Pharmaceuticals International Inc. in a
months-long takeover saga that had started in
April 2014 and intensified over the course of
the summer, with Valeant raising its takeover
offer twice. Actavis seized the opening.
Whereas management at Allergan had
previously said it wasn’t interested in a deal,
now the company sought a white knight.
Actavis stepped in, agreeing to buy Allergan
for $66bn in a deal announced in November
2014. The combination was completed on
March 17, 2015 and in June, Actavis changed
its name to Allergan.
Pfizer had also returned to the drawing
board, evaluating other strategic alternatives,
including a combination with sterile
injectables specialist Hospira Inc. Read
approached Hospira’s then-CEO Michael Ball
to request a meeting in December 2014 and
negotiations continued into February, when
the companies announced a $17bn deal.
But Read spoke openly to investors about
the company’s continued interest in buying
a business that would bolster what it calls its
“innovative core” after acquiring Hospira, which
expanded its established products unit.
Again, Read reached out to Saunders, now
the CEO of Allergan, to discuss a business
combination. The two sides met on several
occasions through April and May of 2015 to
discuss a possible transaction. But again, the
deal fell apart at the board level after Pfizer’s
board of directors scrapped the plan at a
meeting on June 25.
Allergan had been approached by Teva
Pharmaceutical Industries Ltd., which wanted
to buy its generic drug business. Teva had
been trying to buy rival Mylan NV for months,
but Mylan was rejecting those advances.
Allergan accepted Teva’s $40.5bn offer in a
deal announced July 27.
Third Time’s The Charm?
With Allergan shedding its generics business,
Read again brought up Allergan with Pfizer’s
directors, according to the filing, convinced
Allergan would be willing to consider a
combination with Pfizer to occur following
the close of the Teva deal. On Oct. 8, Read
met Allergan’s Bisaro for lunch, a meeting
that turned out to be productive and put the
companies on the path toward finalizing a deal.
@scripnews
The two even discussed details like keeping
some of Allergan’s directors and executives on
the combined team, the filing says, an element
of the final deal that came to fruition, seeing as
Saunders was appointed president and chief
operating officer of the new company.
In a follow up meeting on Oct. 22, involving
Read, Saunders and others, Read laid out a $375
per share offer in stock or mostly stock. He also
told Allergan the deal would need to include
protections to address potential regulatory
or legal changes, according to the filing, likely
referring to any changes related to US tax law
that could potentially eliminate some of the
financial advantages the deal offered.
Under the final breakup arrangement that
was worked out over the following weeks, Pfizer
and Allergan have to pay a $3.5bn termination
fee in certain instances if they back out of the
deal, but only $400m if they terminate the deal
due to an adverse change in law.
From there, negotiations intensified as
Pfizer’s directors gave the green light to
proceed – as long as the parties could work
out a solution to limit the risk of any potential
change to the US tax laws.
An article in the Wall Street Journal reported
Oct. 28 that the two companies were in
takeover talks and the two confirmed the
reports in press releases Oct. 29. From there,
the meetings turned into a steady stream of
back and forth, detailed negotiations and due
diligence. At the last minute, on Nov. 16, Pfizer
agreed to raise the exchange ratio range used
to determine the valuation to 11.3 from 10.9
to 11.1, increasing the value of Allergan to
approximately $376 for each Allergan share, after
Allergan said it would walk.
On Nov. 21 and 22, Allergan’s and Pfizer’s
board of directors, respectively, approved
the merger. The merger agreement was
on the night of Nov. 22 and the news was
announced the following day.
The end of the story is yet to unfold. It
would certainly be a cliff-hanger if anything
derailed the union – like if the US government
takes any steps to block the merger or
eliminate any of the tax benefits behind it.
There’s still a slight risk, but any substantive
action would require Congressional action,
which remains highly unlikely.
Once the deal is done, the “Pfizergan”
integration will be its own challenging
drama, and then all eyes will be on what the
combined company does next.
This article has also been published in “The
Pink Sheet”. Scrip Intelligence brings selected
complementary coverage from our sister
publications to our subscribers.
[email protected]
stockwatch
Lilly And GW Move Goalposts
Gelner Tivadar/shutterstock.com
There were few bright spots last week in
life sciences, with the NASDAQ Biotech
Index finishing down by 4% as it continued,
uncharacteristically, to underperform the
broad S&P 500 index. The handful of positive
announcements from the industry actually
look very fragile on closer inspection, perhaps
marking new lows for an industry where the
integrity of clinical trial announcements and
investment bank analysis can no longer be
believed in.
Investors took an instant dislike to Eli Lilly
& Co.’s announcement that it was changing
the primary endpoint of the EXPEDITION-3
Phase III study of solanezumab in earlystage Alzheimer’s disease. Lilly’s stock price
finished the week down 4.6% following
the relegation of the important functional
measure to a secondary endpoint. There
are no good reasons to change anything
in most clinical trial protocols once the
study is underway. Even if a change is the
result of a simple mistake, cost, statistical
and reputational penalties will almost
certainly be incurred. My rule of thumb as an
investor is to think the worst of a company
until proven otherwise. Applying this rule
helps explain investors’ reaction to Lilly’s
protocol change. EXPEDITION-3 as originally
designed has probably already failed. Sell-side
analysts, increasingly pilloried for their “Buy”
recommendations on failed stocks like Valeant
Pharmaceuticals International Inc., may be
responding to this criticism in their treatment
of Lilly’s changes. The analysts from JP Morgan
– who rate Lilly as “Neutral” – pointed out
that the change “increases the probability
of a successful Phase III readout” but were
joined by the analysts from Jefferies in noting
that the FDA and EMA require statistical
significance in both cognitive and functional
primary endpoints for approval.
It might come as a surprise to some
investors that many individuals outside the
clinical development team know the result
of the clinical trial soon after the clinical
database has been locked. Lilly’s actions may
be more of a surprise since it appears a whole
chain of Lilly employees right up to corporate
and back have been involved in an iterative
process of monitoring the unblinded results
and then changing the primary endpoint to fit
the desired result. Orexigen Therapeutics Inc.
demonstrated the perils of this retrospective
adaptive approach to a fixed and agreed
clinical trial design when it bid goodbye to its
commercial partner Takeda Pharmaceutical
Co. Ltd. last week. Orexigen’s management
and disclosures on the LIGHT cardiovascular
outcomes trial earned it a rare public rebuke
from the FDA, its well-respected principal
investigator and its partner, resulting in the
early termination of the study when Contrave’s
(naltrexone/bupropion) statistical significance
in preventing major adverse cardiovascular
events was eventually lost. The Orexigen stock
price finished the week down 8.7%.
Investors took an instant
dislike to Lilly changing
the primary endpoint of the
EXPEDITION-3 Phase III study
The reason I initially think the worst of
management teams was aptly demonstrated
by CymaBay Therapeutics Inc. last week when
it reported ‘positive’ results for its 13-patient
pilot Phase II clinical study of MBX-8025 in
homozygous familial hypercholesterolemia.
When I read the announcement I could not
find any positive results from the study where
not even two per protocol subset analyses
(which are not accepted for approval by the
FDA because treatment-related drop-outs
are excluded, and must have taken weeks of
post hoc analysis to define after the database
had been locked) could result in a statistical
difference over placebo. CymaBay investors
would not however be pleased to learn that
MBX-8025 did show a worrying statistically
significant 43% increase in PCSK9, which the
analysts at Piper Jaffray omitted to mention in
their “Overweight” rated note. The CymaBay
stock price finished the week up 4%.
The stock price of GW Pharmaceuticals Plc
finished last week up over 90% after it reported
‘positive’ results for its cannabis-derived drug
Epidiolex (cannabidiol) in Dravet Syndrome.
The analysts from Piper Jaffray and Cowen
were effusive in their praise of the results, both
having “Overweight” recommendations on
GW. The analysts from Cowen in particular
declared that the strength of the data “are
@scripnews
likely sufficient to support approval on their
own.” The US public should thank their lucky
stars that the FDA is the gatekeeper for drug
safety rather than the analysts from Cowen,
who were obviously unaware of both the ICH
guidelines on safety database numbers for
drugs for chronic administration and the post
hoc changes to the primary endpoint that
GW made last December. We can thank those
commentators on social media who found the
changes including the primary endpoint from a
mean percentage change in seizure frequency,
to a median percentage change. Ironically,
a mean percentage change could be more
impressive than a median percentage change
but a mean invites measures of variability and
a high variability in the treatment group could
imply hyper-responders or non-responders in an
undefined and non-normal patient population.
This puts me in mind of Sarepta
Therapeutics Inc.’s eteplirsen, which also had
high variability with hyper- or non-responders.
It took nearly three years for the opacity to
clear from Sarepta’s “positive” clinical trial
announcement to the most damming FDA
review I have ever read. Two points are clear
from last week’s clinical trial shenanigans.
Firstly, GW’s first Epidiolex Phase III study
may have shown convincing efficacy on the
original prospectively defined mean primary
endpoint, but a high variation in response may
suggest unpalatable patient heterogeneity.
Secondly, GW should not expect a warm
welcome by the bastions of US drug safety in
Bethesda at a pre-NDA meeting after mucking
about with the primary endpoint of the study
last December. If the FDA has learnt anything
from the Sarepta experience, then it should
reject GWs request for a pre-NDA submission
until it has better defined the target
population, which might suggest diagnosticguided therapy in a new clinical study.
Andy Smith
Andy Smith is chief investment officer of Mann
Bioinvest. Mann Bioinvest is the investment
adviser for the Magna BioPharma Income
fund which has no position in the stocks
mentioned, unless stated above. Dr Smith gives
an investment fund manager’s view on public
life science companies. He has been lead fund
manager for four life science– specific funds,
including International Biotechnology Trust and
the AXA Framlington Biotech Fund, and was
awarded the Technology Fund Manager of the
year for 2007.
For all Stockwatch articles visit
scripintelligence.com/stockwatch
March 25th 2016
21
pipeline watch
Scrip’s weekly Pipeline Watch tabulates the most recently reported late-stage clinical trial and regulatory developments from the more than
10,000 drug candidates currently under active research worldwide.
Late-stage clinical developments for the week 11-17 March 2016
Lead Company
Partner Company
REGULATORY APPROVAL
Bayer AG
–
Ligand Pharmaceuticals,
Spectrum
Inc.
Pharmaceuticals
Inc.
SUPPLEMENTAL REGULATORY APPROVAL
Pfizer Inc.
Merck KGaA
ORPHAN DRUG DESIGNATION
ProNAi
–
Therapeutics Inc.
Dimension
–
Therapeutics Inc.
Drug
Indication
Market
Comments
Kovaltry (antihemophilic
Factor VIII recombinant)
Evomela (melphalan)
hemophilia A in adults
and children
multiple myeloma
US
A full-length human recombinant Factor VIII that is the successor to Bayer’s
marketed rFVIII product, Kogenate FS.
For use as a high-dose conditioning treatment before stem cell transplant in
multiple myeloma; and the palliative treatment of patients with multiple
myeloma for whom oral therapy is not appropriate.
Xalkori (crizotinib)
metastatic non-small cell
lung cancer (NSCLC)
US
For patients with metastatic NSCLC whose tumors are ROS1-positive. Xalkori is
already indicated for patients with metastatic NSCLC whose tumors are
anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
PNT2258
diffuse large B-cell
lymphoma
For ornithine
transcarbamylase (OTC)
deficiency
systemic scleroderma
US
Europe’s EMA granted a similar designation in Aug. 2015.
EU
DTX301 is a recombinant adeno-associated viral (rAAV) vector that uses NAV
vector technology.
Japan
Tocilizumab is a marketed IL-6 receptor targeted monoclonal antibody.
DTX301
US
Chugai
Roche Holding AG
Pharmaceutical
Co. Ltd.
BREAKTHROUGH THERAPY DESIGNATION
NovImmune SA
–
NI-0501
primary hemophagocytic US
lymphohistiocytosis (HLH)
For primary hemophagocytic lymphohistiocytosis (HLH) with refractory disease,
or with recurrent or progressive disease during conventional therapy. Granted on
the basis of clinical data from a Phase II study in children with primary HLH.
SUPPLEMENTAL REGULATORY FILING
Tesaro Inc.
Opko
Varubi (rolapitant)
An intravenous formulation of rolapitant.
Pfizer Inc.
Xalkori (crizotinib)
chemotherapy induced
US
nausea and vomiting
non-small cell lung cancer EU
(NSCLC)
Merck KGaA
PRIORITY REVIEW
Roche Holding AG Chugai Pharmaceutical Co.
Ltd.
Actemra (tocilizumab)
subcutaneous
atezolizumab
Epic Pharma
SequestOX (ELI-200)
Elite
Pharmaceuticals
Inc.
RESPONSE SUBMITTED TO COMPLETE RESPONSE LETTER
–
Yosprala (PA32540/
Aralez
PA8140; pH-sensitive
Pharmaceuticals,
aspirin plus immediateInc. (formed from
release omeprazole, 325
merger of Pozen,
mg/40 mg, and
Inc. and Tribute
81mg/40mg) tablets
Pharmaceuticals
Canada Inc.)
PHASE III TRIAL INITIATION
H Lundbeck A/S
–
Lu AF35700
AbbVie Inc.
–
ABT-494
Quark
Pharmaceuticals
Inc.
Alnylam Pharmaceuticals
Inc., Silence Therapeutics
plc
QPI-1002
PRODUCT LAUNCH
Allergan plc
Gedeon Richter Plc
Vraylar (cariprazine)
For adult patients with ROS1-positive NSCLC. In Europe, Xalkori is already indicated
for the first-line treatment of adults with ALK-positive advanced NSCLC and for the
treatment of adults with previously treated ALK-positive advanced NSCLC.
locally advanced or
metastatic urothelial
carcinoma
US
moderate to severe pain
US
secondary prevention of
CV disease in patients at
risk of aspirin-induced
gastric ulcers
US
The resubmission includes a new primary aspirin API supplier and an alternative
supplier, intended to address deficiencies outlined in the CRL. Final agreement on
draft product labeling is also pending.
treatment-resistant
schizophrenia
moderate-to-severe
active rheumatoid
arthritis
prevention and
amelioration of the
severity of delayed graft
function in kidney
transplant patients
–
-
Lu AF35700 has also been granted fast track designation in treatment resistant
schizophrenia by the FDA.
A second-generation Jak kinase inhibitor that selectively binds Jak1. A study
comparing ABT-494 monotherapy to methotrexate (MTX) in moderately to
severely active RA with inadequate response to MTX is recruiting 600 patients.
A siRNA inhibitor of the p53 gene.
US
A once-daily oral atypical antipsychotic.
acute manic or mixed
episodes of bipolar I
disorder and
schizophrenia in adults
–
In patients with disease progression during or following platinum-based
chemotherapy in the metastatic setting, or whose disease worsened within 12
months of receiving platinum-based chemotherapy before surgery (neoadjuvant)
or after surgery (adjuvant).
The NDA has been accepted and granted priority review by the FDA.
Source: Sagient Research's BioMedTracker
22 March 25th 2016
@scripnews
appointments
CRISPR Therapeutics has appointed Pablo J.
Cagnoni to its board of directors and Tony Coles will
succeed Bradley Bolzon as chair. Cagnoni previously
served as managing director of MPM Capital and is
currently president and CEO of Tizona Therapeutics
and executive chair of Blade Therapeutics.
F-star has appointed Michael Davies vice
president of protein sciences. Davies joins F-star
from CPI Biologics, where he was head of analytical
strategy, biologics and previously he was at Lonza,
where he held leadership roles in analytical strategy
and development.
Medigene AG’s CFO Peter Llewellyn-Davies will
be leaving the company after three years – effective
March 31, 2016. During his time at Medigene,
Llewellyn-Davies contributed to the repositioning
of the company towards cancer immunotherapy.
He also secured financing for the new corporate
strategy through various fund raisings with
participation of international investors.
Johan Frieling has been appointed chief medical
officer of the Dutch biotech Micreos. He has
previously held positions at Bayer, Genzyme
and most recently he was head of global clinical
research at LFB Biotechnologies.
Ultragenyx Pharmaceutical Inc. has appointed
Sofinnova Ventures’ executive partner Lars Ekman
to its board as an independent director – effective
since March 17, 2016. Prior to Sofinnova Ventures
Ekman was president of R&D at Elan and previously
he held various senior scientific and clinical roles at
Pharmacia (acquired by Pfizer Inc.). Currently Ekman
is chair of Amarin Corporation Plc., Sophiris Bio Inc.,
and Prothena Corporation Plc. and is a director of
Spark Therapeutics Inc.
Threshold Pharmaceuticals has appointed
Stew Kroll chief operating officer. Kroll joined the
company in 2005 as director, biostatistics and was
later appointed as Threshold’s senior vice president,
clinical operations and biostatistics. Prior to Threshold,
Kroll was senior director of biostatistics at Corixa Corp.
Oncology focused Onxeo SA. has appointed
Philippe Maitre head of its new US subsidiary as
executive vice president and chief of US operations.
Maitre brings over 35 years’ experience to the
company and previously served as CEO and cofounder of the biotech mAbRx. Prior to this, he was
CEO at the cancer vaccine company Anosys. Onxeo’s
new US subsidiary is headquartered in New York.
Tokai Pharmaceuticals Inc., a company focused
on prostate cancer and other hormonal diseases,
has appointed Kelly A. Lindert executive vice
president and head of development. Lindert joins
the company from Novartis AG where she spent
eight years in various roles, most recently as global
head of development for the company’s influenza
vaccines program.
Vaccine company Novavax Inc. has appointed
Bob Darius senior vice president of quality
operations. Darius was previously vice president of
quality operations at GlaxoSmithKline Biologicals
and most recently transitioned to head quality
advocacy liaison. He also held various positions
of increasing responsibility at the FDA’s Center for
Biologics Evaluation and Research, where he was
a senior reviewer and inspector and advisor to the
deputy center director of medicine on counterbioterrorism products.
The European Medicines Agency’s (EMA)
management board has elected Christa
Wirthumer-Hoche chair for a three-year period.
Wirthumer-Hoche is head of the Austrian Medicines
and Medical Devices Agency and co-chair of the EU
Network Training Centre. She served as vice-chair
of EMA’s management board since March 2015
and previously was chair of EMA’s Active Substance
Master File Working Group.
PierianDx has appointed Bryan J. Carey and
Frederick A. Hessler to its board of directors. Carey is
currently executive vice president, chief financial officer
(CFO) and director of Sunspire Health. Prior to Sunspire
he was president and CFO of 21st Century Oncology
and managing director of Vestar Capital Partners.
Probiodrug AG., a company focused on
Alzheimer’s disease, has appointed Mark
Booth chief business officer and member of the
management board. Booth brings more than
30 years’ experience to the company and most
recently was chief commercial officer at Orexigen
Therapeutics Inc. Prior to this he was president of
Takeda Pharmaceuticals North America.
Let’s get
Social
We are tweeting, chatting, liking and
sharing the latest industry news and
insights from our global team of editors
and analysts, join us!
@scripnews
@scripnews
/scripintelligence
March 25th 2016
23

3795 - Scrip

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