Vol. 78 / No. 21

Pink Sheet
www.ThePinkSheet.com
Vol. 78 / No. 21
May 23, 2016
FDA Biologic Transition
Plan Creates ‘Dead Zone’ For
Applications, Sponsors Fear
Sue Sutter [email protected]
F
Pharma intelligence
informa
vator trade groups, individual insulin manufacturers and legal experts call for a more
balanced approach, suggesting that unexpired marketing protections should carry
over after products transition to BLA licenses
or that such products should have the benefit of 12-year biologic exclusivity dating from
original NDA approval.
These same commenters suggest FDA’s
proposed approach on exclusivity would
represent a constitutional “taking” under
the Fifth Amendment, thereby laying the
groundwork for a legal challenge if the agency sticks to its original plan.
DA’s interpretation of the Biologics
Price Competition and Innovation Act’s
“transition provisions” for certain protein
products would create a “dead zone” or “blackout” period for new applications that could
last several years, industry stakeholders say.
In comments responding to an FDA draft
guidance on the BPCIA’s “deemed to be a license” provisions, representatives from innovator, generic and biosimilar industries say
the agency should allow pending NDAs and
ANDAs for affected products to be reviewed
and approved after March 23, 2020. That is
the date when insulin, human growth hormone and other products that traditionally
have been approved under the Food, Drug
and Cosmetic (FD&C) Act will be deemed
to be licensed as biological products under Section 351 of the Public Health Service
(PHS) Act.
FDA proposes transition products that
have not received final approval by March
23, 2020, would not be approved under the
FD&C Act and must be resubmitted as BLAs.
However, this approach would disrupt ongoing reviews, significantly impact development programs and dissuade companies
from submitting applications under the
FD&C Act long before the transition date, industry representatives said.
“This proposal, if implemented, will have a
devastating effect on current development
programs for many important protein products, including insulin, thereby impairing
competition for lower-cost biological medicines, increasing health care costs in the US
and, most importantly, limiting patient
access to affordable biological products,”
Mylan NV’s comments state.
FDA’s proposal that transition products
should lose marketing exclusivity also drew
fire from some industry stakeholders. Inno-
Reimbursement
R&D
European Notebook
Part B Demo Comments
Overwhelmingly Negative, Uniform
In Content, p. 9
FLAME Shoots LABA/LAMA Combos
Up To First Choice In COPD, p. 15
Bayer Bids For Monsanto; Biosimilar
Uptake Still Sluggish; EMA Enters Drug
Pricing Debate, p. 11
FDA’s approach on
exclusivity violates the
Fifth Amendment’s
Takings Clause and
free trade agreements,
innovators said.
Protests Over Pending
Applications
FDA’s draft guidance, released in March,
marked its first public explanation for how it
planned to implement the BPCIA’s transition
provisions (“BLAs More Appealing As ‘Transition’ NDAs, ANDAs Set To Lose Exclusivity” —
“The Pink Sheet,” March 21, 2016).
The agency said it would not approve any
application under Sec. 505 for a biological
product subject to the transition provisions
that is pending or tentatively approved on
March 23, 2020. Such applications may be
withdrawn and resubmitted under 351(a),
the traditional BLA pathway, or as a biosimilar under 351(k). In addition, FDA said it
would remove affected biological products
from the “Orange Book” on the transition
date because these products would no longer be “listed drugs.”
FDA acknowledged that its interpretation could have a significant impact on
development programs for products in affected classes. It advised sponsors to evaluate
Continued on page 4
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Will Fortune Favor The Brave? Biosimilar Sponsors
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Regulatory framework for biosimilars is still a work in progress,
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the Pink Sheet’s Drug Review Profile of Zarxio.
Expanded Access Programs Need FDA Policy Changes
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Agency should issue statement that deaths occurring during
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development, ethicists from NYU Langone Medical Center say.
inside:
Co v e r FDA Biologic Transition Plan Creates ‘Dead Zone’
For Applications, Sponsors Fear
R e g u l atory Upd at e
7Aegerion Juxtapid Settlement Shows REMS Have Teeth:
Alternate Route To Enforce Off-Label?
11 European Notebook: Bayer Bids For Monsanto; Biosimilar
Uptake Still Sluggish; EMA Enters Drug Pricing Debate
Biosimilars
5Insulin Makers To FDA: Clarify ‘Transition’ Impact On
Drug/Biologic Combos
Generic Drugs
21 FDA’s ANDA Approvals
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25 FDA’s NDA And BLA Approvals
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26 Recent And Upcoming FDA Advisory Committee Meetings
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May 23, 2016 | Pink Sheet |
3
Biosimilars
Continued from cover
whether planned submissions under Sec. 505
would allow adequate time for approval by
the transition date and suggested they may
want to consider submitting an application as
a standalone or biosimilar BLA instead.
Most of the public comments disagreed
with FDA’s proposed handling of applications pending at the time of the transition
date. This approach is contrary to the BPCIA’s
clear language, which allows sponsors to
submit applications under Sec. 505 until the
transition date, the comments said.
“FDA’s proposed policy will force sponsors who are ready to submit applications for
lower-cost biologics prior to March 23, 2020,
to delay their submissions until after March
23, 2020, thereby significantly delaying the
review, approval and availability of biological products that compete with expensive
brand name biologics,” the Generic Pharmaceutical Association (GPhA) and the Biosimilars Council’s joint comments state.
“For example, if a sponsor is ready to
submit a 505(b)(2) application or ANDA for
a transitional biologic in June 2019, FDA’s
proposed policy would provide a strong incentive for the sponsor to forgo any submission at that time because of the meaningful
possibility that the application would not be
approved prior to March 23, 2020,” GPhA and
the council said.
However, it also would be impossible for
a sponsor to submit a biosimilar application
prior to March 23, 2020, because, until that
date, there would be no reference product
licensed under Sec. 351 upon which an applicant could rely.
“FDA’s proposed policy thus creates a
regulatory ‘dead zone’ of a year or more between the time no rational sponsor would
submit a 505(b)(2) application or ANDA (because of the likelihood it would not get approved in time) and the first date a biosimilar
application could be submitted (i.e., March
23, 2020),” GPhA and the council said.
Similarly, the Pharmaceutical Research
and Manufacturers of America’s comments
say FDA’s proposal “would create a blackout
period during which applicants would be
unable to submit either NDAs or BLAs for
their proposed medicines.”
FDA’s approach also would have a detrimental impact on supplemental NDAs
4 | Pink Sheet | May 23, 2016
FDA’s proposal “creates a
regulatory ‘dead zone’ of a
year or more between the
time no rational sponsor
would submit a 505(b)(2)
application or ANDA … and
the first date a biosimilar
application could be
submitted” – GPhA and
the Biosimilars Council
pending at the transition date, commenters
said. “We caution that FDA’s proposal as it
relates to sNDA submissions would slow
down the approval of changes that may offer significant benefit to the public health
(e.g., new indication, dosage form, or other
change that enhances patient compliance
or safety),” the Biotechnology Innovation Organization’s comments state.
“While manufacturers that are considering
an NDA for a new product may have more
flexibility to choose a BLA over an NDA from
the start, a manufacturer pursuing a supplement is forced to work with the regulatory
status of the currently approved product
and thus would have to choose, essentially,
between waiting until March 23, 2020, to
submit its supplement or otherwise go
ahead and submit as an sNDA only to then
have to resubmit as an sBLA after March 23,
2020,” BIO said.
Commenters suggest that NDAs and
supplements pending at the transition date
could be deemed BLAs during review, or
they could retain their status until approval, at
which time they would be licensed as BLAs.
The law firm Hyman, Phelps and McNamara suggests an approach that would
recognize “a narrowly tailored cohort” of applications submitted by the transition date
that would continue to be reviewed after
the listed drugs they reference are deemed
to have a license under Sec. 351. “This would
serve to protect the substantial investment
in a product’s development in the face of
longer than expected FDA reviews, requests
for major amendments or multiple review
cycles,” the firm’s comments state.
Wanted: Compromise On
Exclusivity
In the draft guidance, FDA concluded that
any remaining non-orphan exclusivities –
five-year new chemical entity, three-year
Hatch-Waxman, or pediatric – associated
with an approved NDA subject to the transition provisions would cease to have any
effect on March 23, 2020. Furthermore, nothing in the BPCIA suggests Congress intended
to grant transition products a new 12-year
period of exclusivity available to biologics licensed as standalone BLAs, the agency said.
FDA’s hardline interpretation on exclusivity surprised some industry observers, who
thought the agency would have tried to take
more of a middle-of-the-road approach.
While the GPhA, Biosimilars Council and
Mylan supported the agency’s view, innovator groups said terminating existing exclusivity would be inconsistent with the BPCIA,
harm innovation incentives and disrupt ongoing patent litigation.
“The draft guidance also raises constitutional issues concerning a taking of private
property without just compensation in violation of the Fifth Amendment and threatens
the nation’s compliance with its free trade
agreements,” PhRMA said.
PhRMA and BIO suggest that any exclusivities in effect at the transition date should
carry over until they would have expired under the FD&C Act.
“More broadly, until expiry of every Orange
Book-listed patent, including any pediatric
exclusivity extension, for a given listed drug,
FDA should continue to treat the application
for that drug, as well as the follow-on applications that cite it, as Sec. 505 applications for
exclusivity and patent purposes,” PhRMA said,
asserting that this approach would be less
disruptive to sponsors of transition products
engaged in Hatch-Waxman patent litigation.
Novo, Sanofi Eye Different
Fixes
Insulin makers are expected to be among
the biopharma companies most impacted
by the transition provisions (“Insulin Exclusiv© Informa UK Ltd 2016
Biosimilars
ity: How Big Will The Fight Be?” — “The Pink
Sheet,” March 21, 2016).
Novo Nordisk AS’ Tresiba (insulin degludec), approved in September, would
lose several months of new chemical exclusivity under FDA’s draft guidance. The company’s Xultophy, a combination of Tresiba
and the GLP-1 agonist Victoza (liraglutide),
is under FDA review.
Novo said the exclusivity rights granted
under a sponsor’s chosen regulatory approval pathway should continue to apply
after the transition date until they naturally
expire. “Such an interpretation … not only
prevents conflict with the Takings Clause,
but also avoids upsetting and creating
greater uncertainty around any ongoing
court litigation between sponsors,” Novo
Nordisk’s comments state.
However, Lantus insulin maker Sanofi
takes a different approach, saying that transition products should be eligible for the
balance of 12-year reference product exclusivity for biologics dating back to their
original NDA approval.
“This does not, as FDA asserts, provide
windfall exclusivity to products approved
‘decades ago,’ nor does it stifle biosimilar or
interchangeable competition ‘until the year
2032,’” Sanofi’s comments state, quoting
from the draft guidance. “It is merely consistent treatment of all biological products,
as Congress intended when it directed that
all biological products should be unified
under one regulatory scheme.”
Sanofi said its investigational product
combining Lantus (insulin glargine) and the
GLP-1 agonist lixisenatide would be directly
affected by the transition provisions, and it
urged FDA to issue guidance that specifically addresses the impact on drug/biologic combinations (see related story below).
Insulin Makers To FDA: Clarify ‘Transition’ Impact
On Drug/Biologic Combos
Sue Sutter [email protected]
A
lthough the biopharma industry may
not have liked much of what it saw in
FDA’s initial guidance on the Biologics
Price Competition and Innovation Act’s “transition provisions,” it remains in search of clarity on
a host of issues untouched in the March document, including the impact on combination
products and therapeutic equivalence ratings.
FDA’s draft guidance on the “deemed to
be a license” provisions should be revised to
address the impact on drug/biologic combination products, Sanofi said.
“For drug/biologic combination products
that are approved or will be approved under
NDAs during the transition period, it is possible that – if FDA considers the primary mode
of action for such a product to be attributed
to the transition biologic component – the
approved NDA for the combination product
may in its entirety be ‘deemed to be a license’
as of March 23, 2020,” Sanofi’s comments state.
If that were the case, under the draft guidance all Hatch-Waxman protections would be
extinguished and such products would be removed from the “Orange Book,” Sanofi notes.
“For Sanofi, this issue is not theoretical,” the
company said.
Sanofi’s 505(b)(1) application for a
fixed-dose combination of Lantus (insulin
thepinksheet.com
glargine) and the GLP-1 agonist lixisenatide is undergoing a priority review at FDA,
thanks to the firm’s redemption of a priority review voucher (“Keeping Track: Exelixis,
Sanofi Submit NDAs While AstraZeneca, Actelion Collect Approvals” — “The Pink Sheet,”
Jan. 4, 2016). An advisory committee review
is scheduled for May 25.
Insulin is one of several types of protein
products that will transition from regulation
under Section 505 of the Food, Drug and
Cosmetic Act to Section 351 of the Public Health Service Act on March 23, 2020.
Under FDA’s draft guidance, such transition products will lose any remaining nonorphan exclusivities on that date and be
removed from the “Orange Book” (“Insulin
Exclusivity: How Big Will The Fight Be?” — “The
Pink Sheet,” March 21, 2016).
Innovators have challenged FDA’s approach on exclusivity as contrary to the
statute and potentially unconstitutional.
The agency’s proposed treatment of NDAs
and ANDAs pending on the transition date
also has drawn strenuous objections from
industry (see related story, “FDA Biologic Transition Plan Creates ‘Dead Zone’ For Applications, Sponsors Fear,” cover).
“We expect to obtain approval before the
transition date,” Sanofi said of its combination product. “We also are anticipating that
the lixisenatide component will be granted
five-year NCE exclusivity, that a balance of
this exclusivity will be unexpired on March
23, 2020, and that one or more patents
claiming, among other things, the drug substance will be listed in the ‘Orange Book.’”
The BPCIA transition provisions do not
give FDA authority to deny the drug component of a combination product rights
that flow from approval under the FD&C
Act, Sanofi said, adding, “FDA must address
this issue in its implementation of the transition statute.”
FDA should consider administratively
separating the NDA for the drug/biologic
combination into an NDA for the drug component (with its corresponding exclusivity
and patent listings) and a BLA for the biologic component, Sanofi said. “We recognize
this is a particularly complex issue and we
anticipate that FDA may need to address it
through further proposals and elicitation of
comments from affected stakeholders.”
Sanofi’s insulin market rival Novo Nordisk AS also has a drug/biologic combination under FDA review. Xultophy, which
combines Tresiba (insulin degludec) with
May 23, 2016 | Pink Sheet |
5
Biosimilars
the GLP-1 agonist Victoza (liraglutide), will
be the focus of a May 24 advisory committee meeting.
In contrast to Sanofi’s lixisenatide, which
has not yet been approved in the US, Novo’s
liraglutide has been on the market for six
years. The drug is protected by three-year
Hatch-Waxman exclusivity until April 2019,
11 months ahead of the transition date.
However, Tresiba, which was approved in
September, stands to lose several months
of new chemical entity exclusivity under
FDA’s draft guidance.
In comments, Novo Nordisk also calls on
FDA to clarify the handling of fixed-combination products in which one component
remains in the FD&C Act pathway and the
other transitions to the BLA pathway.
“FDA must address which constituent
party they believe has the ‘single primary
mode of action’ or at least indicate how
they plan to work with the sponsor to determine such criteria, since this determination will affect whether the product transitions or not,” the company said.
What Will ‘Deemed’
Products Look Like?
In their comments on the guidance, innovator trade organizations identify several other
areas in need of agency clarity, including
whether applications approved under Sec.
505 will be deemed standalone BLAs under
Sec. 351(a) or biosimilars under 351(k).
As FDA acknowledged in its draft guidance, 505(b)(2) applications do not completely align with the requirements of either
Section 351(a) or 351(k), the Pharmaceutical
Research and Manufacturers of America’s
comments state. “It is unclear how FDA intends to reconcile these discrepancies when
these applications transition to BLAs.”
“What is clear, however, is that FDA’s approach could have significant implications
for transition biological product sponsors,”
PhRMA said. “For instance, whether an application is deemed licensed under Sec. 351(a)
or 351(k) of the PHSA may affect whether
interchangeability provisions of the PHSA
apply to the application, as well as the applicable patent dispute resolution framework.
So that stakeholders have adequate time
to plan and prepare for these matters before the transition date, FDA should provide
guidance on this issue promptly.”
Innovators also seek clarity as to how
approved NDAs with an “A” therapeutic
equivalence rating will be treated under the
transition with regard to biosimilarity or interchangeability determinations.
“Given the two distinct statutory standards – one for therapeutic equivalence
under the FDCA and the other interchangeability under the PHSA – we urge
that FDA consider a previously A-rated
protein product that transitions to the
PHSA as biosimilar but not interchangeable absent the sponsor providing supplemental data to demonstrate that the
transitioned product satisfies the BPCIA
standards for interchangeability relative
to its transitioned reference product,” the
Biotechnology Innovation Organization’s
comments state.
“In any case,” BIO said, “clarity to stakeholders on this issue is needed.”
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6 | Pink Sheet | May 23, 2016
Pink Sheet
Pharma intelligence
© Informa UK Ltd 2016
R e g u l ato ry U p dat e
Aegerion Juxtapid Settlement Shows REMS Have Teeth:
Alternate Route To Enforce Off-Label?
Cole Werble [email protected]
Michael McCaughan [email protected]
A
egerion Pharmaceuticals Inc.’s proposed settlement with the Department of Justice over its marketing of
the homozygous familial hypercholesterolemia
therapy Juxtapid includes one count related to
violation of the FDA-mandated Risk Evaluation
& Mitigation Strategy for the product.
The company’s May 12 announcement of a
preliminary settlement with DoJ and the Securities & Exchange Commission does not get
deeply into the specifics of the violations. This
is just the press release pre-alert in advance of
the formal settlement agreement; both DoJ
and SEC have to finalize the terms, and then it
will be subject to acceptance in federal court.
The specific reference to a REMS violation
is significant, as it appears to be the first time
a REMS violation has been part of a broader
DoJ marketing settlement. It may also point
to an alternate enforcement mechanism to
punish off-label promotion without raising
First Amendment defenses.
The press release announcing the settlement describes the REMS violation tersely.
One of the two counts of the FD&C violation,
the release says “would involve an alleged
failure to comply with a requirement of the
Juxtapid Risk Evaluation and Mitigation Strategies (“REMS”) program (21 U.S.C. §§ 352(y)).”
The other count is for “marketing of Juxtapid
with inadequate directions for use.” Both are
misdemeanor misbranding violations.
Aegerion is separately settling allegations
brought by SEC related to the performance of
Juxtapid. Altogether, the company says it expects to pay $40 million to resolve the claims.
Juxtapid (lomitapide) was approved for
homozygous familial hypercholesterolemia
(HoFH) at the end of 2012. That approval
was explicitly based on the medical need in
the very limited and seriously affected HoFH
population; lomitapide was not considered
safe for any other uses despite its significant
efficacy in lowering LDL.
The company also got into early trouble
with FDA for statements by the former
thepinksheet.com
CEO, Marc Beer, for statements about the
product soon after approval on CNBC’s Fast
Money which FDA alleged went beyond
approved labeling.
That letter was cited by critics of FDA’s offlabel enforcement policy as an example of
overreach in the context of the broader (and
increasingly successful) effort to expand First
Amendment protections for communications by industry (“FDA’s Strategic Retreat In
Off-Label Case: Concedes Broader Use of Exparel, Gets Firm To File sNDA” — The RPM Report, December 2015).
FDA formally closed out the warning letter
in 2014 – but DoJ subpoenas followed (“Aegerion Resolves FDA Warning About Juxtapid
Promotion But DOJ Probe Continues” — “The
Pink Sheet” DAILY, Aug. 27, 2014).
Two Alternatives To
“Off-Label”
With the settlement disclosure it now appears clear that prosecutors were able to
The investigation
also dispels any sense
that orphan product
companies have special
protection from
government marketing
charges because of
the heightened public
service of addressing
a small underserved
patient market.
use two alternatives to a traditional “offlabel” claims: (1) using SEC disclosure laws
rather than FD&C Act advertising and promotion laws; and (2) focusing on violations
of the REMS agreement rather than tying
claims directly to labeling. (DoJ did also
pursue a misbranding claim based on inadequate directions for use which is presumably more like a traditional “off-label” case.)
There are plenty of pieces of the Juxtapid
REMS from which violations could arise
either from failure to undertake all of the
pieces or assure the effectiveness of training and patient selection. There is a training
requirement, for example, for prescribers
tied to correct patient choice and understanding of hepatotoxicity risks. There is
also a separate prescription authorization
form for each patient to receive a prescription that says that patients have a clinical or
laboratory diagnosis of HoFH and have had
pre-treatment liver-related lab tests.
The press release suggests that Aegerion
also withheld information from investigators related to the REMS. The press release
notes that part of the proposed settlement is
a five-year deferred prosecution agreement
tied to Aegerion engaging “in obstruction of
justice relating to the REMS program.”
The action is also noteworthy as a marketing crack-down on an orphan drug company. The investigation dispels any sense
that orphan product companies have special protection from government marketing
charges because of the heightened public
service of addressing a small underserved
patient market.
Aegerion was more vulnerable than most
orphan companies to a government action
for two reasons: (1) there are other HoFH alternatives and (2) the company created an
on-the-edge marketing push for Juxtapid
almost from the time of approval.
Aegerion has pushed the limits on the
tight manufacturer/patient relationship in
the orphan field since the approval. AeMay 23, 2016 | Pink Sheet |
7
R e g u l ato ry U p dat e
gerion went as far as to recruit current
patients as “ambassadors” to talk to prospective patients. That program does not
appear to be one of the direct causes for
the settlement but is indicative of an approach that pushed the boundaries for
patient support and patient recruitment.
While the FD&C Act violations are misdemeanors with relatively small penalties
directly attached, they provide significant
leverage for prosecutors since they open
up the potential for criminal cases against
individual executives and the potential
for exclusion from federal programs under the False Claims Act.
Juxtapid may be a relatively rare example of an orphan drug where exclusion
could at least be considered as a credible
threat, given the increasing pool of alternatives available for patients. The drug
was approved essentially simultaneously
with another HoFH therapy, Genzyme
Corp.’s mipomersen. More recently, the
new PCSK9 cholesterol lowering class
has entered the market with significant
LDL lowering activity and a non-orphan
price point.
Impact Larger Than Dollar
Value of Settlement
A $40 million settlement is relatively small in an
era of billion-dollar plus False Claims Act cases,
but it is significant relative to Aegerion’s size.
The company says it will report first quarter
sales of about $36 million. So the settlement
is about 10% more than a quarter’s revenue.
Moreover, Aegerion is not a profitable
company and the payment terms noted in
the press release strongly suggest that the
final settlement amount was carefully calibrated to the company’s ability to pay.
The press release describes a five-year
schedule for payments: “approximately $3
million upon finalization of the settlement
with the DOJ and the SEC, approximately
$3.7 million per year, payable quarterly,
for three years following finalization of the
settlement, and approximately $13 million
per year, payable quarterly, in years four and
five following finalization of the settlement.
Outstanding amounts would accrue interest from the date of the final agreements in
principle at a rate of 1.75% per annum, compounded quarterly.” The payments would
be accelerated if Aegerion is purchased or
if the company sells either of its two products, Juxtapid or Myalept (metreleptin).
The timing of the settlement announcement from the company’s perspective is clear:
to address the issue before new management
presents the first quarter results. (Mary Szela
was recruited to be CEO in early January.)
From the government’s perspective, an
announcement a week earlier might have
been more newsworthy as an event for the
annual convening of the food and drug bar
at the FDLI annual meeting – where a settlement with an orphan drug company and
one that enforced REMS might have drawn
even more attention.
[Editor’s note: This article first appeared the
RPM Report. The Pink Sheet brings selected
complementary coverage from affiliated publications to our readers.]
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Reimbursement
Part B Demo Comments Overwhelmingly Negative,
Uniform In Content
Cathy Kelly [email protected]
S
takeholders on both sides of the proposed payment demonstration for Medicare Part B drugs appear to have made efforts
to organize comments to the Centers for Medicare and Medicaid Services, with opponents constituting the overwhelming majority
of the stakeholder submissions.
About 92% of the approximately 1,300 comments posted online at
regulations.gov as of May 18 were negative, based on an analysis by “The
Pink Sheet.” That doesn’t bode well for the future of the demonstration,
which has faced strong opposition since it was announced in March.
The proposal would test an alternative approach to paying physicians
for Part B drugs by reducing the amount of reimbursement that is tied to
a drug’s average sales price (ASP), thereby diminishing incentives for physicians to prescribe higher cost drugs (“CMS Unveils Bold Approach To Managing Medicare Part B Drug Costs” — “The Pink Sheet” DAILY, March 8, 2016).
The demonstration would also test different approaches to paying
for drugs based on value, including reference-based pricing (“Medicare Value-Pricing Options Vary Widely In Part B Payment Experiment”
— “The Pink Sheet,” March 14, 2016). Part B drugs are generally infused
or injected treatments administered in a physician’s office, infusion
center or hospital outpatient center.
The agency’s next steps will be to review the comments, potentially
modifying the proposal in response to them, and then to finalize the
regulation. But the sheer volume of comments, combined with congressional concerns about the proposal – which already resulted in a
House hearing May 17 – and the limited runway CMS officials have
until the end of the Obama administration, suggest the reg is unlikely
to get off the ground anytime soon.
Patients, particularly those with cancer or inflammatory disease,
and individual commenters made up the largest group ( 53%) objecting to the demonstration in terms of sheer numbers of comments
(see chart).
Most of the patient comments focus on the ASP payment part of
the demonstration. They express alarm over the prospect that a reduction in Medicare payments will force their doctor to stop treatments,
requiring them to seek care elsewhere, such as in a hospital, which
they argue would be less convenient and more expensive. Patients
also take issue with the prospect of being forced into an experiment.
Many mention the drug they are taking by name; Janssen Pharmaceutical Cos.’ Remicade (infliximab) is cited frequently. And patients
often indicate their comment had been prompted by their health
A Tough Sell, Any Way You Slice It
Opposed
■ Patients ⁄ patient groups ⁄ individuals
Doctors or
health care
providers
34%
11.5%
■ Rheumatologists 6%
53%
■ Oncologists
5
■ Ophthalmologists ⁄ retina specialists %
11.5%
■ Drug manufacturers ⁄ other industry ⁄ policy experts 5%
■ Other health care providers ⁄ hospitals
In Favor
4
■ Doctors ⁄ medical students ⁄ individuals %
■ Advocacy groups ⁄ policy experts
■ Payers ⁄ unions
0.4%
3.6%
8%
stakeholders
in favor
Stakeholders broke into their expected camps in expressing opinions about the proposed Part B payment demonstration
project. Physicians were somewhat divided, but as a group their comments were still overwhelmingly opposed.
Source: Pink Sheet analysis of comments posted by CMS
thepinksheet.com
May 23, 2016 | Pink Sheet |
9
Reimbursement
Patients often indicate their comment
had been prompted by their health care
provider, noting they received a letter
from their physician’s office saying they
may have to go elsewhere for treatment
because of the demonstration.
care provider, noting they received a letter from their physician’s office saying they may have to go elsewhere for treatment because of
the demonstration.
One typical comment, which is signed by Anthony Scalzo of New
York, states:
“This new payment system is an experiment in which the test subjects (patients) have no protection. It is NOT a model. There has been
no forethought regarding the damaging ramifications of this draconian proposal which will adversely affect thousands of patients and
force the closure of many oncology practices severely limiting the
public’s access to lifesaving treatments. Shame on you!!”
ICER’s Multiple Myeloma Review Called Out
Although most patient comments appeared to focus on the revised
ASP payment part of the test, one subset of that group takes specific
issue with the prospect of CMS relying on the technology assessment
conducted by the Institute for Clinical and Economic Review (ICER) to
develop a value-based approach to reimbursing drugs for multiple
myeloma.
For example, Inez Lensch of Iowa states: “ICER’s inherently flawed
approach in measuring cost-effectiveness fails to take many things
into account, and the results cannot accurately conclude the true
cost-effectiveness of myeloma drugs. Myeloma patients are already
limited in their treatment options and treatment decisions should reflect a conversation between doctors and patients, not what CMS will
cover as a result of ICERs research.”
In the Part B proposal, CMS cites ICER as an independent organization whose value assessments could help facilitate new approaches
to reimbursement, though it does not specifically mention the group’s
review of drugs for multiple myeloma.
A draft version of the ICER report was released in early April (“ICER
Questions Cost Effectiveness Of Empliciti, Kyprolis, Ninlaro” — “The Pink
Sheet” DAILY, April 8, 2016). It will be considered at an expert panel
meeting convened by ICER May 26.
Physicians and healthcare providers comprise the second largest
group in opposition to the demonstration (roughly 34%). They include significant numbers of oncology, rheumatology and ophthalmology specialists, who would be hardest hit by the change because
they prescribe the drugs that make up the largest categories of Part
B expenditures.
Many of the health care providers identify themselves as community practices or infusion centers that would be unable to absorb a
decrease in reimbursement under the demonstration, resulting in
10 | Pink Sheet | May 23, 2016
increasing numbers of patients being sent to hospitals for treatment.
Physician Craig Hildreth, of Missouri, says: “Because the new payment model reimburses us LESS than the acquisition cost of these
new agents, and no professional business can survive being paid less
than the cost of goods, our patients will be forced into hospitals for
treatment, which will insure HIGHER costs to Medicare, restricted access to vital treatments including long waiting periods for treatment
similar to our VA system, and a complete deterioration in the overall
health of our citizens living with cancer.”
Organizations like the Community Oncology Alliance made similar
arguments in their comments (“Medicare Payment Demo Would Put
Often-Prescribed Cancer Drugs ‘Underwater’” — “The Pink Sheet,” May
16, 2016).
Off-Label Avastin Could Be Hurt
Several ophthalmologists argue the proposal would not encourage
physicians to choose the lowest-cost effective option, Roche’s Avastin
(bevacizumab) off label. Instead, the change in payment would encourage the choice of higher-cost options, such as Roche’s Lucentis
(ranibizumab) and Regeneron Pharmaceuticals Inc.’s Eylea (aflibercept) in order to cover costs and reduce losses, they say.
The ophthalmologists also point out their supply of Avastin is already being threatened by an FDA draft guidance regarding compounded biologics. The guidance includes a “beyond use date” of
five days for agents such as Avastin that is considered “unreasonably
short,” according to ophthalmologists.
Avastin is compounded into micro-doses suitable for treating conditions such as age-related macular degeneration off label. The FDA
draft guidance was issued in February 2015 and it is not clear when
the final version will be released (“FDA Compounding Guidances Might
Cull Outsourcing List” — “The Pink Sheet” DAILY, Feb. 13, 2015).
Several drug manufacturers commented on the proposal, all listing numerous objections to the payment revision, the scope of the
demonstration, timing and other issues. Manufacturers also took issue
with the agency’s plan to launch value-based payment approaches
beginning in 2017, maintaining there are many legal and regulatory
obstacles in the way.
The Favoring Few
The relatively small number of commenters who generally support
the demonstration included doctors and medical students, advocacy
and policy organizations and some payers.
Many of the comments by doctors and medical students were similarly worded. They state:
“As a physician advocating on behalf of the patients I see every day,
I support the proposal by the CMS to test a sensible set of models
aimed at changing how CMS pays for medications under Medicare
Part B. High drug prices affect all types of patients... It is only through
this testing of pilot reforms that we will be able to choose the best
option for our health care system and our patients moving forward.”
Advocacy organizations supporting the demonstration include
AARP, the Center for Medicare Advocacy, Families USA and the Medicare Rights Center. Payers commenting in favor of the experiment include Aetna Inc., Blue Shield of California and Kaiser Permanente.
© Informa UK Ltd 2016
e u r o p e a n n o t e b o o k / Recent developments and perspectives, reported by our European bureau
Bayer Bids For Monsanto; Biosimilar Uptake Still
Sluggish; EMA Enters Drug Pricing Debate
John Davis [email protected]
more from europe
Other European developments covered over
the past month include:
CLICK
“Comparing EU Vs. US Accelerated Pathway
Approval Times Makes Senior UK Regulator
‘Slightly Defensive’” — “The Pink Sheet” DAILY,
May 17, 2016
“Biosimilars In EU Seeing Reduced Clinical
Data Requirements” — “The Pink Sheet” DAILY,
May 10, 2016
“France Relaxes Stance On Biosimilar
Switching” — “The Pink Sheet” DAILY, May 6,
2016
“EMA Seeks More Doctor Input Into
Regulatory Decision-Making” — “The Pink
Sheet” DAILY, May 4, 2016
thepinksheet.com
Photo credit: Victor Maschek/shutterstock.com
A
fter a series of new CEO appointments over the past several
months, Europe’s big pharma companies have moved on and are
now looking to strengthen or reorganize parts of their businesses.
Confirmation by Germany’s Bayer AG on May 19 that it was in preliminary
talks to acquire Monsanto Co. is the latest example of an emerging trend
among European pharmaceutical companies to pursue M&A.
Monsanto said May 18 it had received an unsolicited, non-binding acquisition proposal from Bayer, a judicious move that would
strengthen Bayer’s agriculture business, one of three prongs to its
life sciences business that consists of pharmaceuticals, consumer
health and crop science. The proposal comes just weeks after Werner
Baumann stepped up from Chief Strategy Officer to become CEO of
Bayer, suggesting a desire to get on with putting some of his previous
planning into effect (“European Notebook: All Change In The C-Suites;
EMA PRIME Starts; French Experts Recommend Phase I Changes” —
“The Pink Sheet,” March 28, 2016).
Swiss multinational Novartis AG also announced plans May 17 to
reorganize its business, with the formation of two business units both
reporting to CEO Joe Jimenez – Novartis Pharmaceuticals and Novartis Oncology – that will form the Innovative Medicines division of the
company (“Novartis Rejiggers Pharma To Favor Oncology” — “The Pink
Sheet” DAILY, May 17, 2016). Meanwhile, France’s Sanofi has offered just
over $9bn for the US company Medivation Inc., a move that would
add weight to the Paris-headquartered big pharma’s cancer portfolio (“Sanofi Earnings Emphasize Need For Medivation Buy” — “The Pink
Sheet” DAILY, April 29, 2016).
Slowly Growing Biosimilars Market
M&A activity is partly driven by the pressure big pharma will come
under over the next few years from the marketing of biosimilar versions of some of their leading products. But although there are more
biosimilars approved in Europe than in the US, their slow uptake by
physicians is still a cause for concern for biosimilar developers. That
was the view of several speakers at the Medicines for Europe’s (formerly the European Generics Association) annual biosimilars meeting,
held in London at the end of April.
The uptake of biosimilar infliximab has been fairly slow in the five
major EU countries, but has been higher in smaller European countries, according to meeting presentations. For example in Denmark a
proactive approach to using biosimilars has been adopted centrally
by the health service, while in Norway, patients being treated with
infliximab have been switched from one biosimilar, Celltrion Inc.’s
Remsima, to another, Hospira Inc.’s Inflectra, without any problems.
Samsung Bioepis Co. Ltd./Biogen’s etanercept biosimilar, Benepalis, has also taken 20% of the market in Norway in the month after its
launch (“European Roll Out For Samsung Bioepis’s Etanercept Biosimilar” — PharmAsia News, Jan. 19, 2016). But the use of Benapalis has
not taken off in countries with decentralized purchasing, such as the
UK. Some European countries are however dropping their opposition
to biosimilar switching. In France, the interchangeability of biosimilars
is no longer proscribed, although patients who are switched must still
be closely monitored, the regulatory agency ANSM said in a position
statement released May 3.
Alleviating Budget Pain
Officials at Europe’s top regulator, the European Medicines Agency,
have come out in favor of approving “me-too” products at a reasonable speed as one of a series of actions that could be adopted to help
address the “budgetary pain” of high-priced new pharmaceuticals.
May 23, 2016 | Pink Sheet |
11
european notebook
EMA Executive Director Guido Rasi and Senior Medical Officer
Hans-Georg Eichler point out in the May 12 issue of the New England
Journal of Medicine that regulators are being “drawn into the acrimonious debate over the cost of medicine,” and they suggest a series
of measures that could be adopted to ensure a competitive marketplace, including the rapid approval of generics and biosimilars, the
speedy approval of me-toos, and encouraging clinical studies that
measure value.
They concede that drug regulations act to increase R&D costs, but
they are not the only factor, or even the most important one leading to high prices. Not only that, relaxing regulations are not likely to
lead to lower prices, because companies tend to charge whatever
the market will bear. But regulators could facilitate the generation of
patient outcome data in mandated post-approval studies, that could
then be used by payers, the regulators suggest.
Additional food for thought was provided by Rasi and colleagues,
who were giving their personal views and not those of the EMA, included modifying the current development pathway for drugs. This
is economically inefficient, and a more flexible approach, such as the
adaptive approvals pathway that the agency is currently exploring,
might allow companies to stagger costs and generate revenues ear-
R isks O f I nhaled S teroids ,
N e w G eneration Factor V I I I
The risk of pneumonia associated with the use of
inhaled corticosteroids to treat chronic obstructive
pulmonary disease (COPD) is well known and common,
but their benefits continue to outweigh their risks, EMA
said April 29 after the completion of a review; there is no
conclusive evidence of a difference in this risk between
different products, EMA added.
At the latest meeting of the Europe’s pharmacovigilance risk assessment committee (PRAC) on May 10-13,
the committee also concluded there was no evidence
currently to suggest that patients treated with secondgeneration full-length recombinant Factor VIII products
are at a greater risk of developing inhibitors (antibodies)
than those treated with older products.
Published studies involving Bayer’s second-generation
agents, Kogenate and Helixate NexGen (both octocog
alfa), should be monitored by the company to keep data
up-to-date about the potential adverse event, the PRAC
added. Other PRAC reviews, including those involving
Johnson & Johnson’s Invokana (canagliflozin), Gilead
Sciences Inc.’s Zydelig (idelalisib), direct-acting hepatitis
C agents and gadolinium-containing contrast agents,
are continuing.
12 | Pink Sheet | May 23, 2016
lier, without relaxing the need to determine risk/benefit profiles, the
European regulators said (“Regulators Have Ways To Address Drug Affordability, EMA Officials Say” — “The Pink Sheet” DAILY, May 12, 2016).
Other authors of the article included the head of the Netherlands regulator, Hugo Hurts, and the president of the German Federal Institute
for Drugs and Medical Devices, Karl Broich.
Regulators And Brexit
The EMA is located in London, and is doubtless viewing the fast-approaching referendum on whether the UK should leave or remain in
the EU with some trepidation, as a leave vote would mean finding a
new location. A raft of UK pharma CEOs have highlighted the risks to
UK jobs and life science research of leaving the EU, including GlaxoSmithKline PLC’s Andrew Witty, AstraZeneca PLC’s Pascal Soriot and
Pfizer Inc.’s Richard Blackburn.
Close election results are increasingly common in Europe; an inconclusive general election last December in Spain has meant a government could not be formed, and Spain’s voters go to the polls again on
June 26, when increasing government spending on health is again
likely to be an important issue for candidates.
Pricing Debated In Germany, Portugal
In Germany, talks between the pharmaceutical industry and the government in the long-running Pharma Dialog process have come up
with the possibility of updating the AMNOG legislation, including a cap
or discount on spending on drugs in the first year after launch, when
companies are free to set their own prices. The health ministry is assessing whether it should draw up revisions for later this year on AMNOG,
the law on pharma sector restructuring that emphasizes price controls.
In Portugal, the regulator Autoridade National do Medicamento e
Produtos de Saude (Infarmed) has said it will reassess the reimbursement of 115 high-priced medicines, with the aim of saving around
€35m ($39m) annually on the government’s drug spending. There are
lower-priced therapeutic alternatives on the market, and companies
are being encouraged to lower the prices of the high-priced medicines that include antibiotics, antidepressants and cardiovasculars. In
Switzerland, a consultation will take place this year on the proposed
introduction of a reference pricing system.
Pricing And Trade Deals
The European industry is deflecting criticism about high prices by
pointing to treatments that have actually fallen in cost. Denmark’s
pharmaceutical trade association, Lægemiddelindustriforeningen
(LIF), noted May 18 the launch of generics for Alzheimer’s therapies
has led to an 85% reduction in the amount Denmark spends on drugs
for the condition. The annual cost of treating a patient with dementia
has declined from DKK 10,000 ($1,500) in 2012 to DKK 1,500 ($227) in
2015, LIF noted. Between 2007 and 2015, the number of dementia
sufferers in Denmark has increased 57%, to around 164,000.
Denmark is one European country that could benefit from the
signing of the Transatlantic Trade and Investment Partnership (TTIP)
between the EU and the US. Pharmaceuticals account for 13.5% of
all Denmark’s exports, and the number of Danes working in the sector has doubled since 2000. TTIP could further increase jobs and ex© Informa UK Ltd 2016
european notebook
ports in the country, argues a LIF legal advisor. This increase would
come about by mutual recognition of GMP inspections, harmonising requirements for pediatric studies, and the continuation of IP
protection and enforcement for pharmaceuticals.
While all eyes are on the TTIP, the free trade bloc consisting of Argentina, Brazil, Paraguay, Uruguay and Venezuela, known as Mercosur, and the EU, are again taking tentative steps to forge a free trade
agreement, a process that has been on and off for decades. The current program restarted in 2010, and numerous talks have been held
since then. On May 11 negotiating offers were exchanged that will
now be discussed in detail by both sides. Mercosur is the 6th largest
export market for EU pharmaceuticals.
Investing in Europe
Novartis announced it would invest €68m in its cell culture manufacturing facilities in Marburg, Germany, that will produce biologics
and provide 50 new jobs. Previously, the sale of Novartis flu vaccine
business had cast doubt on the company continuing operations at
the site. Troubled Ariad Pharmaceuticals Inc. has stepped back from
Europe by selling its European operations, based in Lausanne, Swit-
zerland, to another US company, Wilmington, Delaware-based IIncyte
Corp., that includes medical, sales and marketing operations.
Going the other way, UK biotech Scancell Holdings PLC has opened
an office in San Diego, California. The company has a novel immunotherapeutic approach to cancer in Phase I/II studies. And Germany’s
Merck KGAA, that operates as EMD Serono Inc. in the US, announced
May 4 an expansion of its facilities in Carlsbad, California, to manufacture viral and gene therapies.
Last Word: Salmon Fishing
And finally, any researcher feeling disappointed by the slow development of human DNA vaccines, particularly against cancer, might be
heartened by the first recommendation from Europe’s Committee
for Veterinary Medical Products at the end of April to approve a DNA
vaccine. Although the recommendation was to protect salmon from
salmon pancreas disease caused by a particular virus, the approach
was judged to be sound, with antigenic proteins being synthesised
within the fish, and with no environmental risk from the product, that
was degraded during passage through the fish gastrointestinal tract.
Vaccinated fish were also safe to eat, the CVMP ruled.
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R & D
FLAME Shoots LABA/LAMA Combos Up To
First Choice In COPD
Emily Hayes [email protected]
S
AN FRANCISCO – New data from
Novartis AG’s head-to-head FLAME
study support wider use of LABA/
LAMA combinations in at-risk patients for
preventing exacerbations in COPD – in
preference to a combination of a LABA with
an inhaled corticosteroid – and could trigger a change in global guidelines for treatment, researchers say.
The FLAME study found that Novartis’s
once-daily Ultibro Breezehaler, which combines the long-acting beta agonist (LABA)
indacaterol with the long-acting muscarinic
antagonist (LAMA) glycopyrronium, was
superior to GlaxoSmithKline PLC’s aging
blockbuster Advair/Seretide, which combines the LABA salmeterol with the inhaled
glucocorticoid fluticasone, in terms of fewer
disease flare-ups. FLAME included 3,362 patients who had an exacerbation within the
last year. The annual rate of exacerbations,
the primary endpoint, was 11% lower for
patients taking Ultibro versus Seretide and
the dual bronchodilator approach was also
superior on secondary endpoints (see box).
The message from the study is that the
treatment with dual bronchodilators is the
“combination of first choice in COPD,” lead
investigator Jadwiga Wedzicha said during
a May 15 briefing at the American Thoracic
Society annual meeting in San Francisco.
Wedziga, of the Imperial College London,
and colleagues published their results in
the New England Journal of Medicine the
same day. Novartis had issued a top-line release last November.
The Ultibro Breezehaler is available in 80
countries, including EU members, but not
in the US. In the US, the company got a
twice-daily product approved in October
2015 and markets it as Utibron Neohaler. Novartis reported strong growth for Ultibro/
Utibron in the first quarter, with sales up by
58% to $78m. For its COPD products altogether, the company reported first quarter
sales of $146m, up by 15% from the same
period in 2015.
thepinksheet.com
Call For Guideline Change
Novartis’ global head of development for the
respiratory franchise Mark Levick stressed that
the results don’t have specific ramifications for
the US market, as Ultibro is not available there.
Tosh Butt, the head of the respiratory business
at competitor AstraZeneca PLC, was reluctant
to speculate on the impact on the US market due to dosing differences but noted that
there’s a place for both combinations: “ICS/
LABA for a certain patient type, LAMA/LABA
for another patient type.”
However, experts think that the FLAME
study broadly supports a class effect for the
LAMA/LABA combinations and therefore has
broad implications globally.
Guidelines will need to be rewritten to position LABA/LAMA as the preferred regimen for
treating COPD patients at risk for exacerbations,
Wedziga said during an ATS press briefing.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines advise
using a long-acting muscarinic antagonist as
monotherapy or a LABA/ICS combination for
first-line treatment in this setting.
During the press briefing, Wedziga said she
prefers once-daily treatment because she
thinks it improves overall compliance, but that
she expects that in terms of efficacy, the twice-
daily product marketed in the US is the same.
“Exhaustive studies were performed to see
how a half dose twice a day works, and the
good news is that it is almost identical to the
once-daily dose,” she said.
A study has not been done comparing
the twice-daily dose to Advair/Seretide, but
Wedziga said that she expects the results
would be “identical” to FLAME.
Wedziga also said that she expects that other LABA/LAMA combinations would also have
similar results, though studies are not available.
Three others are on the market in the US.
GlaxoSmithKline’s AnoroEllipta (umeclidinium/
vilanterol), which is dosed once daily, became
the first LABA/LAMA combination with an approval in 2013 (“FDA Approves GSK’s Anoro Ellipta, The First LABA/LAMA Combination” — “The
Pink Sheet” DAILY, Dec. 18, 2013). Boehringer
Ingelheim GMBH’s once-daily Stiolto Respimat
(tiotropium/olodaterol) received FDA approval in 2015. And most recently, AstraZeneca’s
BevespiAerosphere (glycopyrolate/formoterol)
was cleared for the US in April (“Keeping Track:
Approvals For Nuplazid, Cabometyx, Bevespi And
More; Digital Aripiprazole Tablet Needs More
Study” — “The Pink Sheet,” May 2, 2016).
The GOLD guidelines are revised on a yearly
basis. Claus Vogelmeier, who chairs the GOLD
F L A M E Facts A nd F ig u res
• Tested: Novartis’ Ultibro (LAMA/LABA) vs. GSK’s Advair/Seretide (LABA/ICS) for
reducing exacerbations in noninferiority study of 3,362 patients in 43 countries.
• Primary endpoint: Ultibro proved non-inferiority then superiority in terms
of lower annual rate of exacerbations, in patients with a range of disease
severity and eosinophil counts (3.59% vs. 4.03%).
• Secondary endpoints: Ultibro superior for secondary endpoints related to
the time to first exacerbation of any kind, time to first severe exacerbation, lung
function as measured by forced expiratory volume, and effect on quality of life.
• Safety findings: Similar adverse event rates, but significantly higher rate of
pneumonia for Advair/Seretide (4.8% vs. 3.2%). No difference in mortality.
May 23, 2016 | Pink Sheet |
15
R & D
The FLAME study is the first large study comparing a
LAMA/LABA combination against the LABA/ICS standard
of care, and the results are being viewed as enough to
prompt practice changes.
science committee, attended the FLAME press
conference and after the briefing he told the
Pink Sheet that he believes that a guideline
change toward a preference for LAMA/LABA
over LABA/ICS or a single bronchodilator in at
risk patients will “quite likely” be considered in
the “near future,” with change possible this year
or the beginning of next year.
However, the process is complicated and a
lot of people are involved, so the outcome is
difficult to predict, said Vogelmeier, who is director of pulmonary medicine at the Marburg
University Hospital in Germany.
Typically, the guidelines do not make recommendations for specific doses or particular products, he said. So if there is a change,
it likely would be broadly for the LAMA/LABA
combinations.
LABA/LAMA Migration
The FLAME study is the first large study comparing a LAMA/LABA combination against
the LABA/ICS standard of care, and the results
are being viewed as enough to prompt practice changes.
Novartis’ Levick said that the LABA/LAMA
regimen offers the chance for patients to have
an effective treatment, but without the steroids and side effects that come with steroids.
“From a medical practice point of view it is
significant because it offers an alternative for
prescribers now,” he said in an interview.
In a May 15 NEJM editorial accompanying
FLAME results, the University of North Carolina’s James Donohue said that the study does
appear to be enough to support the use of
LABA/LAMA regimen over the a LABA-inhaled glucocorticoid regimen, though more
trials are needed to be sure that “FLAME has
cast a new light on prevention of COPD exacerbations.”
“The FLAME trial shows that a LABA-LAMA
regimen appears to be safe and efficacious
with respect to a wide variety of outcomes,
including exacerbation rate, lung function and
health status,” Donohue concluded.
Wedziga said at the briefing that normally
one study might not be enough to change
16 | Pink Sheet | May 23, 2016
guidelines, but in this case the “data are extremely persuasive,” to support a change in
treatment algorithms, adding that it would be
good to see similar studies in different patient
populations.
Peter Calverley, professor of pulmonary and
rehabilitation medicine at the University of
Liverpool, expects it’s a class effect and noted
that past studies showing the value of two
bronchodilators over one complement the
FLAME data. “FLAME fills in another part of the
story,” he said in an interview.
The clinician added that there probably is
“enough momentum” now for that to happen,”
with respect to dual bronchodilators as a firstline therapy for people with a history of exacerbations and who are symptomatic.
Payers Focus On Generics
In terms of changing practice, a lot depends
on whether payers feel comfortable with going to a dual bronchodilator approach from
the beginning and ultimately that may be a
financial decision. Calverley doesn’t see a scientific basis for staged therapy, starting with
a single bronchodilator and adding on.
The COPD market is very competitive and
has been confronting generic erosion in recent
years (“COPD Market Snapshot: New Products,
Limited Differentiation” — “The Pink Sheet,” May 6,
2013). Two ANDAs for generic versions of Advair
are pending at FDA, with action dates in 2017.
“US payers plan to use step therapy requirements and co-pay differentials as tools to drive
uptake of generic inhaled corticosteroid/longacting beta 2 agonist (ICS/LABA) inhalers in an
effort to contain costs,” Datamonitor analyst
Astrid Kurniawan said in a May 12 report.
There has been no clear LAMA/LABA winner with payers so far, and success may come
down to pricing, she concluded.
Role For Triple Therapy?
The FLAME data also raise questions about
the role of triple LAMA/LABA/ICS therapy.
The late-stage pipeline for COPD has a
strong focus on these triple combos, with
three in Phase III – GSK’s FF/UMEC/VI, Chiesi
Farmaceutici SPA’s CHF 5993 and AstraZeneca’s PT010, Datamonitor analyst Christina
Vasiliou noted in an April 8 report.
“While pulmonologists and primary care
physicians are excited about the potential of
triple therapies to simplify the management
of COPD for highly symptomatic patients, payers hold a more reserved outlook as they are
unconvinced about the long-term efficacy of
such therapies, and are concerned about their
potential overuse,” she said.
FLAME investigator Wedziga suggested that
there should still be a role for steroids for at-risk
patients who still have exacerbations while on
LAMA/LABA therapy.
Researchers presented a post-hoc analysis
of the effects on exacerbation of withdrawing
inhaled glucocorticoids from dual LABA LAMA
therapy in Boehringer’s WISDOM study at the
ATS meeting on May 17.
The study looked at Boehringer’s LAMA
Spiriva (tiotropium), GSK’s LABA Serevent (salmeterol) and ICS Flonase (fluticasone) in 2,296
COPD patients with a history of exacerbations.
The rate of exacerbations after ICS withdrawal
corresponded to the counts of eosinophils, a
type of white blood cells at various thresholds.
And in those at higher count thresholds, this
was a significant finding. Boehringer reports
that based on the results, only 20% of the
study population benefited from having a
steroid on top of the LABA and LAMA. Eosinophils are already being used as a biomarker in
asthma, though FDA has not fully endorsed its
use (“Birth Of A Biomarker? FDA Doesn’t Define
Eosinophilic Asthma, Defers To Docs On Nucala”
— “The Pink Sheet,” March 21, 2016).
The data raise the question of whether you
might be able to know “from the get go” who
should be on what treatment – prescribing
could be much more rational in the future, said
Calverley, who was an author on the publication
of the WISDOM study in the Lancet on April 7.
The eosinophil count looks like a reasonable biomarker for identifying those who can
benefit from inhaled corticosteroids, he said.
However, prospective datasets that randomize patients by eosinophil counts are needed
to support use in clinical practice, he said.
In his NEJM editorial on FLAME, Donohue
concluded: “I think the final word on the use
of blood eosinophil count as a predictor of
response to inhaled glucocorticoids is not
yet established.”
© Informa UK Ltd 2016
R & D
Can Checkpoint Inhibitors Jump-Start Glioblastoma
Drug Development?
Emily Hayes [email protected]
Bristol’s Early Start
Of the leading four sponsors of PD-1/L1 checkpoint inhibitors, Bristol
is by far the most invested in GBM. Early-stage, investigator-sponsored
studies of Merck’s Keytruda (pembrolizumab) and AstraZeneca PLC’s
thepinksheet.com
Photo credit: www.primalpictures.com
I
t’s early days yet, but checkpoint immunotherapies have the potential to jump-start the high-risk, high reward glioblastoma drug
development space, which has been prone to many a setback, the
latest casualty being Celldex Therapeutics Inc.’s Rintega vaccine.
Checkpoint inhibitors, namely Bristol-Myers Squibb Co.’s Yervoy and
Opdivo, Merck & Co. Inc.’s Keytruda and Roche’s newly approved Tecentriq
(atezolizumab), have dramatically shaken up the oncology landscape.
Among many other studies of its checkpoint inhibitors in various tumor types to be presented at the American Society of Clinical Oncology
annual meeting in June, Bristol will be presenting updated data for GBM
patients enrolled in a Phase I cohort of the Phase III CheckMate 143 trial
(see sidebar, p. 20).
It’s unclear how far the checkpoint inhibitors will go in terms of
breadth of indications, and whether they can score another breakthrough in treating glioblastoma multiforme patients, who have a terribly poor prognosis. The research literature suggests a median survival
of one year for GBM and a five-year survival rate of less than 10%.
Datamonitor Healthcare estimates that the number of GBM cases diagnosed in the US, Japan and five major EU markets will rise from 27,230 in
2013 to 35,420 in 2033, based on demographic trends and other factors.
Merck’s alkylating chemotherapy agent Temodar (temozolomide),
now generic, is commonly used with radiation therapy for first-line patients and may also be used as a monotherapy in the second-line setting.
Roche’s Avastin (bevacizumab) is an option for recurrent GBM. The
drug received accelerated approval for this indication in 2009 from
FDA, but was not approved in Europe. Two Phase III studies in newly
diagnosed GBM yielded mixed results – AVAglio showed an improved
quality of life but an RTOG study showed the opposite, and neither
study showed a benefit for an improvement in overall survival (“Avastin QoL Data In First-Line Glioblastoma Muddy Expansion Plans” —
“The Pink Sheet,” March 3, 2014).
Still, many clinicians still find value in using Avastin in relieving
symptoms, such as edema, and minimizing the need for steroids, and
would like to see it retain labeling for glioblastoma, Patrick Wen, director of the Dana Farber’s Center for Neuro-Oncology, commented in
an interview.
As with other cancer types, interest in using checkpoint inhibitors
has been rising in brain cancer. However, as Johns Hopkins specialist
Michael Lim and colleagues pointed out in an August 11, 2015 article
in Nature Reviews Neurology, they are relying on data extrapolated
from other tumor types, and “at present, the exact involvement of
checkpoint pathways in brain tumor pathogenesis is unknown.”
GBM tumors usually develop in the cerebrum.
PD-L1 inhibitor durvalumab (MEDI4736) are ongoing, and Roche presented preliminary safety results from a GBM cohort of atezolizumab
in a Phase I study in 2015, but the data are very early and in a small
group of patients.
Bristol got an early start with Opdivo (nivolumab) in glioblastoma,
having initiated the Phase III cohort of the CheckMate 143 study of
Opdivo with or without the CTLA-4 inhibitor Yervoy (ipilimumab)
against Avastin for recurrent disease back in 2014. That study is eventdriven and results could be available later this year.
A second Phase III study – CheckMate 498 – tests Opdivo against
Merck’s standard-of care alkylating agent Temodar, both on top of radiation therapy in newly diagnosed GBM with unmethylated MGMT.
Methylation of the MGMT gene is associated with better response to
chemo and a better prognosis, whereas those with unmethylated
MGMT have a poorer prognosis and limited treatment options.
With that study, Bristol “strategically positioned Opdivo head-tohead with Temodar,” in MGMT unmethylated type GBM, Datamonitor
analyst Brandon Goode wrote in a recent report on the GBM pipeline.
“Positive data from this study would propel Opdivo into the market as the only therapy dedicated specifically to the treatment of this
subtype of disease that affects a large share of patients,” Goode noted.
The primary completion date on CheckMate 498 is March 2019.
Tough Nut To Crack
There are many challenges in developing a drug for glioblastoma,
including difficulty getting over the blood-brain barrier, tumor resistance mechanisms, heterogeneity of disease and the fact that microscopic disease is invisible on imaging studies, Mark Gilbert, senior investigator and chief of the National Cancer Institute’s neuro-oncology
branch at the National Cancer Institute, said in an interview.
That has made it tough to get through Phase III and approval (“R&D
Realities Disturb Dreams About Orphan Brain Cancer Blockbusters” —
Pharmaceutical Approvals Monthly, October 2010).
EMD Serono Inc.’s cilengitide and AstraZeneca PLC’s Recentin
(cediranib) are among the drugs that failed in the past. Exelixis Inc.
was bullish on taking its multikinase inhibitor XL184, now marketed
as Cometriq (cabozantinib), into Phase III, but the indication dropped
May 23, 2016 | Pink Sheet |
17
R & D
from its pipeline in 2011 (“Full Steam Ahead For Exelixis’ Phase III Glioblastoma Trial” — Pharmaceutical Approvals Monthly, October 2010).
Celldex’s Rintega (rindopepimut), a cancer vaccine designed to induce immunity against EGFRvIII, a permanently activated mutation
on tumor cells, is the latest failure. The drug had breakthrough therapy
status with FDA for EGFRvIII-positive glioblastoma, which accounts for
about 30% of GBM cases.
Rintega: Lessons Learned
The company announced the failure of the Phase III ACT IV study in EGFRvIII+ newly diagnosed GBM in March. The trial was terminated early
when it became clear the drug was unlikely to improve overall survival,
but it was shown to be safe (“Celldex At A Loss To Explain Why Brain Cancer
Vaccine Rintega Failed Phase III” — “The Pink Sheet” DAILY, March 7, 2016).
Johns Hopkins’ Lim sees a silver lining
in the Rintega trial failure. The study
has hopefully established that Rintega
is safe and the door is still open to
research of well-tolerated vaccines as
part of combinations, including with
PD-1 and IDO inhibitors.
The company said that it was at a loss to explain the outcome because performance in mid-stage single arm studies of newly diagnosed
patients had looked promising in comparison with historical controls
with Temodar. But in the pivotal trial, performance of the comparator
Temodar was far better than expected, according to the company.
Overall survival in an interim analysis was 20.4 months for Rintega
vs. 21.1 months for the comparator Temodar (both drugs were given
on top of radiation).
Researchers interviewed for this article said that they would need to
see the full results to understand what happened in the study.
Some question whether the right historical controls were used for
comparison in the mid-stage studies. Celldex noted that the OS for
temozolomide ranged from 12 months to 18 months across trials.
But there are other historical studies that show similar results for temozolomide as the Rintega pivotal trial specifically in EGFRvIII+ newly
diagnosed patients with stable disease, Datamonitor’s Goode pointed
out. In a trial published by Nicola Montano and colleagues in the journal
Neoplasia in December 2011, the OS for EGFRvIII+ patients treated with
Temodar was 19.3 months, which is close to ACT IV results, he noted.
H.C. Wainwright analyst Swayampakula Ramakanth also highlighted the same study in a March 8 note, observing that “the majority of
the patients in the Montano study had received gross total resection
(59 out of 73 patients) and received standard-of-care treatment consisting of radiotherapy and temozolomide, similar to the patients in
the control arm of the ACT IV study.”
The Montano data suggest EGFRvIII expression was a positive, not a
negative prognostic factor in the pivotal study of Rintega, Ramakanth said.
Rindopepimut did show a survival benefit over Avastin in a Phase II
18 | Pink Sheet | May 23, 2016
study of recurrent GBM, but Avastin is not a terribly effective drug and
that wasn’t the target population for the pivotal trial, Goode added.
The Rintega failure emphasizes the need for more randomized
mid-stage work, because the use of single arm studies with historical
controls can be misleading, Lim, who is director of brain tumor immunotherapy at Johns Hopkins, told the Pink Sheet.
NCI’s Gilbert suggested that the optimal study might be an integrated randomized Phase II/Phase III study, where efficacy is examined early
and researchers move quickly to a fully powered Phase III study if they
see a signal. Gilbert is the principal investigator on a multi-arm study of
checkpoint inhibitors and Temodar that the NCI is running with such
a design (NCT02311920). The first cohort has enrolled and once the
safety evaluation of the patients is complete, the next one will open.
Gilbert commented that the EGFRvIII target was interesting, with
some promising earlier stage results, and that following the failure,
“we need to always, always remember that there are other cancers
that were in the same boat we are in, like melanoma, which now is a
phenomenally successful area.”
Bristol Undeterred
BioMedTracker analyst Edny Inui acknowledges the Rintega failure
was disappointing but does not expect it will keep pharmas from
the space, which offers a large market share for those who can make
even a small impact.
Inui does expect, however, that interest will shift to more targeted
immunotherapy as opposed to global immunotherapy.
No vaccine has succeeded in 50 years of ongoing effort, but that
“will not detract enthusiasm for immuno-oncology approaches for
glioblastoma,” Bristol’s Jean Viallet, global clinical research lead in oncology, asserted in an interview.
Johns Hopkins’ Lim sees a silver lining in the Rintega trial failure. The
study has hopefully established that Rintega is safe and the door is still
open to research of well-tolerated vaccines as part of combinations,
including with PD-1 and IDO inhibitors, he said.
In January, a Duke University investigator started a study
(NCT02529072) of a dendritic cell vaccine developed in-house in
combination with Opdivo in 66 patients.
What’s In The Pipeline
The industry-sponsored pipeline is diverse and includes PD-1 inhibitors, gene therapies and cancer vaccines, Goode noted in his GBM
pipeline report.
According to the BioMedTracker database, for brain cancers overall,
including malignant gliomas, anaplastic astrocytomas and GBM, there
are now nine drugs in Phase III, 39 in Phase II and 24 in Phase I. There
are also 73 suspended programs in the pipeline.
Six drugs are in late-stage development for GBM. In addition to
Opdivo, they include two cellular therapies – Northwest Biotherapeutics Inc.’s DCVax-L vaccine and ImmunoCellular Therapeutics
Ltd.’s ICT-107 autologous dendritic vaccine ICT-107 – and VBL Therapeutics’ gene therapy VBL-111, which is being developed in combination with Avastin (see chart).
In their Nature Reviews Neurology paper, Lim and colleagues noted
that “the traditional assumption has been that immune responses in
© Informa UK Ltd 2016
R & D
the CNS were limited,” because of the blood-brain barrier, among other reasons, but “this view has recently been challenged, as it has become clear the CNS [central nervous system] actively communicates
with the immune system.”
Regarding checkpoint inhibitors, the authors were enthusiastic,
while cautioning of challenges in glioblastoma studies, including the
lack of assays for immune response, the need for different measures of
response for checkpoint inhibitors, and management of immune-related CNS adverse events, they noted.
Bristol’s Viallet said that the field is clearly focusing on reversing
mechanisms of immunosuppression in the tumor microenvironment
as the most promising way to bring immuno-oncology to patients
with glioblastoma.
The rate of PD-L1 expression is very high in GBM at 88% of first-line
tumors and 72.2% in recurrent disease, and PD-1 therapy improved
overall survival in preclinical studies, Goode noted in his report. Furthermore, there are some clinical data; results for 10 patients in a
safety cohort of one study suggested biologic activity of checkpoint
inhibition in GBM.
Goode cautioned in his pipeline report that excitement aside, the
supporting clinical data are lacking for checkpoint inhibitors.
Inui noted that along with increased interest in exploring checkpoint
inhibitors will come a rise in development work to tackle the challenge
of how to sequence and use immunotherapies together and with standard-of-care treatments. A range of checkpoint inhibitors and other
types of immunotherapies could potentially play a role in treatment.
“That’s something you will see more of as immunotherapy fever
takes over in the glioblastoma space,” Inui said.
Glioblastoma tumors are highly immunosuppressive, which suggests a combination approach is needed, and more research is also
needed to develop biomarkers to help predict response, Lim said.
Personalized Approaches
The trend in recent years has been for therapies to be personalized,
based on mutation and MGMT methylation status, the Datamonitor
report notes.
Immunocellular Therapeutics’ ICT-107 autologous dendritic cell
vaccine targets the human leukocyte antigen A2 (HLA-A2), which is
present in about half of patients. This candidate targets six different
antigens associated with GBM and by “targeting multiple biomarkers,
ICT-107 overcomes the tumor escape mechanisms commonly associated with single antigen targeting,” Goode noted.
Glioblastoma: Late-stage Pipeline
Sponsor
Drug
Target+
Drug Type
Pros
Cons
Northwest
Biotherapeutics
DCVax-L
Immune
system
Dendritic cell
vaccine
Could be first brain cancer vaccine
to market. Compassionate use in
Germany lends credibility. Early data
suggest long-term survival benefit.
Safe, infrequent dosing after initial
infusions.
Personalized and complex
manufacturing. Expected to be
expensive. Limited trial data for
small number of patients, not peer
reviewed.
Immunocellular
Therapeutics
ICT-107
AIM-2, gp100,
HER-2, Il13ra2, MAGE1, TRP-2
Dendritic cell
vaccine
Targets multiple biomarkers to
overcome tumor escape. Safe,
infrequent dosing. Works in unmethyated and methylated GBM.
Limited to HLA-A2 positive disease.
Likely to be expensive. Personalized
and complex, Likely to reach market
long after competing DCVax-L.
Bristol-Myers
Squibb
Opdivo
PD-1
Monoclonal
antibody
Bristol’s brand-success in
numerous cancers. Well-tolerated.
Tested in high unmet need subtype:
unmethylated GBM.
Lack of GBM-specific data.
Expensive when used with Yervoy.
Biweekly dosing is more frequent
than vaccines.
Vbl
Therapeutics
VB-111,
developed in
combination
with Roche’s
Avastin
TNF-alfa
Gene therapy
biologic
Novel mechanism involving gene
therapy. Avoids problems with treatment resistance by targeting tumor
vasculature. Less costly to make than
dendritic vaccines.
Use with Avastin means more
expensive and more side effects than
other pipeline drugs. May not enter
EU as Avastin not approved there.
Tocagen
Toca-511 and
Toca Fc
DNA
Gene therapy
biologic
and small
molecule
combination
Novel mechanism of action involving
gene therapy elicits antitumor
autoimmune response and kills
cancers directly. Less costly to make
than dendritic vaccines.
Limited to patients undergoing
planned surgery. Limited to recurrent
GBM. Company lacks experience in
market.
+AIM-2 = absent in melanoma 2; gp100 = glycoprotein 100; HER-2 = human epidermal growth factor receptor 2; IL-13Ra2 = interleukin-13 receptor
alpha 2; MAGE-1 = melanoma antigen-encoding gene 1; PD-1 = programmed cell death protein 1; TNF-alpha = tumor necrosis factor-alpha; TRP-2 =
tyrosinase-related protein 2
Sources: Datamonitor Healthcare, BioMedTracker. Examples of strengths and weaknesses based on Datamonitor assessments.
thepinksheet.com
May 23, 2016 | Pink Sheet |
19
R & D
“Additionally, the therapy targets biomarkers found on cancer stem
cells, which are believed to be a key contributor to the proliferation
and recurrence of tumors,” the analyst added.
However, while ICT-107 improved progression-free survival significantly in a Phase II study, it failed to improve OS, he noted.
A pivotal study will stratify outcomes based on MGMT methylation status, which could enhance positioning with payers, in Datamonitor’s view.
On the other hand, ICT-107 development trails behind NorthWest
Biotherapeutics’ DCVax-L, which Datamonitor points out has a shot
at being the first brain cancer vaccine on the market, with approval
possible as early as the second quarter in 2017 in the US (versus a
third-quarter 2020 US entry for ICT-107).
DCVax-L still needs to prove itself clinically, however. Early stage
data looked promising but were derived from very small trials that
were not peer-reviewed, Goode noted in his report.
Interim Phase III results were expected in 2015 but never materialized. A partial clinical hold was placed on the trial in December, stopping enrollment of new patients. In a May 2 statement, the company
said it has enrolled over 300 out of 348 patients in the pivotal trial and
hopes for a resolution soon.
The company also said it was in talks to run three different Phase
II studies of its vaccine in three different combinations. It did not disclose the tumor types or trial partners, aside from saying the deals
involved “leading participants in the immunotherapy field.”
The partial hold is unlikely to have a big effect on the study considering 300 were already enrolled and continued, Inui commented, but
the hold is not a good sign for development generally if robust results
aren’t observed in GBM.
What To Look Out For In Glioblastoma At ASCO
Highlights of abstracts at the upcoming
American Society of Clinical Oncology
meeting include early studies in recurrent glioblastoma from Bristol-Myers
Squibb Co., Tracon Pharmaceuticals
Inc. and Ziopharm Oncology Inc.,
according to a meeting preview from
BioMedTracker.
Glioblastoma multiforme is a highrisk space, considering all of the past
trial failures, but it also offers rewards
for sponsors that succeed in even
marginal improvements and researchers are hopeful about the potential of
checkpoint inhibitors (see related story,
“Can Checkpoint Inhibitors Jump-Start Glioblastoma Drug Development?” — “The Pink
Sheet,” p. 17).
Bristol is presenting updated data
from the first cohort of the CheckMate
143 study at the ASCO meeting, which
will be held June 3-7 in Chicago.
One ASCO abstract (#2014) includes
data for 20 patients with recurrent GBM
who took the PD-1 inhibitor Opdivo
(nivolumab) alone versus two different
doses of a combination with CTLA-4
inhibitor Yervoy (ipilimumab).
According to the study abstract, the
12-month overall survival rate was 40%
for Opdivo alone versus 30% or 25%
for the combination of Yervoy/Opdivo,
depending on the dose – figures that BioMedTracker described as “encouraging.”
20 | Pink Sheet | May 23, 2016
Opdivo alone was also better tolerated than the combination, “consistent
with observations in other tumor types,”
analysts noted.
Bristol said it will be presenting additional, updated data at the meeting.
BioMedTracker analysts also dubbed
Tracon as one of six companies to watch
at the meeting, based on Phase II recurrent
GBM data for TRC105 (Abstract #2035).
The candidate is a first-in-class human
chimeric monoclonal antibody that binds
to CD105 (endoglin), a receptor overexpressed on proliferating endothelium
that is required for angiogenesis. The drug
has shown efficacy in kidney cancer in the
past and with its novel mechanism could
play a role for multiple cancers treated
with Roche’s Avastin (bevacizumab), the
analysts noted.
The study tested TRC1-5 with Avastin
in Avastin-refractory patients. Median
overall survival for 15 patients in the
study taking the combination was 5.75
months, “which is higher than the 4
month OS historical control data for
[bevacizumab]-refractory GBM, but a
larger controlled study is necessary to
determine the actual clinical benefit,”
the report notes. The combination was
also well-tolerated.
‘While these are early results in only
15 patients, we believe that the benefit of the combination of TRC105 in
bevacizumab-naive patients could be
even greater as endoglin upregulation
is hypothesized to be a VEGF inhibitor
escape pathway,” the report adds.
The combination is in Phase II for
Avastin-naïve GBM.
Ziopharm’s updated Phase I results
for its adenovector-based technologybased candidate Ad-RTS-hiL-12 in
combination with oral veledimex (IXN1001), an activator ligand, in heavily
pretreated, recurrent glioma, including
GBM, at ASCO are also noteworthy.
One injection of Ad-RTS-hIL-12
was administered into patients’ brain
tumors and veledimex was given orally
to activate production of IL-12, an
anti-cancer cytokine, and an immune
response at the tumor site, the abstract
notes (#2052).
“Even at its lowest dose, the presence
of IL-12 in the bloodstream could be detected, demonstrating that veledimex is
bioavailable and crosses the blood-brain
barrier at sufficient levels,” the investigators reported.
With follow-up of 6.2 months, 10 of
11 patients were alive.
BioMedTracker analysts said that the
“results confirm the ability to trigger
an immune response in brain tumor
cells via an oral agent and are encouraging for the further development of this
adenoviral vector-based technology.”
© Informa UK Ltd 2016
Generic Drugs
FDA’s ANDA Approvals
Sponsor
Active Ingredient
Dosage; Formulation
Approval Date
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Dapsone
25 mg and 100 mg; tablet
5/10/2016
Zydus
Glyburide
1.25 mg, 2.5 mg and 5 mg; tablet
5/10/2016
Novel Labs
Desoximetasone
0.25%; topical ointment
5/10/2016
Orion
Propafenone HCl
150 mg, 225 mg and 300 mg; tablet
5/11/2016
Qilu
Oxaliplatin
50 mg/vial and 100 mg/vial; injectable, IV infusion
5/11/2016
Fougera
Acyclovir
5%; topical ointment
5/11/2016
Aurobindo
Zolmitriptan
2.5 mg and 5 mg; tablet
5/11/2016
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Ethinyl estradiol/ norgestimate
0.025 mg/0.18 mg, 0.025 mg/0.215 mg, 0.025 mg/0.25 mg;
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Triamcinolone acetonide
0.1%; topical ointment
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200 mg and 400 mg; tablet
5/16/2016
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Rufinamide
200 mg and 400 mg; tablet
5/16/2016
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200 mg and 400 mg; tablet
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Puracap
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15 mg, 30 mg and 45 mg; tablet
5/12/2016
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Ranolazine
500 mg and 1000 mg; extended-release tablet
5/12/2016
Mylan
Febuxostat
40 mg and 80 mg; tablet
5/13/2016
MacLeods
Vardenafil HCl
10 mg; orally disintegrating tablet
5/13/2016
Aurobindo
Dalfampridine
10 mg; extended-release tablet
5/13/2016
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Olmesartan medoxomil/ hydrochlorothiazide
20 mg/12.5 mg, 40 mg/12.5 mg and 40 mg/25 mg; tablet
5/13/2016
Macleods
Pregabalin
25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg and
300 mg; capsule
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© Informa UK Ltd 2016
d e a l w a t c h / A look at some of the most noteworthy recent biopharma transactions.
“The Pink Sheet” regularly covers business development and deal-making in the biopharmaceutical industry. Below is a roundup of some of
the most noteworthy transactions that occurred between May 14-20.
Deal Watch is supported by deal intelligence provided by Strategic
Transactions.
Pfizer/Anacor
Pfizer Inc. has made its first M&A move since the planned mega-deal
with Allergan PLC collapsed. The big pharma announced May 16 that
it will buy Anacor Pharmaceuticals Inc. for $99.25 per share in cash,
or approximately $5.2bn.
The deal is a bolt-on acquisition by Pfizer’s standards, nothing like
the $160bn merger Pfizer had been planning with Allergan that was
thwarted in April by the US treasury (“With The End Of Pfizergan, Pfizer
Has To Grow It Alone” — “The Pink Sheet” DAILY, April 6, 2016). But it is
in line with the way management has been guiding investors to think
about Pfizer’s M&A strategy, mainly that the company is interested in
on-market or late-stage assets that will help drive growth in the innovative side of the business.
Anacor owns a non-steroidal topical phosphodiesterase-4 (PDE-4
inhibitor), crisaborole, that is currently under review by FDA for the
treatment of mild-to-moderate atopic dermatitis, commonly known
as eczema (“Pfizer Buys Anacor With Blockbuster Ambitions For Crisaborole” — “The Pink Sheet” DAILY, May 16, 2016). The drug, which has an
FDA action date of Jan. 7, 2017, could become an important first-line
treatment in a therapeutic area where there are few safe topical options, according to Pfizer. There have been no new molecular entities
approved for atopic dermatitis in 15 years, the company noted. The
pharma projects crisaborole could achieve peak annual sales exceeding $2bn.
Crisaborole fits neatly in Pfizer’s inflammation and immunology
portfolio, which includes the JAK inhibitor Xeljanz (tofacitinib), approved for rheumatoid arthritis, and prior experience marketing Enbrel (etanercept).
“We believe we are well positioned to maximize crisaborole’s commercial potential through our strong relationships with pediatricians
and primary care physicians,” Albert Bourla, group president of Pfizer’s
Global Innovative Pharma and Global Vaccines, Oncology and Consumer Healthcare Businesses, said in a statement.
Datamonitor Healthcare analyst Christina Vasiliou noted that “the
extent of crisaborole’s uptake will be primarily determined by its cost,
as it will be in direct competition with well-established and low-cost
corticosteroids.”
Pfizer will need to drive blockbuster sales of the drug to get a return on its investment, Deutsche Bank analyst Gregg Gilbert said in a
same-day note. “Achieving accretion to non-GAAP EPS in 2018 should
not be difficult (as per Pfizer’s press release), but achieving a good
financial return on the deal would likely require very significant peak
thepinksheet.com
sales,” he wrote.
“We would expect Pfizer
to remain active on the
business development front
and believe it has plenty of
flexibility to do so while returning cash to shareholders,” Gilbert added. Pfizer
reportedly has thrown itself
into the bidding process to buy cancer company Medivation Inc. as
it looks to strengthen its budding oncology business (“Pfizer Oncology Strategy: Keeping Pace In The Doublet/Triplet IO Race” — “The Pink
Sheet,” May 9, 2016).
Anacor also holds rights to Kerydin, a topical treatment for onychomycosis, a toenail fungus, that is commercialized in the US by Novartis AG’s Sandoz unit and competes with Valeant Pharmaceuticals
International Inc.’s Jublia (efinaconazole).
Celgene/Agios
Photo credit: pio3/shutterstock.com
Anacor Purchase Marks Pfizer’s Post-Allergan
Bolt-On Strategy
Agios Pharmaceuticals Inc. will get $200m to kick off a new partnership with longtime collaborator Celgene Corp. under a complex
agreement to develop therapies that alter the metabolic state of immune cells to enhance the immune response to cancer.
The companies did not disclose any specific immuno-oncology
drug targets, but Agios Chief Scientific Officer Scott Biller said during
a May 17 conference call with analysts that the collaboration will seek
to validate Agios-discovered targets “that are not on the radar screen
of other researchers.”
Yet, while the company granted Celgene a major stake in its earlystage, metabolic immuno-oncology program, Agios also regained
global rights to AG-120, which Celgene previously licensed outside of
the US under a 2010 agreement tied to the smaller company’s cancer
metabolism research platform.
While Celgene returned its ex-US rights to AG-120 to Agios, the big
biotech remains committed to other programs under the companies’
first agreement. Celgene CSO Rob Hershberg said in a statement
that the collaborators’ new deal “builds upon the extremely productive partnership and working relationship that exist between our two
companies.”
The rights to two cancer metabolism programs discovered under
the existing relationship between Agios and Celgene, including one
focused on methylthioadenosine phosphorylase (MTAP) deleted
cancers, will now fall under the companies’ new metabolic immunooncology agreement. Any other cancer metabolism programs discovered at Agios will remain wholly owned by the company, since the
discovery phase of its 2010 deal with Celgene expired on April 14.
The terms of the new agreement are similar to the companies’ 2010
deal. Agios will receive $200m up front to lock in the initial four-year
May 23, 2016 | Pink Sheet |
23
research term, but Celgene can pay an undisclosed option fee to extend up to two years. Agios will lead all early research, discovery, preclinical and Phase I clinical trials.
Celgene may decide which programs it wants to collaborate on
when drug candidates reach the preclinical stage and the company
has until the end of Phase I dose escalation studies to pay a fee of at
least $30m to exercise its option to license an asset.
Celgene and Agios will split worldwide development and commercialization costs and profits for each licensed metabolic immuno-oncology program on a 50-50 basis, and Agios may earn up to $169m in
clinical and regulatory milestone fees for each program. The companies will alternate leadership of US development and commercialization for each asset with Agios leading the first program, but Celgene
will lead ex-US development and sales.
In addition, Celgene may pay Agios up to $209m in milestone fees
in exchange for a 65% share of costs and profits for one program under the agreement. For this program, Celgene will lead worldwide development and commercialization.
Other flexibility pre-written into the deal gives Celgene an option
to license exclusive worldwide rights to any inflammation and autoimmune programs discovered under the companies’ new agreement.
Agios will earn milestone fees up to $386m for each inflammation or
autoimmune program plus double-digit royalties on net sales.
Jefferies analyst Brian Abrahams said in a May 17 research note
about Celgene that its new deal with Agios “is unlikely to have material impact to Celgene in the near/medium term, though we believe
it does reflect Celgene’s continued flexibility leveraging evolving science and partnership learnings to pivot into more strategic areas. We
continue to view Celgene’s growth prospects, pipeline breadth and
R&D strategy as best-in-class and underappreciated.”
Biogen/Regenxbio/University of Pennsylvania
Adding to a deal signed not quite a year ago with Applied Genetic
Technologies Corp. to move into ophthalmic gene therapy, Biogen
Inc. inked a pair of agreements May 16 that will bring it adeno-associated virus (AAV) technology and research assistance to advance
programs for a pair of undisclosed rare genetic vision disorders into
clinical development (“Biogen Expands Gene Therapy Efforts Via Deals
With Regenxbio, Penn” — “The Pink Sheet” DAILY, May 16, 2016).
The big biotech announced a three-to-five year R&D pact with the
University of Pennsylvania, through which it will work with researchers James Wilson, head of the university’s gene therapy program,
and Jean Bennett, director of Penn’s Center for Advanced Retinal and
Ocular Therapeutics. In an interrelated move, Biogen also agreed to
license AAV technology from REGENXBIO Inc., including an exclusive
worldwide license to Regenx’s proprietary NAV (novel adeno-associated virus) AAV8 and AAV9 vectors, with rights to sublicense.
“Bennett is really the world expert in genetic vision disorders using
AAV technology, so we’ve had a relationship with Penn for years, including with both Bennett and with Jim Wilson, our scientific founder,
across a number of indication areas,” Regenx CEO Kenneth Mills explained in an interview.
Biogen has been ramping up its gene therapy R&D efforts in recent
years, as signified by its hiring away Olivier Danos from Kadmon Corp.
24 | Pink Sheet | May 23, 2016
Photo credit: f11photo/shutterstock.com
d e a l watc h
Biogen’s deal with UPenn will tap
into work by James Wilson, head
of the university’s gene therapy
program, and Jean Bennett, director
of Penn’s Center for Advanced Retinal
and Ocular Therapeutics.
LLC in 2014 as head of its gene therapy unit – previously Danos had
been director of the Gene Therapy Consortium at University College
London (“Spotlight Returns To Biogen R&D To Sustain Success” — “The
Pink Sheet,” Feb. 2, 2015).
In 2014, the biotech signed a deal with Sangamo BioSciences Inc.
to develop and commercialize therapies for sickle cell disease and
beta thalassemia. That was followed in 2015 by an agreement with
Italy’s San Raffaele Telethon Institute for Gene Therapy to develop
gene therapies for hemophilia A and B.
Under the new deal, Biogen will pay Penn $20m up front and up to
$62.5m in funding over the next three to five years to fund R&D efforts
under seven distinct preclinical target areas through the labs of Wilson and Bennett. The collaboration will focus on both gene therapy
and gene-editing technologies, Biogen said, and could result in Penn
earning up to $2bn through R&D funding, options and milestones.
Various milestones specified under the agreement could trigger payments ranging between $77.5m and $137.5m per potential product.
The collaboration will address multiple objectives – beyond the
eye, the partners will focus on skeletal muscle and central nervous
system (CNS) therapies. They also will attempt to validate next-generation gene transfer technology using AAV gene-delivery vectors and
explore the expanded use of genome-editing technology as a potential therapeutic platform.
Mills said the agreement between Biogen and his company is a
straight licensing arrangement, but as the Penn/Biogen collaboration develops, opportunities for Regenx to take on a greater role in
the work may emerge. He described the deal as facilitating the Penn/
Biogen work in the two undisclosed indications. Biogen will select a
single vector for each indication.
© Informa UK Ltd 2016
d e a l watc h
Specific financial terms were not disclosed, but Regenx will get an
upfront fee, ongoing fees and can earn milestones and royalties on resulting products. Mills said Regenx will disclose in an SEC filing during
the second quarter the receipt of “low single-digit” millions of dollars
from the deal with Biogen.
The additional investment Biogen is taking should help it move
more quickly into clinical development. Most of the firm’s gene therapy programs remain in preclinical development – Biogen’s lone clinical gene therapy candidate at present is called XRLS Gene Therapy,
now in Phase II in X-linked retinoschisis (XRLS).
That candidate had been advanced to Phase I by AGTC before the
2015 deal with Biogen, which also transferred a preclinical candidate
for X-related retinitis pigmentosa, plus two other preclinical ophthalmology candidates and a third non-ophthalmic candidate, to the big
biotech. Biogen paid AGTC $94m up front, made a $30m equity investment and could pay out up to $472.5m in milestones on the two
most advanced candidates under the agreement.
Janssen/MacroGenics
Janssen Biotech Inc. apparently likes what it’s seen so far from the first
bispecific antibody that it licensed from MacroGenics Inc., because
the Johnson & Johnson subsidiary obtained rights to a second asset
from the Rockville, Md.-based firm’s Dual Affinity Re-Targeting (DART)
platform.
MacroGenics has entered into collaborations with seven different
partners for the development of DART compounds yielding a slew
of upfront and milestone fees to support its wholly-owned and partnered programs. The company will get $75m up front from Janssen
under the companies’ second agreement, which pertains to the pre-
clinical T-cell redirecting compound MGD015, plus up to $665m in
milestone fees and double-digit royalties on global net sales.
Leerink Partners analyst Michael Schmidt wrote in a May 18 report
that “bispecific antibodies are poised to play a more important role in
cancer immunotherapy and MacroGenics has the broadest bispecific
pipeline in clinical development, with multiple shots on goal.”
The company entered into a clinical trial collaboration with Merck
& Co. Inc. in October to test its Phase III HER2-targeting monoclonal
antibody margetuximab in combination with Merck’s PD-1 inhibitor
Keytruda (pembrolizumab) in a Phase Ib/II trial enrolling patients with
advanced gastric cancer.
MacroGenics also initiated a Phase III trial in August to test margetuximab versus Roche’s Herceptin (trastuzumab) – both in combination with chemotherapy – in the third-line treatment of HER2positive breast cancer. All of the DART antibodies in the MacroGenics
pipeline are in Phase I or earlier stages of development, but preclinical data to date have led to some lucrative and flexible collaboration
agreements with big pharma and others.
As with the Phase I asset MGD011, the first bispecific antibody licensed by Janssen, the J&J biotech business group will lead global
clinical development and commercialization for MGD015. However,
MacroGenics may contribute funding to help cover MGD015 clinical
development costs in exchange for a share of profits from US and Canadian sales. The biotech company may also opt in to co-promote
MGD015 in the US.
Joseph Haas [email protected]
Jessica Merrill [email protected]
Mandy Jackson [email protected]
New Products
FDA’s NDA And BLA Approvals
Below are FDA’s original approvals of NDAs and BLAs issued in the past week. Please see key below chart for a guide to frequently
used abbreviations
Sponsor
Product
INDICATION
Tecentriq
(atezolizumab)
Use of the PD-L1 inhibitor to treat locally advanced or metastatic
urothelial carcinoma in patients with disease progression during
or following platinum-containing chemotherapy, disease progression within 12 months of neoadjuvant or adjuvant treatment
with platinum-containing chemotherapy
CODE
Approval Date
1
5/18/2016
New Drugs
Roche
(Genentech)
Key to Abbreviations
Review Classifications
NDA Chemical Types
P: Priority review
S: Standard review
O: Orphan Drug
1: New molecular entity (NME); 2: New active ingredient; 3: New dosage form;
4: New Combination; 5: New formulation or new manufacturer; 6: New indication;
7: Drug already marketed without an approved NDA; 8: OTC (over-the-counter) switch;
9: New indication submitted as distinct NDA – consolidated with original NDA;
10: New indication submitted as distinct NDA – not consolidated with original NDA
thepinksheet.com
May 23, 2016 | Pink Sheet |
25
Advisory Committees
Recent And Upcoming FDA Advisory Committee Meetings
Topic
Advisory Committee
Date
Novo Nordisk’s insulin degludec/ liraglutide injection as adjunct treatment to diet and exercise
to improve glycemic control in adults with type 2 diabetes mellitus
Endocrinologic and
Metabolic Drugs
May 24
Sanofi’s insulin glargine/lixisenatide injection fixed-ratio drug product and lixisenatide injection
for treatment of adults with type 2 diabetes mellitus
Endocrinologic and
Metabolic Drugs
May 25
Teva Branded Pharmaceutical Products R&D Inc.’s hydrocodone extended-release tablets,
Anesthetic and Analgesic
formulated with purported abuse-deterrent properties, for management of pain severe enough to
Drug Products; Drug Safety
require daily, around-the-clock, long-term opioid treatment and for which alternative treatment
and Risk Management
options are inadequate
June 7
Pfizer’s oxycodone/naltrexone extended-release capsules, formulated with purported abusedeterrent properties, for management of pain severe enough to require daily, around-the-clock,
long-term opioid treatment and for which alternative treatment options are inadequate
Anesthetic and Analgesic
Drug Products; Drug Safety
and Risk Management
June 8
Merck Sharpe & Dohme’s bezlotoxumab (MK-6072) for prevention of Clostridium difficile
infection recurrence
Antimicrobial Drugs
June 9
Research programs in the Laboratory of Plasma Derivatives in CBER’s Division of Hematology
Research and Review, Office of Blood Research and Review (open session); intramural research
programs site visit report and personnel staffing recommendations (closed session)
Blood Products
June 20
(teleconference)
Boehringer Ingelheim’s Jardiance (empagliflozin) and Synjardy (empagliflozin/metformin) for
adults with type 2 diabetes mellitus and high cardiovascular risk to reduce the risk of all-cause
mortality by reducing the incidence of CV death and to reduce the risk of CV death or
hospitalization for heart failure
Endocrinologic and
Metabolic Drugs
June 28
Development plans for establishing the safety and efficacy of prescription opioid analgesics for
pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation
Anesthetic and Analgesic Drug
Products; Drug Safety and Risk Sept. 15-16
Management; Pediatric
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