CONCLUSIONS INTRODUCTION METHODS Pieter Okkerse*1

A randomized, blinded, placebo-controlled, multiple ascending dose study of the safety,
tolerability, pharmacokinetics, and efficacy of neublastin in subjects with sciatica
Pieter
1Centre
INTRODUCTION
•  Neublastin (BG00010 / artemin) is a protein in
the glial cell line-derived neurotrophic factor
(GDNF) family. It is a human dimeric
recombinant Chinese hamster ovary
(CHO)-expressed protein.
•  It is a selective ligand for the GFRα3 co-receptor
that normalizes cellular changes resulting from
damage or disease, and potentially alleviates
neuropathic pain. As GFRα3 expression is highly
restricted within the nervous system to small
dorsal root ganglion sensory neurons, there is
a low likelihood of off-target neural effects.
•  Nonclinical data from multiple surgical and
chemical models of nerve injury have
demonstrated that neublastin attenuates
pain-related behaviors and normalizes the
neurochemical status of injured small
DRG neurons.
•  Neublastin is being developed for the treatment
of neuropathic pain.
•  This study was the second study of neublastin
in humans.
METHODS
Primary study objective
•  To evaluate the safety, tolerability, and
pharmacokinetic (PK) profile of 3 intravenous (IV)
injections of neublastin given on 2 fixed schedules
Study design
•  This was a randomized, blinded, placebocontrolled, multiple ascending dose study in
subjects with unilateral sciatica.
1
Okkerse* ,
1
Hay ,
1
Groeneveld
Justin
Geert Jan
, Eve
†
2
†
Tom Tang , Gerald Galluppi , Ernesto Aycardi
2
Versage ,
for Human Drug Research (CHDR), Leiden, the Netherlands; 2Biogen Idec, Cambridge, MA, USA
•  The study was divided in two parts that included
two different dose regimens: in Part I, dose levels
of 50, 150, 400 and 800 µg/kg IV were examined;
in Part II, dose levels of 400, 600 and 1200 µg/kg
IV were examined.
Figure 1-2: Mean neublastin concentration vs. time
by cohort
Figure 3-4: Adverse event overview for Part I
(Figure 3) and for Part II (Figure 4) for pruritus, rash
and temperature related events
Figure 5-6: IENFD median (+/- range) change from
baseline by treatment and visit for Part I (Figure 5)
Part II (Figure 6)
•  Each group consisted of 4 subjects (3 on
neublastin, 1 on placebo).
Safety and pain assessments
•  Routine safety assessments: adverse event [AE]
reporting, standard laboratory tests, physical and
neurological examinations and ECGs.
•  Study specific tests included intraepidermal nerve
fiber density [IENFD] analysis and quantitative
sensory testing [QST] (including vibration, cold and
heat thermal thresholds). Both analyses were
performed on the unaffected leg.
•  There were no SAEs or AEs leading to
withdrawal during the study.
CONCLUSIONS
•  Pain intensity was assessed using a 100-mm
VAS of the short form McGill pain questionnaire
[SF-MPQ] and an 11-point Numeric Rating Scale
(NRS).
•  Neublastin was generally well-tolerated.
•  There were no dose limiting toxicities.
•  The maximum tolerated dose was not identified in
this study.
RESULTS
•  In total, 21 subjects were treated with neublastin.
•  Neublastin concentration time data indicated
relatively low inter-subject variability in the time
course of neublastin serum exposure. There was
a dose dependent increase in serum exposure
from 150 to 1200 µg/kg, but the increase was not
dose-proportional.
•  The most frequently reported AEs in the study for
subjects administered neublastin were headache,
feeling hot, generalized pruritus and pruritus.
The majority of all AEs were mild in severity and
no severe AEs were reported. All subjects
Pruritus events include Pruritus, Pruritus generalized and Eye pruritus. Temperature events
include Feeling hot, Hot flush, Temperature Intolerance, Burning sensation, Feeling cold,
Feeling of body temperature change and Chills. 1=mild; 2=moderate; 3=severe
experienced at least 1 AE that was considered
related to study treatment and the majority of
treatment related AEs had resolved by the end
of the study
•  Overall, the incidence of AEs was greater in
subjects treated with neublastin versus placebo.
There was no indication of a trend for increased
reporting of AEs with increasing neublastin dose
or increasing frequency of dosing of neublastin.
•  No clinically significant changes were found in
vital signs, ECG, IENFD, QST or safety
laboratory tests.
•  In some subjects that received active treatment,
a higher reduction in pain NRS scores post
dosing was observed compared to placebo
treated subjects.
•  One placebo subject withdrew from the trial due
to personal logistical issues.
Centre for Human Drug Research | Zernikedreef 8 | 2333 CL Leiden | The Netherlands | Tel +31 71 52 46 400 | [email protected] | www.chdr.nl
•  Based on the safety, tolerability and observed trend
in the alleviation of pain with active treatment, this
study supports further development of neublastin
for the treatment of neuropathic pain indications.
ACKNOWLEDGEMENTS
Biogen Idec provided funding for this study
(NCT01405833)
†TT
and EA are former employees of Biogen Idec
4th International Congress on Neuropathic Pain
23-26 May 2013
Toronto, Canada
Poster copy