VY-AADC01 improved multiple measures of patients’
motor function and activities of daily living in Cohorts 2 and
3
Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene
therapy company focused on developing life-changing treatments for
severe neurological diseases, today announced positive results from
its ongoing Phase 1b trial of VY-AADC01 in advanced Parkinson’s
disease. The results demonstrated durable, dose-dependent and
time-dependent improvements across multiple measures of patients’
motor function after a one-time administration of the gene
therapy. These measures include patient-reported diaries,
Parkinson’s disease rating scales, and activities of daily living.
“We are very pleased with the updated results
from our dose-escalation trial. By six months in Cohort 3, patients
achieved the clinically meaningful improvements in motor symptoms
that were observed in Cohort 2 and with even lower doses of their
oral Parkinson’s medications, including levodopa,” said Bernard
Ravina, M.D., M.S., chief medical officer of Voyager Therapeutics.
“These data suggest that higher doses of VY-AADC01 result in
greater AADC activity, increasing the patient’s capacity to produce
dopamine and, therefore, reducing their need for oral Parkinson’s
medications. As a result, patients in the trial are spending more
time during the day with good motor function, less time with poor
motor function, and are experiencing less disability. For
patients in Cohort 2 at 12 months, this meant an average increase
during the day of four hours of on-time without dyskinesia, which
is a very meaningful change. We believe the distinct
mechanism of action of VY-AADC01 that allows patients to achieve
this motor function improvement while markedly reducing their
Parkinson’s medications to this extent and duration reflects a
pattern that has not been seen in previous Parkinson’s gene therapy
trials and does not exist with current or emerging treatments.”
Steven Paul, M.D., Voyager’s president and chief
executive officer added, “These encouraging results continue to
de-risk the program and support the use of either dose of VY-AADC01
administered in Cohort 2 or Cohort 3 for our planned pivotal trial.
We continue to be impressed with the Cohort 2 data out to 12
months, namely, the increase in diary on-time of four hours without
dyskinesia, decrease in off-time of 54%, supported by a 56%
reduction in UPDRS-III motor scores while on medication. In
addition, preliminary results from our posterior delivery trial
suggest that even greater coverage of the putamen, the brain region
we are targeting, can be achieved and with shorter administration
times. We are excited to continue to follow the patients in this
Phase 1b trial, particularly patients in Cohort 3 from six to 12
months, and those in the posterior delivery trial, as we approach
the start of the pivotal Phase 2-3 program later this year.”
About the Phase 1b Trial
In advanced Parkinson’s disease, the putamen is
depleted of dopamine and of the enzyme aromatic L-amino acid
decarboxylase (AADC) that is responsible for converting levodopa to
dopamine. VY-AADC01 is Voyager’s gene therapy vector that contains
the gene that encodes the AADC enzyme. A single administration of
VY-AADC01 into the putamen could offer advanced patients’ improved
motor function while reducing their requirements for oral levodopa
and other dopaminergic medications and their associated behavioral
and motor side effects.
- The Phase 1b, open-label trial includes 15 patients with
advanced Parkinson’s disease and disabling motor fluctuations,
treated with a single administration of VY-AADC01.
- The primary objective of the trial is to assess the safety and
distribution of ascending doses of VY-AADC01 administered under
magnetic resonance imaging (MRI) guidance to the putamen, a region
of the brain associated with impaired motor function in Parkinson’s
disease.
- Secondary objectives include assessment of AADC expression and
activity in the putamen measured by positron emission tomography
(PET) using [18F] fluorodopa (or 18F-DOPA), which reflects the
capacity to convert levodopa to dopamine. Other secondary measures
include assessments of motor function and activities of daily
living, as measured by the Unified Parkinson’s Disease Rating Scale
(UPDRS-III and UPDRS-II, respectively), quality of life, and a
patient-completed (Hauser) diary. Daily requirements for levodopa
and related medications are also measured.
Biomarker and Clinical Results
Summary
Today’s interim results include data from all 15
patients treated in Cohorts 1, 2 and 3 (five patients in each
Cohort) including data from patients in Cohort 1 at 24 months,
Cohort 2 at 12 months and Cohort 3 at six months. Patients enrolled
in Cohort 3 received similar infusion volumes of VY-AADC01 compared
to Cohort 2 (up to 900 µL per putamen), but three-fold higher
vector genome concentrations. This volume and concentration for
Cohort 3 represents up to a three-fold higher total dose of up to
4.5×1012 vector genomes (vg) of VY-AADC01 compared to patients in
Cohort 2 who received a total dose of up to 1.5 × 1012 vg. Patients
in Cohort 1 received lower volumes (up to 450 µL per putamen) and
lower vector genome concentrations for at a total dose of up to
7.5×1011 vg.
Patients enrolled in Cohorts 1, 2 and 3
were:
- On average, 58 years of age with a Parkinson’s disease
diagnosis for an average of 10 years.
- Candidates for surgical intervention including deep-brain
stimulation due to disabling motor complications despite treatment
with optimal anti-Parkinsonian medication.
- At baseline, the average patient diary on-time without
troublesome dyskinesia was 10.5 hours, average UPDRS-III on
medication score was 13.5, average diary off-time was 4.6 hours and
average UPDRS-II activities of daily living off medication score
was 16.5.
- At baseline, patients were treated with maximal levels of
multiple dopaminergic medications including, in many cases,
amantadine for the treatment of dyskinesia, or uncontrolled or
involuntary movements. Patients’ average amount of Parkinson’s
disease medications at baseline was 1,526 mg of oral levodopa
equivalents per day.
Putamen Coverage, AADC Activity and
Daily Doses of Oral Levodopa
- The use of real-time, MRI-guided delivery and increasing
infusion volumes resulted in 21% mean coverage of the volume of the
putamen with VY-AADC01 in Cohort 1, 34% mean coverage in Cohort 2,
and 42% mean coverage in Cohort 3.
- VY-AADC01 treatment resulted in a 13% increase, a 56% increase,
and a 79% increase in mean putaminal AADC enzyme activity in Cohort
1, 2, and 3, respectively at six months relative to baseline as
measured by 18F-DOPA PET scans (Figure 1). Coverage of the
putamen and AADC enzyme activity were highly correlated (r=0.84,
p=0.0002)
- VY-AADC01 treatment resulted in reduced daily doses of oral
levodopa and related medications to achieve optimal motor control,
suggesting a greater capacity for patients to make more dopamine
but with less need for oral levodopa. Patients’ Parkinson’s
medications were reduced by a mean of 208 mg (14%), 553 mg (34%)
and 618 mg (42%) for Cohorts 1, 2 and 3, respectively, at six
months compared with baseline (Figure 1).
http://www.globenewswire.com/NewsRoom/AttachmentNg/94e771da-19d6-41b9-a8db-7ad9b0e38b63
Clinical Motor Function, Activities of
Daily Living Data Summary
Treatment with VY-AADC01 resulted in
dose-dependent (Cohorts 2 and 3 versus Cohort 1) and time-dependent
clinically meaningful improvements in patients’ motor function in
diary on-time without troublesome dyskinesia (Figure 2). This
included an increase in diary on-time without dyskinesia of 4.0
hours from baseline to 12 months for patients in Cohort 2 and a
reduction in patients’ on-time with troublesome dyskinesia (data
not shown in Figure 2).
http://www.globenewswire.com/NewsRoom/AttachmentNg/bfc0d503-7d2b-4596-aeca-8865d75a4b38
Scores for UPDRS-III, the physician-rated motor
examination, also improved (reduced scores) while patients were on
their medication in a dose-related manner (Cohorts 2 and 3 versus
Cohort 1). These changes in self-reported diary on-time and
UPDRS-III on medication are consistent with an enhanced response to
oral levodopa and related medications (Figure 3).
http://www.globenewswire.com/NewsRoom/AttachmentNg/458094aa-2cbb-48fa-99fb-b185d03c4777
In addition, VY-AADC01 reduced patients’
off-time as self-reported by diary (Figure 4).
http://www.globenewswire.com/NewsRoom/AttachmentNg/bf6cf439-0645-4b94-9ea1-738037f9f036
VY-AADC01 demonstrated dose-dependent and
time-dependent improvements in patients’ activities of daily living
as measured by reductions in the UPDRS-II off medication score,
including a change in mean score from baseline of -2.4 for Cohort 2
at 6 months compared with a change in score from baseline of -3.6
for Cohort 3 at 6 months (Figure 5).
http://www.globenewswire.com/NewsRoom/AttachmentNg/1b540a6d-9d9b-44ed-8154-4e275efb6dee
Safety Data from Cohorts 1, 2 and
3
The infusion was successfully completed in all
15 patients and infusions of VY-AADC01 have been well-tolerated
with no vector-related serious adverse events (SAEs).
Fourteen of the 15 patients were discharged from the hospital
within two days following surgery. As previously reported, one
patient experienced two SAEs: a pulmonary embolism or blood clot in
the lungs, and related heart arrhythmia or irregular heartbeat. The
patient was treated with an anti-coagulant and symptoms associated
with the SAEs have completely resolved. Investigators determined
that this was most likely related to immobility during the
administration and subsequent formation of a blood clot, or deep
vein thrombosis (DVT), in the lower extremity. Consequently, DVT
prophylaxis was added to the protocol and no subsequent events have
been observed.
Phase 1b Posterior Trajectory Trial
Completes Additional Patient Dosing
Investigators recently completed dosing
additional patients in a separate Phase 1 trial designed to further
optimize the intracranial delivery of VY-AADC01. This planned Phase
1 trial explores a posterior, or back of the head, delivery
approach, compared to Cohorts 1 through 3 from the ongoing Phase 1b
trial that used a transfrontal, or top of the head, delivery
approach into the putamen. A posterior approach better aligns the
infusion of VY-AADC01 with the anatomical structure of the putamen
to potentially reduce the total procedure time and increase the
total coverage of the putamen.
Administration of VY-AADC01 with this posterior
approach was well-tolerated by the three patients dosed since the
start of the trial. No serious adverse events were reported, and
patients were discharged from the hospital the day after surgery.
The posterior approach resulted in greater average putaminal
coverage (approximately 50%) and reduced average administration
times compared with the transfrontal approach of Cohorts 1 through
3. Voyager continues to expect to enroll more patients in this
trial prior to the start of the pivotal Phase 2-3 program.
Pivotal Phase 2-3 Program on Track to
Begin During Late 2017
Voyager remains on track to begin the pivotal
Phase 2-3 program for VY-AADC01 late this year and dose the first
patient during the first half of 2018. The company will continue to
follow patients from Cohorts 1 through 3, and those in the
posterior trajectory trial, and plans to report updated results
from these trials during the first quarter of 2018, prior to the
start of patient enrollment in the pivotal program.
Conference Call Information
Voyager will host a conference call and webcast
today at 8:00 a.m. EDT. The live call may be accessed by dialing
(877) 851-3834 for domestic callers or +1 (631) 291-4595 for
international callers, and referencing conference ID number
80581781. A live audio webcast of the conference call will be
available online from the Investors & Media section of
Voyager’s website at www.voyagertherapeutics.com. The webcast will
be archived for 30 days.
About Parkinson’s Disease and
VY-AADC
Parkinson’s disease is a chronic, progressive
and debilitating neurodegenerative disease that affects
approximately 700,000 people in the U.S.1 and seven to 10 million
people worldwide2. It is estimated that up to 15% of the prevalent
population with Parkinson’s disease, or approximately 100,000
patients in the U.S., have motor fluctuations that are refractory,
or not well-controlled, with levodopa. While the underlying cause
of Parkinson's disease in most patients is unknown, the motor
symptoms of the disease arise from a loss of neurons in the
midbrain that produce the neurotransmitter dopamine.
Declining levels of dopamine in this region of the brain, the
putamen, leads to the motor symptoms associated with Parkinson’s
disease including tremors, slow movement or loss of movement,
rigidity, and postural instability. Motor symptoms during the
advanced stages of the disease include falling, gait freezing, and
difficulty with speech and swallowing, with patients often
requiring the daily assistance of a caregiver.
There are currently no therapies that
effectively slow or reverse the progression of Parkinson’s disease.
Levodopa remains the standard of care treatment, with its
beneficial effects on symptom control having been discovered over
40 years ago3. Patients are generally well-controlled with oral
levodopa in the early stages of the disease, but become less
responsive to treatment as the disease progresses. Patients
experience longer periods of reduced mobility and stiffness termed
off-time, or the time when medication is no longer providing
benefit, and shorter periods of on-time when their medication is
effective.
The progressive motor symptoms of Parkinson’s
disease are largely due to the death of dopamine neurons in the
substantia nigra, a part of the midbrain that converts levodopa to
dopamine, in a single step catalyzed by the enzyme AADC.
Neurons in the substantia nigra release dopamine into the putamen
where the receptors for dopamine reside. In advanced
Parkinson’s disease, neurons in the substantia nigra degenerate and
the enzyme AADC is markedly reduced in the putamen, which limits
the brain’s ability to convert oral levodopa to dopamine4. The
intrinsic neurons in the putamen, however, do not degenerate in
Parkinson’s disease5,6. VY-AADC, comprised of the adeno-associated
virus-2 capsid and a cytomegalovirus promoter to drive AADC
transgene expression, is designed to deliver the AADC gene directly
into neurons of the putamen where dopamine receptors are located,
bypassing the substantia nigra neurons and enabling the neurons of
the putamen to express the AADC enzyme to convert levodopa into
dopamine. The approach with VY-AADC, therefore, has the
potential to durably enhance the conversion of levodopa to dopamine
and provide clinically meaningful improvements by restoring motor
function in patients and improving symptoms following a single
administration.
About Voyager Therapeutics
Voyager Therapeutics is a clinical-stage gene
therapy company focused on developing life-changing treatments for
severe neurological diseases. Voyager is committed to advancing the
field of adeno-associated virus (AAV) gene therapy through
innovation and investment in vector engineering and optimization,
manufacturing and dosing and delivery techniques. Voyager’s
pipeline focuses on severe neurological diseases in need of
effective new therapies, including advanced Parkinson’s disease, a
monogenic form of ALS, Huntington’s disease, Friedreich’s ataxia,
frontotemporal dementia, Alzheimer’s disease and severe, chronic
pain. Voyager has broad strategic collaborations with Sanofi
Genzyme, the specialty care global business unit of Sanofi, and the
University of Massachusetts Medical School. Founded by
scientific and clinical leaders in the fields of AAV gene therapy,
expressed RNA interference and neuroscience, Voyager Therapeutics
is headquartered in Cambridge, Massachusetts. For more
information, please visit www.voyagertherapeutics.com.
Forward-Looking Statements
This press release contains forward-looking
statements for the purposes of the safe harbor provisions under The
Private Securities Litigation Reform Act of 1995 and other federal
securities laws.The use of words such as “may,” “might,” “will,”
“should,” “expect,” “plan,” “anticipate,” “believe,” “estimate,”
“undoubtedly,” “project,” “intend,” “future,” “potential,” or
“continue,” and other similar expressions are intended to identify
forward-looking statements. For example, all statements Voyager
makes regarding the initiation, timing, progress and reporting of
results of its preclinical programs and clinical trials and its
research and development programs; its ability to advance its
AAV-based gene therapies into, and successfully initiate, enroll,
and complete, clinical trials; the potential clinical utility of
its product candidates; its ability to continue to develop its
product engine; its ability to add new programs to its pipeline;
its ability to enter into new partnerships or collaborations; its
expected cash, cash equivalents and marketable debt securities at
the end of a fiscal year and anticipation for how long expected
cash, cash equivalents and marketable debt securities will last;
and the timing or likelihood of its regulatory filings and
approvals are forward looking. All forward-looking statements are
based on estimates and assumptions by Voyager’s management that,
although Voyager believes to be reasonable, are inherently
uncertain. All forward-looking statements are subject to risks and
uncertainties that may cause actual results to differ materially
from those that Voyager expected. Such risks and
uncertainties include, among others, those related to the
initiation and conduct of preclinical studies and clinical trials,
the availability of data from clinical trials and the expectations
for regulatory submissions and approvals; the continued development
of the product engine; Voyager’s scientific approach and general
development progress; the availability or commercial potential of
Voyager’s product candidates; the sufficiency of cash resources;
and need for additional financing. These statements are also
subject to a number of material risks and uncertainties that are
described in Voyager’s most recent Annual Report on Form 10-K filed
with the Securities and Exchange Commission, as updated by its
subsequent filings with the Securities and Exchange Commission. Any
forward-looking statement speaks only as of the date on which it
was made. Voyager undertakes no obligation to publicly update or
revise any forward-looking statement, whether as a result of new
information, future events or otherwise, except as required by
law.
__________________________________
1 Willis et al, Neuroepidemiology.2010;34:143–151
2 www.pdf.org/en/parkinson_statistics
3 Poewe W, et al, Clinical Interventions in
Aging.2010;5:229-238.
4 Lloyd, J Pharmacol Exp Ther. 1975;195:453-464, Nagatsu, J
Neural Transm Suppl.2007
5 Cold Spring Harb Perspect Med 2012;2:a009258
6 Braak et al, Cell Tissue Res.2004;318:121-134
Investor Relations:
Matt Osborne
Vice President of Investor Relations & Corporate Communications
857-259-5353
mosborne@vygr.com
Media:
Katie Engleman
Pure Communications, Inc.
910-509-3977
Katie@purecommunicationsinc.com
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