Robust and durable improvements in patients'
motor function achieved with substantial reductions in use of daily
oral levodopa and other Parkinson’s disease medications; one-time
administrations of VY-AADC well-tolerated now out to three years in
Cohort 1
Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene
therapy company focused on developing life-changing treatments for
severe neurological diseases, today announced longer-term data from
its ongoing dose-ranging Phase 1b trial of VY-AADC in advanced
Parkinson’s disease. The results continue to demonstrate 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
quality of life, with diary on-time without troublesome dyskinesia
at twelve months as the proposed primary endpoint of the planned
pivotal program. The update of results from the ongoing Phase 1b
trial of VY-AADC include a durable 2.1-hour improvement in
patient-reported diary on-time without troublesome dyskinesia from
baseline to three years for patients in Cohort 1, a durable and
clinically meaningful 3.5-hour improvement from baseline to 18
months in Cohort 2, and an improvement from baseline to six months
of 1.5 hours that plateaued from six to 12 months in Cohort 3.
“We continue to be pleased with the duration and
magnitude of effect of VY-AADC on multiple measures of patients’
motor function and quality of life, which is consistent with the
mechanism of action of VY-AADC suggesting a greater capacity for
patients to make more dopamine and improve their motor function
with less need for oral levodopa,” said Bernard Ravina, M.D., M.S.,
chief medical officer of Voyager Therapeutics. “In our dose-ranging
Phase 1b trial, we systematically increased the dose of VY-AADC to
select an optimal dose prior to initiating our pivotal program. We
believe we have achieved this with our Cohort 2 dose, in which
patients increased their on-time without any dyskinesia by five
hours at 18 months and reduced their off-time by more than 60%. Not
unexpectedly, our Cohort 3 dose resulted in greater rates of
levodopa-induced dyskinesia that resolved with marked reductions in
patients’ oral levodopa and related medicines but resulted in less
robust control of motor function compared to Cohort 2 by 12 months.
Given the improvements in motor function and wider spectrum to
titrate oral levodopa with our Cohort 2 dose, we are excited to
consider this as our likely dose in the pivotal program while still
planning to review the six-month results from the Phase 1 posterior
trajectory trial next quarter. We look forward to reviewing these
results from the Phase 1b with the FDA as part of a planned Type C
meeting and we continue to expect to dose the first patient in the
pivotal Phase 2-3 program in mid-2018.”
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-AADC is Voyager’s gene therapy vector that contains
the gene that encodes the AADC enzyme. A single administration of
VY-AADC into the putamen could offer advanced patients improvements
in motor function while reducing their requirements for oral
levodopa and other dopaminergic medications and 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-AADC.
- The primary objectives of the trial are to assess the safety
and tolerability of VY-AADC and to test the distribution of
ascending doses of VY-AADC 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.
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 three years,
Cohort 2 at 18 months and Cohort 3 at one year. Patients enrolled
in Cohort 3 received similar infusion volumes of VY-AADC delivered
with the transfrontal, or top of the head, approach compared to
Cohort 2 (up to 900 µL per putamen), but three-fold higher vector
genome (vg) concentrations. This volume and concentration for
Cohort 3 represents up to a three-fold higher total dose of up to
4.5×1012 vg of VY-AADC 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 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. Patients in Cohort 3 entered the trial with
approximately 50% more severe dyskinesia at baseline than patients
in Cohorts 1 and 2 based on the Unified Dyskinesia Rating Scale,
with a mean score of 30.2 for Cohort 3 compared with a mean score
of 19.2 and 17.4 for Cohorts 1 and 2, respectively.
- 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.
- During the trial, patients were instructed to reduce their
daily doses of oral levodopa and related medications, or levodopa
equivalent doses (LEDs), to achieve optimal motor control in
response to severe dyskinesia observed post-treatment with VY-AADC.
In this trial, patients’ Parkinson’s disease LEDs were reduced by a
mean of 15%, 33% and 42% for Cohorts 1, 2 and 3, respectively, from
baseline to six months. LED reductions were sustained for Cohorts 1
and 2 to eighteen months and for Cohort 3 to 12 months (Figure
1).
http://www.globenewswire.com/NewsRoom/AttachmentNg/2025e32e-fe78-41b7-824c-77ceea0bd7ff
Clinical Motor Function Data
Summary
Treatment with VY-AADC resulted in a durable
2.1-hour improvement in patient-reported diary on-time without
troublesome dyskinesia from baseline to three years for patients in
Cohort 1, a durable and clinically meaningful 3.5-hour improvement
from baseline to 18 months in Cohort 2, and an improvement from
baseline to six months of 1.5 hours that plateaued from six to 12
months in Cohort 3 (Figure 2). Cohort 3 patients had higher levels
of severe dyskinesia at baseline than patients in Cohorts 1 and 2.
This, coupled with treatment with a higher dose of VY-AADC,
resulted in patients in Cohort 3 reducing their LEDs to a greater
extent than patients in Cohorts 1 and 2 and may have resulted in
less robust control of motor function as measured by on-time
without troublesome dyskinesia compared to Cohort 2 by 12 months.
Voyager intends to apply these learnings to the protocols for the
pivotal Phase 2-3 program.
http://www.globenewswire.com/NewsRoom/AttachmentNg/83151e47-1ec2-415f-83c8-56a1fd4841e4
VY-AADC also generated durable improvements in
this trial in other measures of motor function including decreases
in both diary off-time and diary on-time with troublesome
dyskinesia and increases in both diary on-time without dyskinesia
and diary on-time with non-troublesome dyskinesia. In Cohort 2 at
18 months, patients had a mean increase of 5.1 hours a day of
on-time without any dyskinesia and experienced 65% less off-time
(Figure 3).
http://www.globenewswire.com/NewsRoom/AttachmentNg/2b80722a-2913-45b2-a2e6-d02f8c949bc0
In addition to motor function, VY-AADC improved
patients’ quality of life as measured by the Unified Parkinson’s
Disease Rating Scale (UPDRS) Part II activities of daily living
section and the patient-reported 39-item Parkinson’s Disease
Questionnaire (PDQ-39), demonstrating dose-dependent and clinically
meaningful improvements in these scores. For PDQ-39, VY-AADC
improved (reduced) patients’ score by a mean change from baseline
to 12 months of -8.4 and -9.1 for Cohorts 2 and 3, respectively
(Figure 4).
http://www.globenewswire.com/NewsRoom/AttachmentNg/e7ebe7e1-818e-4078-a72f-468af403fadd
Safety Data from Cohorts 1, 2 and
3
Infusions of VY-AADC have been well-tolerated in
all fifteen patients treated in these Cohorts 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.
Pivotal Phase 2-3 Program on Track to
Begin Dosing Patients in Mid-2018
Voyager plans to meet with the Food and Drug
Administration (FDA) during a Type C meeting to discuss the current
Phase 1b data and designs for the pivotal program. Voyager expects
to include information from this meeting, as well as data from
Cohorts 1, 2 and 3 and the Phase 1 posterior trajectory trial, into
the final design of the Phase 2-3 pivotal program, which remains on
track to dose the first patient during mid-2018.
Conference Call Information
Voyager will host a conference call and webcast
today at 8:30 a.m. EST. 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 8774548.
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 1,000,000 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 150,000
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
patients suffering from severe neurological diseases. Voyager is
committed to advancing the field of AAV gene therapy through
innovation and investment in vector engineering and optimization,
manufacturing and dosing and delivery techniques. The company’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,
neurodegenerative diseases related to defective or excess
aggregation of tau protein in the brain including Alzheimer’s
disease, and severe, chronic pain. Voyager has broad strategic
collaborations with Sanofi Genzyme, the specialty care global
business unit of Sanofi, AbbVie Biotechnology Ltd, a division of
AbbVie Inc., 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 perform under existing collaborations with, among
others, Sanofi Genzyme and AbbVie and 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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