MeiraGTx Holdings plc (NASDAQ:MGTX), a vertically
integrated, clinical stage gene therapy company, today announced
positive clinical data from the completed Phase 1 AQUAx study of
AAV2-hAQP1 for the treatment of grade 2/3 radiation-induced
xerostomia (RIX).
“Today we are releasing data from the completed Phase 1 AQUAx
study which now includes the final 12 month data from all
bilaterally treated participants. The data demonstrate clinically
important improvements in two different patient reported outcome
questionnaires for xerostomia, as well as meaningful increases in
absolute saliva production in both bilaterally and unilaterally
treated cohorts at 12 months,” said Alexandria Forbes, Ph.D.,
president and chief executive officer of MeiraGTx. “We are also
presenting additional data from our long-term follow-up study
demonstrating durability of improvement in participants who have
reached the 2- and 3-year post-treatment assessment, as well as
supportive data showing transduction of parotid glands treated with
AAV2-hAQP1 up to 24 months post-treatment and AQP1 protein
expression.”
Dr. Forbes continued, “We are excited to present these data
showing meaningful activity across key endpoints in participants
with intractable grade 2 and 3 xerostomia which has been persistent
for many years prior to treatment with AAV2-hAQP1. We have
initiated a randomized, double-blind, placebo-controlled, Phase 2
study which is currently enrolling and treating participants, and
we look forward to advancing the development of a potential
treatment for this severely debilitating condition.”
Full data from the AQUAx Phase 1 study is expected to be
reported at a scientific meeting in the second half of 2023.
Phase 1 AQUAx Trial of AAV2-hAPQ1 for the Treatment of
Grade 2/3 Radiation-Induced Xerostomia
AQUAx is an open label, multi-center, dose escalation study of a
single administration of AAV2-hAQP1 to one or both parotid glands
in participants with radiation-induced salivary hypofunction and
grade 2/3 xerostomia. There were 4 escalating dose cohorts with 3
participants per cohort for both unilaterallly and bilaterally
treated participants. All participants were followed for 1-year
post-treatment in the Phase 1 AQUAx study and were then enrolled in
a long-term follow-up study for a total of 5 years. The primary
endpoint was safety and the secondary endpoints included change
from baseline to 12 months in patient-reported measures of
xerostomia symptoms using the Global Rate of Change Questionnaire,
or GRCQ, and the Xerostomia Questionnaire, or XQ. In addition,
whole saliva flow rate was assessed. The study was conducted at 4
centers, with 3 in the US and 1 in Canada.
Treatment appears safe and well tolerated at each dose tested
with no dose-limiting toxicity or treatment-related serious adverse
events.
Efficacy Data presented from the 24
participants treated in the AQUAx study
- Improvements observed in both of the patient reported
assessments of xerostomia symptoms, Global Rate of Change
Questionnaire (GRCQ) and Xerostomia Questionnaire (XQ), in both
unilateral and bilateral treated cohorts at 12 months
post-treatment
- Improvements in salivary flow were seen in unilateral as well
as bilateral cohorts
- Early long-term follow-up data suggest durability of
improvement out to at least 3 years post-treatment
McMaster Global Rate of Change Questionnaire
(GRCQ):
Bilateral Cohorts (n=12) to 12 Months
- 10/12 (83%) participants at 12 months reported symptoms of dry
mouth as ”better” following treatment
- Each of these 10 participants rated changes in xerostomia
scores that were “important” or “very important” with a score of 2
or more at 12 months
- 5 participants rated the change in xerostomia symptoms with the
highest improvement scores of 6 or 7 denoting a “very important
improvement”
- No participant reported worsening of xerostomia symptoms
Unilateral Cohorts (n=12) to 12 Months
- 8/12 participants at 12 months reported symptoms of dry mouth
as “better” following treatment
- Each of these 8 participants rated changes in xerostomia scores
that were “important” or “very important” with a score of 2 or more
at 12 months
- 4 of these participants rated the
change in xerostomia symptoms with the highest improvement scores
of 6 or 7 denoting “a very important improvement”
- Improvement in xerostomia symptoms
persisted through 2 years in 4 participants and 3 years in 3
participants who reached these timepoints
- No participant reported worsening of xerostomia symptoms
Combined Unilateral and Bilateral Cohorts
- Overall, the average improvement in GRCQ score was greater in
bilaterally treated participants compared to those treated
unilaterally
- Improvements were maintained and increased over time in both
unilateral and bilateral cohorts
- A 2-point change in GRCQ is considered important by
patients
- Changes of 3 points or greater are considered a substantial
improvement over standard of care and “transformative” by KOLs
- Unilaterally treated cohorts achieved overall improvement of
>3 points at 12 months
- Bilaterally treated cohorts achieved overall improvement of
>3 points at 2 months and an overall improvement of 4 points by
6 months, with this 4-point improvement maintained at 12
months
Xerostomia Questionnaire (XQ):
Xerostomia Questionnaire (XQ) PRO measure scoring
scale
- An improvement (decrease) of 8 points
or more is considered clinically meaningful
- A decrease in score of 10 or greater is considered a
substantial improvement over standard of care and “transformative”
by KOLs
Change from Baseline Unilateral and Bilateral
Cohorts
- Unilateral: 7/12 had score improvements (decrease) ≥8 at 12
months
- Bilateral: 9/12 had score improvements ≥8 at 12 months
- Overall: 16/24 (66%) had an improvement following treatment of
≥8 points
- 50% of unilaterally treated participants and 75% of bilaterally
treated participants at 12 months achieved at least a 10-point
improvement
- There was good concordance between the responses on the GRCQ
and XQ
Average Change from Baseline Unilateral and Bilateral
Cohorts
- In unilaterally treated participants, an average 13-point
improvement from baseline in XQ was seen at 12 months
- In bilaterally treated participants, an average 21-point
improvement from baseline in XQ was seen at 12 months
- In both groups, XQ
scores improved (declined) >8 points soon after treatment, and
>10 points within 2 months after treatment
- This level of
benefit is considered transformative by KOLs
- The degree of improvement in scores was greater in bilaterally
treated participants compared to those treated unilaterally
Whole Saliva Flow:
Bilaterally Treated Participants: Unstimulated Whole
Saliva Flow
- Meaningful increase
in whole saliva flow was seen in bilaterally treated
participants
- The overall
unstimulated whole saliva flow rate improved to an average of 0.33
mL/min which is within the normal range for unstimulated whole
saliva production
- Normal unstimulated
whole salivary flow rate averages 0.3-0.4 mL/min
- The average
percentage change from baseline was 83% at 12 months
- Based on both
absolute whole resting saliva as well as the overall percentage
change from baseline – the improvement in unstimulated salivary
flow in the bilaterally treated participants appears to be of a
clinically meaningful size that could result in improvement in
xerostomia symptoms
Unilaterally Treated Participants: Absolute Whole Saliva
Measures (Stimulated)
- Increase in whole salivary flow was also observed in
unilaterally treated participants despite the data being confounded
by significant manipulation of the salivary glands just prior to
stimulated saliva collection, and only a single treated gland
contributing to the whole saliva volume
- Stimulated whole saliva in the unilaterally treated cohorts
increased to greater than 0.7ml/min which is above the range of
stimulated saliva flow that is considered hyposalivation
- Hyposalivation is <0.5 to 0.7ml/min for stimulated whole
saliva flow
AAV2-hAQP1 Persists in Parotid Gland for at Least 24
Months After Treatment
- Biopsies were obtained in 7/15 participants enrolled in the
National Institutes of Health (NIH), single site, Phase 1 study
MGT001, using the same batch of drug product used in the AQUAx
study
- 6/7 biopsies showed the presence of AAV2-hAQP1 genomes ≥12
months post-treatment
- There is an increase in copy number of transduced vector
genomes normalized to DNA with increasing dose
- Immunohistochemistry of tissue from a core needle biopsy showed
AQP1 protein expression in acinar cells transduced with
AAV2-hAQP1
Initiation of Phase 2 Study:
Study Design
- Randomized, double-blind, placebo-controlled
- 120 participants: Two active doses of AAV2-hAQP1 vs Placebo.
Randomization 1:1:1.
- Active Doses: 0.4E12 and 1.2E12 (n=40 per arm)
Primary Efficacy Endpoints
- Change from Baseline to 12 Months in symptom-specific XQ
Key Secondary Endpoints
- Change from Baseline to 12 Months in Whole Saliva Flow
Rate
- Safety and tolerability of AAV2-hAQP1 treatment
- GRCQ is also being assessed as a secondary endpoint
Grade 2/3 Radiation-Induced Xerostomia unmet medical
need and market size:
There are currently more than 170,000 patients in the U.S. with
grade 2/3 RIX1,2,3 two or more years out from successful radiation
treatment for head and neck cancer. Each year in the U.S.,
approximately 54,000 new patients with head and neck cancer are
treated with radiation1,2, with an estimated >15,000 developing
persistent grade 2/3 RIX2,3. Current treatment options for grade
2/3 RIX are few and are of limited benefit. The sialogogues
pilocarpine (approved for RIX) and cevimeline (used off-label) are
minimally effective in patients with grade 2/3 radiation induced
xerostomia where the gland structure and function have been
significantly impaired. No new medications for RIX have been
approved in over 20 years.
MeiraGTx’s xerostomia clinical program update details
are as follows:
- Tuesday, June 27, 2023, at 8:00 a.m. ET.
- To register and attend the event, please click here
A live webcast of the event, as well as a replay, will be
available on the Investors page of the Company’s website at
www.investors.meiragtx.com/.About the Phase 1 AQUAx
Clinical Trial
The Phase 1 AQUAx clinical trial is an open-label,
non-randomized, dose escalation trial designed to evaluate the
safety of MeiraGTx’s investigational gene therapy AAV2-hAQP1 when
administered via Stensen's duct to one or both parotid glands in
patients who have been diagnosed with grade 2 or 3
radiation-induced xerostomia and who have remained cancer free for
at least five years (or at least two years if HPV+) after receiving
radiation treatment for head and neck cancer. Primary endpoint of
the trial is safety. Secondary endpoints include change from
baseline in patient reported measures of xerostomia symptoms and in
unstimulated and stimulated salivary flow rates.
About the Phase 1 NIH StudyThe Phase 1 NIH
study is an open-label, dose-escalation study evaluating the safety
of a single administration of an adeno-associated virus vector
encoding human aquaporin-1 to one parotid salivary gland in
individuals with irradiation-induced parotid salivary
hypofunction.
About the McMaster Global Rating of Change Questionnaire
and the Xerostomia QuestionnaireThe McMaster Global Rating
of Change Questionnaire is a validated Patient Reported Outcome
measure wherein the patient rates the severity of their dry mouth.
Patients are asked, “Overall, has there been any change in your Dry
Mouth since you received the study treatment?” Patients may reply,
“Better”, “Worse”, or “About the Same”. If the patient replies
“Better” or “Worse”, they are asked to quantify the change for
better/worse on a 7-point scale, with 7 a very important change
from baseline, and 1 being minimal. A two-point change is important
to the patient. This PRO measure was accepted by the FDA in its
review and approval of cevimeline4.
The Xerostomia Questionnaire is a PRO measure consisting of 8
symptom-specific questions wherein the patient rates each symptom
from 0 (not present) to 10 (worst possible). The responses are
summed (0-80), providing an overall measure of disease burden. This
PRO is refined from the Xerostomia Inventory which consists of 11
questions and for which a 6-point change in disease burden is
defined as a clinically meaningful improvement. Drugs approved
based on positive McMaster Global Rating of Change assessments have
failed to demonstrate clinically meaningful improvement on this
measure in registrational studies.
About MeiraGTxMeiraGTx (Nasdaq: MGTX) is a
vertically integrated, clinical-stage gene therapy company with six
programs in clinical development and a broad pipeline of
preclinical and research programs. MeiraGTx has core capabilities
in viral vector design and optimization and gene therapy
manufacturing, and a transformative gene regulation platform
technology that allows precise, dose responsive control of gene
expression by oral small molecules with dynamic range that can
exceed 5000-fold. Led by an experienced management team, MeiraGTx
has taken a portfolio approach by licensing, acquiring, and
developing technologies that give depth across both product
candidates and indications. MeiraGTx’s initial focus is on three
distinct areas of unmet medical need: ocular diseases, including
both inherited retinal diseases as well as large degenerative
ocular diseases, neurodegenerative diseases and severe forms of
xerostomia. Though initially focusing on the eye, central nervous
system, and salivary gland, MeiraGTx plans to expand its focus to
develop additional gene therapy treatments for patients suffering
from a range of serious diseases.
For more information, please visit
www.meiragtx.com
1 SEER, Cancer.net2 Marta GN et al (2014). Intensity-modulated
radiation therapy for head and neck cancer: systematic review and
meta-analysis. Radiother Oncol. 110(1):9-153 Jensen S.B., et al.
(2010). A systematic review of salivary gland hypofunction and
xerostomia induced by cancer therapies: prevalence, severity and
impact on quality of life. Support Care Cancer. 18(8):1039-10604
Mark S. Chambers, Marshall Posner et al., Cevimeline for the
Treatment of Postirradiation Xerostomia in Patients With Head and
Neck Cancer, 2007. Int. J. Radiation Oncology Biol. Phys., Vol. 68,
No. 4, pp. 1102–1109
Forward Looking StatementThis press release
contains forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995. All statements
contained in this press release that do not relate to matters of
historical fact should be considered forward-looking statements,
including, without limitation, statements regarding the development
and efficacy of AAV2-hAQP1, the advancement of AAV2-hAQP1 into a
Phase 2 clinical trial and anticipated milestones regarding our
clinical data and reporting of such data and the timing of results
of data, as well as statements that include the words “expect,”
“will,” “intend,” “plan,” “believe,” “project,” “forecast,”
“estimate,” “may,” “could,” “should,” “would,” “continue,”
“anticipate” and similar statements of a future or forward-looking
nature. These forward-looking statements are based on management’s
current expectations. These statements are neither promises nor
guarantees, but involve known and unknown risks, uncertainties and
other important factors that may cause actual results, performance
or achievements to be materially different from any future results,
performance or achievements expressed or implied by the
forward-looking statements, including, but not limited to, our
incurrence of significant losses; any inability to achieve or
maintain profitability, raise additional capital, repay our debt
obligations, identify additional and develop existing product
candidates, successfully execute strategic priorities, bring
product candidates to market, expansion of our manufacturing
facilities and processes, successfully enroll patients in and
complete clinical trials, accurately predict growth assumptions,
recognize benefits of any orphan drug designations, retain key
personnel or attract qualified employees, or incur expected levels
of operating expenses; the impact of the COVID-19 pandemic on the
status, enrollment, timing and results of our clinical trials and
on our business, results of operations and financial condition;
failure of early data to predict eventual outcomes; failure to
obtain FDA or other regulatory approval for product candidates
within expected time frames or at all; the novel nature and impact
of negative public opinion of gene therapy; failure to comply with
ongoing regulatory obligations; contamination or shortage of raw
materials or other manufacturing issues; changes in healthcare
laws; risks associated with our international operations;
significant competition in the pharmaceutical and biotechnology
industries; dependence on third parties; risks related to
intellectual property; changes in tax policy or treatment; our
ability to utilize our loss and tax credit carryforwards;
litigation risks; and the other important factors discussed under
the caption “Risk Factors” in our most recent quarterly report on
Form 10-Q or annual report on Form 10-K or subsequent 8-K reports,
as filed with the Securities and Exchange Commission. These and
other important factors could cause actual results to differ
materially from those indicated by the forward-looking statements
made in this press release. Any such forward-looking statements
represent management’s estimates as of the date of this press
release. While we may elect to update such forward-looking
statements at some point in the future, unless required by law, we
disclaim any obligation to do so, even if subsequent events cause
our views to change. Thus, one should not assume that our silence
over time means that actual events are bearing out as expressed or
implied in such forward-looking statements. These forward-looking
statements should not be relied upon as representing our views as
of any date subsequent to the date of this press release.
Contacts
Investors:MeiraGTxInvestors@meiragtx.com
Media:Jason Braco, Ph.D.LifeSci
Communicationsjbraco@lifescicomms.com
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