Improved Muscle Strength and Attainment of Motor Milestones in Boys with X-linked Myotubular Myopathy (XLMTM) Administered Single-dose Gene Replacement Therapy (resamirigene Bilparvovec)

Background: ASPIRO (NCT03199469), a Phase 1/2/3 randomized, open-label study of the safety and efficacy of AT132 (resamirigene bilparvovec), a single-dose gene replacement therapy for patients with X-Linked Myotubular Myopathy (XLMTM). XLMTM is a rare, life-threatening congenital myopathy caused by mutations in the MTM1 gene resulting in profound muscle weakness, and early death. Patients with extensive ventilator dependence (>16 hours/day) do not achieve critical motor milestones.

Methods: Participants were boys (aged <5 years at day 1 and/or enrolled in INCEPTUS, NCT02704273, a prospective run-in study) with genetically confirmed XLMTM. Motor development, a secondary efficacy endpoint, was assessed in 23 AT132 treated participants (n=6, lower-dose of 1 x 1014 vg/kg; n=17, higher-dose of 3 x 1014 vg/kg) and compared with 15 untreated controls (including 12 participants from INCEPTUS). We report motor skills assessed using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and motor development assessed in each participant via a Motor Developmental Milestones assessment (10 developmental items based primarily on the Bayley III, assessing typical development, such as sitting, standing and walking unsupported) as of 29 Jan 2021.

Results: Most subjects at baseline had significant impairment in CHOP INTEND scores: LSM(SE), low-dose, 37.7(3.6); high-dose, 30.7 (2.1); control, 33.0 (2.3). At baseline, 83.3% (5/6) and 94.1% (16/17) (lower-dose and higher-dose, respectively) vs 93.3% (14/15) control participants were unable to sit unassisted for >30 seconds. At baseline, no participants were able to stand or walk independently. By 48 weeks, 83.3% (5/6) lower-dose and 58.8 % (10/17) higher-dose (vs 0% [0/15] control) participants achieved a CHOP INTEND score >50 which has been correlated with the ability to sit unsupported (which occurs at 6-9 months in unaffected children (Duong 2021)). At last assessment, 100.0% (6/6) lower-dose and 76.5% (13/17) higher-dose (vs 33.3% [5/15] control) participants were able to sit independently without support for 30 seconds; 83.1% (5/6) lower dose and 5.9% (1/17) higher dose (vs 0% control) participants were independently ambulatory without support or assistive device. Motor developmental milestone progression has generally followed a normal developmental timeframe post dosing (as most subjects initiated the study with developmental skills approximating those of a hypotonic neonate), with 78.3% (18/23) of treated subjects (vs 26.7% [4/15] control) participants achieving independent sitting within 6–9 months of dosing (or baseline visit for controls). Following AT132 dosing, 6 participants were independently ambulatory, which occurred at a median of 19.5 months post-dosing. Further analysis of motor development utilizing MFM-32 and Bayley III assessments will be presented.

Conclusion: In XLMTM patients, a rapid increase in muscle strength and motor developmental milestone acquisition was observed subsequent to AT132 treatment compared to untreated controls.

Presenting Author(s)

Lindsay N. Alfano, DPT
Principal Investigator
The Abigail Wexner Research Institute at Nationwide Children’s Hospital
Nationwide Children’s Hospital Center for Gene Therapy
Columbus, OH, Ohio
Disclosure: Audentes Therapeutics (Grant/Research Support)

Co-Author(s)

JJ
James J. Dowling, n/a
Professor
Hospital for Sick Children, Toronto, Canada
toronto, Ontario, Canada
Disclosure: Astelles (Products/Services: contract research to study liver disease in XLMTM) (Grant/Research Support)Dynacure (Products/Services: scientific advisory board; sponsored research to examine DNM2 lowering in RYR1 related myopathy) (Grant/Research Support, scientific advisory board)Kate Therapeutics (Products/Services: clinical and scientific consultant) (Consultant)
PS
Perry Shieh, PhD, Md
Professor
University of California, Los Angeles, CA
Los Altos, California
Disclosure: Astellas Gene Therapies (Products/Services: Grant/Research Support/Contracted Research: Investigator in ASPIRO) (Grant/Research Support)
WM
Wolfgang Müller-Felber, n/a
Professor
Klinikum der Universität München, Munich, Germany
Munich, Bayern, Germany
Disclosure: No Financial Relationships Disclosed
CG
Carsten G. Bönnemann, n/a
Senior Investigator
National Institute of Health
Bethesda, Maryland
Disclosure: No Financial Relationships Disclosed
AM
Andreea M. Seferian, n/a
Professor
I-Motion, Institite of Myology, Paris, France
Paris, Ile-de-France, France
Disclosure: Astellas Gene Therapies (Products/Services: Grant/Research Support/Contracted Research: ASPIRO) (Grant/Research Support)
BS
Barbara K. Smith, n/a
Research Assistant Professor
University of Florida Department of Physical Therapy
Gainesville, Florida
Disclosure: Amicus Therapeutics (Consultant, Educational seminar on outcome measures)Sarepta Therapeutics (Consultant, advisory board meeting)
JL
Jun Lee, n/a
N/A
Formerly of Astellas Gene Therapies
San Francisco, California
Disclosure: Astellas Gene Therapies (Products/Services: Former employee of Astellas Gene Therapies (August 2018 to July 2021)) (Employee)
MN
Mojtaba Noursalehi, n/a
Former Head of Biometrics
Fomerly of Astellas Gene Therapies
San Francisco, California
Disclosure: Astellas Gene Therapies (Products/Services: Employee: Ex employee (heading biostats) at Astellas Gene Therapies) (Employee)
Salvador Rico, MD, PhD
N/A
Fomerly of Astellas Gene Therapies
San Francisco, California
Disclosure: Astellas Gene Therapies (Products/Services: Ex-employee: Head of Clinical Development) (Employee)Encoded Therapeutics (Products/Services: Chief Medical Officer) (Employee)
SP
Suyash Prasad, n/a
N/A
Fomerly of Astellas Gene Therapies
Woodacre, California
Disclosure: Astellas Gene Therapies (Products/Services: Ex-Employee: CMO) (Employee)Prothelia (Consultant, Stockholder/Ownership Interest (excluding diversified mutual funds))Taysha Gene Therapies (Products/Services: Employee) (Employee, Stockholder/Ownership Interest (excluding diversified mutual funds))
JC
Julie Coats, n/a
N/A
Astellas Gene Therapies
San Francisco, California
Disclosure: Astellas Gene Therapies (Products/Services: Manager-Clinical Science, Physical Therapist.) (Employee)
WM
Weston Miller, n/a
N/A
Astellas Gene Therapies
San Francisco, California
Disclosure: Astellas Gene Therapies (Products/Services: Employee: Medical Director) (Employee)
TD
Tina Duong, n/a
Clinical Researcher
Stanford University, Palo Alto, CA
Stanford, California
Disclosure: Astellas Gene Therapies (Products/Services: Consultant for ASPIRO) (Consultant)
NK
Nancy L. Kuntz, MD, FAAN
Professor
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois
Disclosure: Audentes (Contracted Research (Principal Investigators must provide information, even if received by the institution))Biogen (Contracted Research (Principal Investigators must provide information, even if received by the institution))Genentech (Contracted Research (Principal Investigators must provide information, even if received by the institution))Novartis (Contracted Research (Principal Investigators must provide information, even if received by the institution))Sarepta (Contracted Research (Principal Investigators must provide information, even if received by the institution))