New Medicines

X-linked myotubular myopathy (XLMTM) in boys aged< 5 years


New molecular entity
Astellas Gene Therapies
Astellas Gene Therapies

Development and Regulatory status

Apr 22Astellas is continuing development of resamirigene but has revised the eligible treatment population (details not stated) [15].
Dec 21Astellas announces that, based on clinical hold letter from the FDA, it plans to release additional participant data from the autopsy and follow-up analysis. Also, to interact with the regulatory agencies in early 2022 based on consultations with key opinion leaders, results from scientific investigations and additional participant data. Filings will be delayed beyond FY2022 [14].
Sep 21FDA orders a new clinical hold on the ASPIRO trial after another patient death [13].
Sep 21Astellas announces that they have suspended dosing in ASPIRO after a serious adverse event linked to possible liver damage but that an Investigational New Drug (IND) clinical hold has not been issued [12].
Dec 20With the clinical hold on the ASPIRO trial removed, Audentes is now working to complete all clinical and regulatory activities necessary to resume dosing and plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132 [11].
Jun 20An investigation into the SAEs will inform the development plan, but it is currently unclear when Audentes will be in a position to file for approval [10].
Jun 20Following a patient death, the company have put the ASPIRO trial on hold and are assessing the impact on potential regulatory filing timelines - they will not be filing in mid-2020 as previously planned.[6]
Apr 20Audentus Therapeutics plans to submit a Biologics License Application to the US FDA in late 2020 [5].
Apr 20Audentes Therapeutics was acquired by Astellas Pharma in Jan 20 [5].
Mar 20AT132 has been granted Regenerative Medicine and Advanced Therapy (RMAT), Rare Pediatric Disease, Fast Track and Orphan Drug designations by the FDA, and Priority Medicines (PRIME) and Orphan Drug designations by the EMA [3].
Oct 19Audentes (an Astellas company) is preparing for filing of a Biologics License Application (BLA) for AT132 in the US planned in mid-2020 and filing of a Marketing Authorisation Application (MAA) in Europe planned for H2 2020 [4].


Gene therapy made of a viral vector AAV8 that contains normal copies of the MTM1 gene which is responsible for producing the myotubularin protein. When injected into the patient it is expected that the virus will carry the gene into muscle cells.
XLMTM is caused by mutations in the myotubularin (MTM1; Xq27.3-q28) gene. The incidence of XLMTM is estimated at 1/50,000 male births. The disease is characterised by a severe phenotype in males presenting at birth with marked weakness, hypotonia and respiratory failure. In the majority of cases, the course is fatal within the first months of life. There is currently no curative treatment available. Management is supportive [1].
X-linked myotubular myopathy (XLMTM) in boys aged< 5 years
Intravenous infusion

Trial or other data

Sep 21Astellas reports that the boy most recently reported to have experienced a SAE with resamirigine has passed away [13].
Sep 21Astellas halts dosing in the ASPIRO trial for the second time after another serious adverse event (SAE) linked to possible liver damage. Abnormal LFTs were seen in a patient receiving the gene therapy, and information on the adverse event has been shared with regulators. In the previously reported cases who received a high dose (3.5 x 10_14 vg/kg) of resamirigene, all three patients were older, heavier in weight, and showed signs of pre-existing liver-related disease. The latest case of abnormal LFTs was seen in a patient treated with a lower dose (1.3 x 10_14 vg/kg) and a normal liver ultrasound at enrolment. The FDA only relaxed its clinical hold on ASPIRO after Astellas and Audentes agreed to reduce dosing to the lower level. The participant associated with this current SAE was dosed in the summer of this year, after the original clinical hold was lifted [12].
Dec 20FDA lifts the clinical hold for the ASPIRO trial [11].
Nov 20PI/II ASPIRO trial is active but not recruiting. Collection of primary outcome data expected to be complete in Mar 24, as originally planned [9].
Aug 20To date, 17 boys have received AT132 at 3 × 1014 vg/kg, in the initial dose escalation cohort of ASPIRO or in a later expansion cohort, which proceeded after careful assessment of prior dosed patients, including by an independent monitoring committee. Two of the 17 boys who received AT132 at the 3 × 1014 vg/kg dose experienced fatal liver dysfunction and one has ongoing severe liver dysfunction. These three boys, who were in the later expansion cohort, shared several notable features: they were older, heavier (and thus received among the highest total vg, range: 4.80 × 1015–7.74 × 1015 total vg), and all had evidence of likely pre-existing intrahepatic cholestasis. Although the two deaths occurred months after dosing, all three boys demonstrated signs of liver dysfunction within 3–4 weeks after receiving AT132. The investigators plan to publish the full data set as soon as is practicable [8].
Aug 20A third patient in the ASPIRO trial has died. The cause of death was gastrointestinal bleeding. This patient is one of three who experienced worsening of pre-existing hepatobiliary disease. The trial is still on hold and there are no plans to file for regulatory approval yet [7].
Jul 20A second patient in the ASPIRO trial has died of sepsis following progressive liver dysfunction characterized by hyperbilirubinemia that occurred within 4-6 weeks following dosing. The pt was 1 of 3 older pts who received AT132 at a dose of 3x10 (14) vg/kg in whom new serious adverse events of hepatobiliary disease have occurred. The company have put the clinical trial on hold and there is an ongoing investigation to examine what factors contributed to these adverse effects - early findings suggest older age, heavier weight, evidence of pre- existing hepatobiliary disease and use of the higher dose. [6]
Oct 19Data including safety and efficacy assessments as of the August 7, 2019 data cut-off date for 12 patients enrolled in the ASPIRO dose escalation cohorts reported by Audentes. The data includes 48 weeks or more of follow-up for seven patients enrolled in Cohort 1 (1×1014 vector genomes per kilogram (vg/kg); six treated and one untreated control) and 24-48 weeks of follow-up for five patients in Cohort 2 (3×1014 vg/kg; four treated and one untreated control). Key assessments include neuromuscular function as assessed by the achievement of motor milestones and improvement in CHOP INTEND score, and respiratory function as assessed by reduction in ventilator dependence and improvement in maximal inspiratory pressure (MIP). Patients receiving AT132 have achieved significant and durable reductions in ventilator dependence, an endpoint considered to be closely correlated with morbidity and mortality in XLMTM patients. To date, the first seven patients treated (all six treated patients in Cohort 1 and the first patient treated in Cohort 2) have achieved ventilator independence. All treated patients continue to show gains in neuromuscular function, with the first seven patients treated achieving the ability to rise to a standing position, or walk. AT132 has been generally well-tolerated and has shown a manageable safety profile across both dose groups. Since the last data update in May 2019, there has been one new serious adverse event (SAE) in Cohort 2, an episode of joint swelling that resolved without treatment. Results to date indicate no clinically meaningful differences in the safety and tolerability profile of AT132 between the 1×1014 vg/kg and 3×1014 vg/kg dose cohorts [4].
Sep 19PI/II ASPIRO study is recruiting [2].
Aug 17PI/II ASPIRO study to evaluate the safety and efficacy of AT132 in subjects with X-Linked Myotubular Myopathy aged less than 5 years old starts (NCT03199469). This multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study will recruit 24 subjects from the US, Canada, France and Germany and patients will receive a single dose of AT132 and will be followed for safety and efficacy for 5 years starts. Collection of primary outcome data (adverse events and change from baseline in hours of ventilation support over time through Week 24) is expected to complete Mar 24 [2].