Reported death of children on non-Haemophilia Gene Therapy clinical trial

In recent days, we have been made aware of the death of 2 children who were being treated as part of a clinical trial for Gene Therapy for a very serious childhood condition called X- linked myotubular myopathy (XLMTM). This clinical trial was using an adeno associated viral vector (AAV) to deliver the Gene Therapy. The European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD) have issued a joint statement on these deaths. The World Federation of Hemophilia (WFH) have also issued a statement. We reproduce both statements below (or link to them here.)

The statements are similar and give the information which is now available. It is worth setting out a number of points:

• XLMTM is a very serious condition. Without treatment, 25% of affected children die in the first year of life and a further 10% each year after that. The risk / benefit ratio for Gene Therapy in this condition is very different to Haemophilia.

• This condition affects children and the Gene Therapy was carried out on young children under the age of 5 years. Currently, Gene Therapy clinical trials in Haemophilia are carried out only in adults.

• Some children with XLMTM develop underlying liver disease and the Gene Therapy is directed at the liver. The death of these 2 children was linked to severe liver damage following the Gene Therapy

• The highest dose used in the XLMTM gene Therapy was 5 times higher than the highest dose used in any current Haemophilia Gene Therapy in clinical trials.

• No person with Haemophilia has died during a Gene Therapy clinical trial

• We remain very optimistic regarding the prospects for Haemophilia Gene Therapy but this tragedy does point to the need for each person to be fully informed and aware of benefits and potential risks before embarking on any Gene Therapy treatment.

Please also see the joint EAHAD & EHC statement and the WFH and NHF joint statement below.

EAHAD & EHC Joint statement on AAV8-based ASPIRO clinical trial

The European Haemophilia Consortium (EHC) and European Association for Haemophilia and Allied Disorders (EAHAD) have become aware of two deaths in patients with X-linked myotubular myopathy (XLMTM) on an AAV8-based gene therapy (AT132) in the phase 1/2 ASPIRO[1] clinical trial conducted by Audentes, a subsidiary of Astellas. EHC and EAHAD are closely monitoring developments in this area due to this adeno-associated viral vector (AAV8) also being used in haemophilia gene therapy trials.


XLMTM is a very rare disorder with an estimated mortality of 25% in the first year of life and 10% per year after age one[2]. It is characterized by progressive muscle weakness and decreased muscle tone that impair the development of motor skills and may disrupt primary functions such as breathing.

About AT132

The candidate therapy AT132 was granted Priority Medicine (PRIME) designation by the European Medicines Agency (EMA) in 2018 and Fast Track designation by the US Food and Drug Administration (FDA). AT132 is comprised of an AAV8 vector containing a functional copy of the missing or defective MTM1 gene.


As a phase 1/2 clinical trial, the goal of ASPIRO is to investigate the safety of AT132, its optimal dose and its effectiveness in producing the MTM1 gene. The inclusion criteria age is under 5 years old. The dosing cohorts are 1 x 1014 vg/kg and 3 x 1014 vg/kg.

About the recent deaths[3]

At the highest dose of 3 x 1014 vg/kg, patients developed severe liver inflammation. In two patients, this liver damage resulted in multiple complications within weeks following AT132 dosing leading to death. XLMTM patients have a range of medical complications, which may have contributed to the deaths. Investigations around both deaths are ongoing but preliminary reports indicate a similar clinical course. Both patients were of an older age within their paediatric cohort, heavier weight and showed evidence of pre-existing hepatobiliary disease. The company reports that among the six patients treated at the lower dose of 1 x 1014 vg/kg none have developed liver SAEs years out from the treatment.

Differences with gene therapy in haemophilia

Although The information published to date on the complications of the ASPIRO clinical trial is very limited, there is evidence of significant differences in the treatment modalities and characteristics of patients treated with gene therapy for haemophilia.

The highest dose being investigated for haemophilia gene therapies (1013 vg/kg range) is significantly lower than the highest dose used in the ASPIRO trial. The age criteria for haemophilia gene therapy trials is above 18 years of age, whereas in the ASPIRO trial it is under 5 years of age. In addition, hepatobiliary disease was described in the deceased patients of the ASPIRO trial, which is an exclusion criterion for the gene therapy trials in haemophilia.

The haemophilia patient and healthcare provider community continue to closely monitor these and other developments in all relevant gene therapy trials to ensure maximum learning, understanding and safety of these novel therapies. We maintain continuous and close engagement with regulators.

[1] https://clinicaltrials.gov/ct2/show/record/NCT03199469?view=record
[2] https://www.ncbi.nlm.nih.gov/books/NBK1432/
[3] https://www.joshuafrase.org/get-involved/recensus-stu


Joint WFH and NHF statement issued regarding two deaths reported in orphan disease gene therapy clinical trial

We have become aware of two patient deaths in an AAV8 gene therapy Phase 1/2 clinical trial in X-linked myotubular myopathy (XLMTM). This is a devastating disease with survival frequently not beyond early childhood. Children born with XLMTM are missing a protein important for muscle function, and often need ventilator assistance shortly after birth. The gene and protein have been identified, thus the prospect of using gene therapy to replace the defective gene is being pursued by biopharma and academics. A dose escalation trial to establish safety and efficacy of an intravenous AAV8 gene therapy conducted by Audentes Therapeutics, a subsidiary of Astellas, found that at the highest dose level, 3E14 vector genomes/kg (3×1014 or 300 trillion vectors per kilogram), three participants developed severe hepatobiliary disease, which is liver and bile duct damage. In two participants, multiple complications led to death. Individuals with XLMTM have a range of medical complications due to multi-organ system damage beyond the muscles, which may also have contributed to their deaths. Patients treated at 1/3 the dose, 1E14 vector genomes/kg (1×1013 or 100 trillion vectors per kilogram), were reported as doing well. Our thoughts are with the families of the young boys who died.

The dose of vector, 3E14 vector genomes/kg (3×1014 or 300 trillion vector genomes/kg), is among the highest used in AAV clinical trials. Some groups, largely those targeting muscle, are delivering intravenous doses in this range, including an approved product for spinal muscular atrophy (Zolgensma). Some evidence of toxicities from other AAV vectors has been seen at these dose levels in other clinical trials and preclinical non-human primate studies. For comparison, natural infections with any viruses may expose us initially to hundreds or thousands of viral particles. Vaccines often deliver 1E6 (1×106), or 1 million inactivated or killed viruses in order to make antibody responses. Since most AAV traffics to the liver when delivered intravenously, regardless of where its intended target organ is, the liver must manage a large viral load, which can cause toxicity to the organ, especially if the liver is damaged beforehand. Individuals with XLMTM have a number of multi-organ system problems that may have contributed to the deaths, but Audentes did not specify such conditions in the deceased patients.

XLMTM is a rare (1 in 50,000 males) serious, life threatening, neuromuscular disease that impairs muscle development. Due to severe breathing problems individuals usually survive only into early childhood. To be included in the study, patients were required to need mechanical ventilatory support. Patients with significant underlying liver disease were excluded from the XLMTM study. (NCT03199469, www.clinicaltrials.gov). Unlike hemophilia, where clinical trial participants are age 18 or older, all of the participants in the Phase 1/2 XLMTM study were 5 years of age or younger.

In hemophilia studies, where participants in clinical trials are screened for good liver function, the highest AAV vector dose used in clinical studies is 6E13 vector genomes/kg (6×1013 or 60 trillion vector genomes/kg), or about 20% of the dose administered in the Audentes trial. Other clinical trials in hemophilia use AAV doses approximately 1-3% of those used in the Audentes trial.

Thus, the vector doses used in hemophilia are significantly lower than those used in this trial. It is important to emphasize that the assays used to measure the vector are not standardized between laboratories, therefore the dose in the Audentes trial implicated in the deaths should be considered approximate. In addition, empty viral capsids in the material were not stated and may contribute to the total AAV8 burden delivered to the patients.

In each disease-specific gene therapy, the patient population, and individual patients need to assess the benefit/risk of undergoing the therapy. XLMTM, in which significant illness and death develop at a very young age, is different from other diseases such as hemophilia, where multiple therapeutics are available to effectively manage the disease.

Please see the letter sent from Audentes to a X-linked myotubular myopathy patient organization. We do not have a complete story, and the company has not made a clarifying statement other than the attached letter to the XLMTM organizations. We will update this as more information becomes available and hope the company will provide more information soon.

To read the Audentes letter please click here.