Astellas Pharma has seen their ASPIRO trial put on clinical hold for the second time after the fourth patient passed away. The Phase I/II trial is evaluating AT132, a potential gene therapy intended to treat X-linked myotubular myopathy (XLMTM). It was initially put on hold after three patients died while being treated with 3.5×1014 vg/kg of the adeno-associated virus (AAV) gene therapy but allowed to continue after the dose was lowered to 1.3×1014 vg/kg. Now, the future of the trial is uncertain.
About the ASPIRO Trial
Initially, this open-label, delayed-treatment concurrent control, ascending dose trial was designed to enroll 26 patients across multiple countries. These patients were all under age five and had received an XLMTM diagnosis. As of now, 24 participants have received the lower dose, and 17 patients were previously treated with the higher dose.
Of the 17 patients who were administered 3.5×1014 vg/kg of AT132, three began to experience the signs and symptoms of liver dysfunction before developing progressive cholestatic hepatitis, which then progressed to liver failure. This led two patients to develop fatal cases of sepsis, while the third passed away due to a gastrointestinal bleed. These issues all began three to four weeks after dosing.
These patient deaths led the FDA to place the trial under clinical hold. It was not until December 2020 that the trial was allowed to resume, and this was only after Astellas agreed to treat patients with a lower dose.
While the dose was decreased, it is important to note that 1.3×1014 vg/kg is in no way a “lose dose.” Nicole Paulk, PhD, of UCSF stated that doses this high, especially when administered via IV, are related to serious adverse events (SAEs).
Resuming the Trial at a Lower Dose
The fourth patient was dosed with 1.3×1014 vg/kg of the AAV gene therapy over the summer. In a matter of weeks, he showed abnormal results on his liver function tests (LFTs). Immediately, researchers working on the trial reported this SAE to the proper agencies and opened up a dialogue. They also stopped screening and dosing other trial participants.
After this occurred, the FDA placed the trial on another clinical hold.
AT132, also referred to as bilparvovec, is an AAV gene therapy that was created to deliver a functioning version of the MTM1 gene. Through an AAV serotype 8 vector, AT132 allows myotubularin to be expressed in skeletal muscle cells.
This gene therapy was acquired by Astellas at the beginning of 2020 and has received the Orphan Drug, Rare Pediatric Disease, and Fast Track designations from the FDA. Additionally, the European Medicines Agency (EMA) has granted the Orphan Drug and PRIME designations.
Astellas extended their “deepest sympathies to the participant’s family” and will continue to investigate and review the circumstances of this tragedy. As of now, there is no concrete cause of death.
According to the U.S. National Library of Medicine, X-linked myotubular myopathy is a rare condition characterized by weakness and decreased muscle tone of the skeletal muscles. Because it is inherited in an X-linked recessive pattern, it almost exclusively impacts males. A mutated MTM1 gene is passed down on the X chromosome, which then disrupts the production of the enzyme myotubularin. This enzyme plays a role in the development and function of muscle cells.
- Muscle weakness and decreased muscle tone
- Impaired motor skills
- Walking, sitting up, standing, etc.
- Feeding difficulties
- Respiratory issues
- Many patients require mechanical ventilation
- Absent reflexes
- Weak facial muscles
- Weakness in the muscles that control eye movement
- Fragile bones
- Large head, narrow face, high palate
Other possible symptoms include seizures, respiratory infections, liver disease, and peliosis hepatitis. Because of these effects, most commonly respiratory issues, XLMTM patients often do not survive past early childhood.
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