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Thread: Third Patient Dies in Audentes' Gene Therapy Study for Neuromuscular Disease

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    Senior Member JohnLanders's Avatar
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    Third Patient Dies in Audentes' Gene Therapy Study for Neuromuscular Disease

    A third pediatric patient involved in a gene therapy trial for a rare, neuromuscular disease conducted by Audentes Therapeutics has died. The trial remains on clinical hold and continues to indefinitely delay the company?s plans to seek regulatory approval for the treatment.

    This morning, Audentes, which was acquired by Astellas Pharma late last year, announced the death of the third patient involved in the company?s ASPIRO clinical trial evaluating AT132 in patients with X-linked Myotubular Myopathy (XLMTM). The disease is a life-threatening neuromuscular disease that almost exclusively impacts males and is characterized by extreme muscle weakness, respiratory failure and early death. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development. The disease affects approximately 1 in 40,000 to 50,000 newborn males. X-linked Myotubular Myopathy also disrupts normal bone development and can lead to fragile bones and joint deformities. Those diagnosed with the disease usually only survive into early childhood. Audentes? gene therapy uses an AAV8 vector to deliver a working copy of the myotubularin 1 gene into the patient to correct the disease.

    According to the company, preliminary findings indicate that the immediate cause of death in this patient was gastrointestinal bleeding. In its announcement this morning, Audentes said the patient was one of three study patients previously disclosed to have received AT132 at the dose of 3x1014 vg/kg who began to demonstrate signs of liver dysfunction within three to four weeks after dosing. All three patients demonstrated evidence of pre-existing hepatobiliary disease and Audentes noted that more than half of the patient enrolled in the ASPIRO study show evidence of pre-existing hepatobiliary disease. However, the company said that has not been associated with similar progressive liver dysfunction in any of the patients who received AT132 at the 1x1014 vg/kg dose nor in the other patients who received the 3x1014 vg/kg dose.

    The U.S. Food and Drug Administration placed the ASPIRO study on clinical hold in June after Audentes disclosed two pediatric patients who received the higher doses of the gene therapy developed sepsis and died.

    Audentes said it is closely monitoring all patients in the study. To date, 23 patients in the ASPIRO study have received AT132. Six patients received the gene therapy at the 1x1014 vg/kg dose and 17 patients received AT132 at the 3x1014 vg/kg dose, the company said. There are no other patients in the study known to be currently experiencing similar liver dysfunction, Audentes said.

    ?Audentes, together with the ASPIRO investigators and independent Data Monitoring Committee, continue to closely monitor all patients enrolled in the study. Additionally, Audentes? investigation regarding why these three patients developed progressive liver dysfunction is ongoing,? the company said in its announcement.

    The company plans to provide further information on the ASPIRO program based on both ongoing data collection and future regulatory status updates. Last year Audentes presented positive data from ASPIRO at the 24th International Annual Congress of the World Muscle Society. It was this data the company hoped to build upon in order to file a Biologics License Application with the FDA.

    A third patient in the trial of a gene therapy for treating a rare and life-threatening neuromuscular disease that has already been placed on clinical hold has died, the company developing the therapy said Friday.

    Audentes Therapeutics ? which Japanese drugmaker Astellas acquired in December 2019 for $3 billion ? disclosed that the immediate cause of the death of a third patient in its Phase I/II ASPIRO trial of AT132 in X-linked myotubular myopathy, or XLMTM, was gastrointestinal bleeding.

    Shares of Astellas fell slightly on the over-the-counter market, where they trade in the U.S. The Tokyo-based company?s shares principally trade on the Tokyo Stock Exchange.

    The patient was one of three in the trial who had received the gene therapy at a dose of 300 trillion viral vectors per kilogram of body weight and had begun to demonstrate signs of liver dysfunction within three to four weeks after receiving the dose. The trial is enrolling boys up to the age of 5.

    All three of the patients demonstrated signs of pre-existing hepatobiliary disease, a term referring to disease of the liver and bile ducts or gall bladder. However, more than half of the patients enrolled into the study so far showed signs of such disease, though the gene therapy has not been associated with similar complications when administered at the 100 trillion vector per kilogram dose. To date, 23 patients have received AT132, including six at 100 trillion vectors and 17 at 300 trillion vectors.

    Audentes had previously said in late June that a patient in ASPIRO had died of sepsis, a month after another patient had also died.

    The announcement marks the second significant setback this week for gene therapies. On Wednesday, San Rafael, California-based BioMarin said the Food and Drug Administration had delivered a complete response letter for its application to secure approval for valoctocogene roxaparvovec, a gene therapy for hemophilia A. The news came as a surprise to many, given that the therapy was widely expected to win approval, and the company itself said the issues raised in the CRL had not been raised previously.

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    Senior Member JohnLanders's Avatar
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    Update: On Aug. 20, Audentes announced that a third patient in the AT132 clinical trial has died.

    Dive Brief:
    Three children with a rare neuromuscular disease have died after receiving a high dose of a gene therapy in a clinical trial run by Audentes Therapeutics. The first two deaths were disclosed in letters sent by the company to patient groups in June. Audentes reported the third in August.
    Each of the children suffered liver problems that ultimately led to fatal complications. The most recent death occurred this month, though the letters revealed Audentes halted dosing of new patients before anyone had died. The Food and Drug Administration subsequently placed the study on a formal clinical hold.
    The gene therapy, called AT132, is designed to treat X-linked myotubular myopathy, a deadly disease caused by mutations in a single gene. Audentes, which was bought by Japan's Astellas Pharma for $3 billion in December, aimed to submit the treatment for approval this year, but those plans are now on hold, according to the letter.

    Dive Insight:
    Gene therapy has emerged rapidly in recent years because the field overcame safety concerns — most notably, the tragic death of teenager Jesse Gelsinger in a clinical trial in 1999 — that cooled initial optimism and slowed research.

    Newer methods to deliver genetic medicine have been proven out in clinical testing and two therapies are now approved in the U.S., both for rare inherited diseases. Others, for diseases like hemophilia and Duchenne muscular dystrophy, could soon follow.

    So far, this current wave of therapies have generally appeared safe. Encouraged, developers have tested higher and higher doses of gene therapies, aiming to expand their potential effectiveness. Higher doses are particularly important for neuromuscular diseases, since the treatment must travel through the bloodstream to reach the right tissue.

    Two years ago, gene therapy pioneer Jim Wilson — who led the Gelsinger trial at the University of Pennsylvania two decades ago — expressed concern about the strategy, fearing that pushing doses too high might lead to safety problems. Wilson and UPenn colleagues published a paper in the journal Human Gene Therapy noting liver and nerve damage in animal experiments with a certain type of gene therapy, and called for researchers to do more monitoring.

    While other gene therapy studies have been stopped in recent years, the deaths observed in Audentes' trial are particularly worrisome.

    Audentes' therapy has shown promise in early tests, enough for Astellas to pay $3 billion for the company in December. The pivotal study of AT132 began in 2017 and Audentes aimed to submit an application with the Food and Drug Administration this year.

    According to a letter Audentes sent to patient groups, however, that will no longer happen.

    On May 6, Audentes told the groups that a patient treated with a high dose of AT132 had died from sepsis. Two others also given the high dose had then experienced serious side effects.

    Six weeks later, on June 23, Audentes CEO Natalie Holles and chief medical officer Edward Conner sent a second letter explaining that one of those two had also died. That patient experienced progressive liver dysfunction, which didn't respond to standard treatment. His condition worsened and he ultimately died from a bacterial infection and sepsis.

    "There have been some incredible outcome measures with some of the children but the science needs to continue to evolve," said Alison Rockett Frase, president of the Joshua Frase Foundation, one of the patient groups Audentes wrote. "Our community is devastated by the loss of these two children," she added in an interview.

    On Aug. 20, Audentes reported that a third patient, also treated with a high dose of the gene therapy, had died from gastrointestinal bleeding.

    Audentes is still collecting information, monitoring all of the study's other patients and is in touch with regulators. A total of 17 patients have been treated with the high dose of AT132 — 300 trillion vector genomes per kilogram of body weight.

    "We are taking all necessary steps to understand these events and incorporate what we learn into our development plan going forward," Holles and Conner wrote in their letter. "We are currently assessing the impact on potential regulatory filing timelines, however we will not be filing in mid-2020 as previously communicated."

    They added, however, that none of these issues have been seen in the six patients treated with a lower dose, and all of those patients are "years out from treatment." Four of those patients had a history of liver or biliary system problems.

    All three of the patients who died also had evidence of pre-existing liver problems and showed signs of liver dysfunction within a month of treatment with AT132, Audentes said. All three patients with liver problems were of older age and heavier weight.

    None of those treated with a high dose currently have the type of liver dysfunction seen in the patients who died, Audentes said.

    Audentes uses a type of adeno-associated virus, called AAV8, to deliver its gene therapy. Other companies, including Ultragenyx, RegenxBio and Biogen are developing gene therapies that also rely on AAV8.

    The high dose Audentes uses is among the largest being tested in gene therapy.

    Ned Pagliarulo contributed reporting.

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