Astellas sees gene therapy as a key part of its growth and is strategizing in this emerging therapeutic area even amid the setbacks of its programs. Its two most advanced gene therapy candidates have been on clinical hold for most of last year. Review of preclinical data led to termination of three other gene therapies for a rare muscle disease.
Still, there are signs of progress. FDA last week lifted the hold of one of these halted programs, a potential gene therapy for the enzyme-deficient Pompe disease. The company has also become an active intermediary as it adds gene therapy candidates and introduces various gene therapy technologies.
“We’re aiming to have that goal to end the gene therapy capacity: research, manufacturing, development, commercialization,” said Richard Wilson, Astellas’ senior vice president of gene regulation, who came to the Tokyo-based company through Acquisition of Audentes Therapeutics for $3 billion.
Astellas has gene therapy candidates spanning various stages of development. It also has a manufacturing facility to support their clinical development. In order to achieve commercialization, the company must overcome the failures of its clinical trials.
Last June, the FDA placed a clinical detention in a phase 1/2 trial of the Pompe gene therapy, AT845, following a report of a complication, peripheral sensory neuropathy, in one patient. Although the investigator classified the adverse event as mild in severity, the complication raised questions for the FDA. Wilson said Astellas’ search for the cause of the neuropathy included processing product characteristics, gene therapy dose levels and the patient’s past. Based on the rigor of that research, Wilson said the FDA is comfortable lifting the hold.
“To get to the point, we didn’t hook up [the complication] to one particular point,” Wilson said. “Importantly, this means we have not identified a smoking gun in the program. That’s why we feel comfortable moving forward here.”
Astellas trial holds are not extraordinary. Many biotech companies have temporarily halted gene therapy clinical trials as complications arise and the FDA asks questions. In some cases, the agency puts a pause on a study before it even begins. Wilson said these challenges are part of developing a brand new type of therapy. These suspensions do not indicate that these therapies are intrinsically dangerous, but they are part of moving medicine into new frontiers, he said.
Astellas is still working through a separate clinical hold for AT132, a gene therapy candidate for the rare neuromuscular disorder X-linked myotubular myopathy. Two patient deaths in 2020 resulted in a clinical holdwhich is followed by the report of a death of a third patient in the study. All three had pre-existing hepatobiliary disease, a condition affecting the bile ducts, gallbladder and pancreas. The trial was allowed to resume, but a the fourth death reported in 2021 resulted in another clinical hold.
Wilson said Astellas’ investigation into the patient deaths in that study is ongoing. One hypothesis is hidden cholestatic syndrome – liver disease. This disease can lead to liver toxicity, Wilson said. The company has conducted tests on animals to try to find the problem. But Wilson said there was no signal of these complications in any preclinical model. Astellas also continues to optimize the gene therapy product itself. Such chemical and manufacturing changes can take several months to a year to get FDA approval, Wilson said. The company also needs to work out with the agency what protocol changes will be needed to restart the clinical trial. These changes will include minimizing the chance of enrolling a patient who may be susceptible to a liver complication.
Myotubular myopathy has a hepatobiliary component that wasn’t clear until Astellas began studying patient deaths, Wilson said. He added that Astellas has been talking to other gene therapy developers to try to learn from them. Wilson clarified that this approach does not mean there is an open door to data sharing. But companies can talk about certain things under confidentiality agreements. Gene therapy research is a small field and everyone knows everyone, he explained. Whenever one company faces a problem, others are naturally curious to see if that problem points to something to look for in their respective clinical trials.
“We feel really strongly as we look at these new modalities, we’re going to have to collaborate more, especially in some of these rare diseases where there’s so little data,” Wilson said.
Delays in the Pompe and myotubular myopathy programs prompted Astellas to consider expanding its approach to gene therapy, Wilson said. The company aims to have a pipeline of products in three main areas: neuromuscular diseases, central nervous system (CNS) diseases and ophthalmology. In November, Astellas strikes deal with Taysha Gene Therapies, paying $50 million for stake in biotech and option to license two CNS gene therapiesone for giant axonal neuropathy and the other for Rett syndrome.
Astellas followed the Taysha deal with a research collaboration with Dyno Therapeutics, a startup that uses artificial intelligence to discover new capsids, the protein coats that envelop a genetic payload and deliver it to its cellular destination. Astellas paid its new partner $18 million upfront. The alliance’s therapeutic areas were not specified, but Cambridge, Mass.-based Dyno could earn up to $1.6 billion in milestone payments and royalties.
Earlier this month, Astellas closed another deal, this time licensing bacteria-derived protease from Selecta Biosciences. This enzyme offers the potential to neutralize preexisting antibodies against the engineered viruses and capsids used to deliver gene therapy. By neutralizing these antibodies, Selecta’s licensed technology, called Xork, could make more patients eligible for clinical trials. The company plans to use the technology in combination with its experimental gene therapy for Pompe disease. Wilson said Astellas isn’t done making deals that could bring new opportunities, but the company won’t tip its hand about potential next moves.
“It’s a pretty interesting deal-making environment,” Wilson said.
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