Astellas to revisit fatal neuromuscular condition in partnership with startup Kate Therapeutics

Four years ago, a biotech company presented data so powerful it made scientists cry.

Speaking to a packed room at an annual cell and gene therapy conference in 2019, Audentes Therapeutics played a video of a young boy who could scarcely move and required a ventilator to breathe. Born with a fatal neuromuscular condition called X-linked myotubular myopathy, for which there are no treatments, he was out of options until Audentes came along.

The company had developed a gene therapy designed to replace the broken muscle protein that causes weakness, difficulty breathing and early death. A second video, taken some time after the boy got the experimental treatment, showed him bouncing and smiling at a doctor’s visit. The dramatic transformation moved many in the audience to tears and later that year moved the Japanese drugmaker Astellas to acquire Audentes for $3 billion.

But then three boys died in 2020 after receiving the gene therapy, followed by a fourth in 2021, likely due to a combination of the incredibly high dosages of virus known as AAV that is widely used by gene therapy developers to shuttle the healing gene into their muscles that caused liver failure in the boys.

The program, which has been on hold ever since, serves as a heartbreaking reminder of the inherent risks of any new genetic medicine. It also raised the need for new viruses that are better at delivering their genetic cargo into muscle cells and less prone at congregating in the liver, where they may cause or heighten life-threatening disease.

Now Astellas believes it might have a solution to the deadly problem.

Richard Wilson

On Thursday, the drugmaker announced it struck a deal with San Diego-based startup Kate Therapeutics to develop, produce and commercialize a new therapy for the disease based on experimental AAV capsids that may work as well as older versions but at one-fifteenth the dose. The startup, founded in late 2020, also launched from stealth with $51 million in Series A financing led by Westlake Village BioPartners and Versant Ventures.

“We got very excited talking to Kate Therapeutics about their approach,” Richard Wilson, SVP of gene therapy at Astellas, told Endpoints News. “We are committed to this patient population, and importantly we are very committed to AAV. Astellas has a bit of a culture of perseverance, and we are trying to signal that we are in this for the long haul.”

Getting the doses lower

KateTx is one of several startups that have cropped up over the past few years to devise new ways to help genetic medicines get where they need to go. For many companies, the destination is muscle.

It’s one of the most vexing problems. A direct injection into the muscle doesn’t get the therapy very far. Infusions of AAVs tend to glom up in the liver, and the most widely used versions of the virus have only modest proclivity for muscle. In an effort to get enough of the viruses to muscles throughout the body, drug companies have pushed the doses higher and higher.

For some patients, the brute force approach partially works, as evidenced by children who’ve retained or gained some muscle function in clinical trials. Yet the outcomes are often far from curative, and the high doses have been linked to liver, heart, and lung damage. At least two patients with Duchenne muscular dystrophy died from high doses of experimental AAV therapies — one from Pfizer’s study and another made by the nonprofit Cure Rare Disease.

The specifics of those two deaths and the four deaths from the Audentes trial differ in their details, but a common thread is high doses of viruses, known as AAV8 or AAV9, often surpassing 100 trillion viruses per kilogram of body weight. “Getting the doses lower is universally seen as where we want to go in the field,” Wilson said.

Clare Ozawa

Even before those tragedies, several biotechs were tinkering away on new versions of AAVs that instead make a beeline for muscle and bypass the liver. Hundreds of millions of dollars have already been poured into discovering or designing better viral vectors. And although scientists are still awaiting the first clinical evidence that new viruses are, in fact, improved, that hasn’t stopped investors from placing more bets on fresh ideas for delivering genetic medicines.

“It’s an area that we really believe in and an area where there’s a lot of room for improvement,” Clare Ozawa, managing director at Versant, told Endpoints. “The barrier is getting into the tissue in the first place. That’s been a huge problem that I think Kate is solving with the new vectors.”

Purpose-built viruses

Those new viruses were almost an afterthought for KateTx, which was originally planning on developing muscle disease therapies with an older virus. “We still thought that AAV9 could get the job done,” said Kevin Forrest, Kate’s president and CEO.

Beth Seidenberg

Beth Seidenberg, the managing director of Westlake who was a founding investor in KateTx, convinced Forrest that for his company to succeed, he needed a suite of novel viruses purpose-built for shipping genes into muscles.

They found a solution in Pardis Sabeti’s lab at the Broad Institute of Harvard and MIT. Her group made and screened millions of synthetic variants of AAVs, each with a slightly different arrangement of amino acid building blocks jutting from its surface, to find ones that expressed their genes in muscles the best. A specific trio of amino acids emerged in all the top hits, giving them a lead for optimizing the viruses to target muscles even better.

The work led to a family of new viruses dubbed MyoAAV, a finding that the group published in the journal Cell in 2021.

Sharif Tabebordbar, a researcher from the Sabeti lab who pitched the work to KateTx, made such an impression on Forrest that he offered to make him a co-founder of the startup in the middle of their Zoom call. Tabebordbar, who is now KateTx’s chief scientific officer, said his team has made viruses that are roughly 14 to 15 times better at targeting muscle cells in monkeys than AAV9.

Sharif Tabebordbar

The work is personal for Tabebordbar, whose father has a genetic disease that causes progressive muscle loss in the face and upper body in adults. “This has been basically the mission of my life since I was an adult,” he said. “I started studying biology because of this.”

That disease, known as facioscapulohumeral muscular dystrophy (FSHD), and another condition called myotonic dystrophy type 1 (DM1), are the two conditions that the company is initially focused on treating. The therapies, which repress toxic molecules that cause those diseases, are based on work of Eric Wang, a co-founder and University of Florida researcher. The company’s namesake comes from a girl with DM1 that Wang knows from his work.

KateTx licensed a third program, for X-linked myotubular myopathy (XLMTM), to Astellas for an undisclosed upfront payment, plus potential milestone payments. “At a time when ultra-rare diseases have fallen somewhat out of favor with the investment community, I think it says a lot about Astellas,” Tabebordbar said.

Towards the clinic, again

Astellas hopes that the MyoAAV can lead to an equally if not more effective therapy at a lower dose, which Wilson hopes will “take away some of the anxiety” about starting a new program in XLMTM. But with an incomplete understanding of why the Audentes therapy was fatal for roughly 1 out of 6 children in its study, it’s hard to know how much safer the new therapy will be.

Wilson said that Astellas has conducted “extensive non-clinical investigations” to figure out what caused the liver problems that ultimately killed the boys in its trial. Crucially, the company thinks that an overwrought immune reaction to AAV — which has caused harm and death in other gene therapy trials — was “not sufficient to cause these deaths,” he said.

Rather, the company believes that some XLMTM patients have an “underlying susceptibility” to liver failure due to a previously underappreciated hepatobiliary condition that disrupts liver and bile duct function. How exactly that susceptibility and high doses of AAV are linked is not clear.

“We are still trying to pin down the mechanism of that toxicity,” Wilson said. “We are trying to dig in and understand who is at risk.”

Wilson said that Astellas remains committed to developing its original XLMTM gene therapy, adding that his company has had ongoing discussions with the FDA to resume clinical testing. “We still have some manufacturing work that we owe the FDA, but plan to be back in the clinic in 2024,” Wilson said. Its new program from KateTx could follow close behind.

The company is considering restricting the therapies to the youngest patients where risks appeared to be lower in its earlier trial. It will also intensely monitor bilirubin levels, which can indicate liver or bile duct damage.

Astellas still follows the progress of the 20 patients who are alive from its gene therapy study. “We’ve seen some amazing transformative benefits,” Wilson said.

“Sixteen of them are able to sit unassisted for 30 seconds. Twelve of them can pull themselves to a stand. Eight of them are able to walk independently,” he added. “And this is a condition where natural history suggests that 50% of kids diagnosed won’t live past their first 18 months of life.”

The same intense emotion that researchers felt four years ago when they saw the video of the boy regaining his muscle strength is still alive today, Wilson said: “This program changes you.”

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