How patients’ families pushed rare-disease therapy to cusp of clinical trial — until biotech’s cash halted progress

By Ron Leuty

Senior Reporter, San Francisco Business Times

For the first decade of their daughter’s life, Tessa Nye‘s parents desperately sought to find the cause of her hundreds of daily seizures. But after her brother Colton started having seizures shortly after birth, their search narrowed to genetics, and the quest for a cause became a hunt for a cure.

A gene replacement therapy now is within reach. Thanks in large part to the TESS Research Foundation, the Menlo Park nonprofit that Kim and Zach Nye started, a fast-growing biotech company licensed the therapy and pledged to start a clinical trial by the end of last year.

But the company has yet to start the study, and there are indications it never will. The company’s plans were put on hold as it bled cash, exacerbated by generalist investors pulling out of the biotech industry.

The turn of events has left hopeful families of children with a rare epilepsy-causing mutation to a single gene, called SLC13A5, searching for answers again.

Taysha Gene Therapies Inc., which rolled more than two dozen gene therapy product candidates for central nervous system diseases into a single portfolio, last year prioritized four programs and cut about 60 staffers. It scaled back further to two programs in October and, in December, Taysha founding president and CEO RA Session II stepped down.

The company last month said Chief Medical Officer Suyash Prasad left the company, and earlier this month it told investors it cut more jobs as its lead program would require an additional clinical trial it is unlikely to be able to afford.

Since the company (NASDAQ: TSHA) filed in September 2020 for an initial public offering — grossing $181 million on top of the $126 million it had raised since its founding a year earlier — NASDAQ’s biotech index has been on a rollercoaster ride. Gene therapy companies have been hit particularly hard as some companies have reported deaths in clinical trials, regulators have demanded more studies and questions have emerged about the durability of treatments.

Dallas-based Taysha saw its stock price climb from its $20 IPO to more than $33 in mid-January 2021 to a 52-week low of $1 on Friday. The company’s cash and equivalents, it has said, will cover operating expenses and capital requirements into first-quarter 2024.

A Taysha spokesperson said in an email last week to the San Francisco Business Times that the company is “evaluating potential options” for its program in SLC13A5 epilepsy “as we know patients and advocacy groups are eager to move the program forward.”

The future for epilepsy patients with SLC13A5 deficiency, their families and Taysha looked vastly different three years ago.

Taysha was founded in partnership with the University of Texas Southwestern with the potential to deliver life-changing therapies — perhaps with just one infusion — and generate strong returns. Investors flocked to the biotech industry in 2020 in the hopes of catching the next big thing that would transform human health, like messenger RNA, or mRNA, turned the search for Covid-19 vaccines into multibillion-dollar businesses.

If years of scientific discovery and clinical development could lead to an approved therapy, investors could count on insurers paying upwards of $2 million to cover each patient.

What’s more, Taysha’s rollup of gene therapies on a platform that used the same delivery mechanisms could bring scale to expensive manufacturing processes.

Families with young children with the genetic diseases were hungry for answers and full of hope.

Colton’s seizures shortly after birth had changed everything for the Nye family and a growing community of families with children with unexplained epilepsy. No one had connected a gene to the disorder, but advances and lower costs for gene sequencing increased the likelihood of finding a gene.

Colton’s exome sequencing — a deep-dive into the protein-coding regions of genes — came back as normal. But Matthew Bainbridge, then an assistant professor at Baylor College of Medicine, gathered more information from Tessa, Kim and Zach Nye and their other two girls, Maggie and Lily.

“I think I found the gene,” Bainbridge told Kim Nye, “and I think there’s something to do about it.”

Tessa, now 19, and Colton, age nine, were identified as patients one and two, among the first in medical literature to have the SLC13A5 gene marked as the root of their seizures.

Both parents must contribute a copy of a mutated SLC13A5 gene, which normally encodes a protein that carries a type of salt, called citrate, to neurons in the brain. When that protein is deficient, brain signaling is interrupted, seizures begin, speech is limited and kids ultimately have trouble standing or walking. Yet those children continue to comprehend and respond to the world around them.

With a target gene, TESS Research Foundation’s work shifted to better diagnosis and finding and de-risking possible treatments to put companies at ease about taking on the capital-intensive work of therapy development.

Some 100 families with 140 children now have been diagnosed with the rare mutation.

Then, in 2017, Kim Nye heard of University of North Carolina assistant professor Steven Gray‘s work with a gene therapy for giant axonal neuropathy, or GAN, a rare inherited disorder. GAN affects the peripheral nervous system that sends signals that control movement and sensation between the brain and spinal cord and other parts of the body.

The Nye family jumped a plane to North Carolina, where Kim asked Gray, “Do you think you can help my daughter?”

“Yes, I think I can,” said Gray, who later that year joined UT Southwestern and became head of its viral vector facility.

Rachel Bailey, a postdoctoral fellow in Gray’s lab at North Carolina, followed her mentor to Dallas and was funded in part by TESS Research Foundation awards. She ultimately developed a SLC13A5 gene replacement therapy, packaging a correct gene in a shelled out virus shot into the spinal cord.

Taysha licensed the therapy from North Carolina, and Gray, whose GAN therapy also had been taken in by Taysha, served as the company’s chief scientific advisor.

“Our program is far along, and Taysha put in more money than we put in,” Nye said. “They’ve probably moved us along faster than we could have done without them.”

By the time of Taysha’s IPO, its TSHA-105 program for epilepsy in SLC13A5-deficient patients was one of the potential therapies highlighted for investors.

But as money has run low, the company has prioritized its GAN therapy, thanks to a $50 million investment in October from Astellas Pharma Inc. Its other leading program in Rett syndrome, a genetic mutation affecting brain development in girls, is expected to dose its first adult patient in the first half of this year.

Astellas has the option of licensing the GAN and Rett syndrome therapies from Taysha but not the SLC13A5 program.

How corporate problems have brought a halt to an SLC13A5 gene replacement therapy on the cusp of a clinical trial has bewildered some people familiar with the story of the Nye family, TESS Research Foundation and rare disease therapy development in general.

“Literally (Kim Nye) went from having ‘patient one’ and ‘patient two’ in her living room to finding all the other humans in the world who had it, to compiling all the data, to then developing a treatment — and she literally has a treatment — and because of ‘market conditions’ the biopharma she was going to partner with is in a situation,” said Sandra Abrevaya, who co-founded I AM ALS patient advocacy organization with her husband, Brian Wallach, after he was diagnosed in November 2017 with Lou Gehrig’s disease.

Speaking on a panel earlier this month highlighting the Chan Zuckerberg Initiative’s “Rare As One” project, Abrevaya was dismayed that no one has stepped forward to move the SLC13A5 program into a clinical trial.

“So, we’re in the Bay Area, and I’m just going to make a play: If you know anybody in biopharma who is interested in seeing a very, potentially, high-value epilepsy drug come to the market, please give them a call,” Abrevaya said to cheers.

Taysha has continued to update TESS Research Foundation, SLC13A5 patients’ families and key researchers, Kim Nye said. The goal, however, remains the same.

“The goal is to get a gene therapy into a small population of patients. The goal is to get an FDA approval,” Kim Nye said. “We’re trying to have a treatment that every kid in our population can have access to.

“We’re still trying.”

Originally posted here.