NEW YORK – Taysha Gene Therapies expects to engage with the US Food and Drug Administration late this year or early next year to discuss advancing its lead candidate, TSHA-102, for Rett syndrome into the dose-expansion portion of ongoing Phase I/II clinical trials, company executives said during a virtual presentation to market analysts Tuesday.
Four patients have received the gene therapy across two open-label and dose-escalation Phase I/II clinical trials — one of which is testing the gene therapy in adult and adolescent patients in the US and Canada, the other of which is evaluating it in children in the US and UK — all of whom have experienced early improvements in motor skills and other outcomes.
After gene therapy administration, "we saw consistent … improvement across multiple clinical domains," Sukumar Nagendran, president and head of R&D at Taysha, said during the call.
Rett syndrome is a rare, X-linked progressive neurodevelopmental disorder that's caused by certain mutations in the MECP2 gene and is primarily seen in women. Patients with the condition can experience a host of symptoms related to impaired brain development, including intellectual disabilities, loss of communication, and seizures.
TSHA-102, which is administered to the spinal cord through a minimally invasive outpatient procedure, uses an adeno-associated virus 9 (AAV9) vector to deliver a truncated version of MECP2, which it refers to as miniMECP2. The transgene functions like the full-length MECP2 gene, according to the company, and is designed to regulate cellular MECP2 protein expression.
In Part A of the Phase I/II clinical trials, the company is evaluating two dose levels, and in the Part B dose-expansion portion will test what it determines is the maximum administered or tolerated dose. In the pediatric clinical trial, Part B will also begin enrolling younger patients.
The low-dose cohorts are fully enrolled in both clinical trials with two subjects in the adult and adolescent clinical trial and two subjects in the pediatric clinical trial.
The two adult patients have experienced multiple functional improvements that have sustained through recent follow-up assessments of 52 and 25 weeks, respectively, suggesting that the gene therapy's effects are durable, Nagendran said. The first patient, who entered the study with a severe disease presentation, experienced an improvement in hand function and gained the ability to sit unassisted, for example. Her seizures are now stable and well controlled, and she's able to take lower levels of anti-seizure medications.
Before treatment, the patient had been in a "constant state of hypertonia," Nagendran said, "with complete loss of ambulation and was wheelchair bound."
The second patient, who had a milder disease presentation, experienced improved posture and stability by 25 weeks, and has been free of seizures for more than eight months.
Among the two pediatric patients, 6 and 7 years old, the first patient treated had a moderate disease phenotype, while the second had milder disease. Investigators observed improved hand function in both patients by 12 weeks and 8 weeks post-treatment, respectively. The first patient can now walk with assistance and sit unassisted for longer than she was able to at baseline, and the second patient has demonstrated improvements in speed and stability when walking. Seizure events are stable in the first patient, and the second patient has reported more seizure-free days.
The 6-year-old pediatric patient has also experienced improvements on the Adapted Mullen Scales of Early Learning (MSEL-A), a scale designed to assess childhood cognitive development in patients with Rett syndrome. These improvements included new developmental gains in visual reception, receptive language, and fine motor skills, per the presentation.
The patients in the clinical trials have had different genetic mutations and levels of disease severity, suggesting broad treatment potential of TSHA-102 across multiple genotypes, according to Sean Nolan, Taysha's CEO and board chairman. The first adult and pediatric patients treated had MECP2 deletions, while the second adult and pediatric patients had missense mutations.
"We believe the improvements observed across consistent clinical domains, regardless of baseline disease severity, support the broad treatment potential of TSHA-102 across patients of different ages and genetic mutation backgrounds," Nolan said.
Investigators have not observed any serious adverse events related to TSHA-102 or dose-limiting toxicities through any of the four patients' latest follow-up assessment. However, the pediatric patients experienced serious adverse events related to the immunosuppressive regimen that subjects undergo before receiving the gene therapy.
Dallas-based Taysha's stock price dipped after the call, which had taken place before the market opened Tuesday. Its shares opened at $3.78 on Tuesday, down from Monday's close of $4.03, and declined further to close at $2.97.
TSHA-102 is the only clinical-stage candidate listed on Taysha's website, which says the company is "laser-focused" on advancing the program. Taysha previously has said it is deprioritizing other early-stage gene therapies in its pipeline, including seeking other organizations to take on the programs, as it looks to extend its cash runway into 2026. Last year, it discontinued development of a gene therapy candidate for giant axonal neuropathy.
Taysha's primary competitor in this space is New York City-based Neurogene, another biotech company that's developing a gene therapy candidate for Rett syndrome. The gene therapy, NGN-401, uses an AAV9 vector to deliver a full-length copy of the MECP2 gene. On Tuesday, Neurogene announced it had moved into the high-dose cohort of its ongoing open-label Phase I/II clinical trial of NGN-401.
Taysha is advancing its evaluation of TSHA-102 into high-dose cohorts, in which it plans to enroll three more patients in each of the clinical trials. The company has already dosed the first patient in the high-dose cohort of the clinical trial for adult and adolescent patients in Q2 2024 and expects to dose the first pediatric patient in Q3.
"We're focused on moving to the high-dose cohort and collecting data across a broad spectrum of patients to further inform the next phase of our studies," Nolan said. Testing the higher dose is a "critical step that accelerates our ability to further inform our clinical development and regulatory plan for Part B," he added.
Taysha is still exploring what measurements it will use as endpoints in Part B of the Phase I/II clinical trials as well as future studies.
"There could be multiple avenues we could go down with clinically meaningful and objective endpoints," Nolan said. "But we want to collect more data before we make that final decision."