Avrobio Reports Positive Data from Phase 1/2 Clinical Trial of Investigational Cystinosis Gene Therapy

Avrobio reported new interim data, including on new visual motor integration, motor coordination and visual perception measures, from a collaborator-sponsored, ongoing phase 1/2 gene therapy clinical trial of AVR-RD-04, an investigational gene therapy for cystinosis, at the 25th Annual Meeting of American Society for Gene and Cell Therapy (ASGCT) in Washington D.C.

Photo: Avrobio Chief Medical Officer Essra Ridha

The new early data show key visual motor integration, visual perception and motor coordination measures impacted by cystinosis stabilized or improved post gene therapy.

Cystinosis is a rare, progressive disease marked by the accumulation of cystine in cellular organelles known as lysosomes. This buildup causes progressive organ damage and debilitating corneal damage, swallowing dysfunction, chronic kidney disease leading to end-stage renal disease and muscle wasting leading to a shortened lifespan. Currently, more than 90 percent of treated cystinosis patients require a renal transplant in the second or third decade of life. The current standard of care for cystinosis is cysteamine, a treatment regimen that can require dozens of pills per day, does not prevent overall disease progression and carries side effects, such as breath and body odor and gastrointestinal complications, which may be difficult to tolerate.

The collaborator-sponsored phase 1/2 clinical trial is evaluating the safety and efficacy of AVR-RD-04 in adult patients diagnosed with the infantile form of cystinosis who previously had been treated with the current standard of care (SOC) cysteamine. AVR-RD-04 genetically modifies patients’ own hematopoietic stem cells (HSC) to express a functional version of cystinosin, the protein that is deficient in people living with cystinosis. Preliminary data suggest that post gene therapy, functional cystinosin has been produced throughout the body as evidenced by clinical measures in multiple tissues, including the eyes, skin, gastrointestinal mucosa, and neurocognitive system. No adverse events related to the drug product have been reported to date.

“Now with data from up to five patients, we have observed a strong safety and tolerability profile, as well as a reduction in the harmful accumulation of cystine crystals in cells across multiple tissues. All five patients dosed to date remain off oral cysteamine,” said Stephanie Cherqui, lead investigator of the clinical trial and associate professor of Pediatrics at the University of California San Diego. “We believe the results to date for this investigational gene therapy show its potential to stabilize or reduce impact of cystinosis on different tissues with a single dose.”

The collaborator-sponsored Phase 1/2 clinical trial of AVR-RD-04 is funded in part by grants to UCSD from the California Institute for Regenerative Medicine, Cystinosis Research Foundation, and National Institutes of Health.

“We believe the interim data from this ongoing clinical trial demonstrate the potential of gene therapy using patient’s own hematopoietic stem cells to impact the body head-to-toe by restoring functional cystinosin and reducing the accumulation of cystine crystals systemically,” said Avrobio Chief Medical Officer Essra Ridha. “Cystinosis is a devastating disease that currently carries a 5-year treatment cost of more than $4 million per patient in the U.S. and impacts approximately 1,600 patients in the U.S., Europe and Japan alone. With proof-of-concept demonstrated, we continue to lay the groundwork for an Avrobio-sponsored clinical trial planned to begin in 2023.”

Key motor coordination and visual perception measures stabilize or show positive trends post gene therapy. Visual motor integration (VMI) measured with the Beery-Buktenica Developmental Test of VMI, a standardized test evaluating the ability of the brain to interpret and translate visual information into an exact motor response, has been shown to be a consistent indicator of visual spatial and visual motor dysfunction in patients with cystinosis. These measures do not generally improve over time in this population.

Early data indicate that post gene therapy the two patients with data to date show stabilization of scores on the Beery-Buktenica Developmental Test of VMI and importantly, improvement in the subtests of motor coordination and visual perception, suggesting a potential impact on the neuropathology of the disease. In patient 1, an approximate 20-point improvement was evident in both visual perception and motor coordination, and in patient 3 a 5-point increase in visual perception was detected, with motor coordination rising by 45 points in the first six months post treatment and a more modest rise thereafter.

In addition, following discontinuation of cysteamine, average hand grip strength remained stable up to 27 months after dosing.

Systemic reach of AVR-RD-04 was also seen across measurements of blood, eye, skin, and gastrointestinal mucosa. Early data indicate that post gene therapy, patients have been able to produce and distribute functional cystinosin protein throughout the body, which prevents the pathological accumulation of cystine crystals​.

Photophobia, or extreme visual sensitivity to light, is a hallmark of cystinosis. In a patient-reported outcome scale of photophobia severity, the first three patients for which data are available, reported improved or stable photophobia scores.

A decline in cystine crystals was observed in skin and gastrointestinal mucosa biopsies from the first three patients. Patients with cystinosis accumulate cystine crystals in cells, which leads to tissue and organ damage and results in debilitating co-morbidities.

Patients with cystinosis also frequently exhibit blond or lighter-colored hair and fair complexion because of reduced levels of melanin in their skin. In vitro studies have demonstrated that cystinosin is located in melanosomes of melanocytes and when functional cystinosin is absent or reduced, melanin pigment synthesis is inhibited. New early quantitative data suggest that gene therapy-derived cystinosin may restore melanin production. Twelve months after infusion, two patients exhibited progressively darkening hair color.

Importantly, sustained engraftment has been observed in the first three patients, as evidenced by stable vector copy number (VCN) levels. At 17- to 27-months post gene therapy.

Based on the reported data, combined with feedback provided by the U.S. Food and Drug Administration after a fall 2021 Type C meeting, and pending the outcome of further planned regulatory authority interactions this year, Avrobio expects to initiate an Avrobio-sponsored trial in 2023 in the United States, followed by sites in the U.K. and Europe. The plan involves a two-part strategy, beginning in a pre-renal transplant population followed by a post-renal transplant population.

Author: Rare Daily Staff