Cystinosis Results Help Rebuild Confidence In AvroBio’s Gene Therapy

The lentiviral gene therapy company is still trading below cash, but the cystinosis results add extra momentum to its comeback.

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AvroBio has presented positive updated Phase I/II data of its AVR-RD-04 gene therapy in cystinosis, helping to lift investor sentiment around the company and its lentiviral-based gene therapy platform.

The company’s share price hit rock bottom last year after it abandoned Fabry disease gene therapy candidate AVR-RD-01, but the latest results could help the Cambridge, MA-based company rebuild its portfolio and reputation.  (Also see "Avrobio Plots Plan B After Fabry Disease Gene Therapy Problems" - Scrip, 5 Jan, 2022.)

The investigator-led study in six patients was presented at the American Society of Gene and Cell Therapy congress on 18 May and provided proof-of-concept for a registration-enabling Phase I/II trial, expected to start in the second half of 2023.

Cystinosis is a rare, progressive disease marked by the accumulation of the amino acid cystine as crystals inside the body. This causes progressive organ damage and debilitating corneal damage, swallowing dysfunction, chronic kidney disease and muscle wasting,ultimately leading to a shortened lifespan.

The data showed that the lentiviral-based gene therapy, carrying genetically modified versions of the patients’ own hematopoietic stem cells (HSC), allowed expression of a functional version of the missing cystinosin protein. As a result, leukocyte cystine levels in the blood decreased below baseline in all six patients and stabilized up to 36 months out from treatment.  Follow-up data suggest that after receiving HSC gene therapy, patients can produce functional cystinosin protein throughout the body, indicating the one-time treatment’s effects are durable.

Skin and gastrointestinal mucosa biopsies revealed a decline in tissue cystine crystals below baseline in the first four patients, who have been observed for at least 12 months, with two patients observed up to 24 months.

The disease heavily impacts the eye and there were early indications that the treatment helped improve visual spatial or visual motor function. The first four patients treated with gene therapy showed improvement or stabilization of scores on visual motor integration, up to 36 months after treatment, suggesting a potential impact on the neuropathology of the disease.

On safety, there were no adverse events related to the drug product, and on efficacy, the data is an extension of trends previously measured, confirming a treatment effect up to 36 months.

One disappointment from these early results was the lack of benefit to patients’ kidney function, another key consideration in the condition, with four out of the six participating patients having had kidney transplants because of the disease, although equally no negative effects were observed.

The company also reported constructive dialogue with the UK’s Medicines and Healthcare products Regulatory Agency and US Food and Drug Administration, which it hopes can result in agreement on endpoints and design of the potentially registrational Phase I/II study.

Rebuilding After Fabry Setback

The AVR-RD-04 results are another step forward after it scrapped its Fabry disease gene therapy candidate in January 2022 after disappointing Phase II results. That setback raised doubts about how effective the company’s lentiviral vector-based platform could be in treating other lysosomal storage disorders, but AvroBio believes the failure related to specific engraftment issues in Fabry disease.

The company received a major boost in December when it unveiled positive Phase I results from its Gaucher disease candidate AVR-RD-02, providing proof-of-concept in this condition and the platform. This is now the company’s lead asset, and a Phase I/II study in Gaucher type 1 is now recruiting, while a global registrational Phase II/III trial in patients with the more severe Gaucher type 3 is due to start later this year.  There remain wider questions, however, about how effective gene therapies can be in treating lysosomal storage disorders, and also alternatives to existing enzyme replacement therapies.  (Also see "Avrobio Plots Comeback With Early Data From Gaucher’s Gene Therapy" - Scrip, 9 Dec, 2022.)

The updated cystinosis results have given the NASDAQ-listed company’s shares a major lift, raising its stock price 27% to $0.84 on 19 May. However, the company is not yet out of the woods, as its current market capitalization of $37m makes it one of many biotechs currently trading below cash, and it currently only has the finances to keep trading into Q1 2024.

AvroBio is also looking for a new CEO, after Geoff MacKay departed in early May to join an as-yet-unnamed early-stage company. Erik Ostrowski, the company’s chief financial officer, is acting as interim CEO while the board looks to appoint a permanent leader.