The European Society for Gene and Cell Therapy (ESGCT) recently held its Annual Congress from October 11-14, 2022. During the ESGCT Congress, various stakeholders discussed data, trends, and new research within the fields of gene and cell therapy. One particular presentation from biotechnology and gene/cell therapy company Sangamo Therapeutics (“Sangamo”) centered around promising data from a Phase 1/2 clinical study evaluating ST-920 for patients with Fabry disease. In addition to sustaining α-Gal A activity, ST-920 was safe, well-tolerated, and had many other benefits for patients.

Can ST-920 reduce the need for enzyme replacement therapy (ERT) or provide an alternative treatment option? Considering that ST-920 targets the underlying cause of Fabry disease, rather than offering symptom management, it’s very possible.

Recently, I sat down with Dr. Bettina M. Cockroft, MD, MBA, who is the Chief Medical Officer at Sangamo, to discuss Fabry disease, the challenges and rewards of medical research, and what data from the Phase 1/2 STAAR study says about ST-920.

About Bettina M. Cockroft, MD, MBA

Dr. Bettina M. Cockroft earned her M.B.A. from MIT’s Sloan School of Management and her M.D. from the University of Genova. A neurologist by trade, Dr. Cockroft previously worked at Cytokinetics, Inc., where she assisted in clinical development for fast skeletal muscle troponin activators. She joined Sangamo in 2019 as the Chief Medical Officer (CMO). According to Dr. Cockroft, Sangamo offers a rich pipeline of gene editing, gene therapy, and cell therapy approaches; she enjoys the opportunity to contribute to developing these therapies and improving patient outcomes. Outside of Fabry disease, Sangamo also has programs for hemophilia A, sickle cell disease, and mismatched renal transplants.

Learn more about Dr. Bettina M. Cockroft.

Fabry Disease: An Overview

Fabry disease is a genetic lysosomal storage disorder in which a type of fat called globotriaosylceramide accumulates in the cells. Normally, the GLA gene encodes for the production and function of an enzyme called α-Gal A that helps to process this fat. However, GLA mutations cause this enzyme to not function properly, or for patients to not have enough α-Gal A. As a result, globotriaosylceramide builds up in the cells, causing damage and other health issues. Males are impacted more than females. However, the impact of Fabry disease on females is under-researched and poorly understood; some research suggests that females with Fabry disease often experience pain, cerebrovascular events, gastrointestinal symptoms, and occasionally renal involvement.

In many cases, symptoms of Fabry disease begin in childhood, though some individuals may have a later onset. Symptoms can (but do not always) include:

• Acroparesthesias (recurrent pain or burning in the feet and hands)
  • Note: This may worsen with stress, exercise, fatigue, or hot weather.
• Hypohidrosis (loss of the ability to sweat), which can lead to heat intolerance and impact the ability to participate in sports
• Angiokeratomas (small bundles of dark, red spots on the skin)
• Stomach pain
• Cloudy vision (corneal opacity)
• Tinnitus (ringing or roaring in the ears)
• Hearing loss

Currently, treatments for Fabry disease are symptomatic. The standard-of-care is enzyme replacement therapy (ERT).. However, Dr. Cockroft believes that gene therapy, like ST-920, could be an effective option. She explains:

Because there are different mutations that cause Fabry disease within GLA, the disease lends itself to treatment through AAV-based gene therapy. ST-920 ensures that liver cells receive a transgene which makes up for the deficient or mutated genetic code, and that transgene is able to produce functional α-Gal A.

What is ST-920?

At the ESGCT Annual Congress, Sangamo presented data from the Phase 1/2 STAAR trial that evaluated ST-920 for Fabry disease. To understand the data, it’s first important to understand what ST-920 is. On the company’s website, ST-920 (isaralgagene civaparvovec) is described as:

a liver-tropic rAAV 2/6 vector carrying the cDNA for human α-Gal A that is delivered through a single dose IV infusion.

Dr. Cockroft further explains:

With this infusion of ST-920, we expect to have long-term production of the enzyme at a stable concentration and that will obviate the need for enzyme replacement therapy. ERT is done every two weeks, which can be disruptive to patients and their lives. With those infusions come side effects and high peaks of the enzyme with a very short half-life, where those peaks then return to baseline levels. If we can provide more long-term care with ST-920, we hope that would ideally improve patient lives.

Presenting Fabry Disease Data at the ESGCT Annual Meeting

The STAAR study is a first-in-human study designed to evaluate the safety and tolerability of ST-920. While the study is ongoing, data presented at the Annual Meeting was cut in July 2022. This data includes nine male patients treated during the dose escalation phase. Five patients have also been treated with the highest ST-920 dose in the expansion phase, though this data was not available at the time of the data cut. While only males were included in the dose escalation phase, females are now also included in the expansion phase. Dr. Cockroft explains:

In the expansion phase, we want to also focus on patients who don’t necessarily present with classic Fabry disease or who might have more organ involvement such as the heart or kidney. It will include more monitoring and more cardiac MRIs. People who are not on ERT will undergo kidney biopsies to see if the kidneys are affected positively by ST-920. Ultimately, we hope to develop a more comprehensive understanding of the potential benefit on people across the Fabry disease spectrum.

So what data has come out of the STAAR trial so far? The first important finding is that ST-920 was safe and well-tolerated. In other AAV-based products, patients must sometimes be treated with steroids to avoid ALT or liver enzyme elevations. However, this has not been the case with ST-920. Dr. Cockroft shares:

At the time of sharing the data, four patients were able to be withdrawn from ERT and displayed significantly elevated α-Gal A. Since presenting, another has also been withdrawn. The elevated activity ranges from 2-fold to 30-fold of the mean normal. We’ve seen this sustained over our follow-up period. The α-Gal A expression has come to supraphysiological levels, which was our target. This is reassuring and means that we’re now planning a Phase 3 study in the future. We really look forward to impacting patients in this community and seeing that happen will be incredibly rewarding.

Another positive finding from the study so far is plasma Lyso-Gb3 reduction. Dr. Cockroft explained that Lyso-Gb3 can be a biomarker for Fabry disease; patients often have high levels of these substrates. In patients receiving the highest ST-920 doses, Lyso-Gb3 has been reduced by 40-55%.

Future Research

Moving to the future, Sangamo hopes to continue positively and meaningfully impacting the patient community through research and drug development. Of course, this process comes with its challenges. For example, Dr. Cockroft explains:

In rare disease, there’s a limited number of patients who are able to participate in clinical trials. So to do this research, one must open centers in many locations. We have around nineteen sites in the US, UK, and Australia, and we’re moving towards opening sites in Canada, Italy, Taiwan, and Germany. With gene therapy, you have to keep data collection, shipping, storage, and assays in mind. It is a logistically complex process.

However, getting the research started and hearing from patients can be incredibly rewarding, and balances out the challenges faced. Dr. Cockroft shares that she loves hearing feedback from patients who are gaining hope for the future, for treatment, for themselves and their family. Because Fabry disease is genetic, many patients have family members who also have Fabry disease. So this research can be incredibly personal. If treatment is effective and administered early enough, it could also help patients receive treatment before more significant disease impact.

Outside of Fabry disease, Sangamo will continue to focus on using cell and gene therapy for a variety of different disorders. Dr. Cockroft says:

Sangamo has been testing its own gene therapy technology for many years now. Gene editing is at the heart of what we do. We have a group of so many highly skilled, talented employees coming up with some very innovative concepts. I’m so eager to think through, with them, how we can deploy these technologies across multiple indications.