Gene Therapies Show Efficacy in Fabry Disease, Choroideremia


4D Molecular Therapeutics announced positive data from trials assessing 2 of their gene therapies.

Two gene therapies from 4D Molecular Therapeutics have shown positive data in their phase 1/2 clinical trials for Fabry disease (NCT04519749) and choroideremia (NCT04483440).

“Today we announced the first ever clinical data reported with an intravenous product invented from our Therapeutic Vector Evolution platform at 4DMT. These interim data demonstrate clinical proof-of-concept for tolerability and clinical activity,” David Kirn, MD, co-founder and chief executive officer, 4DMT, said in a statement. “These data support our belief that 4D-310 is well-tolerated and has the potential to deliver patient benefit after a single intravenous injection. Importantly, the post-treatment AGA enzyme activity in patients’ blood was within, or significantly above, the normal range despite the presence of pre-existing anti-AGA antibodies, which are a result of prior ERT in these patients. To our knowledge, these initial clinical data are the first demonstration of durable serum AGA activity within the normal and above normal range following gene therapy in a difficult to treat classic Fabry disease patient population.”

The gene therapy 4D-310 uses a proprietary C102-targeted and evolved vector invented through Therapeutic Vector Evolution. It is being assessed in an ongoing, phase 1/2 dose-escalation and dose-expansion clinical trial. The trial’s primary end point is safety and tolerability, and secondary end points include change from baseline in serum AGA activity and serum lyso-Gb3. 

As of October 12, 2021, 3 patients with Fabry disease were enrolled in the trial to be treated at the lower-dose of 1E13 vg/kg. Six more patients are planned to be evaluated in the lower-dose cohort and a higher dose-escalation scheme starting at 3E13 vg/kg will also be evaluated in other future participants. An oral corticosteroid prophylaxis taper was administered over 10 weeks post-dosing. The patients had follow-up ranging from 6 weeks to 6 months. 

READ MORE: Fabry and Gaucher Gene Therapies Well-Tolerated

Investigators found that the 3 participants treated with 4D-310 had mean serum AGA enzyme activity within or significantly above the normal range. All 3 participants had previously had anti-AGA antibody titer positivity. Lyso-Gb3 substrate concentrations significantly decreased in 1 patient and remained low and stable in the other 2 without enzyme replacement therapy (ERT).

“We designed 4D-310 for a unique dual mechanism of action, enabling the potential treatment of target tissues such as heart, blood vessel walls, and kidney through cross-correction from high and stable serum AGA activity, as well as through direct transduction and AGA expression in target cells,” Raphael Schiffmann, MD, senior vice president and clinical therapeutic area head, lysosomal storage diseases and cardiology, 4DMT, added to the statement. “This dual MOA opens the potential to effectively treat the broadest possible range of Fabry patient populations.”

In terms of safety, the gene therapy seemed to be well-tolerated, with no dose-limiting toxicities (DLTs) observed. Two of the 3 patients experienced no serious adverse events (AEs), atypical hemolytic uremic syndrome (aHUS) or liver toxicity. One patient experienced transient, self-limited aHUS within 1 week of treatment which quickly resolved without intervention. This was considered a serious AE since the patient was admitted to the hospital for observation and hydration. The patient also had transient and asymptomatic grade 1 transaminitis.

“Given the encouraging initial clinical activity and tolerability profile of 4D-310, we plan to continue enrolling a broad patient population, including both anti-AGA antibody positive and negative patients, as well as classic and late-onset patients,” Schiffmann added.

4DMT’s therapy for choroideremia, 4D-110, is also being studied in an ongoing phase 1/2 dose-escalation trial in which 6 patients with clinically advanced choroideremia have been enrolled. The trial is using a standard 3+3 dose escalation design and patients are enrolled in either the 3E11 vg/eye (n=3) or 1E12 vg/eye (n=3) cohorts.

The lower dose of 4D-110 has been well-tolerated, with no DLTs or serious AEs observed. Anatomical measurements of the retinal pigment epithelium by fundus autofluorescence area and photoreceptors by ellipsoid zone area suggest initial signs of clinical activity.

The higher dose of 4D-110 has demonstrated 3 cases of pigment dispersion 7 to 9 months after treatment. These cases were asymptomatic in 2 participants while the third reported mild glare. These events were classified as serious AEs, although no medical intervention was needed. The finding seems to be consistent with REP1 transgene overexpression in iris pigment epithelial cells and investigators did not observe any associations with inflammation.

4D Molecular Therapeutics reports interim results from the 4D-310 phase 1/2 clinical trial in patients with Fabry disease and provides clinical data update from the 4D-110 phase 1/2 clinical trial in patients with choroideremia. News release. 4D Molecular Therapeutics. October 25, 2021.
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