Etravirine — an approved anti-viral therapy for HIV — is expected to soon enter clinical testing as a potential new treatment for Friedreich’s ataxia (FA) in a pilot Phase 2 trial taking place in Italy.
The proof-of-concept study (NCT04273165), called FAEST1, which is being conducted by the IRCCS Eugenio Medea Scientific Institute in collaboration with the University of Rome Tor Vergata, aims to evaluate the safety and effectiveness of etravirine tablets in children and adults with FA.
The open-label, single-site trial is being supported by four European patient groups: Italy’s Ogni giorno per Emma, the main contributor; Italy’s Il Sorriso di Ilaria; Spain’s Babel FAmily; and Switzerland’s Association Suisse de l’Ataxie de Friedreich (AChAF).
Expected to launch in late March, the study aims to enroll up to 30 children and adults with FA, ages 10 to 40, at the Referente Clinico-Scientifico di Polo, a research hospital near Venice.
To be eligible, patients must be able to complete a functional test that consists of riding a stationary bicycle in a laid-back reclining position at 60 rpm (rotations per minute) for at least three minutes. Participants will also have to stop current treatments four weeks before entering the trial.
“The size of the treated population is at its minimum due to the exploratory nature of the trial and the tightly limited financial support,” Andrea Martinuzzi, MD, PhD, the trial’s lead co-investigator, said in an email response to Friedreich’s Ataxia News Today.
Once enrolled, participants will be randomly assigned to either 200 mg (two 100 mg tablets twice-a-day) or 400 mg (two 200 mg tablets twice-a-day) of etravirine daily for four months. The study’s main goal is to evaluate treatment safety and tolerability, which will be assessed by analyzing the number and severity of adverse events.
Secondary goals include assessing treatment efficacy at increasing patients’ lung function — measured by the maximum rate of oxygen consumption during exercise of increasing intensity, in this case using a bicycle.
Other goals include assessing ataxia severity using the Scale for the Assessment and Rating of Ataxia (SARA); heart wall thickness, measured through echocardiography; frataxin protein levels in immune cells; and patients’ quality of life, using the SF-36 Health Survey.
Data will be collected four months before starting the treatment, at treatment initiation, and again at two, four, and eight months later.
Martinuzzi, a neurologist, said the trial is currently awaiting approval from the Italian Medicines Agency, due by the end of February, and from the Institutional Review Board (IRB).
“We hope to see confirmed the safety and tolerability of etravirine in FA patients and we hope to detect in our indicators of efficacy … a significant positive trend,” Martinuzzi said.
He also noted that if the trial supports etravirine’s therapeutic potential in FA, its results will have to be confirmed “by a larger placebo-controlled trial in which we hope the pharma industry might get directly involved.”
The rationale for testing etravirine in people with FA stemmed from a preclinical study showing the medication increased the production of frataxin — a protein that is thought to control the production of energy in mitochondria and whose production is impaired in FA — in cells from patients grown in the lab.
In the study funded by Fratagene Therapeutics, researchers at University of Rome Tor Vergata and their colleagues found that etravirine raised frataxin production by boosting the production of its messenger RNA (mRNA), the molecule that serves as a template for the production of a protein.
In addition, they showed that patient cells treated with etravirine became more resistant to oxidative stress — cell damage caused by high levels of oxidant molecules, or reactive oxygen species — and showed no signs of treatment-associated toxicity.
These findings, together with the well-established safety and tolerability profile of life-long treatment with etravirine, Martinuzzi said, suggested this well-known HIV therapy could be repurposed to treat FA.
In addition to etravirine, Martinuzzi’s team, along with collaborators at University of Rome Tor Vergata, Harvard Medical School, and Fratagene Therapeutics, are developing another potential FA therapy. This investigational treatment — interferon-gamma (INF-gamma) — has recently shown promising results in a small clinical trial in young FA patients.
While previous preclinical studies showed that INF-gamma-1b — a signaling molecule involved in immune responses — increased the levels of frataxin, inconsistent data was obtained from clinical trials (NCT01965327, NCT02415127, and NCT02797080) regarding its potential therapeutic benefits.
Results of the small open-label trial of IFN-gamma-1b given for six months to children was detailed in the study, “Safety and Efficacy of Interferon γ in Friedreich’s Ataxia,” published as a letter to the journal Movement Disorders in January, with Martinuzzi as its lead author.
Results from the 11 patients who completed the trial showed that IFN-gamma-1b (sold as Imukine by Boheringer Ingelheim) was generally safe and effectively halted disease progression (assessed through SARA and heart features).
The researchers highlighted, however, that future trials are necessary to more fully assess INF-gamma’s therapeutic potential, and need to be designed with sensitivity to non-responders to INF-gamma.
Fratagene Therapeutics, whose focus is Friedreich’s ataxia, holds a U.S. patent on the use of etravirine as an FA treatment, and a U.S. and European Union patent on the use of INF-gamma to also treat FA.
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