MOXIe, the Phase 2 study of oral omaveloxolone (omav), is now the first trial to show significant neurological benefits in a broad population of patients with Friedreich’s ataxia (FA), Reata Pharmaceuticals announced last week.
Its major finding was a 2.40-point improvement in the modified Friedreich’s ataxia rating scale (mFARS) in 82 patients without pes cavus (a foot deformity) after almost one year of treatment.
They called this mFARS change potentially historic, and noted it’s also in defiance of the disease’s natural history. FA has no approved targeted treatment because no previous investigative therapy was able to show a significant slowing in disease worsening and a partial recovery of neurological function in trial participants.
Here, they talk about steps taken to ensure the reliability — the trustworthiness — of benefits measured and their applicability to a broad range of patients. They also speak to omav’s safety.
“MOXIe was the largest global interventional study ever conducted in FA and was the first to demonstrate a statistically significant improvement in neurological function in patients with FA … a clinically meaningful benefit,” said Warren Huff, Reata’s founding president and CEO.
A big question, at least a year away from being answered, is whether regulators with the U.S. Food and Drug Administration and agencies elsewhere will agree. Huff and other Reata scientists have said they are planning to meet “soon” with these regulators, starting with the FDA, to begin an approval process.
But, as Huff added, “we believe it [omav] has the potential to become the first FDA-approved therapy for this disease.”
Limiting ‘variability,’ ensuring trustworthiness
Considered cellular “power plants,” mitochondria produce less energy than is normal for cells in FA patients. This lack seems to account for the poor coordination, progressive muscle weakness, exercise intolerance, and fatigue they experience.
Harmful molecules called reactive oxygen species (ROS) also accumulate in patients’ tissues, leading to oxidative stress that can damage or kill cells.
Omav, as reported in a first detailed look at this trial, works by activating the Nrf2 protein, and triggering pathways that can help to resolve neuroinflammation, poor energy production, and oxidative stress.
This prompted Reata to launch MOXIe, a two-part Phase 2 international trial (NCT02255435) of omav in 103 teenagers and adults, ages 16 to 40, with an average mFARS score of 40 at the study’s start (on a 0–99 scale).
“I think a key aspect of this trial was our insight from the first part of the trial” — whose goal was safety, tolerability, and establishing an optimal dose — that researchers relied on for the trial’s second and pivotal part, said Colin Meyer, MD, chief medical officer and executive vice-president of product development at Reata.
For example, interested patients took two “independent … [mFARS] test runs” before the study opened, Meyer said, in an effort to best “limit variability” and ensure reliability. To be allowed to enroll in MOXIe, a patient’s mFAR scores on these tests had to be within 4.5 points of each other.
Multiple mFARS exams were also given throughout the trial, helping to confirm “the placebo effect was out and any training effect was normalized” and investigators “were able to detect a clear signal,” Meyer added.
“We feel the mFARS results are robust,” he said of the 2.4-point difference seen in treated patients’ scores against those on placebo (a 150 mg omav or sham capsule, once a day) after 48 weeks among people without pes cavus — the 82 patients who made up the trial’s primary population.
Among all patients (those with and without pes cavus), a 1.93-point mFARS improvement against placebo was recorded.
mFARS is a four-section, physician-assessed neurological exam — accepted by the FDA as a relevant judge of omav’s efficacy — that measures a broad range of physical abilities, including speaking and swallowing (bulbar function); use of arms, hands, and legs (upper and lower limb coordination); and an ability to stand and walk (upright stability).
As FA progresses, mFARS rises an average one-to-two points annually. “Once their score reaches approximately 55-60, they become wheelchair-bound and can no longer walk,” Meyer said.
“Our trial was successful because the treatment effect was greater ” than any placebo effect, “and demonstrated not just slowing the progression but improvement in omav-treated patients from baseline,” Meyer said.
This 2.4 mFARS change was “statistically significant,” he added, carrying a p-value of 0.014.
Among these 82 people, in fact, “patients treated with omav experienced a mean improvement in mFARS of -1.55 points from baseline [study start], while patients treated with placebo experienced a mean worsening in mFARS of + 0.85 points from baseline.” (Rising mFAR scores indicate greater disability.)
Another critical aspect highlighted by Reata executives were improvements in “the way patients reported how they felt or functioned.”
Specifically, a greater sense of well-being among people on omav was seen in the Activities of Daily Living (ADL) and Patient Global Impression of Change (PGIC) surveys, which measure patients’ perceptions of treatment efficacy based on their abilities to perform everyday tasks (like speaking and swallow, or standing and walking) and impressions of changes in their overall health.
“We think those are critical aspects of the overall data package,” Huff said.
Safety and omav’s potential
The most common side effects related to omav use, relative to people on a placebo in MOXIe, were headache (37% omav vs. 25% placebo), nausea (33% vs. 14%), increased liver enzymes (aminotransferases, ALT and AST — ALT, 37% vs. 2%; AST, 22% vs. 2%), fatigue (22% vs. 14%) and abdominal pain (22% vs. 6%).
These side effects “were generally mild to moderate in intensity,” Meyer said, with omav “generally reported to be well-tolerated.”
Only a small number of patients left the study due to side effects — 8% in the omav group and 4% in the placebo.
“Notably 98% of eligible patients [those in MOXIe, part 2] elected to enroll in the extension phase of the trial,” a long-term efficacy and safety study, now underway, where all will be treated omav.
“We think that’s a remarkably high number and demonstrates” both interest in the treatment and its tolerability, Meyer added.
No new safety signals were seen, he said, and serious adverse events were “sporadic” and limited to those “generally expected in FA patients” — three in the omav and placebo groups each, with two additional such adverse events in omav patients around week 50, or about two weeks after their final treatment.
Elevated liver enzymes, or aminotransferases, can indicate inflammation or damage in liver cells. But such increases are also a part of omav’s mechanism of action, and evidence indicated this rise was “clearly a pharmacological effect, and not associated with injury,” Meyers said.
“We believe they are related to the restoration of mitochondrial function because these enzymes play an important role in cellular energy production,” he said. “In support of this, changes in ALT at week four in MOXIe significantly correlated with improvements in mFARS at week 48.” A rise in these enzymes was reported in the liver, kidneys, muscles, and other tissues.
A common and serious complication of FA is heart disease, a leading cause of patient death, but the trial did not look for changes in muscle tissue because of the “more sophisticated assessments” that would require.
Rather, like most trials, it looked for impact on patients’ cardiovascular status, and Meyer noted that about half of enrolled MOXIe patients had cardiomyopathy or disease of the heart muscle. “We did ECGs — echocardiograms — and notably saw no adverse effects … on the heart,” he said.
In its webcast, Reata also reported that cardiac and vascular adverse events were low overall, and further “reduced in the omav group.”
“We would likely need to do MRI imaging of the heart in a separate trial to really understand how it may benefit,” Meyers said in the interview.
For now, Reata is readying for an expected meeting with FDA officials as a first step in preparing a request for approval, and to continuing to work closely with FARA, which it called an “excellent partner.”
And it’s looking to see what other diseases, those also linked to problems with cellular energy (mitochondria), that omav might treat, like Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), Huntington’s disease and epilepsy.
“We plan to develop Omav clinically for one or more of these diseases,” Huff said.