Reata, Friedreich’s Ataxia Patients Await Potential First Approval

 There are currently no disease-modifying treatments for Friedreich’s ataxia (FA), a rare, degenerative neuromuscular disorder. That could change on Feb. 28, as the FDA is expected to make a decision about Reata Pharmaceuticals’ omaveloxolone. 

Touted as one of the top potential neurodegenerative approvals to watch in 2023, omaveloxolone activates Nrf2, a transcription factor that helps resolve inflammation by restoring mitochondrial function, reducing oxidative stress and inhibiting pro-inflammatory signaling.

In a registrational trial of 103 patients, a group of physicians and Reata representatives writing in the Annals of Neurology said omaveloxolone “significantly improved neurological function compared to placebo and was generally safe and well tolerated.”

Named after the German physician Nikolaus Friedreich, who first discovered it in the 1860s, Friedreich’s ataxia affects approximately 5,000 people in the U.S.

It is caused by a trinucleotide repeat expansion in the first intron of the frataxin (FXN) gene, which encodes the mitochondrial protein frataxin. This expansion leads to reduced frataxin expression, resulting in mitochondrial iron overload and uncoordinated muscle movement (ataxia).   

FA typically begins in childhood, with most patients succumbing to the disease by their mid-30s, often from cardiovascular problems.  

While Reata is up first with the FDA, several other companies are vying to be next.

PTC Therapeutics: Q2 Readout

PTC Therapeutics is expecting data from the Phase II/III MOVE-FA trial in the second quarter of 2023.

MOVE-FA is assessing vatiquinone, an experimental small molecule that inhibits 15-Lipoxygenase, a primary regulator of the oxidative stress and inflammation response pathways.

 Stuart Peltz, Ph.D.

A key part of FA disease pathology, oxidative stress leads to chronic neural inflammation, where the inflammatory response can’t be turned off.

“When things go wrong with mitochondria, that can lead to disease states like FA,” Stuart Peltz, Ph.D., CEO, told BioSpace.

Adenosine triphosphate (ATP), the body’s primary energy source, is made in the mitochondria using an electron transfer chain. But these electrons need to be carefully regulated. If released from the mitochondria, they can interact with proteins and DNA and can cause loss of activity, Peltz said.

The 15-Lipoxygenase enzyme plays a key role in regulating neuroinflammation.  

“If the 15- Lipoxygenase pathway is activated as a consequence of dysregulation of the mitochondrial electron transfer pathway, then you’ve got a problem,” Peltz said. “The inflammatory system is chronically on and instead of protecting the body, you have this inflammatory milieu that starts to cause damage.” 

In a previous Phase II trial, vatiquinone demonstrated what the company called “a statistically significant effect” at the 24-month mark. It also had a “favorable” safety profile in more than 500 patients. 

Patients typically lose about two points per year on the modified Friedreich’s Ataxia Rating Scale (mFARS), which measures disease progression, Peltz said. “If you can stabilize the patient, you're doing a good thing.” 

Targeting the Root Cause

Pennsylvania-based Larimar Therapeutics expects topline data from a Phase II trial of CTI-1601 during the second half of 2023. The company’s sole clinical-stage product, CTI-1601, is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of FA patients.

In healthy people, a small protein sequence attached to frataxin carries the frataxin molecule across the mitochondrial membrane. It is cut off by an enzyme once in the mitochondria.

Carole Ben-Maimon, M.D.

“[CTI-1601 has a cell-penetrating peptide attached to the frataxin molecule. The cell-penetrating peptide is a short sequence that's intended to get the molecule across the cell membrane and across the mitochondrial membrane,” Carole Ben-Maimon, M.D., president and CEO, told BioSpace. 

It also contains a cleavage site that enables the cell-penetrating sequence and mitochondrial targeting sequence to be removed so the frataxin stays where it’s supposed to.  

When the Phase II data reads out, Larimar will be looking for safety pharmacokinetics and changes in frataxin levels. Ben-Maimon hopes to repeat Phase I data that showed daily injections of CT1-1601 given at 50 mg or 100 mg led to increased levels of frataxin in buccal cells in the skin, which are correlated to FA disease burden. 

She said CTI-1601’s differentiator is that it gets at the root cause of the disease, replacing the frataxin of which FA patients don’t make enough.

Conversely, Reata’s omaveloxolone activates Nrf2, which stimulates the production of certain proteins. Therefore, the drug works as an antioxidant, she said.

While omaveloxolone will not be curative, “I think the different mechanisms could potentially be synergistic. I don't think it's one or the other.”

Regulatory Precedent

PTC and Larimar are both following the upcoming Reata decision closely.

While Peltz would not comment directly on omaveloxolone’s chances of approval, he said it would be interesting to see the point of view taken by the FDA’s neurology division.   

Ben-Maimon agreed that it is a precedent-setting decision.

‘If omaveloxolone is approved, that will set the gold standard from the standpoint of what FDA is willing to accept or not accept,” she said.

To date, the expectation has been a double-blind, placebo-controlled trial, and Larimar expects to have to do the same. Though, Ben-Maimon added that her company might be able to use frataxin levels as a surrogate endpoint in addition to clinical outcomes.

Reata’s NDA for omaveloxolone was granted priority review in May 2022. The PDUFA date was later extended until Feb. 28, 2023, to allow the FDA additional time to review confirmatory evidence submitted by Reata in response to concerns raised by the regulator.

“If it gets approved, it's really good for patients,” Ben-Maimon said. “These patients have nothing.”  

Reata declined to comment.

https://www.biospace.com/article/reata-friedreich-s-ataxia-patients-await-potential-first-approval/