Washington, DC – In February 2024, Larimar Therapeutics released positive Phase II data for its injectable subcutaneous investigational agent nomlabofusp in treating Friedreich’s ataxia, a rare disease that causes neuromuscular degeneration. The data indicate that Larimar could go head-to-head in the market with Biogen’s Skyclarys, the only disease-specific therapy for Friedreich’s ataxia to so far receive FDA approval.
A mitochondrial disorder, Friedreich’s ataxia is characterized by low frataxin (FXN) levels in the body due to mutations in the FXN gene. It affects 1 in 50,000 people in the U.S. and symptoms usually begin when patients are between 8 and 15 years old.
Nomlabofusp is an injected, modified FXN protein that has the engineered ability to enter the mitochondria to increase FXN levels directly. This is a different mechanism than Skyclarys, an oral medication that activates the pathway of Nrf2, a transcription factor that decreases cells’ oxidative stress; its exact therapeutic mechanism is unclear.
According to Larimar, the Phase II data reinforce what was previously known about nomlabofusp from Phase I trials. In the two experimental arms that received 25 mg or 50 mg of nomlabofusp, dose-dependent increases in FXN levels from baseline were observed in skin and buccal cells over four weeks. The FXN level increases were higher for the experimental arms compared to placebo.
More-frequent doses—up to every 24 hours—led to higher FXN levels in skin cells compared to placebo compared to dosing every two days. However, the frequency of administration did not matter significantly for buccal cells, which displayed similar increases in FXN levels compared with placebo regardless of dosing intervals.
Nomlabofusp was well-tolerated, with the most common adverse event being injection site reactions. While there was one case of liver enzyme increase in the Phase I single ascending dose study of nomlabofusp at 25 mg, this was not seen at higher doses. Conversely, SkyClarys’ label lists an increase in blood liver enzymes as a possible serious side effect.
While Larimar’s Phase II results seem to be positive and indicate that the company is going in the right direction, much work remains to be done.
Larimar has proven that nomlabofusp can increase FXN levels in the short term, but given the poor prognosis and disease progression in untreated Friedreich’s ataxia patients, measuring clinical outcomes will be a key determinant in convincing practitioners to prescribe nomlabofusp over Skyclarys.
In addition, given the rareness of Friedreich’s ataxia and therefore the relatively small size of trials, capturing relevant clinical outcomes in a way that maximizes the data output from this patient population will be crucial in future study designs.
Another reason for caution is that gene therapies for Friedreich’s ataxia that increased FXN expression have been ruled out in the past due to toxicity and organ damage. Although there have been no signs of liver enzyme increases caused by nomlabofusp, the fact that FXN overexpression may cause liver damage is a point to be aware of. And while Skyclarys has a different mechanism of action, the uncertainty about how it works and the fact that elevated liver enzymes occurred in some patients within 12 weeks of starting the drug reinforces the need to keep a close watch on this biomarker.
Finally, because Phase I and Phase II data for nomlabofusp are currently only available for up to four weeks, the drug’s long-term safety is still unknown.
Nevertheless, given the unmet need when it comes to treating Friedreich’s ataxia, it’s worth keeping an eye on nomlabofusp’s progress in the coming years. If the cards play out right for Larimar, the company could give Biogen a run for its money.
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Jia Jie Chen writes analyses focusing on drug development in the biotech and pharma industries for BioSpace. He has a doctorate degree in pharmacy and experiences ranging from biotech equity research to business intelligence analysis. Follow him on LinkedIn.