Larimar Challenges Biogen in Ataxia Treatment

In early 2024, Larimar Therapeutics announced encouraging results from the Phase II clinical trials of its subcutaneously administered investigational drug, nomlabofusp, for the treatment of Friedreich’s ataxia, a rare neuromuscular degenerative disorder. Friedreich’s ataxia is a mitochondrial disorder that typically manifests in early adolescence and is marked by a deficiency of frataxin due to mutations in the frataxin gene, affecting approximately one in every 50,000 individuals in the United States.

Larimar's nomlabofusp is a modified frataxin protein designed to penetrate mitochondria and elevate frataxin levels. This is a distinct approach compared to Biogen's Skyclarys, an oral medication that is FDA-approved for Friedreich’s ataxia and is thought to activate the Nrf2 pathway to reduce oxidative stress in cells, though its precise mechanism of action remains somewhat enigmatic.

The Phase II data from Larimar corroborated earlier findings from Phase I studies. Patients who received either 25 mg or 50 mg of nomlabofusp exhibited an increase in frataxin levels in skin and buccal cells over a period of four weeks, with the increases being dose-dependent and more pronounced than those in the placebo group. Moreover, more frequent dosing intervals, such as every 24 hours, resulted in higher frataxin levels in skin cells compared to less frequent dosing or placebo.

Nomlabofusp demonstrated a favorable safety profile, with the most common side effect being local reactions at the injection site. Notably, while there was an instance of elevated liver enzymes in the Phase I study at the 25 mg dose, this adverse effect was not observed at higher doses. In contrast, Skyclarys carries a warning of potential serious side effects related to increased blood liver enzymes.

Despite the promising Phase II outcomes, Larimar faces significant challenges ahead. The short-term increase in frataxin levels must be sustained over the long term, given the progressive nature of Friedreich’s ataxia and the poor prognosis without treatment. Additionally, the rarity of the disease necessitates careful study design to ensure that clinical outcomes are captured effectively from a relatively small patient pool.

Furthermore, previous gene therapies aimed at increasing frataxin levels have been discontinued due to concerns over toxicity and organ damage. While nomlabofusp has not shown signs of liver enzyme increases, the potential for liver damage from overexpression of frataxin cannot be overlooked. The safety of Skyclarys is also a concern, given that some patients experienced elevated liver enzymes within the first 12 weeks of treatment.

The long-term safety of nomlabofusp is yet to be established, as current data only extend to four weeks. However, the potential for a new treatment option for Friedreich’s ataxia is significant, and if Larimar can successfully navigate the remaining hurdles, it could become a formidable competitor to Biogen in this niche market. As the race for effective therapies continues, the progress of nomlabofusp will be closely monitored in the coming years.