Lexeo ties gene therapy to rare heart disease improvements, but investors disappointed

Lexeo Therapeutics' recent advancements in their gene therapy for Friedreich ataxia (FA) have shown mixed results. The company has directed its efforts towards addressing cardiac dysfunction associated with FA by increasing the expression of FXN, a critical protein for heart muscle function. Data from Lexeo's phase 1/2 study, combined with an investigator-initiated phase 1a trial at Weill Cornell Medicine, form the basis of these findings.

The trials, which have monitored eight participants for at least six months, aimed to determine if their gene therapy candidate, LX2006, could improve cardiac function in FA patients. At the outset of the study, four participants had elevated left ventricular mass index (LVMI), a measure linked to higher risks of cardiac morbidity and mortality. Notably, three of these subjects saw a reduction of more than 10% in LVMI within 12 months. Additionally, reductions in lateral wall thickening and biomarkers of myocardial injury were observed, and FXN expression levels increased in evaluable patients.

However, Lexeo encountered challenges when assessing the impact of LX2006 on patients' cardiorespiratory fitness using VO2 max, a measure of peak oxygen uptake. Baseline levels of VO2 were found to be extremely low, which the company attributed to a combination of neurological impairment and diminished cardiac functional capacity in FA patients. Among the eight participants, three were unable to exert the necessary effort to reliably measure peak VO2. The remaining five showed modest improvements of 1% at six months and 4% at 12 months. Lexeo intends to continue evaluating peak VO2 and is exploring other cardiopulmonary exercise test measures that might be more indicative of patient improvement.

While the current evidence for LX2006 primarily stems from its impact on cardiac health, the company is optimistic about the potential for regulatory approval based on LVMI or transgene expression. Eric Adler, Lexeo's chief medical officer and head of research, highlighted the association between increased LVMI and adverse outcomes in FA, noting that a 10% increase in LVMI correlates with a 20% rise in mortality risk. This regulatory precedent bolsters Lexeo's confidence in the potential success of their therapy.

Lexeo is now progressing into the third dose cohort of their study. CEO Nolan Townsend expressed optimism that a higher dosage could yield enhanced protein levels, referencing preclinical data that supports the benefits of increased doses. The safety profile observed in the two trials, which reported no treatment-related serious adverse events, further supports this move.

Despite the promising data, Lexeo has not provided a specific regulatory timeline but sees potential for accelerated approval due to the scarcity of existing treatments for FA. The recent FDA approval of Reata Pharmaceuticals’ Skyclarys, acquired by Biogen for $7.3 billion, underscores the need for effective treatments in this area, although Skyclarys demonstrated efficacy primarily on neurological metrics.

Lexeo's focus on cardiac measures distinguishes LX2006 from Skyclarys, but competition in the market is expected to grow. Competitors like Voyager Therapeutics, Neurocrine Biosciences, Solid Biosciences, Lacerta Therapeutics, Prime Medicine, and Tune Therapeutics are also developing gene therapy and gene-editing programs targeting FA.

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