Lexeo links gene therapy to improvements in rare heart disease but disappoints investors

Lexeo links gene therapy to improvements in rare heart disease but disappoints investors

Lexeo Therapeutics has guided its Friedreich ataxia (FA) gene therapy through an early test, generating evidence of improvements in cardiac status in early-phase trials. But the biotech ran into problems when testing the effect of the candidate on fitness and was left with a gap in evidence.

The analysis pooled data from Lexeo’s phase 1/2 study and an investigator-initiated phase 1a trial run at Weill Cornell Medicine. Lexeo struck a deal with Weill Cornell for the data in April. The studies are testing whether LX2006 can treat cardiac dysfunction in FA by increasing the expression of FXN, a protein that is involved in the function of heart muscle. Lexeo has at least six months of data on eight participants.

Four people had elevated left ventricular mass index (LVMI), a predictor of cardiac morbidity and mortality, at the start of the study. Three of those subjects experienced a more than 10% reduction in LVMI at 12 months. Lexeo also saw declines in lateral wall thickening, an early indicator of an inefficient heart, and drops in a biomarker of myocardial injury. FXN expression increased in evaluable patients.

Lexeo tried to assess LX2006’s effect on patients’ lives using V02 max, a measure of cardiorespiratory fitness. However, the researchers saw baseline peak VO2 levels were extremely low, a finding that Lexeo said likely reflects a combination of neurological impairment and reduced cardiac functional capacity.

Three of the eight participants were unable to reach the level of effort needed to reliably interpret peak VO2. Across the other five subjects, Lexeo tracked average improvements of 1% after six months and 4% after 12 months. The biotech will continue evaluating peak V02 in its studies and is looking into other cardiopulmonary exercise test measures that may be more useful in the patient population.

While the evidence supporting LX2006 comes from cardiac assessments, for now, Lexeo said there are precedents for drugs winning approval on the strength of LVMI or transgene expression. Eric Adler, chief medical officer and head of research at Lexeo, made the case for LVMI on a call with investors to discuss the data.

“It has regulatory precedent behind it, obviously we’ve seen recently, and we know specifically in FA increases in LVMI are associated with bad outcomes. A 10% increase in LVMI is associated with a 20% increased risk of death,” Adler said. “So, we have a high degree of confidence that that should be an excellent potential outcome moving forward that we should look at in our trials.”

Lexeo has moved into the third dose cohort. Nolan Townsend, CEO at Lexeo, told investors “we believe a higher dose cohort could achieve higher protein levels” and quoted preclinical data showing benefits at higher doses to make his case. The move into the higher dose is supported by the safety profile seen in the two trials, neither of which has reported any treatment-related serious adverse events.

The biotech declined to discuss the regulatory timeline on the call with investors but sees potential for accelerated approval. The belief LX2006 may benefit from accelerated approval reflects a lack of existing treatments. Reata Pharmaceuticals, which Biogen bought for $7.3 billion, won FDA approval for Skyclarys in 2023 but it only showed efficacy on neurological measures.

Lexeo’s focus on cardiac measures differentiates LX2006 from Skyclarys but the market could become more competitive in the coming years. Voyager Therapeutics and Neurocrine Biosciences are working on an FXN gene therapy. Solid Biosciences and Lacerta Therapeutics have gene therapies in the works, too, while Prime Medicine and Tune Therapeutics have early stage gene-editing programs.

Shares in Lexeo opened down 17%, deflating the stock to below $15.

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