Cardiology Pharmaceuticals

Applied Therapeutics’ AT-001 Trial Misses Mark

Applied Therapeutics saw its shares fall 40% late last week after revealing that its diabetic cardiomyopathy drug candidate AT-001 (caficrestat) didn’t meet its phase 3 trial’s primary endpoint. However, the trial did show enough “encouraging results” for Applied to assert that AT-001 could still become the first diabetic cardiomyopathy treatment.

  • Diabetic cardiomyopathy (DbCM) describes diabetes-associated changes in the structure and function of the heart’s myocardium, often leading to heart failure. 
  • AT-001 is an investigational oral Aldose Reductase inhibitor being developed for the treatment of diabetic cardiomyopathy.
  • There are no other drugs specifically approved to treat DbCM, although some patients are prescribed SGLT2 inhibitors

The ARISE-HF phase 3 trial had 675 DbCM patients at high risk of progression to overt heart failure take either AT-001 or a placebo, as an add-on to standard diabetes therapies.

The study didn’t show statistically significant improvements or prevention of worsening DbCM (the primary endpoint) — the AT-001 and placebo groups had -0.01 and -0.31 ml/kg/min Peak VO2 declines over 15 months (p = 0.210).

However, there was some secondary silver linings:

  • AT-001 achieved statistically significant improvements among the 62% of participants who weren’t also taking SGLT2 or GLP-1 inhibitors (+0.08 vs. -0.54 ml/kg/min Peak VO2).
  • Far fewer participants in the AT-001 group experienced “clinically significant worsening in cardiac functional capacity” than the placebo group (32.7% vs. 46%).
  • AT-001 was generally safe and well tolerated, as both groups had similar rates of serious adverse events and low incidence of treatment-related discontinuations.

These secondary outcomes were enough for Applied Therapeutics to call its results “encouraging” and position AT-001 as an “important potential tool for physicians in treatment of DbCM patients,” especially considering that DbCM patients still don’t have an approved therapy.

However, Applied Therapeutics is apparently more “encouraged”about its galactosemia drug govorestat, announcing plans to find a partner to bring AT-001 to approval and commercialization, so it can focus its resources on govorestat.

The Takeaway
Although most headlines focused on Applied Therapeutics’s stock decline, and some folks on Twitter/X mocked its mention of “encouraging results,” the fact that AT-001 stabilized cardiac functional capacity (especially among those not on SGLT2 or GLP-1 inhibitors) might actually be encouraging for DbCM patients currently living without an approved therapy.

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