CNS-penetrant oral RIPK1 inhibitor flops for ALS

The selective, oral, central nervous system-penetrant reversible RIPK1 inhibitor SAR443820 appears to have limited clinical benefit in amyotrophic lateral sclerosis (ALS) and is even associated with greater hepatic enzyme increase, according to the phase II HIMALAYA trial.

Conducted at multiple clinical sites across 13 countries, HIMALAYA included 305 adults (mean age 56.9 years, 60 percent male) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS.

The participants were randomly assigned to receive either SAR443820 20 mg (n=203) or matching placebo (n=102) in the 24-week double-blind period. Treatment was administered orally twice per day.

The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score at week 24. Safety was also assessed. Of the participants, six were excluded in the primary analysis due to missing baseline ALSFRS-R values.

From baseline to week 23, ALSFRS-R total scores decreased by a mean of 6.73 (95 percent confidence interval [CI], −7.48 to −5.98) in the SAR443820 group (n=169) and by 6.32 (95 percent CI, −7.36 to −5.27) in the placebo group (n=87). The difference did not meet statistical significance.

In terms of safety, adverse events occurred more frequently in the SAR443820 vs the placebo group (85 percent vs 78 percent), as did treatment discontinuations (14 percent vs 5 percent). Elevated hepatic enzymes were the most common cause of treatment discontinuations.

Seven participants in the SAR443820 group and two in the placebo group died, but none of the deaths were attributed to the study drug.