Zontivity Might Increase ALS Risk, but Certainty Will Be Difficult to Prove

A cardiovascular medication called Zontivity (vorapaxar) may be linked to a slight, but still increased, risk of amyotrophic lateral sclerosis (ALS), according to a review of U.S. Food and Drug Administration (FDA) documents on data from the drug’s clinical studies.

While researchers noted that the risk of developing ALS is very small — about one case in every 10,000 treated people — they judged it likely to be tied to the treatment.

Greater certainty will be difficult to ascertain, they said, as the extreme rarity of ALS in this population will continue to complicate efforts at reaching the sufficient numbers of patients needed for a clear answer through observational registries and postmarketing surveillance.

The study, “Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?” was published in the American Journal of Therapeutics.

Zontivity is an anticoagulant factor that acts to block a molecule called PAR-1, which exists in platelets. The treatment is approved for use after heart attacks and in patients with peripheral artery disease who also use clopidogrel and aspirin.

Researchers at Johns Hopkins University in Baltimore and Dong-A University in South Korea noted that although the publications of the two clinical trials (NCT00527943 and NCT00526474) did not mention ALS, the FDA review of the New Drug application that preceded Zontivity’s approval in 2014 did.

In one of the trials, three patients receiving Zontivity and one in the placebo group developed ALS, and one additional Zontivity-treated patient had an “upper motor neuron lesion” that was judged as a likely case of primary lateral sclerosis — a condition closely related to ALS.

In the other trial, one placebo-group patient developed ALS. Given the known prevalence of this disease, the researchers calculated that eight people in 100,000 patient-years of follow-up would develop ALS. With the number of patients included in the trials, and the amount of time they were followed, this would translate to 2.8 cases in each treatment arm of the combined trials.

The observation of four probable or possible ALS cases among treated patients, and two in the placebo groups, is not a huge deviation from this calculation.

If it were not for the known role of PAR-receptors in neurotransmission, with several studies suggesting they can be targeted in diseases such as Alzheimer’s, the small deviation would not be reason for concern.

“The ‘bad news’ is that vorapaxar per se cannot be definitely exonerated from the observed ALS harm because impaired synaptic transmission in the spinal cord, critical to ALS development, is indeed heavily modulated by PAR receptors,” the researchers wrote.

Nevertheless, the very small risk makes it very difficult to prove the relationship, as even postmarketing surveillance studies and observational registries — so-called Phase 4 studies — may not include enough patients to establish a clear link.

Instead, the researchers suggested that data from future trials of other PAR receptor blockers may offer insights into the potential risk of neuronal degeneration and impaired neuromuscular activity of PAR receptor blockers as a drug class.