Cortexyme and Lilly remind investors that Alzheimer’s failures happen

Cortexyme’s theory that hitting the cause of gum disease could treat Alzheimer’s had always looked like a long shot. So perhaps the most surprising thing about the failure of the phase 2/3 Gain study of atuzaginstat, announced after-hours yesterday, was that it surprised investors.

The company’s stock opened down 68% this morning on the news, but the group is not done with atuzaginstat yet, having found a subgroup to pursue. However, signs of liver toxicity could scupper the project even if lack of efficacy does not.

Meanwhile, the tau hypothesis took another blow yesterday with the mid-stage failure of Lilly’s anti-tau antibody zagotenemab, slipped out during third-quarter results. With several other flops in the tau space this year it will be a nervous time for the host of other groups betting on this mechanism.

Gingipain pain

Cortexyme’s atuzaginstat, or COR388, is an oral inhibitor of gingipains, enzymes produced by and needed for survival of Porphyromonas gingivalis, the bacterium involved in gum disease. The company reckons that P gingivalis infection causes Alzheimer’s, by triggering the release of amyloid and promoting inflammation.

This theory now looks in doubt after the 643-patient Gain study failed to show a difference between atuzaginstat and placebo on its co-primary endpoints, Adas-Cog11 and ADCS-ADL.

Cortexyme is clinging to results in a prespecified subgroup of 242 patients with detectable levels of P gingivalis in their saliva. Here the higher dose of atuzaginstat, 80mg twice daily, led to a 57% slowing of cognitive decline, as measured by Adas-Cog11. Cortexyme cited a nominal p value of 0.02, but this finding can only be considered exploratory.

No benefit was seen in this subgroup on the ADCS-ADL co-primary.

During a bizarrely upbeat conference call yesterday, Cortexyme’s chief executive officer, Casey Lynch, said the company was “poised to execute very quickly” on a confirmatory study in patients with P gingivalis. 

Still, execs did not rule out filing for early approval based on the Gain data. Cortexyme is already in the process of scheduling a meeting with the FDA.

The regulator might have something to say about atuzaginstat’s safety profile, though. The open-label portion of Gain has been on clinical hold since February because of adverse liver events, and yesterday’s data were hardly reassuring on this point. 

Gain found liver enzyme elevations above three times the upper limit of normal in 7% and 15% of patients receiving atuzaginstat 40mg and 80mg twice daily, respectively. Two patients in the 80mg arm also had concomitant bilirubin elevations without an alternative explanation.

This could put atuzaginstat at risk of meeting Hy’s law, suggesting risk of fatal drug-induced liver injury, according to the FDA’s definition. In its defence, Cortexyme said the liver enzyme increases were not clinically significant, and that both patients with bilirubin increases recovered fully with no long-term effects.

The group reckons it can combat these issues with dose titration, but the path forward for atuzaginstat looks questionable.

Tau takedown

Elsewhere, Lilly has called it quits on anti-tau antibodies after zagotenemab fell short in its phase 2 study.

The group now reckons this is the wrong approach, given that the relevant tau is mostly inside cells, where antibodies cannot reach. If true this would be bad news for the various groups developing anti-tau antibodies, listed in the table below.

But this is only the latest setback in this space, with the likes of Biogen’s gosuranemab and Abbvie’s ABBV-8E12 also failing this year. And a recent success with AC Immune and Roche’s semorinemab was far from emphatic.

Still, Lilly is not out of tau completely, and yesterday highlighted an oral O-GlcNAcase inhibitor, LY3372689, which recently went into phase 2. 

The table in this story has been updated to include Asceneuron's ASN51.