Another One Bites the Dust: J&J Kills Early Alzheimer’s Program

Johnson & Johnson’s Janssen division has decided to end its trials of atabacestat, a BACE inhibitor, for Alzheimer’s disease.

The company indicates that it is shuttering the program because of safety issues, rather than any question about the drug’s efficacy. Patients in the EARLY Phase IIb/III clinical trial with preclinical Alzheimer’s disease, as well as a Phase II long-term safety trial, had elevated liver enzymes. EARLY launched in 2015 and was scheduled to wrap in 2024.

The company stated that “the benefit-risk ratio is no longer favorable to continue development of atabacestat for people who have late-onset preclinical stage Alzheimer’s disease.”

Despite the setback, the company indicates it “continues to maintain a strong commitment to discovery and developing new treatments for this devastating disease.”

BACE1 is an enzyme involved in creating beta-amyloid, which forms and causes plaques in Alzheimer’s patients. It is the predominant theory about the damage caused by Alzheimer’s disease, although a very long string of drug failures has cast doubts on the theory.

Other companies have had failures with BACE inhibitors as well, including Eli Lilly for two of its drugs, including LY2886721, which also showed liver toxicity, and Roche’s RG7129.

In February, Merck & Co.’s verubecestat (MK-8931), being evaluated in the APECS Phase III trial, was halted after an external Data Monitoring Committee (eDMC) recommended ending it after an interim safety analysis. The committee indicated that the likelihood of benefits didn’t outweigh the risks.

Although many companies are still continuing work on developing treatments for Alzheimer’s, notably Biogen, it seems that a month doesn’t go by without news of a failed Alzheimer’s clinical trial.

Tim Anderson, an analyst with Sanford C. Bernstein & Co. was reported by Bloomberg to say, “Because the risk of failure is high, we have not been willing to give these compounds the benefit of the doubt. Neuroscience drug development is tricky, and Alzheimer’s disease is the trickiest of them all, it seems.”

FierceBiotech reports that Bernstein analysts queried Janssen’s head of research and development Roger Perlmutter last month on its Alzheimer’s portfolio, and he said the company was going to continue with Alzheimer’s work and BACE inhibitors.

“According to the analysts,” FierceBiotech writes, “Perlmutter said one of the imperatives is to gain a better understanding of the natural disease process so as to identify people early on who are at risk of developing Alzheimer’s. It’s also important to understand the nature of that progression and subset people into those that will progress early versus late, and then direct the right therapies to the right patients.”

Recent efforts, such as the relevant Janssen trials, have focused on patients with earlier and earlier stages of the disease. At least part of the rationale is to try and prevent the accumulation of beta-amyloid before it causes damage to the brain. Although many of the drugs developed to stop the development of beta-amyloid, and even clear it from the brain, are effective in doing so, study after study has shown that it doesn’t reverse the damage to cognition and memory. As a result, companies are working with patients with far earlier signs of the disease. So far, no luck.