Conference Coverage

New BACE1 study launches in the shadow of verubecestat’s demise

Generation 2 targets cognitively normal ApoE4 carriers



– Undeterred by a failed BACE inhibitor study with worrisome adverse events, an ambitious new clinical trial will investigate a different BACE-inhibiting molecule as an Alzheimer’s preventive in people at high genetic risk of Alzheimer’s disease.

The global Generation 2 trial intends to recruit about 3,300 cognitively normal subjects aged 60-75 years, who have either one or two copies of the apolipoprotein e4 (ApoE4) allele, said Pierre Tariot, MD, who announced the new study during the Clinical Trials on Alzheimer’s Disease 2017 meeting.

Dr. Anton Porsteinsson (left) and Dr. Pierre Tariot are hopeful that a new BACE1 inhibitor will prevent Alzheimer's in cognitively normal ApoE carriers.
Both homozygous and heterozygous subjects will be randomized to either placebo or a molecule investigators call CNP520. The oral drug inhibits the production of beta secretase 1, an enzyme that is important in trimming beta amyloid proteins into the neurotoxic forms that aggregate into amyloid brain plaques. Homozygous subjects must be amyloid-positive by PET imaging or cerebrospinal fluid. No amyloid testing is required for ApoE4 subjects.

The Alzheimer Preventive Initiative and industry partners Novartis and Amgen are sponsoring the trial, which is a sister study to Generation 1. Generation 1, now ongoing, targets cognitively normal ApoE4 subjects only. It is a four-armed trial, comparing placebo to both CNP520 and an active immunotherapy called CAD106. Together, the studies comprise the Generation Program.

Both trials are event-driven, and will run 5-8 years. Generation 2 has a dual primary endpoint – a successful trial will find either a delay in progression to mild cognitive impairment or dementia relative to placebo, or significant differences from baseline in cognitive change as measured by the Alzheimer’s Preclinical Composite Cognitive test, or both.

The study partners are enthusiastic about CNP520, which performed well in its safety and tolerability studies. In an interview, Dr. Tariot called the CNP520 “likely a best-in-class molecule.”

“The only adverse events we saw in the entire safety program were a few cases of itchy skin,” said Dr. Tariot, director of the Banner Alzheimer Institute in Phoenix. “One of the reasons we chose Novartis as a study partner is that this drug of theirs looked remarkably clean – so clean that when we were deciding what doses to look at, the decision related only to what degree of BACE inhibition we wanted, not safety.”

The drug seemed very well-tolerated at every dose tested (1 mg, 10 mg, 25 mg, and 75 mg). Generation 1 employs a 50-mg oral dose per day. Generation 2 will investigate both 50 mg and 15 mg.

Site investigators are solidly behind the choice, said Anton Porsteinsson, MD, a Generation investigator at the University of Rochester (N.Y.) Medical Center, despite the unveiling at CTAD of worrisome adverse events seen in Merck’s failed EPOCH trial.

“I am even more convinced now that BACE inhibitors are drugs that need to be used early and that are probably highly indicated for this population,” he said in an interview. Dr. Porsteinsson wasn’t overly disturbed by data that Merck released during the meeting on its BACE inhibitor, verubecestat. In February, the company pulled the plug on its EPOCH trial investigating verubecestat in patients with mild-moderate AD. An interim analysis determined that there was no chance of success with the molecule.

Despite the general disappointment of yet another rainy-day parade in late-stage AD drug trials, researchers who heard the EPOCH post-mortem during CTAD expressed considerable concern over the unexpected, wide-ranging, and serious adverse events the trial accumulated.

Although there were no cases of Amyloid-Related Imaging Abnormalities (ARIA), a number of adverse events occurred significantly more often in the active groups than the placebo group. These included rash, falls and injuries, insomnia, headache, anxiety, suicidal ideation, diarrhea, dizziness, and weight loss.

At least some of these were hinted at in the bench science that brought verubecestat to late-stage clinical development. BACE is important for proper muscle function, and some BACE-knockout mice displayed a decrease in muscle spindles, receptors that sense changes in the length of muscle fibers. Other peculiarities in the mice have included axon targeting errors, reduced myelination, memory impairment, neurochemical abnormalities, alterations in neurogenesis and astrogenesis, increased age-related neurodegeneration, reduced spine density, retinal pathology, endophenotypes of schizophrenia, and seizures.

But the verubecestat findings aren’t a show-stopper for the more target-specific CNP520, Dr. Porsteinsson said. Verubecestat inhibited both BACE1 and BACE2; CNP520, only BACE1. And Dr. Porsteinsson, like most researchers, believes that preventing the accumulation of neurotoxic AB species will probably be much more effective clinically than trying to dissolve large stubborn brain plaques, which have already wreaked cognitive havoc.

In EPOCH, “even in people with advanced disease and a high load of insoluble plaques; they saw an 80% reduction in the production of AB and a 4% decrease in plaque burden. To me that signals this is not the class to use in moderate patients, or even mild, but in these very early stages where you don’t have full saturation, it might just be perfect,” he said.

“Do the side effects give me pause? Obviously and maybe mostly because we don’t know exactly what the driver was. But what we do is keep a close eye on everyone, maybe do extra safety monitoring, Most importantly, we picked a drug that shows less issues with any of these problems.”

Cognitively normal ApoE4 carriers – especially homozygotes – are an extremely important population to study, both in terms of clinical and scientific need. The gene is the single largest genetic risk factor for Alzheimer’s; those who carry two copies are 60% more likely than the general population to develop Alzheimer’s.

“These people truly need an effective intervention,” said Dr. Porsteinsson. “At the preclinical stage, they don’t truly have a disease yet; they are living their lives unimpaired. But something is percolating, and the results won’t be good. Even early on, there are fairly significant changes going on in the brain: a buildup of amyloid and tau, excess oxidative damage, inflammation. And if you don’t deal with it early on, it’s like trying to cure cancer once it’s metastasized.”

In the larger scientific picture, success in a primary prevention trial would finally put to rest questions about the amyloid cascade hypothesis and explain the long string of anti-amyloid drug trial failures, all of which were targeted at people with more advanced disease.

To enroll the entire cohort, Generation 2 will need to screen about 30,000 people. This sounds like a daunting task, but a new digital platform makes it eminently do-able, Dr. Tariot said. Both Generation studies are enrolling online. The consumer-friendly website offers detailed information about Alzheimer’s disease in general, ApoE4 risk, the studies’ structure, and the investigational medications. Most importantly, Dr. Tariot said, the website has a direct link to GeneMatch. Hosted by Banner Alzheimer Institute, GeneMatch prescreens potential trial participants (U.S. residents aged 55-75 years) by taking baseline demographic information, and mailing out free, simple-to-use cheek swab kits for genetic analysis. The program then stores and sorts the information, matching volunteers with appropriate trials according to location, age, interest, and genetic status. People don’t necessarily learn their ApoE4 status, unless they are recruited into a genetics-driven trial.

Launched 2 years ago, GeneMatch has already accrued more than 280,000 volunteers – a pretty remarkable achievement in itself, Dr. Tariot said. “People are very motivated to help find a cure for Alzheimer’s. Many of them have a family member who has the disease. Others are concerned about themselves, and many people just want to be part of something important.”

Dr. Porsteinsson agreed, relaying a startling interaction he had with a patient, who found out he was not qualified for a Generation study, meaning, of course, that he was ApoE4 negative.

“He told me he was actually kind of disappointed, because he believes so much in this study, and wanted to be part of doing something important for humanity,” Dr. Porsteinsson said. “Of course, I didn’t let him off the hook. I directed him to a bunch of other studies he was qualified for. We need everyone’s help to solve this.”

Both Dr. Tariot and Dr. Porsteinsson have reported financial relationships with numerous pharmaceutical companies.

* This story was updated 11/7/17.

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