Potential Alzheimer’s Drug Shows Promise, But Falls Short

Two drug companies for weeks have teased the results of a promising new drug to treat Alzheimer’s disease.

In early July, Biogen, a Boston-based biotech, and Eisai, a Tokyo-based pharmaceutical company, announced the upcoming release of “positive topline results” for a large clinical trial of a drug designed to remove amyloid plaque build-up in the brain, a potential cause of Alzheimer’s disease.

The much-anticipated results of a Phase 2 clinical trial for an Alzheimer’s disease drug were released last week.

For investors, that teaser proved promising enough: the day before the full results were released Biogen stock hit a three-year high. For patients and industry experts, the news sparked hope that a treatment had at last passed an elusive clinical trial benchmark. Currently, there is no effective treatment for Alzheimer’s disease, which afflicts nearly 5.7 million Americans, with cases expected to triple by 2050.

But last week, when the full results were released at the Alzheimer’s Association International Conference in Chicago, high hopes turned into cautious optimism. Several nuances in the study’s design have raised some questions about the findings’ significance.

Rudy Tanzi, a geneticist and Alzheimer’s expert at Massachusetts General Hospital and Harvard Medical School, was at the presentation when the results were presented.

“Did we see in the actual presentation what the top-line results promised? No. Did we see failure? No,” Tanzi said. “Did we see enough success to merit a Phase 3. Yes.”

According to the study, 856 patients with early Alzheimer’s disease were given the drug, known as BAN2401, in one of five doses over an 18-month period. In one group, 80% of patients who received BAN2401 showed sizable reductions in amyloid plaque build-up on the brain. Those patients also performed 30% better on cognitive tests than patients receiving a placebo. Those two findings, at first glance, seem promising proof that removing amyloids in the brain helps improve mental functioning.

“I’ve been in the field for 18 years, and I’m very encouraged by these results,” said Samantha Budd Haeberlein, vice president of Alzheimer’s late stage clinical development at Biogen. “It also gives us confidence that, in Alzheimer’s disease and in the amyloid pathway, we’re on the right track.”

Cautious Optimism

The results came from a large Phase 2 trial, which is conducted to gauge the safety and efficacy of a drug before a larger, more expensive Phase 3 trial. Among drugs intended to treat Alzheimer’s, no other large-scale Phase 2 trial has shown that drops in amyloids lead to significant improvements in mental functioning.

“I think it’s equivocal,” Tanzi said of the results. “I think they have enough to do a Phase 3. I don’t think it’s enough to get approval at this point.”

While some argue that the drug is aimed at the wrong target–that amyloids are just a sign, not the root cause, of Alzheimer’s disease–Tanzi believes the drug is based on a reasonable hypothesis. Rather, his concern is that several of the study’s design features make it impossible to draw concrete conclusions about the drug’s efficacy.

“Believe me, there’s no one who wants an amyloid therapy to work more than me,” he said. Tanzi was the first to clone the amyloid gene and named the amyloid precursor protein in 1987. “It kills me to say all of this, but you got to say what it is, right?”

Wall Street was not impressed with the less-than-anticipated findings, either. By close of market on Thursday, shares of Biogen had fallen 12%.

The drug only outperformed placebo in one of the five doses—the highest dose, which was 10 mg given biweekly to 161 patients. In that group, only 30% of patients had a gene called APOE4, which triples one’s risk of developing Alzheimer’s disease. Meanwhile, 71% of patients in the placebo group had the APOE4 gene. Biogen and Eisai say that split is the result of a recommendation (but not requirement) made in 2014 by a regulatory agency in another country. The other dose groups had similar percentages of APOE4 patients to the placebo group.

Because the cognitive functioning of patients with the gene tends to decline faster, Tanzi said, the positive result at the highest dose—which had the fewest patients with APOE4—raises doubts that the benefits can be attributed solely to BAN2401.

The silver lining, he added, is that the second highest dose group—10 mg, which was given monthly to 253 patients—had a more equal APOE4 distribution and also saw positive cognitive improvement. Though the finding was not statistically significant, Tanzi thinks the trend is promising.

Neither Biogen or Eisai have announced whether they plan to conduct a Phase 3 trial, which would take years to complete.

Haeberlein says that Biogen and Eisai will take the data to regulators, like the FDA, for guidance on the next steps. Early approval is “theoretically one outcome,” she said. “But there are other outcomes of an additional trial needed and what might that trial needs to look like.”