An experimental Alzheimer’s disease medicine from Roche failed two large Phase 3 clinical trials, a major setback to the Swiss company’s yearslong effort to prove the drug might slow the progression of the disease.
Study results showed the drug, called gantenerumab, didn’t perform meaningfully better than a placebo in the two studies, known as GRADUATE I and II. Treatment led to only a 6% slowing of Alzheimer’s symptoms versus placebo in one study and 8% in the other. Neither of those results, obtained after 27 months with a commonly used ratings scale, were statistically significant.
Treatment was associated with higher rates of an imaging abnormality that’s often observed with drugs like gantenerumab and can involve swelling or small bleeds in the brain. Roche said about 25% of all patients who received gantenerumab had that abnormality and evidence of swelling. The “vast majority” of cases were not symptomatic, however, and “very few” led patients to drop out of testing, it said in a statement.
Roche didn’t provide detailed data from the studies. The results will be presented at a medical meeting on Nov. 30.
“While the GRADUATE results are not what we hoped, we are proud to have delivered a high quality, clear and comprehensive Alzheimer’s dataset to the field, and we look forward to sharing our learnings with the community as we continue to search for new treatments for this complex disease,” said Roche chief medical officer Levi Garraway, in the statement.
Roche shares fell about 4% on the Swiss stock exchange.
The findings are the latest negative result for gantenerumab, a drug Roche has spent years developing in the hopes that it might effectively treat Alzheimer’s.
Like several other Alzheimer’s medicines in clinical development, gantenerumab is meant to eliminate the toxic buildup of a protein called amyloid in the brain that research has long pointed to as the disease’s possible cause. Most amyloid-busting drugs have failed in clinical testing. But research has been reinvigorated over the past few years by the controversial approval of Biogen and Eisai’s Aduhelm and, more recently, the surprise Phase 3 success of their next Alzheimer’s drug lecanemab. Lecanemab’s results, in particular, raised hopes that other drugs like it, among them gantenerumab, might succeed as well.
Roche’s drug, however, has a checkered past. In 2014, gantenerumab failed a Phase 3 study in patients with mild Alzheimer’s symptoms. Six years later, gantenerumab provided no benefit in a trial that evaluated it and an Eli Lilly drug called solanezumab as a preventive therapy in pre-symptomatic patients.
Roche had been hoping the GRADUATE studies might be different. The company tested a higher dose of gantenerumab than it had previously, and ran two simultaneous large trials in patients with mild cognitive impairment. The trials enrolled a combined 1,965 study participants across 30 countries and randomized them to receive either gantenerumab or a placebo every two weeks. The drug’s main goal was to show a benefit on the main symptom rating scale, known as CDR-SB, after 27 months.
In absolute terms, the difference in scores between gantenerumab and placebo recipients was 0.31 in one study and 0.19 in another, neither of which met the bar for statistical significance. Roche additionally said the level of amyloid lowering gantenerumab achieved was “lower than expected,” but didn’t provide details.
Roche has a newer version of gantenerumab meant to more easily get to the brain, a drug candidate that’s currently in Phase 2 testing. In the meantime, however, gantenerumab’s failure puts Roche’s research further behind Biogen, Eisai and Eli Lilly, which also has an Alzheimer’s drug under FDA review.
Lecanemab slowed clinical decline by 27% over an 18-month period in clinical testing, a statistically significant result that could lead to regulatory approval within the next few months. Gantenerumab’s failure to match Biogen and Eisai’s drug increases the likelihood that lecanemab “could be the leading anti-amyloid therapy,” wrote Stifel analyst Paul Matteis, on Monday. But the findings may also raise more questions about the merits of targeting amyloid with drugs given there are “so many more failures than successes,” he added.
Still, Matteis speculated that gantenerumab failed because it is less effective at clearing amyloid than the others.
“In order to have any benefit, one needs a potent drug that acts fast,” he wrote. “To us, this meant that even in the best case scenario, gantenerumab was likely to produce a smaller effect size and take longer to show any efficacy in general.”
Biogen shares surged 5% in pre-market trading Monday. Lilly shares climbed about 2%. Shares of MorphoSys, Roche’s development partner for gantenerumab, plummeted 30%.