In Phase 3 trials, Roche's experimental Alzheimer’s drug gantenerumab has failed to meet its objectives for slowing cognitive decline.
Most Alzheimer’s treatments on the market today help manage symptoms, like memory loss — but they don’t get at the root cause. Roche hoped their monoclonal antibody drug, gantenerumab, would prove to be disease-modifying — meaning that it could halt or slow the progression of the disease itself, not just address the symptoms. Unfortunately, today Roche announced that gantenerumab has failed to meet trial objectives in a pair of large clinical studies. Despite promising early results, ultimately the drug didn’t prove to slow clinical decline in people in early stages of Alzheimer’s disease.
This comes on the heels of Roche’s crenezumab for Alzheimer’s failing in Phase 2 trials this July.
From ‘breakthrough’ to breakdown
In October of 2021, the FDA issued gantenerumab its breakthrough status designation to help expedite the evaluation process. Breakthrough status doesn’t guarantee an approval.
“We don’t understand the pathophysiology of Alzheimer’s disease, and we’re targeting something that [there is] huge evidence is linked to Alzheimer’s, but the causative role that it plays, we don’t know,” Roche’s pharma chief Bill Anderson told Fierce Biotech at the time of the drug’s breakthrough status designation.
But they did have a theory: the amyloid hypothesis — the idea that Alzheimer’s is caused by clumps of proteins known as beta-amyloid. Gantenerumab is a lab-made antibody protein designed to target these toxic plaques in the brain, slowing or reversing plaque build-up to theoretically improve memory and cognition.
Other -mab drugs for Alzheimer’s — including the one so far that has landed FDA approval, aducanumab (brand name Aduhelm) — take this same approach. After attaching to amyloid proteins clumped in the brain, the antibodies in gantenerumab draw in immune cells that attack and pare back the plaques. Aduhelm is administered via periodic spinal injections (that is, if you can find it). Gantenerumab, on the other hand, was designed to be more accessible, administered via injections under the skin, which can be done at home.
(In February 2024, Biogen took Aduhelm off the market indefinitely.)
The people who got the Roche drug in each of the two trials showed rates of clinical decline at 8 percent and 6 percent lower, respectively, compared to the placebo. These percentages aren’t deemed statistically significant. Roche has yet to release the full study results.
Some experts have been skeptical of the Alzheimer’s amyloid hypothesis from the start, their skepticism fueled by research that indicates beta-amyloid aggregation in the brain could be a symptom of the disease, not the cause — even that it could be the brain’s attempt at a protective response. This camp wishes more funding would go to research into other potential causes, like viruses and bacteria.
Hope persists for Alzheimer’s anti-amyloids
Others aren’t ready to give up on beta-amyloid as a drug target.
“While this is discouraging news for the many patients and families living with Alzheimer’s, anti-amyloid therapies are just a starting point in new therapies for Alzheimer’s patients,” Alzheimer’s Drug Discovery Foundation Cofounder and Chief Science Officer Dr. Howard Fillit said in a statement. “If you’ve seen one anti-amyloid therapy, then you’ve seen one anti-amyloid therapy. The results we’ve seen from drugs in this class point to the urgent need to bring a range of amyloid and non-amyloid therapies to market to slow the course of Alzheimer’s disease.”
To Fillit’s point, Eisai and Biogen’s experimental antibody lecanemab recently showed an encouraging 27-percent reduction in cognitive decline in patients with Alzheimer’s — compared to gantenerumab’s 8 percent — according to early trial data released this fall.
Thus, advocates are hopeful the approach will yet prove out. “The drugs offer hope to millions of people worldwide who are currently living with Alzheimer’s without a therapy available that can alter the course of the disease,” advocacy organization Voices of Alzheimer’s said a statement.
“The lecanamab results were particularly striking given the failure of gantenerumab,” added VOA founding board member Jay Reinstein, who is living with early onset Alzheimer’s.
“It is important to evaluate each new treatment independently,” the Alzheimer’s Association said in a statement. “We know that current anti-amyloid approaches are not a cure, nor will they stop the disease on their own, but they are the first wave of effective treatments for Alzheimer’s, with more to come.”
What’s next for gantenerumab?
Roche isn’t giving up either. Rachelle Doody, global head of neurodegeneration at Roche, said in a statement: “We are committed to going after this disease, and we will continue to study molecules that target amyloid in different ways to different degrees, as well as other molecular targets.”
In the pipeline, Roche has an alternate version of gantenerumab they believe will be better able to cross the blood-brain barrier. It will be in development for a few more years.
UPDATE, Mon. November 14, 2022, 5:56 P.M. ET: This article was updated with quotes from representatives at Voices of Alzheimer’s and the Alzheimer’s Drug Discovery Foundation which were received after the initial publication.
UPDATE: 3 March 2024, 9:27 P.M. ET. In February 2024, Biogen took Aduhelm off the market, citing financial concerns. Although the drug did receive accelerated, conditional FDA approval for the treatment of early Alzheimer’s disease in 2021, it is no longer available to new patients. The company announced it would sunset trials in May 2024 and cease supplying the drug to current patients in November 2024.