Many researchers believe anti-amyloid antibodies may offer the most benefit in a preventative paradigm, before plaques have triggered extensive downstream damage. Now Roche will test this idea in a Phase 3 secondary prevention trial of its anti-amyloid antibody gantenerumab. At the 16th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 15-20 in Barcelona, Spain, and virtually, Roche’s Szofia Bullain offered an overview. Dubbed Skyline, the trial will enroll 1,200 cognitively healthy, amyloid-positive participants in 17 countries. Researchers will look for delayed decline on a sensitive cognitive composite after four years on drug or placebo. “This trial will tell us if going quite early with this molecule can delay or avert symptoms,” Rachelle Doody at Roche told Alzforum.
- Skyline trial will enroll 1,200 cognitively healthy, amyloid-positive older adults.
- Participants will be able to self-administer at home on a weekly or biweekly basis.
- Primary outcome will be change on PACC5 cognitive composite over four years.
Others hailed the news. “I am very excited that with the launch of Skyline, a third promising anti-amyloid immunotherapeutic is being tested in the presymptomatic (preclinical) sporadic AD population,” Paul Aisen at the University of Southern California, San Diego, wrote to Alzforum. He collaborates on the trial.
Jeffrey Cummings at the University of Nevada, Las Vegas, noted broader implications. “Initiation of the Skyline trial suggests that industry sponsors will continue to investigate treatment of Alzheimer’s disease despite the reimbursement uncertainties created by the Coverage with Evidence Development (CED) requirement proposed by the Centers for Medicare and Medicaid Services,” he wrote (full comments below).
So far, most trials of anti-amyloid antibodies have enrolled people with early symptomatic AD. Secondary prevention studies are harder to run, because it is difficult to recruit participants and detect changes in people who have no overt symptoms of the disease. To design Skyline, Roche scientists teamed up with researchers at Massachusetts General Hospital in Boston, the Banner Alzheimer’s Institute’s Alzheimer’s Prevention Initiative in Phoenix, and the University of Southern California Alzheimer’s Therapeutic Research Institute in San Diego. These groups have designed previous secondary prevention trials in sporadic AD, including A4, AHEAD 3-45, and API’s Generation program, and were able to offer advice on how to recruit and screen presymptomatic candidates and choose outcome measures.
Skyline will enroll people from 60 to 80 years of age who are amyloid positive by either PET scan or cerebrospinal fluid Aβ. Sites have the option to prescreen potential participants by plasma p-tau181 and plasma ApoE protein isoform levels to identify those likely to be amyloid-negative, cutting down on screen failures. Bullain expects this step to raise the amyloid positivity at screening from 15 to 30 percent. Audience members at AD/PD suggested recruits should be PET positive for tangles as well as amyloid, to ensure they are likely to progress to symptoms within the time frame of the trial.
Roche aims to recruit a diverse population. Since 2019, an external diversity council has advised Roche on outreach to underrepresented groups. Strategies can include providing practical resources, such as transport to medical appointments, Doody noted.
Half the participants will receive placebo and half gantenerumab, but dosing will be more frequent than in the Phase 3 GRADUATE studies, in which participants received two subcutaneous injections of 510 mg per month. Because some people find it easier to take medication on a weekly schedule, Roche has been testing a weekly dosing regimen in its ongoing Graduation program of newly recruited people with prodromal to mild AD.
In Skyline, participants will have the option to take 510 mg biweekly or 255 mg weekly. In either case, injections can be administered at home by the participants themselves or a family member, lessening travel time and the overall burden of trial participation. Most amyloid immunotherapies are administered by intravenous infusion in the clinic, but that is starting to change, with other programs testing subcutaneous administration as well. “We view subcutaneous administration as a major public health benefit,” Doody said.
If participants on placebo develop symptoms during the trial, they will be switched to active therapy, effectively making the trial an open-label extension for people in the prodromal phase of the disease. This assumes gantenerumab demonstrates efficacy in the Phase 3 prodromal trials reading out later this year. Patients already on drug who develop symptoms will undergo a mock titration to maintain the study blind up to that point, Bullain said.
Pierre Tariot at Banner praised the gantenerumab flexible dosing schedule, and other innovative aspects of the trial design. “I believe these features will appeal to a large number of people around the globe,” he noted (full comment below).
The primary outcome measure will be change on the PACC5 cognitive composite, which detects subtle memory deficits in preclinical AD (Jun 2014 news). As a secondary outcome, researchers will assess the time it takes participants to progress to cognitive impairment, defined as a CDR greater than zero. Doody considers both measures important. The PACC5 may be more sensitive because it assesses change along a continuum, while progression to symptomatic disease is more clinically meaningful. The Food and Drug Administration has said it would consider slowing of cognitive decline alone as the basis for a drug approval, though the agency did not specify particular tests that would qualify (Nov 2018 news).
Other secondary outcomes will include functional measures such as the Activities of Daily Living and the Cognitive Function Instrument. For biomarkers, all participants will undergo volumetric MRI and donate blood, which will be assessed for Aβ42, Aβ40, p-tau181, and the neuronal injury marker NfL. A subset of participants will undergo lumbar puncture and amyloid and tau PET.
Cummings welcomed the inclusion of blood biomarkers, which he noted would help researchers learn which of them changes first as a person develops AD. “[That] is encouraging as a means of identifying individuals who would benefit from prevention therapy,” Cummings wrote.
Gantenerumab was previously tested in the Dominantly Inherited Alzheimer Network secondary prevention study, where, in addition to mopping up plaques, it dropped CSF p-tau181 and total tau and slowed the rise in CSF NfL (Jun 2021 news). “That increased our confidence that there is a biologically relevant outcome from lowering amyloid,” Doody noted.
Gantenerumab continues to be evaluated in an open-label extension of that study, and has also been chosen for DIAN’s forthcoming primary prevention study in familial AD mutation carriers who do not yet have amyloid (Dec 2021 press release). The only previous AD primary prevention trial was API’s Colombian study, which is evaluating Roche and Genentech’s crenezumab in presenilin mutation carriers (Aug 2019 news). That trial is expected to read out this year, as are gantenerumab’s GRADUATE studies.
Doody stressed that Roche is committed to the AD field and increasing its investment every year. “That needs to be understood, so people don’t hang their hopes on the outcome of one study,” she said.
Meanwhile, several other anti-amyloid antibodies are in secondary prevention studies, including lecanemab in AHEAD3-45 and donanemab in TRAILBLAZER 3. Tariot noted that each of these trials is important, as the antibodies have different mechanisms of action and the trials test different treatment regimens. “Together, these trials represent a huge investment, for which I give thanks: We should not put all of our eggs in one basket,” Tariot said. “The stakes are enormous. ‘Merely’ delaying the onset of AD symptoms would cut the prevalence of the symptomatic phase of the disease in half.”—Madolyn Bowman Rogers
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