The trial will run for two years, with the primary endpoint being change in tau PET, and a secondary endpoint of CSF p-tau217. If these biomarkers are positive, the trial will run for two more years to assess cognitive change. The cognitive benefit emerged at the final 78-week time point, and only in the high-dose group, Massie noted. Because only a single time point showed a change from placebo, the data cannot prove that the treatment slows disease progression, he said. Furthermore, the analysis plan specified that secondary outcomes were only meaningful if the low dose outperformed placebo. The low dose did not outperform placebo, hence findings on these secondary outcomes cannot be considered significant, Massie said.
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The Biogen application further argued that positive clinical data from the Phase 1b PRIME study could be considered supportive for approval. The study was not powered to detect cognitive benefits, and leading trialists have previously noted issues with double blinding in aducanumab price in india dose-escalation trials (Q&A in Nov 2015 conference news). BIIB037 is a high-affinity, fully human IgG1 monoclonal antibody against a conformational epitope found on Aβ. It was originally derived by the biotech company Neurimmune in Schlieren, Switzerland, from healthy, aged donors who were cognitively normal.
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Gantenerumab’s Phase 3 program, called GRADUATE, is the most advanced of the three investigational antibodies in that its two trials are scheduled to read out in 2022 (May 2019 conference news). However, gantenerumab’s Phase 2 trials, which used a much lower dose, showed no cognitive benefit. It is unclear if Roche will apply for accelerated approval based on these data, or await Phase 3 results. Plasma Phospho-Tau Strengthens the Case Eisai’s Chad Swanson added data from the open-label extension of this Phase 2 trial.
CTAD speakers gave updates on screening improvements in the Phase 3 Clarity trial and the AHEAD 3-45 prevention study, which enrolls cognitively healthy people with amyloid plaques. Lecanemab has also been selected for the DIAN-TU Tau Next Generation trial, which enrolls people with an autosomal-dominant AD mutation. Tau NexGen will be the first trial to test combined amyloid and tau immunotherapies.
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Aducanumab’s path to market became fraught when its Phase 3 trials were stopped early for futility before the drug was suddenly resurrected (Mar 2019 news; Oct 2019 news). The U.S. Food and Drug Administration greenlit aducanumab under its accelerated approval pathway after its advisory committee had rejected the drug; regulators in other countries rejected it (Nov 2020 community news; Jun 2021 news). Overall, 41 percent of people taking the highest dose developed ARIA, compared to 10 percent of controls. However, 1 percent of participants experienced serious side effects, i.e., those requiring hospitalization or causing long-lasting impairment. Some of these data were previously reported at the 2021 Alzheimer’s Association International Conference (Aug 2021 conference news).
- Notably, ARIA-E was much more common in APOE4 carriers, with an incidence of 42 percent, compared to 20 percent in noncarriers.
- Later, some participants are switched to placebo, and worsening then indicates there was a drug benefit.
- At AAIC, researchers said the limited access is likely to deepen racial and geographic inequities in healthcare.
- Meanwhile, Biogen is still facing headwinds in its effort to roll out aducanumab, trade name Aduhelm.
Budd Haeberlein noted that these two measures are more sensitive indicators of change than the CDR and MMSE. Analysts on the investor call questioned why the low-dose group appeared to reap more benefit than the high-dose group in this study. Budd Haeberlein replied that the high-dose group had more interruptions due to ARIA and also more dose changes due to the protocol amendments, making dosing less consistent for these participants. On the FDA website, public comments submitted prior to and around the time of the meeting ran two to one against approval. Massie determined that many of the findings in PRIME indeed were discordant with the Phase 3 trials. For example, in PRIME, APOE4 carriers fared worse than noncarriers, whereas in EMERGE they fared better.
- Because carriers are more prone to ARIA, the initial protocol called for them to titrate to a maximum of 6 mg/kg aducanumab, but this was revised in protocol amendment 4 to allow carriers to reach 10 mg/kg.
- Biogen had been planning an early stage trial but canceled it in 2019, to the chagrin of site leaders at the time.
- Massie’s analysis also focused on potential effects of unblinding.
- It did not recognize monomers or oligomers, and bound protofibrils transiently, with a fast on and off rate.
Aducanumab Still Needs to Prove Itself, Researchers Say
They have far too few dementia specialists, neuropsychologists, and neuroradiologists with the requisite expertise, and insurance coverage remains up in the air. “The resources necessary to provide treatment with anti-Aβ antibodies to the right patients with the necessary safety precautions are woefully inadequate,” he wrote to Alzforum (full comment below). Meanwhile, Biogen is still facing headwinds in its effort to roll out aducanumab, trade name Aduhelm.
If lecanemab mostly targets protofibrils, how does it clear fibrillar plaque? Lannfelt believes the antibody shifts the equilibrium in the brain by depleting soluble species. This would cause more Aβ to solubilize off plaques, dissolving these deposits, he suggested.
In September, researchers from Lund University, Sweden, reported that solanezumab, bapineuzumab, gantenerumab, and aducanumab, interfered with different steps of the aggregation process (Sept 2020 news). Aducanumab was better able to prevent a process called secondary nucleation, which is how many oligomers or seeds are formed. Jucker and colleagues believe that aducanumab also binds to seeds that form from primary nucleation, which is a much rarer event. In fact, they were able to neutralize seeds that had formed before any plaques were detectable by histology.
At CTAD, Donald Berry of the University of Texas MD Anderson Cancer Center in Houston put these findings into context. Berry’s consulting group designs Bayesian trials, including the lecanemab trial. He noted that the goal of the 12-month endpoint was to show “super-superiority” over placebo, defined as an 80 percent probability that lecanemab would slow decline by 25 percent or more. At 12 months, lecanemab fell short of this, with a 64 percent probability of being super-superior to placebo. However, at this early point in time lecanemab was 98 percent likely to be superior to placebo, indicating there was a genuine drug effect.
Adieu to Aduhelm: Biogen Stops Marketing Antibody
Swanson updated the CTAD audience on the Phase 3 Clarity trial, which now has 1,795 participants. Demographics are similar to the Phase 2 trial, except the participants are more diverse. Phase 2 was 90 percent Caucasian, whereas Clarity’s population is 17 percent Asian, 13 percent Hispanic, and 3 percent black (Nov 2020 conference news). Christopher van Dyck of Yale University in New Haven, Connecticut, agreed that plasma biomarkers need further validation before they can be used to predict clinical outcomes. Nonetheless he was impressed with the lecanemab data, noting that the cognitive benefit maintained off drug strongly suggests a disease-modifying effect.
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Centers for Medicare and Medicaid Services (CMS) issued a national coverage decision restricting Aduhelm coverage to clinical trials (see Apr 2022 news; Feb 2022 news; Jan 2022 news and commentary). Soon after, Biogen withdrew its marketing application before the EMA (press release) and announced cutbacks in its Aduhelm marketing efforts but a continuation of some ongoing Aduhelm clinical studies (May 2022 news). On May 20, the company terminated the ICARE-AD real-world use study. Also at AAIC, an observational study to obtain real-world effectiveness and safety measures was introduced. Called ICARE-AD, the study will follow 6,000 people on Aduhelm for up to five years, aiming for at least 1,000 African-American and Latino participants.
The lack of effect in noncarriers, who on the whole received more doses at the maximum 10 mg/kg, suggests either the treatment does not work for them, or the dosing issue was less critical than Biogen claimed, Massie said. That the APOE4 subgroup who had the greatest response to the drug also had the most unblinding raises the specter that this could have been a placebo effect. In a question-and-answer session, Craig Mallinckrodt of Biogen disagreed with Massie’s conclusion, saying the company’s own analysis found the differences in placebo decline to have had a minimal effect. The discussion was cut short for time, and the panelists remained unconvinced. Biogen has thrown in the towel on its controversial anti-amyloid antibody aducanumab.