Total tau dropped by up to 160 picograms/ml in EMERGE, though curiously not on the high dose in ENGAGE; these changes missed statistical significance. “The CSF p-tau data are quite encouraging, supporting the idea that reducing amyloid has a beneficial effect on downstream neurodegeneration,” Aisen noted. Other biomarker researchers called the numbers hard to evaluate without baseline levels given. Several commentators told Alzforum they would like to see spaghetti plots of how individuals fared on CSF tau, amyloid PET, and CDR-SB, saying that this way of showing the data would help make sense of this heterogeneous dataset.

• They were dismayed at having to stop, and are now pleased to be able to invite the participants back.
• “This confirms the importance of Aβ in disease pathogenesis,” said David Holtzman at Washington University in St. Louis (full comment below).
• They complained that the sponsor and FDA presenters “talked down the clock” and did not adequately answer their questions.
• If aducanumab were to be approved, it could transform the practice of Alzheimer’s medicine within a year or two, Sabbagh predicted.
• Developed originally by Lars Lannfelt of Sweden’s Uppsala University, lecanemab, aka BAN2401, had shown a cognitive benefit in Phase 2 as well.

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This difference was because ApoE4 carriers are more susceptible to ARIA, the fluid retention in the brain that accompanies treatment with many amyloid-removing therapies. In the high-dose group, ApoE4 carriers initially titrated up to 6 mg/kg; noncarriers to 10 mg/kg. However, in March 2017, about 18 months into the trial, the protocol was amended to allow ApoE4 carriers to titrate up to 10 mg/kg, as well.

Other talks at CTAD touted the consistency of lecanemab Phase 2 data, and added more evidence that it curbs tau pathology. Analysis of the more recent, larger dataset suggested that duration of treatment at the high dose was the key factor. In addition, Budd Haeberlein said, interruption of treatment played a role. In EMERGE, participants on the low dose had a trend of declining more slowly than those on placebo on the primary outcome, the CDR Sum of Boxes, but this was well shy of statistical significance. Participants on the high dose declined 23 percent more slowly than those on placebo, with a significant p value of 0.01. The high-dose group declined about a quarter less on the ADAS-Cog13, a cognitive battery, and up to 46 percent more slowly on the ADCS Activities of Daily Living, a caregiver assessment.

• The low dose did not outperform placebo, hence findings on these secondary outcomes cannot be considered significant, Massie said.
• The panel urged that anyone who has cerebral amyloid angiopathy, a blood clotting disorder, or takes anticoagulants should not be on aducanumab, because they are already at higher risk for the brain swelling and microhemorrhages known as ARIA.
• “We learned from our early studies with low doses of gantenerumab that exposure is what drives amyloid lowering as well as clinical signals,” Rachelle Doody of Roche wrote to Alzforum (full comment below).

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Each day includes three meals and three snacks and contains a balance of carbohydrates, fats, and protein. The meal plan also includes plenty of fiber, vitamins, minerals, and antioxidants from whole grains, vegetables, fruits, and legumes. You can swap out similar menu items for others, aducanumab price in india but make sure to use the same cooking method.

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Others said they are awaiting the full dataset to examine issues such as subgroup effects, especially for APOE4 carriers, potential unblinding due to ARIA, and safety data. As of this writing, about 100 patients across the U.S. have begun to get the treatment (STAT news). Marwan Sabbagh at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas told Alzforum that he has prescribed aducanumab for some patients, but has had to scramble to find places where they can get the infusions. “I’ve gotten names of doctors around the country who are infusing, but it’s been piecemeal,” Sabbagh noted.

Importantly, cognitive decline is expected to continue even if aducanumab works, and notoriously variable rates of decline in AD will make it challenging to determine if aducanumab is slowing it down, the panel acknowledged. No guidelines are in place to determine if any such slowing exceeds a minimum clinically important difference (Liu et al., 2021). Many researchers have questioned whether the small benefit seen in the aducanumab trials would be detectable to patients. Caveats Raised for Positive Findings The FDA’s advisory committee meeting cast doubt on this analysis. In their comments and questions, panelists repeatedly referred to the review from the FDA biostatistician, Tristan Massie (narrated slide presentation 3, available via FDA website).

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To address this, Uhlmann and colleagues profiled the types of Aβ assemblies each antibody bound. Because the structures of Aβ seeds have never been determined, the researchers relied on size fractionation. They found that in the brains of 26-month-old APP23 mice, which have rampant amyloid plaques, solanezumab, gantenerumab, and crenezumab recognized a variety of species, including smaller oligomers and monomers. In contrast, aducanumab and donanemab specifically recognized high-molecular-weight species.

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.

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).

On July 27, at this year’s Alzheimer’s Association International Conference from July 26–30 in Denver, Cummings and a panel of experts outlined the AUR and addressed questions and concerns in a series of three panel discussions. Berry next addressed the robustness of the findings, analyzing the three cognitive endpoints—ADCOMS, ADAS-Cog14, and CDR-SB—using six different statistical methods. No matter the method or the end point, the findings were consistent, he found. In every analysis, the two highest doses of lecanemab, 10 mg/kg monthly and 10 mg/kg biweekly, were superior to placebo in a dose-dependent fashion.

Biomarker endpoints will include amyloid-PET, tau-PET and CSF in a subset of participants, and volumetric MRI in all. As of November 2021, the study had enrolled 1,770 participants (Nov 2021 conference news). This is not the first time scientists have discovered that different antibodies can prevent Aβ fibrillization in different ways.

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The trial first read out at 12 months, but at that time failed to meet its prespecified endpoint of dramatically slowed decline on the ADCOMS composite (Dec 2017 news). Lecanemab may soon become widely available; Eisai/Biogen have begun submitting data to the Food and Drug Administration to support its accelerated approval (Oct 2021 news). In the meantime, studies are ongoing, with this passive immunotherapy now in a trio of trials.

The different binding properties of each antibody may influence their clinical effects, Lannfelt noted. For example, ARIA, a type of brain edema caused by immunotherapy, may arise through antibodies binding to fibrils deposited along blood vessel walls, causing inflammation and leakiness of these vessels, he suggested. If so, lecanemab’s lower affinity for fibrils may explain its lower rate of ARIA compared to other antibodies, with an incidence of about 10 percent rather than 35. Sandrock touched on the issue himself, saying that in AD trials, the clinical benefit may lag behind amyloid removal. In PRIME, amyloid removal became significant at six months but a clinical signal did not appear until 12 months, he noted.