Novel Alzheimer's Therapies Target APP, Tau, and ApoE4 in Early-Phase Trials
核心洞察
Mivelsiran, an siRNA targeting APP, demonstrates durable reduction of APP metabolites in CSF and is being evaluated for cerebral amyloid angiopathy (搜索) (CAA).
BIIB080, an antisense oligonucleotide, shows promising tau (搜索)-PET trajectories, slowing tau accumulation across Braak regions in Phase 1 trial participants.
LX1001, a gene therapy delivering ApoE2, increases CSF ApoE2 levels and stabilizes tau (搜索) deposition in ApoE4 (搜索) homozygotes with MCI or mild to moderate AD.
At the Clinical Trials in Alzheimer’s Disease (CTAD) conference in Madrid, researchers presented early-phase trial results for novel Alzheimer's therapies targeting amyloid precursor protein (APP), tau (搜索), and apolipoprotein E4 (ApoE4 (搜索)), alongside exploring the modulation of inflammation and metabolism. These approaches aim to address the limitations of current anti-amyloid monoclonal antibodies like lecanemab and donanemab.
Silencing APP Production with Mivelsiran
Mivelsiran, developed by Alnylam and Regeneron, is a small interfering RNA (siRNA) designed to degrade APP transcripts, reducing the production of Aβ42 and Aβ40. In a Phase 1 trial involving early-onset MCI or mild AD patients, intrathecal infusions of mivelsiran at 50 mg and 75 mg resulted in a sustained 30% reduction in CSF sAPPβ levels over 12 months. Six-month data showed a 27% and 40% reduction in Aβ40 and Aβ42, respectively, in the 75 mg group. According to Alnylam's Tim Mooney, the drug's durability stems from modifications to the siRNA backbone, allowing it to repeatedly silence mRNAs. Mivelsiran is also in Phase 2 development for cerebral amyloid angiopathy (搜索) (CAA), with the cAPPricorn-1 trial evaluating its impact on microbleeds and cerebrovascular signs in sporadic CAA patients, as explained by Jin-Moo Lee of Washington University, St. Louis. A separate cohort will include patients with Dutch-type CAA, a rare, familial form caused by the APP E693Q mutation.
Targeting Tau with Antisense Oligonucleotides
Biogen's antisense oligonucleotide BIIB080, which reduces tau (搜索) expression, demonstrated a reduction in tau tangles in a Phase 1 trial, as measured by tau-PET. Catherine Mummery presented individual participant data showing slowed tau accumulation across Braak regions. BIIB080 is currently in a fully enrolled Phase 2 trial. Eli Lilly has also initiated a Phase 1 trial with an siRNA targeting tau.
Gene Therapy to Boost ApoE2 Expression
Lexeo (搜索)’s LX1001, an adeno-associated virus (AAV) carrying the ApoE2 gene, aims to mitigate the effects of the ApoE4 (搜索) isoform by increasing expression of the protective ApoE2 isoform. Kim Johnson from Duke University presented interim findings from a Phase 1/2 trial in ApoE4 homozygous carriers with MCI or mild to moderate AD. The trial involved single ascending doses of LX1001, administered intrathecally. Twelve-month follow-up data from cohorts 1 to 3, and six-month data from cohort 4, indicated that LX1001 was largely safe and well-tolerated. CSF ApoE2 levels increased in a dose-dependent manner, while CSF ApoE4 remained stable at lower doses but appeared to rise in cohort 4. Tau (搜索)-PET scans suggested stabilization, and in some cases, a reduction in tau deposition. Gil Rabinovici of UCSF confirmed that tau-PET scans were corrected for volume loss. Complete data from the 52-week trial will be available soon, with a long-term extension planned to measure CSF ApoE2, CSF biomarkers, and amyloid- and tau-PET annually for four years. Ronald Crystal, Lexeo’s founder, presented a mouse study suggesting that adding a protective Christchurch mutation to the AAV-packaged ApoE2 might further enhance protection.
Modulating Inflammation and Metabolism
ImmunoBrain Checkpoint is conducting early dosing studies of an anti-PD-L1 antibody in people with early AD, based on preclinical work from Michal Schwartz’s lab at the Weizmann Institute of Science. The studies involve intravenous infusions of placebo or the antibody every quarter for 12 months. Suzanne Craft of Wake Forest School of Medicine reported biomarker data from a one-month trial of intranasal insulin alone or in combination with empagliflozin in 47 people with MCI or early AD. The trial used a new intranasal device, Apgar CPS, to deliver insulin more effectively. Exploratory findings included improved scores on the PACC5 and more intact white matter among people on intranasal insulin alone or with empa. Empagliflozin, with or without insulin, reduced CSF total tau (搜索). Intranasal insulin increased brain-derived neurotrophic factor and reduced the synapse-targeting complement protein C1qa in CSF, while empagliflozin reduced pro-inflammatory proteins including IL-6 and TNFα. Both treatments also affected plasma markers, with intranasal insulin reducing pro-inflammatory proteins and empagliflozin reducing levels of immune regulators NAMPT and SIRPa. These effects were strongest among those with higher baseline p-tau217.
Catherine Mummery envisions combination therapies targeting multiple mechanisms contributing to AD, deployed at different stages of the disease, guided by biomarkers. She leads the U.K.’s Dementia Translational Research Collaboration (D-TRC), a network of clinical trial sites across the U.K. for Phase 1 and 2 trials of innovative therapies, including gene therapies.