Earlier this year, Eli Lilly announced it had met the primary endpoint in a Phase III study of donanemab, having slowed clinical decline in patients with mild to moderate Alzheimer’s disease (AD) by 35% compared to placebo. As against previously approved anti-amyloid therapies like lecanemab marketed as Leqembi, and Biogen’s aducanumab marketed as Aduhelm, donanemab showed higher levels of efficacy indicating another success for those researching AD.
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According to GlobalData’s Pharmaceutical Intelligence Centre, there are 402 ongoing and planned AD trials of 347 drugs. GlobalData is the parent company of Clinical Trials Arena. Are there any drugs with alternative methods of action in the pipeline that could also be effective treatments? Could pipeline drugs have better safety profiles making them a better choice for patients? Or are any pipeline drugs being trialled that could be used in combination with these amyloid plaque-targeting drugs to reduce the severity of adverse events?
Simufilam hydrochloride may help but may not be as effective as others
Cassava Sciences is coming to the end of two Phase III trials, RETHINK and REFOCUS, of its pipeline candidate simufilam hydrochloride. Simufilam is a filamin A (FLNA) inhibitor. FLNA is involved in amyloid deposits and tau phosphorylation. The drug candidate acts by binding to FLNA to prevent amyloid toxic cascade.
In the RETHINK trial (NCT04994483) ending in October 2023, Cassava is testing 100mg simufilam hydrochloride in patients with mild to moderate AD. The randomised, double-blind, placebo-controlled, parallel-group study took place for over 52 weeks evaluating safety and efficacy. There are two arms to the study – an experimental group with patients taking 100mg simufilam hydrochloride twice a day for 52 weeks and a second arm where patients receive placebo. The study is due to end in October 2024.
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By GlobalDataIn REFOCUS (NCT05026177), Cassava is testing simufilam 50mg or 100mg for patients with mild-to-moderate AD. The randomised, double-blind, placebo-controlled, parallel-group study took place over 76 weeks evaluating the efficacy and safety of two doses of simufilam. There are three arms to the study – one experimental group receiving 100mg simufilam hydrochloride twice per day, a second experimental group receiving 50mg of simufilam hydrochloride twice a day and a placebo group. The study is due to end in July 2024.
Rose Joachim PhD, director of Neurology at GlobalData, has hopes for simufilam hydrochloride saying it has appeared promising in earlier studies. “Simufilam is targeting patients with mild to moderate AD dementia, a sizeable patient population with significant need,” Joachim says. “From its Phase II data, the drug looks promising at addressing cognitive decline with a good safety profile. This will be an exciting product to watch.”
Dr Dennis Selkoe, the Vincent and Stella Coates professor of Neurologic Diseases at Harvard Medical School and Brigham and Women’s Hospital, says that he believes that amyloid and tau-lowering medicines will be the way forward. “I think it's good that these drugs are being tried but I think the main targets that look attractive now are amyloid lowering and tau lowering,” Selkoe says.
Alzheon’s APOLLOE4 trial could bring about another amyloid targeting therapy
Alzheon Inc is conducting a Phase III trial (NCT04770220) a beta-amyloid protein 42 inhibitor valiltramiprosate. The APOLLOE4 trial, which will conclude in May 2024, is an efficacy and safety study of valiltramiprosate in patients with early AD. The randomised, placebo-controlled, parallel assignment, double blind trial has two arms. In the experimental arm, patients receive 265mg oral valiltramiprosate, twice per day. The second arm is a placebo arm.
Also known as ALZ-801, valiltramiprosate works at the beginning of the oligomer formation process, preventing protein misfolding at the initiation stage. Additionally, the drug candidate inhibits the growth of existing oligomers, thereby stopping the progression into insoluble amyloid protofibrils and fibrils that form plaques in brains of AD patients.
Dr Stephen Arnold, neurologist at Massachusetts General Research Institute does not have much hope for the pipeline drug. “Its predecessors failed their primary outcomes,” Arnold says. “I think that there were problems in the study designs of those trials, so I think the jury is still out. It's an interesting mechanism of action and I would like to see the study proceed.”
Selkoe agrees, saying: “The exact mechanism by which that would really interfere with the Alzheimer pathobiology is unclear and earlier results didn't show benefit from that. I've followed their work and I know some of the people working there and there's a chance that it could work.”
Joachim has more hope that it will be efficacious as it would resolve a big unmet need. “Although poorly understood why, people with two copies of APOE4 are at higher risk of developing AD. The search for new disease-modifying therapies for this population is very important, as the anti-amyloid mAbs, like leqembi, are actually contraindicated in these patients.” Joachim explains. “If valiltramiprosate is found to slow the progression of amyloid build-up and cognitive decline, it could be an important new therapy option for these patients.”
Athira’s fosgonimeton is a hepatocyte growth factor activator
Athira Pharma is currently conducting a Phase II/III trial (NCT04488419) of its candidate fosgonimeton, a hepatocyte growth factor (HGF) activator. Some scientists theorise that a high concentration of HGF in cerebrospinal fluid is related to AD, resulting in faster cognitive decline in non-demented participants.
The LIFT-AD trial is a randomised, placebo-controlled, double-blind study testing fosgonimeton in patients with mild to moderate AD. The trial has two arms, an experimental arm testing 40mg per day of subcutaneous fosgonimeton, also known as ATH-1017, over 26 weeks. It is being compared against a placebo. The trial is due to end in January 2024.
“Maybe that could work,” Selkoe says. “I do subscribe to the notion that we need more than one or two drugs for a complex disease like Alzheimer’s, but that approach is a guessing game. There is no definite genetic evidence that hepatocyte growth factor has contributed to Alzheimer's.”
“The drug is a once daily subcutaneous injection, which could be preferred by some patients over IV drugs, like the anti-amyloid mAbs, but may be shunned by the needle-shy in favour of various oral therapies in the pipeline,” Joachim says. “Compared to products targeting amyloid beta, the ongoing trial for fosgonimeton is focusing on patients who are more progressed in their dementia—mild to moderate AD vs. early AD. If effective, a drug like this could provide some hope to patients who are a bit further along in their disease.”
Despite the success, concerns remain about amyloid treatments
Despite the success, there is concern about the safety profile of some of these drugs due to amyloid-related imaging abnormalities (ARIA). Eli Lilly reported in the Phase III donanemab trial that incidents of ARIA-E occurred in 24% of treated participants, with 6.1% experiencing symptomatic ARIA-E. The incidence of serious ARIA was 1.6%, including two participants whose deaths were attributed to ARIA and a third participant who died after an incident of serious ARIA.
A Lilly spokesperson says: “We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening.
“Like all amyloid-targeting therapies that remove plaque, the key risk associated with donanemab is ARIA, which may be serious and even fatal in some cases. This risk should be managed with careful observation, monitoring with MRIs, and appropriate actions if ARIA is detected.
“Lilly is committed to better understanding ARIA for this class of therapies, including patient risk factors and potential mitigators to improve patient safety. Accordingly, Lilly has also initiated the TRAILBLAZER-ALZ 6 trial to provide deeper understanding of ARIA’s relationship to amyloid lowering as well as patient characteristics that increase ARIA risk.”
The European Medicines Agency (EMA) recommended the refusal of the marketing authorisation for Aduhelm in December 2021 due to concerns about side effects before Biogen withdrew its application the following year. Biogen has also halted almost all marketing of the drug.
Arnold believes that although these anti-amyloid therapies are a ‘tremendous scientific advance’ due to the safety concerns with ARIA, they are not a ‘tremendous clinical advance’.
“That's for two reasons,” Arnold says. “One, because the dementia does still progress. Two, the safety profile really is a burden of treatment. Every two weeks or every month, patients receive treatment with MRIs and are monitored, and there is a risk of potentially serious or even fatal adverse effects. These are important.”
Selkoe agrees that there should be concerns about safety but that lecanemab seems to be a better option for long term use due to lower ARIA incidents. “If you give certain antibodies at low doses and start gradually, you can avoid most patients getting ARIA,” Selkoe says. “Leqembi was a big success story because it really hit all of its clinical endpoints of cognitive benefit while only having a 2.8% rate of symptomatic ARIA. Leqembi right now looks like it's the most promising antibody that can be used for treating people for many months or years.”
