The complexity of Alzheimer’s disease makes it an enigma. A genetic basis for the disease pathogenesis is still poorly understood, with 95% of the disease being sporadic. There are several pathways that drive disease progression, with each new development refining our understanding of the disease and revealing untapped targets.
In recent times, regulations like the Inflation Reduction Act have extended more support to biologic development than to small molecules by protecting them from price negotiations for an additional four years. And while some Alzheimer’s biologic therapies have pushed the field forward, they offer moderate benefits at best alongside a host of limitations. Given the chronic and costly nature of the disease, experts emphasise the need for Alzheimer’s therapies that provide both economic and clinically significant benefits.
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Small molecule clinical trials are “easier”
For a study to meet the FDA’s standards, it needs to have a design that takes into account both scientific and operational considerations. Moreover, the sponsor must choose robust endpoints, have well-founded dosing regimens, and ensure representative enrolment to conduct a trial that can generate ironclad data.
The efficacy and safety requirements in an Alzheimer’s clinical trial are similar regardless of the type of investigational drug molecule, says Rockville, Maryland-based SciNeuro Pharmaceuticals CEO Min Li. However, operational complications such as a lack of compliance and complicated administration—which can also spell trial failure—is where clinical trials studying small molecules have an advantage, Li elaborates. SciNeuro will study SNP-318, its lipoprotein-associated phospholipase A2 (Lp-PLA2)-inhibiting small molecule candidate designed to improve cognition by targeting neurovasculature, in a Phase II trial in H2 2024.
It’s logistically difficult to have patients going to centres regularly for a treatment that is also complicated to administer, explains Christopher Missling, CEO of Anavex Life Sciences Corp, another company developing small molecules for Alzheimer’s disease. The Phase III study (NCT03887455) of Biogen and Eisai Pharmaceuticals’s FDA-approved Leqembi (lecanemab) required eligible patients to go into a clinic every two weeks to receive an infusion of either intravenous Leqembi or placebo. In addition, the trial called for MRI scans at specific timepoints over 91 weeks to monitor for amyloid-related imaging abnormalities (ARIA).
Simplified medication delivery is especially important in certain EU countries like Romania or Hungary where access to MRIs and treatment facilities is not guaranteed, as it would be in a densely populated city like Paris, Missling adds.
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By GlobalDataSmall molecules, the stars of symptom management
Investigational treatments have targeted amyloid removal for many years, Li notes. But it so happened that monoclonal antibodies succeeded at demonstrating a disease-modifying effect, which also contributes to why FDA approval of Biogen’s Aduhelm (aducanumab) was followed by Leqembi, with Eli Lilly’s donanemab application hot on its heels.
However, the problem with amyloid removal drugs is in the word “removal,” says George Perry Ph.D, professor of Neurobiology at the University of Texas at San Antonio, because forcibly removing amyloid deregulates a normal response and imbalances the brain, causing clinically significant risks in exchange for a moderate shift in deterioration. The FDA granted Leqembi full approval with a black box warning, as three patients in the open-label extension study died due to side effects attributed to the medication.
Managing cognitive decline is where small molecules shine because an amalgam of symptom-managing small molecule therapies can mitigate decline by improving cognition, global function, and quality of independent life in ways that disease-modifying monoclonal antibodies cannot, says Sharon Rogers, CEO of AmyriAD Therapeutics. Trials that study Alzheimer’s symptom management therapies, like IGC Pharma’s Phase II study (NCT05543681) of IGC-AD1, are also easier to conduct, IGC Pharma CEO Ram Mukunda comments. IGC-AD1, a cannabinoid-based small molecule candidate being developed to treat Alzheimer’s disease-related agitation, can mechanistically be “disease modifying” as it modifies the debilitating neuropsychiatric symptoms of the disease, explains Mukunda.
But in order to be a trial that evaluates whether a therapy is modifying the disease, the hypothesis would need to change and trial design would need to be altered to have longer timeframes and extensive monitoring of the risks associated with modifying pathogenesis, says Mukunda.
Another advantage of studying small molecules that impact Alzheimer’s symptoms is that patient screening failures are lower, explains Missling. The Phase III trials for Leqembi saw 70% of patients being excluded due to screening failures (van Dyck et al., N Engl J Med. 2023 Jan 5;388(1):9-21). In contrast, patients in Anavex’s Phase IIb/III trial (NCT03790709) studying its small molecule blarcamesine are enrolled based on a physician-assessed diagnosis of Alzheimer’s, as opposed to PET scans or invasive lumbar punctures. Higher screen failure numbers are an indication of higher market penetration limitations, he elaborates.
Targeting other disease drivers with small molecules
Alzheimer’s disease therapy development was derailed by amyloid beta-targeting monoclonal antibodies, as they were seen as a potential cure for the disease, says Rogers. As a result, the emphasis on managing the disease with polydrug treatments over a prolonged period of time was lost, she adds.
Rogers believes the key to Alzheimer’s management is in additive therapies, and this is where small molecules shine. While the benefit of monoclonal antibodies is that they can reveal different pathways to disarm the disease, they are not an economical long-term solution, she says. “Small molecules are cheaper, shelf stable, easy to distribute and use, and they usually do not require any type of specialised academic facility for PET scanning or cerebrospinal fluid (CSF) tapping or biomarkers.”
The diagnostic requirements of current monoclonal antibodies also increase their cost. Leqembi costs $26,500 per year, and per its label, requires periodic MRI scans throughout treatment and additional imaging for monitoring ARIA. Aduhelm originally had a $56,000 price tag that was slashed to $28,000 earlier this year.
Rogers painted a scenario to explain how different therapies could be layered to targets can be studied in such trials. For example, Los Angeles, California-based AmyriAD’s AD-101/ Aricept combination, which is approaching Phase III trials for mild to severe Alzheimer’s, works by promoting the release of neurotransmitter acetylcholine and preserving it. The next layer could be a CAMK2 inhibitor like the company’s preclinical AD-201 to promote synaptic plasticity and memory formation. At some point in the treatment course, AD-401 could be added to stimulate neuron regrowth and arborization.
Biologics, however, will not lose their place in the treatment landscape, and newer versions can address the challenges seen with those already approved. Anti-tau antibodies like Seoul, South Korea-based Adel’s biologic ADEL-Y01 do not pose a risk of ARIA because tau is not accumulated in blood vessels like amyloid, says Adel CEO Seung-Yong Yoon. A tau target brings an added bonus of having an aggregation rate that correlates with patient symptoms, which means that targeting tau presents a longer therapeutic window than amyloid beta.
“Amyloid beta accumulation begins about 20 years before neurodegeneration,” says Yoon. So in practice, this approach can only be administered in the late stages of amyloid beta pathogenesis, which is clinically quite late, Yoon adds.
The current trend in Alzheimer’s drug development is to target the disease earlier, which inherently makes any clinical trial more difficult, regardless of whether it is for a small molecule or a biologic, says Perry.
So if patients are being selected for mild cognitive impairment—which is hard to diagnose and is the root of many misdiagnoses—this means that the trial needs more patients to account for error and enough to accurately represent the disease population, says Perry. If the trial enrols patients in an even earlier stage, then even more time and analysis is required to screen the patients, which calls for increased PET scans or biomarkers, and ultimately drives up the cost of the trial.
“As patients go through a disease that is at least 25 years in the making, if not more, there’s always going to be this need for symptom therapy to help maintain functional outcomes and to maintain quality of independent life,” says Rogers.
