Alzheimer’s disease treatments


BtoBio Innovation


Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation






Note from the editor: this article was published in a shorter version in the July-August 2021 MedNous edition.





Alzheimer’s disease treatments



The Aduhelm saga


The US Food and Drug Administration’s approval of Alzheimer’s disease drug Aduhelm or aducanumab, on 7 June, co-developed by Biogen and Eisai, has been one of the agency’s most controversial decisions. The drug was authorised on the basis of a reduction in amyloid-beta plaque, a surrogate endpoint for clinical benefit. While the aducanumab lacks evidence to demonstrate it can improve Alzheimer’s symptoms, such as slowing down cognitive decline, the reduction of amyloid plaque is thought to alter the course of the disease, the FDA officials said. The supporting studies failed to get the endorsement of the FDA’s own advisory committee of experts in neurology, leading to the departure of three of the committee’s members. In a rather surprising move, the FDA has issued a lengthy review document and memos detailing its arguments for approving aducanumab.


The loud uproar around the approval has become political with a letter from moderate Senator Joe Manchin, D-West Virginia to President Joe Biden asking to “outs the FDA’s interim commissioner Dr. Janet Woodcock and quickly nominate an acceptable permanent chief”. Last week Rep. Katie Porter, D-California charged Biogen with “undue influence” over the FDA’s review process. Those comments came less than two weeks after the House Committee on Oversight and Reform said it would conduct its own probe into the approval as well as Biogen’s pricing strategies. On 9 July, Janet Woodcock, the acting FDA commissioner, took the unusual step of asking federal officials to investigate interactions between agency staff and the drug’s sponsor Biogen in the lead up to the approval in order to rule out any breach of agency procedures. The Aduhelm saga is far of being over. Investigations into possible breaches of acceptable conduct from Biogen employees or FDA agents are likely to take some time to resolve.


Then there is the additional issue of the drug’s price. Biogen has set a price of $56,000 for one year’s supply of the drug, a figure that is well above what independent bodies such as the Institute for Clinical and Economic Review (ICER) which had determined through modelling that Aduhelm should be priced at $2,500 to $8,300 per patient per year. At this steep price and under a conservative estimate, if half of the 500,000 newly US diagnosed Alzheimer’s patients were receiving the drug, the total cost for Medicair would be exceeding $10 billion annually.


But stepping back from the immediate controversy, it is possible to identify other trends flowing from this decision that may have lasting impact. First, there will likely be rapidly more anti-amyloid-beta products coming up for a regulatory review now that one product of this type has been approved. Second, the Aduhelm decision is expected to boost deal-making in the neurodegenerative disease space. Third, researchers may be emboldened to try new approaches which go beyond plaque destruction to examine other biological features of Alzheimer’s disease. In this article, we argue that the time is ripe for new approaches.


For more than 20 years, Alzheimer’s disease research has been dominated by a single theory: the amyloid cascade hypothesis which suggests that the accumulation of amyloid-beta peptides in the brain drives the pathology of the disease – a vicious cycle of amyloid-beta peptide accumulation, nerve cell death and inflammation and more nerve cell death. This progressively destroys memory and thinking skills. Drugs that are developed on the basis of this theory, such as Aduhelm, are designed to bind to amyloid-beta in order to reduce destructive plaques in the brain. In approving Aduhelm, the FDA noted that patients receiving the drug had a significant dose and time-dependent reduction in plaques while those receiving a placebo saw no reduction. Yet amyloid-beta reduction was still considered as just a surrogate measure of clinical benefit.  The agency gave Aduhelm an accelerated approval which means the company will need to demonstrate actual clinical benefit in follow-up trials which could last up to nine years. According to a discussion guide of a meeting held on 14 July by the Duke Margolis Center for Public Health, the issue of the confirmatory trial was raised. “A key question is whether surrogate endpoint validation can occur in a more expedited way” the document states. “Many patients’ families made it clear that they are willing to accept the trade-off of some uncertainty about clinical benefit in exchange for earlier access to a potentially effective drug, which is the exact premise and intent of accelerated approval” the FDA officials said.


The amyloid beta pathway.


The Aduhelm approval has been a boost to other companies using a similar approach. On 24 June, not long after the Aduhelm approval, Eli Lilly received a breakthrough therapy designation from the FDA for donanemab, a monoclonal antibody targeting a pyroglutamate form of amyloid-beta that aggregates in amyloid plaques. This is different from other amyloid-beta antibodies which bind to soluble or insoluble amyloid. The strategy is to target deposited plaque in order to clear existing amyloid from the brain, rather than trying to prevent the deposit of new plaque. The breakthrough designation was awarded on the basis of data from a Phase 2 trial in patients with early, symptomatic Alzheimer’s disease. The trial met its primary endpoint of slowing disease progression as measured by the integrated Alzheimer’s disease rating scale at 18 months. Lilly has announced plans to file an application for an accelerated approval of donanemab later this year on the basis of the Phase 2 data. In the meantime, it has started a Phase 3 trial with 1,500 participants.


Biogen and Eisai, who co-developed Aduhelm, have received an FDA breakthrough designation for a second Alzheimer’s drug – lecanemab. This is a monoclonal antibody that binds to soluble amyloid-beta protofibrils. Protofibrils are intermediates in the process leading to peptide aggregation into amyloid plaques. Like many prospective Alzheimer’s disease treatments, lecanemab has had a chequered clinical history. But a recently concluded Phase 2b study of 856 patients with mild cognitive impairment showed a reduction of amyloid beta and clinical decline on biomarker metrics in patients receiving the highest dose. This is the data on which the breakthrough designation is based.


According to a report from Jefferies, Roche has been in discussions with the FDA on whether they can expect an “expedited” filing for gantenerumab, their own Alzheimer’s drug, and receive an accelerated approval in the coming months. That would be more than a year ahead of when the Swiss company had originally hoped to file and well before the company will have final data from their Phase 3 trials testing whether the drug does actually slow cognitive decline. Several analysts now predict the late 2022 launch of gantenerumab with peak sales of $6 billion by 2032.


Up until the end of the first quarter of this year, drug development programmes based on the amyloid-beta hypothesis were still predominant. According to the open access journal, Translation Research & Clinical Interventions, there were 126 agents in 152 trials evaluating new therapies for Alzheimer’s disease at the end of the quarter. Twenty-eight treatments were in Phase 3; 74 were in Phase 2 and 24 were in Phase 1. The majority of agents, or 104, targeted the biology of Alzheimer’s disease with the goal of modifying the disease; 13 were cognitive enhancing agents; and nine were intended to reduce neuropsychiatric symptoms. Among the disease modifying agents, 16 drugs had amyloid-beta and 11 had tau as a primary target or as one of several potential effects. The other targets were inflammation, synaptic plasticity, neuroprotection and bioenergetics/metabolism.


The Aduhelm approval is also having an impact on biopharma dealmaking.


On 24 June, Bristol Myers Squibb exercised an option in a licensing agreement with the Ireland-based company Prothena for exclusive US rights to the anti-tau antibody PRX005. Tau proteins form part of microtubules which help transport nutrients from one part of a nerve cell to another. In Alzheimer’s disease, tau proteins are misfolded. These misfolded proteins create neurofibrillary tangles which, together with amyloid-beta plaques, are part of the pathology of Alzheimer’s disease. PRX005 targets the microtubule binding region. In preclinical studies, this region has reportedly been linked to the spread of misfolded tau protein. The antibody therapy has only recently entered a Phase 1 study.


On 2 July, GlaxoSmithKline and Alector, a South San Francisco, US company, announced a $700 million upfront deal in the neuro-immunology field with a focus on genetically defined populations. The two antibodies acquired by GSK target progranulin, a protein which regulates immune response, lysosomal function and neuronal survival in the brain. Decreased levels of the protein are linked to a number of neurodegenerative disorders including Alzheimer’s disease. The lead drug, AL001, already in phase 3, is targeting frontotemporal dementia with a separate phase 2 in symptomatic patients bearing a mutation in the C9orf72 gene.


New approaches


A paper recently published in The Lancet notes that the amyloid-beta cascade hypothesis has been modified over the past five years to take account of new knowledge about the cellular, preclinical phase of Alzheimer’s disease. Up to 80% of Alzheimer’s disease cases are due to genetic factors. Recent studies have identified many more genes involved in the disease than in the past.


This raises the possibility that approaches dismissed or side-lined in the past could be revived. An increasing number of neuroscientists believe that targeting neuron protection is not sufficient and that the role of the microglia and the brain vasculature is crucial in the development of Alzheimer’s disease. The more recent approaches that are receiving new attention include synapse modulation, brain immune system stimulation as well as reductions in oxidative stress and chronic neuroinflammation. The following companies and academic institutions are pursuing research that could take the industry in a new direction.


Vivoryon Therapeutics, a German company based in Munich, focuses on small molecule inhibitors of glutaminyl-peptide cyclo-transferase (QPCT), a post-translational enzyme which catalyses the pyroglutamate formation in substrate proteins. In Alzheimer’s disease, QPCT has been identified as an important human brain enzyme generating stable neuro-and synaptotoxic pyroglutamate species of beta amyloid. Varoglutamstat, (PQ921), the company’s most advanced product, is in a Phase 2b trial in patients with mild cognitive impairment and early-stage Alzheimer’s disease. A read-out of data from the trial is expected in 2023. On 29 June, Vivoryon announced a regional licence with Simcere Pharmaceutical Group Ltd of China to develop and commercialise Alzheimer’s medicines for mainland China and neighbouring geographies.


Vigil Neuroscience of Cambridge, US, has ongoing research and development efforts to treat neurodegenerative diseases by restoring the vigilance of microglia, the sentinel cells of the brain immune system and maintain normal brain function.  Recent human genetic studies have pinpointed to the importance of the triggering receptor on myeloid cells 2 (TREM2) as an essential microglia sensor that mediates its response through its associated protein kinase complex DAP12/SYK. Additional studies show that through TREM2 signalling, microglia change phenotype called diseased-associated microglia (DAM). Vigil’s small molecule programme is still at the preclinical stage.


Alector Inc follows a similar route by using genetic insight to identify mutations in the immune system genes of the microglia. The company has two Alzheimer’s disease products in clinical development. They are AL002, a monoclonal antibody targeting TREM2 and AL003, a monoclonal antibody targeting Siglec-3 (CD33), to improve microglial clearance of toxic proteins. Both programmes are partnered with AbbVie Inc.


Athira Pharma, based in Seattle, USA, has been on the radar of many investors since they published data showing that ATH-1017, a small molecule, rapidly rebuilds deficient synapses. The approach followed by Athira consists in promoting naturally occurring repair mechanisms like HGF/MET (Hepatocyte growth factor-induced MET tyrosine kinase receptor), a signalling pathway already evaluated in oncology. ATH-107 has the potential to protect existing neurons from damage, reduce inflammation, promote regeneration of neurons, enhance synaptic plasticity and positively modulate brain activity.  In June, Athira made the headlines when it announced that Dr. Leen Kawas, its founding CEO, was placed on temporary leave, pending board review actions stemming from doctoral research she conducted while at Washington State University. Nevertheless, on 6 July, the company announced the enrolment of patients into an open label extension study for its ongoing phase 2/3 LIFT-AD and phase 2 ACT-AD studies of ATH-107 for the treatment of mild-to-moderate Alzheimer’s disease.


AlzeCure Pharma, a Swedish company, has started a Phase 1 study of ACD856, a small molecule drug which binds to neurotrophin Trk receptors with the goal of stimulating nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) signalling in nerve cells.  The levels of NGF and BDNF are disturbed in several disease states and this impairs communication between synapses, giving rise to cognitive impairment. ACD856 has reportedly improved memory function in a number of preclinical models.


The University of Southern California, a private research institution in Los Angeles, US, is studying the biological ageing of neural stem cells, which are highly vulnerable and contribute to age-related cognitive decline and Alzheimer’s disease. Scientists in the laboratory of Michael Bonaguidi have been able to show that by blocking the gene Ab11 in mice with the oral chemotherapy drug imatinib, a non-selective kinase inhibitor, they were able to stimulate neural stem cells to divide more and proliferate in the hippocampus, the part of the brain responsible for learning and memory. According to Professor Bonaguidi, the next step will be to induce the stem cells to make more neurons. Then, the scientists hope to be able to demonstrate that the new neurons improve learning and memory.


– Finally, AB Science of Paris, France, is evaluating masitinib, a pan-kinase inhibitor, already assessed in oncology settings, in Alzheimer’s disease. The therapeutic benefit of masitinib is expected to be exerted through multiple mechanisms of action including inhibiting mast cell activity which impacts neuroinflammation. It is also expected to help regulate the permeability of the blood brain barrier and inhibit the protein kinase Fyn which is involved in amyloid-beta signalling and tau phosphorylation. Masitinib has successfully completed a Phase 2b/3 trial. The enrolment of patients in France can now restart after the validation of its Risk Management Plan approval by the French National Agency.


None of the drugs targeting non-amyloid pathways has undergone sufficient clinical testing to constitute a solid alternative to Adulhem. But they do build an interesting repertoire based on new fundamental neuroscience biological knowledge.


The brain complexity


Neurodegenerative diseases are highly complex and difficult to treat using a single pharmacological approach. Numerous single-intervention failures, mainly aimed at the removal of amyloid plaques, mask the crucial need for a multimodal approach. In our view, the approaches most likely to succeed will be those where the neural system, the immune system and the vascular system are part of the therapeutic solution. Two recently identified companies have engaged in this new paradigm.


NeurMedix, a San Diego, US, based company, has received FDA authorisation to initiate a pivotal phase 3 clinical trial in Alzheimer’s disease with NE3107. NE3107 or 17α-ethynyl-androst-5-ene-3b,7b,17b-triol, is a small molecule with anti-inflammatory, an insulin-sensitising agent with a novel mechanism of action. The drug binds to extracellular signal regulated kinases (ERK1 and 2) and nuclear factor kappa B (NFkB) in inflammatory signalling pathways without inhibiting ERK and NFkB homeostatic functions.


NervGen Pharma, based in Vancouver, Canada, is preparing for a Phase 1b clinical trial of its lead compound NVG-291, an inhibitor of protein tyrosine phosphatase sigma (PTPσ), a neural receptor. NGV-291 promotes axonal regeneration, remyelination, plasticity, autophagy and an anti-inflammatory microglial phenotype. NVG-291 provides the potential to improve cognitive deficits by enhancing the nervous system’s natural repair mechanisms.


Targeting several major pathways involved in Alzheimer’s disease might be very difficult to achieve with a single drug. But it could be considered through the use of combination therapies, similar to successful strategies being employed in oncology. The accelerated approval of Aduhelm may pave the way for clinical studies where an amyloid-beta pathway drug can be combined with agents which restore synaptic plasticity, insulate neurons from injury, activate the microglial function and remove debris from Alzheimer patients’ brains. 


This will be the last report before our usual summer break.



Paris July 23, 2021



This document has been prepared by btobioinnovation and is provided to you for information purposes only.  The information contained in this document has been obtained from sources that btobioinnovation believes are reliable but btobioinnovation does not warrant that it is accurate or complete. The views presented in this document are those of btobioinnovation’s editor at the time of writing and are subject to change.  btobioinnovation has no obligation to update its opinions or the information in this document.







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