Targeting Alzheimer’s Disease: A New Wave

by Irina Bilous   Contributor

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The overall technological progress in medicine and the overall increase in the quality and safety of life, compared to even a century ago, led to a substantial growth of the population, and longer life expectancy for humans -- more and more people live up to their  60s, 70s, 80s and longer. However, living longer results in the substantially increased risk of developing one excruciating disease for which scientists have no cure and no clear understanding of its biological roots. This is about Alzheimer’s disease, the debilitating disorder that causes cognitive decline and eventually leads to full patient dependence on a caregiver. There are currently 35 million people with Alzheimer’s disease dementia worldwide and this number will continue to grow. 

It was estimated that one Alzheimer’s disease drug discovery program may cost around $5.6 billion and usually takes up to 13 years. Despite a lot of research and efforts in this area, the success rates of clinical trials for Alzheimer’s disease account for something on the order of 1%. 

Attempts to create AD drugs began from the observation of amyloid-beta plaques in disease brains. Amyloid beta (Aβ) is produced from its precursor protein - APP, which is cleaved by beta-secretase (BACE) and γ‑secretase. Aβ is a hallmark of Alzheimer’s disease, it spreads through the brain with the progression of the disease. Another pathological feature of AD is neurofibrillary tangles inside axons that are composed of abnormally phosphorylated tau protein. Later research indicates that tau accumulation correlates better with worsening cognitive functions.

The idea of targeting amyloids seemed appealing for pharmaceutical companies which led to the hegemony of the amyloids hypothesis for many years. However, at least 25 clinical trials have failed to show efficacy in slowing symptoms. For example, Eli Lilly's solanezumab, a monoclonal antibody that was designed to clear amyloids out of the brain tissue, failed in Phase III clinical trials. Several inhibitors of γ‑secretase that were anticipated to prevent the formation of Aβ also appeared inefficient.

After numerous setbacks the field is shifting toward pursuing new targets, especially looking for genes associated with high risk to develop the disease.  

Image reproduced from: Alzheimer's Association

 

Gene therapy for Alzheimer’s disease is in Phase I of clinical trials

One such gene is known to be apolipoprotein E (APOE), which is the major transporter of cholesterol in the brain. Humans carry different variants of this gene - APOE4, APOE3, and APOE2. One allele, APOE4, is associated with a more frequent onset of Alzheimer’s disease. APOE2, on the contrary, has been shown to delay or reduce the chances to develop the condition. 

LEXEO Therapeutics, a clinical-stage biotechnological company from New York, is currently conducting the Phase I clinical trial to deliver gene therapy for Alzheimer’s disease patients. They deliver APOE2 gene, packed inside AAV viruses, directly into the central nervous system (CNS), expecting that the expression of this protein form will improve the symptoms. At the beginning of the year, the company raised $85 M in its first investment round. 

 

Focus on immuno-neurology

Owing to the feasibility of genomics and transcriptomics studies, new genes linked to the high risk of Alzheimer’s disease that is involved in brain immune cell functions have been identified. These cells are called microglia, and there are emerging approaches to target them to treat neurological diseases which have given rise to a new field of immuno-neurology.  

Alector is a company pioneering the immuno-neurology approach. Their pipeline includes several Alzheimer’s disease candidates, with the most advanced AL002 being in Phase II clinical trials as of today. AL002 is a monoclonal antibody that targets the TREM2 receptor on the surface of microglia. The investigational drug is expected to slow down the disease progression. AL003 in Alector’s pipeline also targets microglia. Both drugs are in development in collaboration with AbbVie, from which Alector received $ 205 M upfront in 2017. The company also generated $176 M in IPO in 2019. 

 

Massive iPSC project to uncover the interaction between multiple genes

Knowledge about the aforementioned genes involved in the disease resulted from many solitary studies in individual laboratories. Recently, a new ambitious gene-editing project was launched to approach the understanding of Alzheimer’s disease in a completely new way -- via a high-throughput identification and analysis of interplaying genes potentially involved in the origination and progression of Alzheimer’s disease. 

The iPSC Neurodegenerative Disease Initiative (iNDI) will use induced pluripotent stem cells and CRISPR to create a unique library of cells containing genes from different donors with AD. Scientists will then use these cells to study interactions between many genes. Another advantage of the project is that created cell lines can be shared with other laboratories all over the world.

 

Gene therapies delivery

To make an Alzheimer’s disease therapy work, it needs, in the first place, to be successfully delivered to the brain. The complexity of the brain is complemented by the existence of the blood-brain barrier (BBB) that covers the blood vessels. BBB consists of endothelial cells that are tightened together preventing the penetration of many types of molecules. 

The BBB can also be an obstacle to delivering gene therapies to the brain. Many drugs, for example, need to be delivered to cerebrospinal fluid (CSF). Most often, a biological drug is getting packed inside a shell of the AAV9 virus to be delivered through the bloodstream. The drawback of the virus-based approach is its poor capacity to cross the BBB. Although Zolgensma, a therapeutics for Spinal muscular atrophy (SMA) uses AAV9 as a vector, it can only be given to young infants due to their immature and “leaky” BBB. 

Capsida Biotherapeutics is one recently founded start-up catching attention. In April 2021 they debuted with $140 M of investment, of which $90 M came from AbbVie. Capsida’s innovative platform is leveraging methods of directed evolution and machine learning to generate AAV9 variants targeted specifically for desired tissue types. For example, they generated capsids capable of better transduce neurons compared to other cell types in the brain. The technology itself emanated from the research of Viviana Gradinaru, Romanian-American neuroscientist, Director Caltech's Center for Molecular and Cellular Neuroscience. Today, Capsida collaborates with AbbVie on three undisclosed programs. 

 

Delivery of small molecules and antibodies

Denali Therapeutics’ transport vehicle platform technology will allow enhanced uptake of therapeutics antibodies from the blood into the brain, which accounted for only 0,1% in the brain compared to circulation in blood. The company created a vehicle that works through transferring receptors that are abundantly expressed in brain vessels. The antibody that binds these receptors can be transferred to the brain without affection transferrin transport. Small molecules also can be linked to that construct. 

Denali Therapeutics has over a dozen programs in development. Among their pipeline, there is an antibody targeting trem2 -- a target used also by Allector. Denali Therapeutics established a research collaboration with Takeda in 2018, where Takeda would pay an initial 150M for and would follow up with more milestone payments.

 

Conclusion 

While the Alzheimer's field was dominated by the amyloid hypothesis for decades, most of the clinical candidates failed to demonstrate efficacy in clinical trials. But the failure of previous drugs doesn’t mean that the amyloid hypothesis should be abandoned altogether. The negative results from clinical trials can be explained by insufficient doses of drugs. Right now Biogen is striving to get approval for its drug aducanumab, an antibody that clears amyloids. In 2019 Biogen stopped trials due to lack of efficacy. But later, after reviewing their own data, they decided to file for the FDA approval.  Although the results of clinical trials are ambiguous, the FDA decision is expected soon.

Additionally, Eli Lilie’s donanemab is in clinical trials right now. According to Eli Lilly’s CSO Dr. Skovronsky, amyloid accumulates in the brain for years before patients show symptoms, that’s why the company is testing its drug in presymptomatic patients. Testing therapies in patients with advanced Alzheimer’s disease might be too late for an efficient cure. That's why many clinical trials are currently recruiting patients with early onset of the disease or with mild symptoms.

As time goes by, the number of people suffering from Alzheimer’s disease is projected to grow due to the fact that the world’s population is aging, so the disease is a serious bottleneck for the development of the aging research and so-called “longevity industry”. Despite many failures and disappointments in Alzheimer's disease research, the new wave of ideas may finally change the unlucky pattern -- and once the first successful treatment option is achieved, it will be among the most sought-after medical remedies of all time. 

Topics: Industry Trends    Novel Therapeutics   

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