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Biotech is full of surprises; getting a drug to market and then being successful needs luck and a lot of patience. Biogen (NASDAQ:BIIB) has acknowledged that Aduhelm isn’t going to make it, partly because of serious side effects, but in partnership with Eisai (OTCPK:ESALF) it remains in the game with another monoclonal antibody drug lecanemab. Both Aduhelm (aducanumab) and lecanemab target amyloidβ, but lecanemab has fewer problems with a serious side effect. Here I dig deeper into the Alzheimer’s story. Investors interested in really hard unsolved diseases need patience. Biogen is a company that has been involved with this space for a long time and I suspect this interest will persist, notwithstanding many challenges and setbacks.
Comparing Aduhelm (aducanumab) with lecanemab
Five monoclonal antibodies targeting Amyloidβ have been studied in clinical trials, but they have mostly failed in the clinic over the past 20 years. The key issues have been absence of clinically significant benefit and serious side effects, notably ARIAs (Amyloid-Related Imaging Abnormalities) which involve brain bleeding. Up to 40% of patients treated with Aduhelm experience brain swelling and bleeding (which is diagnosed by MRI, Magnetic Resonance Imaging). The cost of multiple MRI examinations and seriousness of ARIA is a major negative for Aduhelm and has most likely contributed to Biogen finally giving up on Aduhelm.
On the other hand lecanemab has a less concerning safety profile in terms of ARIA side effects, with 9.9% ARIA in recent trials. Eisai is leading development of lecanemab and a proposal for BLA with the FDA is proceeding now. If any monoclonal antibody Amyloidβ drug is going to be successful it is likely to be lecanemab, and indeed Eisai seems confident about receiving approval in the US, Europe and Japan in the near term. While Eisai is leading the registration of this drug, Biogen is still a partner and is responsible for manufacture of the lecanemab drug substance in its Swiss Solothurn plant, with an agreement to manufacture extended from 5 to 10 years.
Eisai’s Q4 2022 earnings call transcript on May 13, 2022 covered in some detail the progress towards seeking regulatory approval for lecanemab. The summary is that Eisai hopes in fiscal 2022 to receive approval from the FDA in the US, based on an ongoing BLA rolling submission, and from EU and Japanese authorities for lecanemab treatment of mild cognitive impairment (due to Alzheimer’s disease) and mild Alzheimer’s disease with confirmed presence of amyloid pathology in the brain. A confirmatory Phase 3 trial (Clarity AD) involving 1,795 patients is underway and will report data in the fall of 2022.The FDA has agreed that this trial can be included in the application to verify the clinical benefit of lecanemab. The company made clear that they have learned much from the challenges of seeking approval for Aduhelm.
Notwithstanding Eisai’s optimism, lecanemab has conducted several clinical trials that were largely negative with lack of clinical effects. However, it seems that the story isn’t over for lecanemab, even if it is apparently safer than Aduhelm.
Corporate responsibilities between Biogen and Eisai on Aduhelm and lecanemab
Recently the partnership between Biogen and Eisai concerning Aduhelm has been reviewed and Biogen has assumed full control of the development, with a single digit tiered royalty to Eisai rather than co-development.
Recent moves at Biogen concerning Aduhelm suggest that its future is bleak, with termination of the Phase 4 trial required of Biogen by the FDA.
On the other hand the joint collaboration and commercialization between Eisai and Biogen concerning lecanemab is unchanged, with both parties sharing economic benefit although Eisai will book global sales and Biogen will reflect its 50% share of profits and losses. Eisai will continue lead development of lecanemab and manage regulatory submissions globally. Eisai has the final decision-making authority.
Watch this space for perhaps the final attempt to succeed with an Amyloidβ drug for treating early stage Alzheimer’s disease, noting that Biogen is still at the table.
Is targeting extracellular Amyloidβ chasing the wrong solution?
Biotech specialises in complicated titles, which makes it hard for investors. How about this for a title pointed at experts and which comes over as gobbledegook for the average investor : “Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques”? The point is that this scientific paper recently published in Nature Neuroscience may help explain why Biogen’s Aduhelm (and Eli Lilly’s (LLY) donanemab) and maybe lecanemab have struggled to be effective in treating Alzheimer’s disease. This is a very technical paper but the findings are clear, at least in several animal models, with confirmatory hints in humans.
Amyloid plaque starts inside brain cells
Previously it has been thought that Amyloid plaques form outside of cells and cause chaos by killing nerve cells. The current paper reverses that and shows that the amyloid plaques form inside of nerve cells and cause chaos from within, before accumulating outside the dying cells. This sounds esoteric, but it has implications for treating Alzheimer’s disease.
Indeed the paper claims that the defect (which involves problems within structures inside the cell called lysosomes) can be treated in a model system by drugs that address the problem in the lysosomes. The drugs are not described in the paper, but this has to be interesting to Alzheimer’s drug developers. I would be surprised if Biogen isn’t interested in this new possibility for treating Alzheimer’s disease and stopping the amyloid problem before it gets out of control. The current generation of drugs (including lecanemab) are trying to clean up the mess after it has done its damage.
So it looks like the Amyloidβ monoclonal drugs being pursued so far (eg Aduhelm, lecanemab) are targeting a downstream aspect of the formation of Amyloidβ plaques. If you are looking for where plaque gets formed and does its damage, it seems now that you need to look at defects in lysosomes inside nerve cells. The fun thing is that this provides those paying attention a guide to where they should be looking for breakthroughs in Alzheimer’s research. It also proves that biotech investing is slow and not for the faint hearted
The paper hones in on the acidity of lysosomes and it also makes clear that new techniques described make possible testing out new therapeutic agents. The paper also makes the point that there are congenital lysosomal disorders which show similar brain changes to those seen in Alzheimer’s disease (eg Niemann-Pick type C and mucopolysaccharidosis type III). This is an exciting new discovery. Of course it isn’t so simple as the search for a relationship between Alzheimer’s disease and Niemann-Pick type C has been sought for a long time. (see Pub Med search “Niemann-Pick type C and Alzheimer’s disease”). Biotech is complicated. My bottom line is, pay attention to lysosomal defects and drugs to treat them as a possible new avenue for Alzheimer’s drugs.
Where to look for solutions for Alzheimer’s disease
Before we get too excited about a new angle for treating Alzheimer’s disease it is worth noting that an astonishing 6,767 scientific papers using the key words “Alzheimer’s treatments” are cited in PubMed in the past 12 months! Or to get really up to date results 3,685 scientific papers cover the period Jan1 through to the present in 2022 for the same key words.
Of course many of these publications address the recent anti-Amyloid drugs of Biogen/Eisai and Eli Lilly, but there are also indications of the net being spread more widely in looking for treatments. A paper from a Taiwanese group considers new therapy approaches in five categories : i) anti-amyloid therapy (includes Biogen and Eli Lilly drugs); ii) anti-tau therapy; iii) anti-neuroinflammatory therapy; iv) neuroprotective agents; v) brain stimulation.
Since being able to measure something is the key to sorting out how it works, new results about blood markers for Alzheimer’s disease are very interesting.
Biotech is hard and slow, but there are times when significant new directions become evident. The finding discussed above opens up new ways to think about Alzheimer’s disease and studies on lysosomal defects might be a good place to look, even though the current focus on lysosomal disease is mostly on rare genetic diseases, such as Pompe’s disease and glycogen storage disorders.
I doubt that Alzheimer’s disease is likely to be addressed by gene therapy approaches, but what can be learned from genetic lysosomal diseases may lead to development of treatments that can correct lysosomal disfunction. For left field investors there are some starters but nothing really investible yet; perhaps Maze Therapeutics might be worth paying attention to even though it is privately held.
Without wishing to be too negative, it is important to be clear that the amyloid hypothesis may still be a consequence of and not directly related to the development of Alzheimer’s. There is a long way to go for effective treatments for Alzheimer’s, but canny investors might have success in backing companies that will become leaders in the field. Biogen is still in the game.
Conclusion
Alzheimer’s is a huge issue and an area where it is becoming clear that ideas about its cause may have missed the point. For a long time the “Amyloid hypothesis” has been a dominant theme in Alzheimer’s research, and it has produced recent drugs seeking to address amyloid plaque deposition in the brain. The research covered in the paper I’ve addressed here makes clear that if Amyloid plaque is a key part of the development of Alzheimer’s (and this is still not clear) then the way that Biogen and Eisai have approached drug developments is targeting downstream of where the problem arises. Biogen/Eisai’s Aduhelm addresses removing amyloid plaque formed outside of cells in the brain. Now it is clear that these plaques first start to form inside brain cells. This adds to my caution about Aduhelm’s ineffectiveness.
There remains the question as to whether the problem inside brain cells that leads to forming amyloid plaque is consequential for the development of Alzheimer’s or just another secondary effect, but it changes where investors need to look for Alzheimer’s treatments. The focus might shift to mistakes in the operation of lysosomes, the rubbish collectors inside cells. This takes Alzheimer’s research back several steps, so this is not of interest to investors looking for companies that are heading into clinical trials with drug candidates. It becomes interesting for those (like me) looking for the very early stage opportunities that can have interesting investment outcomes as early breakthroughs point to success down the track, but also potentially early stock price rises based on euphoria about breakthroughs. Watch out for companies with programs on lysosomal function and of course to see how Eisai/Biogen gets on with getting approval for lecanemab.
I am not a financial advisor but I’ve researched and been involved with commercialisation of biotech discoveries for a long time. I hope that my perspective is of some use to you and your financial advisor as you contemplate risky biotech investment.
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