Biotech
Saving Synapses from Alzheimer’s Disease with Nutlin
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From Cancer Drug To Alzheimer's Therapy?
The more novel molecules are discovered for specific medical needs, like cancer therapies, the more potential there is for new applications of these molecules.
A good example is the recent discovery that the experimental cancer drug Nutlin could help reduce the impact of Alzheimer's Disease.
This was achieved by researchers at the University of Colorado Anschutz Medical Campus, with Tyler Martinez, a PhD student and lead author of the scientific study.
This study found that Nutlin can reduce the pruning of the synapses linked to the accumulation of amyloid-b protein in the patient’s neurons, often considered a key cause of Alzheimer's Disease.
This is a truly innovative approach, as most Alzheimer's Disease research is focused on eliminating or preventing the accumulation of amyloid proteins. However, it seems that preventing the effects of amyloid accumulation could also work. So this opens a whole new realm of possible Alzheimer's Disease therapies.
How Does Nutlin Work?
Nutlin is a relatively new drug that was discovered in 2004. It inhibits the interaction between a protein called MDM2 and the very important cancer suppressor p53. Nutlin was found thanks to the screening of a chemical library.
MDM2 can impair the activity of p53, which explains why blocking MDM2 interactions with p53 can help in some types of cancer.
But MDM2 is also involved in a phenomenon referred to as “pruning of synapses”, which is normal in the post-natal brain but can be abnormally accelerated in Alzheimer's Disease.
MDM2 is especially active in the presence of amyloid proteins. This abnormal synapse pruning in turn causes loss of memory and learning, especially when affecting the hippocampus.
The study was performed on a rodent animal model used for Alzheimer's Disease. It showed that inhibiting MDM2 link to p53 “completely blocked dendritic spine loss triggered by amyloid-b. So inhibiting this protein is clearly working”.
The Next Step
The advantage of using Nutlin is that it is already a well-studied drug thanks to its anti-cancer application and its known safety and toxicity profile. So turning it into an Alzheimer's Disease therapy should be easier than a whole new molecule.
Still, it is possible that another chemical could inhibit MDM2 even more efficiently and with an even better safety profile. The problem is finding it.
Can AI Help?
Precision medicine today is boosted by AI to analyze a volume of data that would be impossible to do manually. Considering that Nutlin was discovered thanks to a labor-intensive screening of a chemical library in 2004, it is likely that the same type of process 2 decades later, AI-powered this time, could result in even more discoveries.
It is also possible that computational chemistry could custom design from scratch a molecule to specifically affect MDM2.
AI can also help better understand the amyloid protein accumulation's effects and discover targets other than MDM2.
Overall, it is likely that progress in computation and AI will help us both make new discoveries and speed up the pace of discovery, in finding new drugs and in innovation in general. We discussed that topic further in our articles “Changing the Timeline for Discoveries through Use of Artificial Intelligence (AI)” and “Disruptive Industries Coalescing Around a Core Technology – Artificial Intelligence (AI)”.
Alzheimer's & Neurology Biotech Stocks
1. NVIDIA
NVidia initially had a dominant position in the graphics card (GPU) market, mostly used for high-end gaming and 3D modelization. GPUs can run calculations in parallel and differ in that regard from processors (CPU).
It appears that it is equally powerful for training AIs, making Nvidia’s hardware the backbone of the AI revolution.
NVidia is now developing custom computing systems for different AI applications, from self-driving cars to speech and conversational AIs, generative AIs, or cybersecurity.
Likely, Nvidia is not done finding new use cases for its AI hardware. For example, NVidia is now developing a whole range of solutions for drug discoveries, as well as AI-powered medical devices and AI-assisted medical imaging.
So, Nvidia will likely be an essential actor in AI-powered drug discovery, either through its sold hardware or directly.
Source: NVidia
Because of its expertise in hardware, Nvidia has been able to create many partnerships with innovative AI-powered drug discovery companies, including Schrödinger’s computational drug discovery platform and chemical databank, Roche's Genentech, GSK’s AI Hub (including for vaccines), Amgen for generative AI models, Recursion’s integrated wet lab & dry lab, and Alphabet’s spin-off SandBoxAQ for quantum-based software.
2. Intra-Cellular Therapies
Intra-Cellular Therapies has one approved treatment, CALYPTA, for schizophrenia and Bipolar depression. The authorization for treating bipolar disorders is recent (2022) and has strongly accelerated the drug's sales growth, tripling in 2022.
The drug has only one competitor in this application. This is a problem affecting 11 million adults in the US. The company hopes to expand CALYPTA's label for other mood disorders in the future, which could reach up to 21 million adults in the US.
Intra-Cellular's pipeline is focused on neuropathology, including a phase 3 clinical trial for major depressive disorders and 6 other trials in phases 1 & 2 which include Alzeihmer’s Diseases potential therapies.
Source: Intra-Cellular Therapies
Intra-Cellular Therapies is growing quickly in a profitable niche with little competition for now. Future expansion of CALYPTA prescriptions and labels should support revenue growth. The promising pipeline should have solid synergies in the sales network with the already-approved drug.
3. Karuna Therapeutics
Karuna does not have any approved drug yet, and so is fully pre-revenue.
Karuna pipeline includes one drug investigated in three different clinical trials, all in phase 3, for schizophrenia and psychosis from Alzheimer's disease. The schizophrenia drug's potential approval and launch are scheduled for the end of 2024.
Source: Karuna Pharmaceuticals
By potentially reaching both some Alzheimer's patients and schizophrenia patients, this makes the total addressable market for the drug in phase 3 trial up to 10-15 million people.
Investors in Karuna are betting on its most advanced drug approval by 2024. Funding to reach that milestone is adequate, but failing to get FDA approval would likely prove negative for the stock price.
4. BrainStorm Cell Therapeutics
Brainstorm is focused on neurological diseases like Multiple Sclerosis, Alzheimer’s, Parkinson’s, Huntington’s Disease, or Autism Spectrum Disorder. The ALS treatment is the only one in phase 3, with hopes to get it approved quickly, and preliminary results seemingly indicate it could help if used preventively.
Source: Brainstorm Cell
Brainstorm Cell uses its autologous cellular technology platform (NurOwn®): the company takes the patient’s bone marrow cells and turns them into neurons and other nerve cells. This is a rather short process, taking only 7 days.
Overall, Brainstorm seems an interesting company from a technological point of view, but with some financial risks. Risk-taking investors might want to monitor the situation closely and buy only when they understand both the sciences and the financial situation of the company.
