When Arimoclomol debacle was announced I was stunned. After all, it was supposed to have a precise mechanism of action in ALS, and this was not so frequent in ALS clinical trial. Most ALS cases are characterized by misfolded, mislocated TDP-43 protein accumulation in granules. This is similar to what appears in Alzheimer's and other neurodegenerative diseases.
Arimoclomol was supposed to activate the cellular heat shock response by activating molecular chaperones. As molecular chaperones' role is to fold proteins correctly, it seemed evident that they would correctly fold the misfolded proteins.
Yet this ignores that those corrected proteins are still mislocated in the cytosol and as they do not enter the ER and Golgi apparatus, they are not sent to the nucleus. The phase III ALS clinical trial was a failure, but the drug works in other diseases.
Wave's WVE-004 targets C9orf72 mutations in ALS. C9orf72 hexanucleotide GGGGCC repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and WvE-004 targets them in a very smart manner.
C9 mutations are much more complicated than SOD1 mutations which are already numerous and present very different phenotypes, with some patients dying one year after diagnosis, and others living two decades. An ASO therapy, Tofersen, was conditionally approved for medical use in the United States in April 2023. Yet it is useful for only one mutation in the SOD1 gene, found in less than 2% of all ALS cases, and therefore it will be useless for most ALS patients. But for those patients that are targeted, it works, kind of.
WVE-004 uses an approach known as ‘antisense’, where the drug directly interferes with the faulty instructions for making a protein.
So an ASO for C9orf72 which targets mutations in the C9 chromosome, should in principle result in good results.
The C9orf72 gene contains three different sets of instructions (RNA) to make the C9orf72 protein and these three RNA are called V1, V2, and V3. In some forms of MND, mutations in the C9orf72 gene cause the V1 and V3 instructions to be faulty and this leads to the production of toxic proteins which build up in the neurons. WVE-004 targets the faulty V1 and V3 RNA and signals to the cell that they need to be destroyed, leaving the V2 instructions functional so that a healthy version of the C9orf72 protein can still be made.
So what went wrong? We will never know as Wave will discontinue developing the therapy, and its open-label extension study will be stopped. Yet strong reductions in poly(GP) were observed, with patients on a single 20 mg dose and those in the multiple dose groups all having a roughly 50% decrease in poly(GP) levels over the start of the study.
This is hard to understand, there were more than 500 clinical trials on ALS drugs, and most of them did not have a theoretical principle of action. Here is a drug that has a sound principle of action, that apparently works at biomarkers levels. Yet it is stopped in phase I!
What if, as common sense tells us, there is a need for much more than 24 weeks to heal an ALS patient? Even at a purely statistical level, 42 (patients) is a too small number to rise any meaningful conclusion.
It's a financial reasoning, for investors in biotechs it's a game, biotechs often lose but if they win then it's the jackpot for investors. In this paradigm, you have to invest small amounts and know how to move on to another target if there are no quick results.
Here most likely the biotech Wave was unable to convince its investors of the value of their drug and the investors decided it was time to stop funding.