RNA-based+2591PW, page-5

Hi Sillazze

I am not certain that I have fully understood your post. However I think that, in the first part of your post, you are expressing concern with the growing competition in drug development, especially from RNA and gene therapies, for the same indications that Neuren is targeting with NNZ-2591.

You mention Amo Pharma, which has got Michael Snape and Joe Horrigan on board, and is developing AMO-04 for Rett syndrome and AMO-01 for Phelan McDermid syndrome.

AMO-04 is tianeptine, a repurposed, oral, anti-depressive drug that acts as a glutamate modulator. Obviously, Amo will be able to cut some corners through using a repurposed drug. Preclinical efficacy signals were good but the drug has reported side effects that include nausea, constipation, abdominal pain, headache and dizziness. The FDA has also warned that tianeptine has a risk of misuse and abuse. Taking high doses can cause drowsiness, confusion, difficulty breathing, coma and death and long-term use can cause dependence and withdrawal.

AMO-01 is a small molecule that inhibits RAS-ERK, which is a pathway more typically targeted in cancer. In the one clinical trial to date, the drug was given as a single 6-hour intravenous infusion. Side effect profile seems OK but the company didn’t release the efficacy data. Private companies like Amo are better placed to take a stealth approach!

You mention LocanaBio and the collaboration between Shape Therapeutics and Roche.

LocanaBio is developing drugs for neuromuscular and neurodegenerative disease but not in any of the indications being targeted by Neuren. It is focused on gene therapy (so-called "one and done" treatment) and uses AAV9 vector delivery. There is cause to be wary of vector delivery and specifically AAV9 vector delivery (see here and here + additional links below).

Shape Therapeutics also develops gene therapies but delivers them with what it calls “next-generation” AAVs which are supposedly more specific and easier to manufacture. Shape and Roche are reported to be looking at a range of therapeutic areas, including Parkinson’s disease, Alzheimer’s disease, alpha-1 antitrypsin deficiency and Rett syndrome. If they do proceed with a Rett syndrome candidate, commercialization is a long way off because, to date, there have been no clinical trials. And while a “next-generation” AAV vector may be used for delivery, it is still unproven as to both efficacy and safety.

Not surprisingly, you mention the Acadia and Stoke Therapeutics collaboration to pursue multiple RNA-based treatments for severe and rare genetic neurodevelopmental diseases, including Rett syndrome.

Stoke Therapeutics is focused on antisense drug development. Its proprietary research platform, TANGO, is designed to address protein deficiency by precisely upregulating target protein expression. Antisense therapies are typically dosed once monthly or quarterly and are delivered by injection into the spinal canal.

Antisense drugs have the advantage of specificity but balancing safety with sufficiently high doses for efficacy has been a challenge (another company I'm in, PYC Therapeutics, is tackling this antisense challenge using cell-penetrating peptide delivery). As with gene therapies, there have been severe adverse effects seen in some clinical trials (see here).

You are probably questioning why it is that biopharma and pharma seem to be flocking to RNA and gene therapies?

Simply, these approaches are seen as the future of medicine. Cutting edge. Sexy. The irresistible promise of a “cure” rather than just treatment of symptoms.

However, RNA and gene therapies are still at an early stage of development and there are still many challenges to overcome. To date, there have been multiple failures in clinical trials on grounds of efficacy as well as some very frightening adverse events, including death, both during trials and several years after treatment. For “one and done” gene therapies that have been approved (which can be priced at up to US$2m), questions have also arisen about duration of effect. Oh, and did I mention payer pushback?

Dr Michael Snape says that he believes that developing a drug to form new synapses and enable learning is, for now, a better approach than gene therapy.

“In an ideal world, gene therapy would be a perfect solution,” Dr. Snape said, but gene therapy comes with serious concerns.

“Even if a gene therapy was directly injected into the brain, it would reach only about 5% of the neurons, and you need to impact them all,” he said. The other issue is that inserting a gene into the brain to compensate for a missing or mutated gene may introduce the same problem or a similar one. “Ultimately this will be solved, but it’s an elastic time period.”

I’m not sure if I’ve answered your question, Sillazze, but I hope this is of some use. I’ve provided some additional reading below in case you're interested.

Ciao!

https://hotcopper.com.au/threads/th...sible-editing.6283772/page-6?post_id=56069153

https://hotcopper.com.au/threads/co...for-vaccines.5969206/page-43?post_id=55900460

https://hotcopper.com.au/threads/co...for-vaccines.5969206/page-29?post_id=55768055

https://hotcopper.com.au/threads/it-will-not-go-unnoticed.6112526/?post_id=53867633

https://hotcopper.com.au/threads/an...ific-officer.5566385/page-16?post_id=51065947

https://www.frontiersin.org/articles/10.3389/fonc.2019.00297/full

https://www.nature.com/articles/s41591-021-01333-6