Making Sense of it All

We live in a world of instant access to information. This is true not only for world, national and local news but also Rett news. On a daily basis our inboxes and social media accounts are flooded with all sorts of alerts, announcements, press releases, analyses and more. It can be confusing to understand how all this information fits into the greater scheme of things and where exactly are we in our quest for a cure for Rett?

Key to understanding where we are on our quest is to first understand the various stages of research. The effort to cure a disease typically starts in academic labs run by basic scientists. From a non-profit perspective this stage of research involves funding scientifically sound and well-hypothesized efforts in many different areas (genetics, biochemistry, neurobiology, physiology, etc.) but also includes funding research in an ad-hoc, more forgiving fashion (throw stuff at the wall and see what sticks) as well. Over time the general knowledge base expands and becomes the foundation that supports the next steps.

The next stage involves enabling the key basic science discoveries to generate a “lead compound” that can be taken to the next level of development. One that would give the lead compound legs to become a real therapy for Rett and attract biotech and pharma companies. For my colleagues and me this requires assembling teams of academic and industry scientists, with not only experience and skill but also a collaborative spirit. It means larger multi-million dollar awards, a clear path for development identifying key success and failure points, constant monitoring of milestones and vigilance for new technologies that might be relevant. These efforts are anything but ad hoc.

All of our Roadmap to a Cure programs (gene therapy 2.0, RNA and DNA editing, RNA trans-splicing, MECP2 reactivation, protein replacement) are in this phase. Our expectation is to move these programs through the lead compound stage to the next stage, IND enabling studies, within one to two years.

An IND, or Investigational New Drug Application, is the required program to develop a therapy for a specific indication (like Rett Syndrome) in the US and is submitted to and approved by the FDA before human trials can begin and remains active as long as the therapy is being developed.

IND-enabling studies include all the experiments that are required by the FDA before applying for permission to start human clinical trials. These studies include:

• Animal pharmacology and toxicology studies – experiments which assess whether the product is safe to test in humans
• Chemistry and manufacturing information – experiments which ensure the product can be adequately and consistently produced
• The clinical protocol and investigator information – detailed clinical trial protocols and information on the investigators who would participate in the trial.

The timeline to complete IND-enabling studies is typically 18 to 24 months with an average cost of $10 to $15 million per lead compound. If the FDA approves the IND it’s off to the races with clinical trials in humans.

The AveXis/Novartis product is currently at this phase of development. The basic science and lead compound development work was funded by RSRT through our Gene Therapy Consortium 1.0. We purposefully recruited Brian Kaspar into the Consortium with the hope that the data generated would be sufficiently encouraging that his company, AveXis, would want to pursue Rett as an indication. A million things could have gone wrong but fortunately the pieces fell into place. AveXis funded the IND-enabling experiments and filed the IND application with the FDA. We are currently awaiting word regarding when the clinical trial will start.

When the human trials are completed and the company is confident of safety and efficacy of the therapy a New Drug Application, or NDA, is submitted to the FDA for review. If the treatment has demonstrated sufficient safety and efficacy up to FDA standards, drug approval and commercialization follow.

So now you know the process and at which stage our programs fall. What you may not know is how difficult every step of this is. Each step comes with its own set of challenges not to mention expense. And none of it happens on its own. Academics are great at making discoveries but they are not the ones who develop drugs. The great divide between an academic discovery and lead compound development is aptly called the “Valley of Death”. One of the key responsibilities of RSRT’s research team is to not only ensure that discoveries are made but to then ensure that they don’t languish. Each program needs to be nurtured and the right partners brought in to move it along. Fortunately our research team collectively has decades of drug development experience as well as business development experience. We are well suited to take on this massive responsibility.

We are thrilled that gene therapy trials in Rett will begin soon. If that proves to be a cure, our work will expand to include ensuring that gene therapy is widely accessible for all with Rett. In the meantime we continue to move our rich pipeline of potential products forward. Our goal is to bring a gene therapy 2.0 product to the clinic by 2021 followed by four other non-gene therapy products. I and my team look forward to keeping you updated.