The market appears to be nervous of the pending outcome of Neuren’s Breakthrough Therapy Designation application. Although I can understand the reasons for skittishness and am fully aware that there is no such thing as a guarantee when it comes to any FDA decisions, I am still of the view that Neuren has a better than even chance of achieving Breakthrough Therapy status for NNZ-2566 in the treatment of Rett Syndrome. Why? Well, as far as I can see, it ticks all the boxes.
Breakthrough Therapy Designation Checklist
- Must meet the criteria for a “serious condition”, as defined by the FDA. Careful reading of the FDA's criteria suggests that it does. Tick.
- The FDA says it wants clinical data as supporting evidence. Neuren is obliging. Tick.
- The FDA says it doesn’t want data which is dependent on a post-hoc analysis of a failed trial. Neuren’s data isn’t. Tick
- The FDA says that substantial improvement over available therapies on at least one clinically significant endpoint must be proven. This is not so hard for Neuren as there is no currently available therapy. To add to certainty, Neuren’s Phase 2 trial data demonstrates improvement on three clinically significant endpoints. Tick.
- The FDA says that evidence should not be too preliminary eg. a trial which is too small or too short. In previous guidance, the FDA has said that the Breakthrough Therapy program will ideally assist the accelerated development of products at the end of Phase 1 or 2. Neuren has reached that stage as it has completed one Phase 2 trial. Although its trial numbers (53) could be considered fairly small, it should be taken into account that Rett Syndrome is categorised as a rare disease. The FDA has historically shown flexibility in its consideration of rare disease trial data. It’s also worth noting that Breakthrough designations based on much smaller trial numbers have already been granted by the FDA. Tick.
- The FDA says that sponsor companies must be able to justify the endpoints used in their trials. Joe Horrigan (VP of Clinical Development and Medical Affairs) and Larry Glass (CSO), as discussed in a previous post (20/1), are considered by their peers to have expertise in evaluating clinically meaningful endpoints. Tick.
- A key maxim of medicine is “Do no harm”. The FDA has stated that superior safety and tolerability is the key factor when considering designation on the basis of early data. Both dose levels of NNZ-2566 used during the trial were found to be well tolerated and no safety concerns were observed. Tick.
- The FDA says that a Breakthrough Therapy will typically have a compelling scientific rationale and promising mechanism of action. Interestingly, a published paper which discusses the efficacy, pharmacokinetics and mechanisms of IGF-1 derivatives on protecting acute brain injury, preventing memory impairment and improving recovery from neurological degenerative conditions has just been published online (prior to journal publication). Prof. Margaret Brimble, designer of NNZ-2566, is a co-author.* Tick.
- The FDA wants to see evidence that the sponsor company has made adequate CMC preparation. Neuren flagged its preparations some time ago (post on 22/01). Tick.
- As proven in the case of the rare disease Duchenne (post on 23/11), patient advocacy can be of crucial importance in swaying the FDA. In a video last November, Dr Kaminsky (CSO of Rett advocacy group, Rettsyndrome.org) could be seen to be visibly delighted with Neuren’s Phase 2 results and clearly stated that his organization would be working together with the FDA and Neuren to determine “the next step” for NNZ-2566. Tick.
- Kaminsky’s latest video makes it quite clear that Rettsyndrome.org is now actively lobbying for the FDA to accelerate the clinical development of NNZ-2566. As he says, both he and Rett sufferers cannot wait for the “perfect” drug that addresses all parts of the biology of the syndrome to become available. He stresses that if a safe drug is available NOW that can correct even some parts of the biology of Rett Syndrome, the FDA needs to accelerate development of that drug NOW. Tick.
- Neuren has made the decision to announce its application for Breakthrough Therapy designation. Some might view this as a strategic error because it means that a knockback by the FDA would become public knowledge. I think that Neuren’s strategy of going public is carefully calculated to harness the strong support/pressure that it knows the Rett community will bring to the FDA in support of its application. Tick.
A cautionary note– this checklist simply reflects my (inexpert) opinion, albeit based on many hours of research.
* http://informahealthcare.com/doi/abs/10.1517/14728222.2015.1010514?journalCode=ett
(20min delay)