Personally, I don’t think Neuren will be receiving Breakthrough Therapy designation (BTD) for NNZ-2591 in Phelan McDermid syndrome at this stage.
Linked below is a study on non-oncology BTD requests from 2017-2019. Findings include:
Of 240 non-oncology BTD requests, 93 requests (39%) were granted and 147 requests (61%) were denied.
The therapeutic area of neurology accounted for 12% of BTD requests.
Of the 133 (55%) of the 240 requests that were submitted for indications for which no approved therapies were available, 63 (47%) were granted and 70 (53%) were denied.
Among 63 (68%) of 93 granted BTD requests, no therapy was available for the indication for which the BTD was requested.
Of 240 BTD requests, 90 (42%) were for orphan drugs, of which 47 (52%) were granted and 43 (48%) were denied. In contrast, of 150 (58%) requests that were not for an orphan drug, 46 (31%) were granted and 104 (69%) were denied.
26% (n = 63) of the BTD requests were for drugs designated as orphan and with no available therapy; the rate of granting BTD requests is highest (56%) for this subset of requests.
The latest trial phase supporting a majority of the BTD requests was Phase 2 (n = 50) or Phase 3 (n = 15).
The studies supporting granted BTD requests included at least one randomized trial in 71 (76%) of requests, the majority of which (n = 58; 82%) were blinded.
In 71 (76%) BTD requests, a placebo, vehicle, active control, or no treatment was used in a concurrent control group.
In 60 (65%) of 93 granted BTD requests, information about the statistical significance of the data supporting the requests was included in the BTD request review, and in 90%, the p value was less than 0.05 (including 57% < 0.01).
Insufficient treatment effect was identified as the most frequent reason for denial (n = 50; 58%).
Aspects of trial design were the second most common (n = 46; 53%) reason for denial, including problems related to short study duration making it difficult to assess preliminary evidence of substantial benefit.
Another reason (n = 28; 33%) for denial related to endpoints. Examples of endpoint issues identified include a lack of supportive evidence that the endpoint used by the sponsor predicted a clinically meaningful benefit, or the endpoint did not represent a serious aspect of the disease.
Safety was cited as a reason for denial in 14 (16%) requests.
NNZ-2591 in Phelan McDermid has the advantage of being a post-Phase 2, orphan drug in an indication for which there is no approved treatment. Further, it has a great safety profile and key endpoints in its Phase 2 study were met with high statistical significance.
However, to date, there is no randomized, blinded, controlled trial data to support its case for BTD and, as we already know, the FDA has had an issue with choice of key endpoints.
Hence, I think that BTD at this stage is unlikely. However, if Phase 3 is successful, I would think that a BTD request would certainly be warranted and would have better than even odds of success.
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