Relief Therapeutics Holding AG (RLFTF)

[J-Belfort]

DD From WHINO
- Based on the below, the inputs for the primary endpoint calculation was definitely changed between the interim 28 day PR/SSRN on Feb 23rd and final 60 day PR on March 29th . The interim Feb 23rd, 28 day PR included the primary endpoint for all 196 patients (Hazard Ratio 1.53; P=.08) AND also sub-grouped to 94 patients in tertiary care (HR 1.84; P=.058). These results were calculated by controlling for 4 factors: baseline age, baseline NIAID score, baseline Respiratory Distress Ratio, and previous antiviral therapy using, the Cox Proportional Hazards Model

- The 60 day PR we got March 29th, specifically mentions controlling for ventilation status and treatment site. CLEARLY, these factors were not included in the interim 28 day calculations we got on Feb 23rd. So, they seemed to CHANGE the controlling factors between Feb 23rd and March 29th. In the 60 day data, the primary endpoint was controlled for site where as on Feb 23rd, it was not, and instead tertiary sites were broken out into a sub-group p-value (HR 1.84; P=.058).
- Controlling for ventilation status, which I take to mean use of a ventilator (mechanical/NIPPV) or not (HFNC) is a measure of 'severity'. They Feb 23rd already controlled for some form of severity using baseline NIAID scale and respiratory distress ration - so perhaps ventilation status was used to gain further precision on severity.
- Remember, NRX seems to have a good working relationship with the FDA. Endpoints have changed (60 day, no relapse, composite) even after trial completion. We have over an ENTIRE MONTH between 28 day Feb 23 and 60 day March 29th. It is HIGHLY likely NRX and FDA had some form of correspondence between Feb 23 and Mar 29. Given this, it is worth asking this question: Did NRX discuss with the FDA the change of parameters to use in the Cox model to use ventilation status and site? Controlling is OK and as FDA guidance clearly says: "Scientifically justified changes based on information external to the trial can be acceptable and sponsors are encouraged to discuss these changes with FDA." It appears controlling for treatment site falls in the category of 'scientifically justified changes...external to the trial'. I think controlling for severity using ventilation status is already covered likely wouldn't need too much FDA discussion.
- Again, let's go back to TRUST - Lavin is the GOAT and JJ has has brought many FDA approved products to market. They KNOW they data will be fully scrutinized by peers and the FDA. They would not put out these numbers unless they believed they would hold up to scrutiny. I trust these numbers are legit for the FDA to grant EUA.
- Quotes from 28 day interim SSRN:
- "The lifetable (Fig 1) depicts the prespecified primary endpoint of recovery from respiratory failure with discharge and continued survival through 28 days. When this endpoint is analyzed by the Cox Proportional Hazards Model, correcting for age, baseline NIAID, baseline severity of respiratory failure and use of previous antiviral therapy, the cumulative probability of recovery from respiratory failure, Aviptadil-treated participants were 35% (calculated as (1-(1/HR))) more likely to reach the prespecified composite endpoint than were participants treated with placebo (Hazard Ratio 1.53; P=.08). Participants treated in tertiary care hospitals demonstrated a 46% increased likelihood of reaching the composite endpoint (HR 1.84; P=.058)."
- "All analysis was by “intention to treat”; no subjects were excluded from any analyses. The primary composite endpoint of “alive to day 28 and free of respiratory failure was assessed based on (1) survival, (2) discharge from acute care hospital to either home or long term care, and (3) reaching NIAID score of 6-8. The cumulative distribution of the composite endpoint was displayed with censoring for death only at day 28 as is standard in a cumulative probability lifetable. Differences between drug and placebo were ascertained by Cox Proportional Hazards model controlling for baseline age, NIAID score, Respiratory Distress Ratio, and previous antiviral therapy. Median Time in hospital for participants who recovered from Respiratory Failure was calculated together with 95% confidence intervals."