Very interesting to compare what Clene is reporting with what we have seen from our phase 1 MEND study and the approach taken to the data analysis:
The study regimen enrolled 161 participants - 120 on the active arm and 41 placebo - of which 145 completed the study - 11 on the active and 35 on placebo. There was an additional 123 patients enrolled across three other regimens (regimens A,B, and D) who added to the number of petients in the placebo arm.
The primary outcome measures for this 24 week study were:
1. Disease progression as measured using the ALSFRS-R. CNM-Au8 was shown to slow disease progression, but not by a lot. The analysis produced a ratio between the rate of decline seen in active vs placebo arms, with a ratio of "1" meaning no difference and values less than "1" representing a slowing. The value observed was 0.98. (The actual rate of decline in the ALSFRS-R scores were -1.01 points per month for the active group vs -1.03 points per month in the placebo group).
2. Mortality event rate (death or death equivalent - permanent assistaned ventilation more than 22hrs / day for more than 7 consecutive days).Over the 24 week study, patient mortality events occurred at a rate of 0.006 per month in the active group, compared to 0.007 per month in the placebo group.
Secondary outcome meaures were:
3. Respiratory function (Slow Vital Capacity or SVC). Active group SVC declined by 9.32% vs 8.53% in the placebo group.
4. Isometric muscle strength (hand-held dynamometry). Muscle strength in the active group declined by 27.54 percent over the 24 week trial period (just think abou that rate of decline for a second) vs 24.44 percent in the placebo group.
5. Number of patients experienceing death or death equivalent (permanent assistend ventilation as per outcome measure 2). 3 pax (2.5 percent) in the active group vs 5 pax (3 percent) in the placebo group.
While the study drug didn't demonstrate adequate separation from placebo to warrant accellerated approval over the trial period, longitudinal data from study patients has now shown a significant survival benefit and falling NfL levels.
Why is this important for us?
Three reasons.
First, the comparison point being used for the longitudinal study is matched controls from the PRO-ACT database - sound familiar? (You can read a summary in plain English of the survival benefit here: https://www.neurologylive.com/view/new-healey-als-trial-results-show-cnm-au8-effect-survival-neurofilament-light). This data has now been submitted by Clene to the FDA to support registration discussions, perhaps demonstrating an increasing willingness on the part of regulators to accept this sort of analysis to support drug approval decisions.
Secondly, the sorts of reductions in NfL we saw in three patients (yes, small number) in our MEND study compares favourably to the 28 percent fall observed after 76 weeks of treatment with CNM-Au8 - partiularly the reductions seen in the higher dose cohort. Finally, the study demonstrates that missing trial endpoints during the trial period isn't the end of the road - particularly when the study drug is giving those signals of efficacy. We've already seen these signlas - very clearly - from the MEND phase 1 results and I expect we will see more supporting evidence from the upcoming update to the OLE study (which has all patients on the higher 10mg/kg dose that was associated with the best results during the study period).
So, although our phase 1 MEND study involved a small number of patients, the signals it is providing are very clear and extremely encouraging.
One closing comment - MND/ALS is invariably fatal. This is why mortality rate is included as an outcome measure in studies. At some point trial patients will succumb to this terrible disease. Let's all hope that MPL can be the drug that slows disease progression in a significant way to give families more time with loved ones and deferring the onset of the worst of its symptoms.
(20min delay)