This concerns multiple sclerosis (MS) drug…

By December 31, 2036, will results be reported from a Phase 3 trial in progressive or non-relapsing MS in which the investigational agent achieves a hazard ratio <=0.60 on a prespecified primary endpoint of 6-month confirmed disability progression, versus placebo or an active comparator?✓#1

probability: 24%

rationale:

The Historical Benchmark As of August 2026, no Phase 3 trial in progressive multiple sclerosis has reported a hazard ratio (HR) at or below 0.60 on a 6-month confirmed disability progression (CDP) primary endpoint. The current high-water mark remains Sanofi’s HERCULES trial of tolebrutinib in non-relapsing secondary progressive MS (nrSPMS), which achieved an HR of 0.69 3 sources. Historical successes have reliably clustered around modest effect sizes—ORATORIO (ocrelizumab) yie

Maintained at 24% as this remains consistent with the steep drop-off in probability for highly transformative efficacy thresholds, sitting logically above the stricter threshold .

Weighed against 3 other forecasts.

dentinstitute.comeuclinicaltrials.eusigma.larvol.comclinicaltrial.beaan.com+213 more

By December 31, 2036, will results be reported from a Phase 3 trial in progressive or non-relapsing MS in which the investigational agent achieves a hazard ratio <=0.50 on a prespecified primary endpoint of 6-month confirmed disability progression, versus placebo or an active comparator?✓#2

probability: 7%

rationale:

The Efficacy Ceiling in Progressive MS Reaching a hazard ratio of 0.50 or lower in non-relapsing progressive multiple sclerosis (MS) would represent an unprecedented leap in efficacy. The best historical benchmark in this space is tolebrutinib’s HERCULES trial in non-relapsing secondary progressive MS (nrSPMS), which achieved a 31% risk reduction (HR 0.69) sanofi.com. Older landmark trials like ORATORIO in primary progressive MS (PPMS) and EXPAND in SPMS achieved hazard ratios around 0.75 and

Retained at 7%, confirming that this exceptionally strict efficacy threshold is far less likely to be met than more moderate benchmarks .

Weighed against 3 other forecasts.

roche.commultiplesclerosisnewstoday.comannerowlingclinic.orgresearchonline.lshtm.ac.ukpharmabiz.com+204 more

By December 31, 2036, will any non-BTK-inhibitor mechanism (e.g. anti-CD40L such as frexalimab, CAR-T or other B-cell depletion approaches, EBV-directed therapies, remyelination agents, or other novel mechanisms) report a statistically significant positive Phase 3 primary endpoint in progressive MS?✓#3

probability: 85%

rationale:

Horizon and Endpoint Hurdles

The overarching driver of this high probability is the combination of a low outcome hurdle and a very long horizon. The criteria require only statistical significance (p<0.05) on a prespecified clinical disability primary endpoint in a Phase 3 trial of 300+ patients, without mandating a specific hazard ratio threshold. Over the ~10.5 years to December 2036, there will be multiple independent non-BTK clinical programs advancing, providing a robust cumulative prob

Held at 85% because a deep clinical pipeline and low threshold for mere statistical significance make this far more likely than strict effect size hurdles .

Weighed against 3 other forecasts.

reddit.comgene.comcgtlive.comclinicaltrials.ucsd.edulinkedin.com+185 more

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