MSL: Thank you for taking the time to meet with me today, Dr. Chen. I wanted to discuss our S1P receptor modulator for ulcerative colitis and the recent phase 3 data.
Dr. Chen: I've been following the development of S1P modulators with interest. The oral route of administration is certainly appealing to many patients. What can you tell me about the efficacy data?
MSL: In our phase 3 induction studies, we demonstrated clinical remission rates of 18% at week 10 compared to 6% with placebo. For maintenance, among those who responded to induction, 38% achieved clinical remission at one year versus 12% on placebo. Importantly, we saw mucosal healing in 42% of patients in the maintenance phase.
Dr. Chen: How do those results compare with biologics? The remission rates seem somewhat lower than what we see with advanced therapies.
MSL: You're right that the absolute remission rates appear lower than those reported for some biologics, though cross-trial comparisons have limitations. However, it's important to note that our trials included a high proportion of patients who had failed biologics – 56% had prior TNF failure and 25% had failed both a TNF and an integrin inhibitor. In the biologic-naïve population, our remission rates were 24% at induction and 45% in maintenance.
Dr. Chen: That's helpful context. What about onset of action? Speed can be critical for patients with active disease.
MSL: We observe symptomatic improvements as early as week 2, with significant differences in rectal bleeding and stool frequency subscores. However, the full treatment effect develops over 8-10 weeks, which is somewhat longer than what's typically seen with IV biologics. This is consistent with the mechanism of action, which involves preventing lymphocyte trafficking rather than directly neutralizing inflammatory cytokines.
Dr. Chen: Safety is a major consideration with S1P modulators given what we've seen in multiple sclerosis. What's been observed in IBD patients?
MSL: The most common adverse events are consistent with the class: lymphopenia, which is an expected pharmacodynamic effect, mild transient bradycardia with first dose, and ALT elevations in about 4% of patients. For serious adverse events, we observed herpes zoster at a rate of 2% versus 0.5% for placebo, and a small increase in non-melanoma skin cancers (1.1% vs 0.4%). We haven't observed the opportunistic infections or PML cases that have been concerns with other immunomodulators.
Dr. Chen: Do you require first-dose observation like some other S1P modulators?
MSL: Our label does recommend 6-hour monitoring after the first dose for patients with certain cardiac risk factors, including heart rate <55 bpm, second-degree or higher AV block, or history of myocardial infarction or heart failure. For patients without these risk factors, 4-hour monitoring is sufficient. Importantly, we don't require a dose titration schedule, which simplifies the regimen.
Dr. Chen: What about pregnancy considerations? Many of my UC patients are women of childbearing age.
MSL: Animal studies have shown teratogenicity, so the drug is contraindicated during pregnancy. We recommend effective contraception during treatment and for 1 month after discontinuation. There's a pregnancy registry collecting outcomes for any inadvertent exposures. For patients planning pregnancy, we typically recommend transitioning to an alternative therapy with better established pregnancy safety data.
Dr. Chen: I've had some concerns with vaccinations with other agents. Any specific guidance here?
MSL: Live attenuated vaccines are not recommended during treatment due to the immunomodulatory effects. For non-live vaccines, the responses may be diminished but still protective. We recommend completing any needed vaccinations, including zoster vaccination for eligible patients, before initiating therapy. Once on treatment, annual influenza vaccination is still recommended despite potentially reduced immunogenicity.
Dr. Chen: What about combination therapy? Many of my patients are on multiple agents.
MSL: Our phase 3 program allowed stable doses of oral 5-ASA and low-dose corticosteroids (≤20mg prednisone equivalent). About 30% of patients were on concomitant immunomodulators at baseline. We didn't observe any unexpected safety signals with these combinations. However, we don't have dedicated studies on combination with biologics, which would theoretically increase immunosuppression and is not currently recommended.
Dr. Chen: This is very helpful information. I have several biologic-refractory patients who might benefit from a different mechanism of action. Are there any predictive biomarkers of response?
MSL: We've analyzed various baseline parameters. Interestingly, patients with elevated fecal calprotectin (>500 μg/g) actually showed higher remission rates than those with lower levels, which differs from what's been observed with some other agents. We're also investigating gene expression profiles and histologic features that might predict response, with data expected later this year.
Dr. Chen: I'd be very interested in those results when available. One more question – are there any head-to-head studies against other advanced therapies planned?
MSL: We're initiating a pragmatic, phase 4 study comparing our S1P modulator to ustekinumab in biologic-experienced patients, with a primary endpoint of steroid-free clinical remission at week 52. This will include endoscopic endpoints as well as patient-reported outcomes and quality of life measures.
Dr. Chen: That study will provide valuable comparative data. Thank you for the scientific exchange today.
MSL: Thank you for your time and thoughtful questions, Dr. Chen. I'll send you the subgroup analyses for the biologic-refractory population.