Q&A: Alumis Inc. Initiates Phase 3 Clinical Program for ESK-001 in Plaque Psoriasis

Alumis Inc. recently announced it has commenced patient dosing in its ONWARD phase 3 clinical program evaluating ESK-001, an oral allosteric TYK2 inhibitor, for moderate to severe plaque psoriasis.¹

The program includes 2 24-week trials, ONWARD1 and ONWARD2, which will assess the drug's efficacy and safety, along with a long-term extension trial, ONWARD3, for evaluating durability and long-term safety. The program aims to confirm positive phase 2 findings and support global regulatory approvals.

Martin Babler, CEO of Alumis, recently spoke with Dermatology Times to discuss the significance of this clinical program and the potential of ESK-001 in the psoriasis treatment landscape.

"There's a lot of broad immunosuppression currently used in many diseases and immune-mediated diseases, and our goal is to have either a monotherapy or combination therapy with very precise, very well-validated therapies and targets in immunology, with the goal to go from, 'It might work for me; it might not work for me,' to medicines that really work for all the patients," Babler said.

Q&A

Q: Can you provide an overview of the significance of the initiation of the ONWARD phase 3 clinical program? What are the main objectives of the program for ESK-001, and how do they build on previous research?

A: The ONWARD program is built on STRIDE, which is our phase 2 program. One of the most fascinating things that we learned about the mechanism that we're pursuing, which is TYK2, which is a very unique mechanism, is that, because it hits mostly IL-23, it also hits IL-12, but it's very, very selective for those 2 targets. In the STRIDE program, we found not only that there were responses in pretty much every patient, but that more than 90% of the patients actually achieved PASI75, so we believe there's a very significant opportunity here in 2 ways.

One is a potential high efficacy oral therapy that could get closer, maybe similar responses, to biologics. The other opportunity we are now looking at is oral therapies in patients with a high level of symptoms who may not have benefited in the past. We are reaching levels of efficacy where we see a benefit in nearly every patient. We believe that is a very different proposition. The ONWARD program aims to confirm not just the phase 2 results, but our phase 2 program extension, where every patient is now on an active dose. More than 150 patients have now been treated for about a year, and we are seeing really fantastic results in that long-term data, a very good safety profile, and efficacy that is beyond what has been seen before with oral therapies. In our phase 3 program, we want to confirm that data to make sure we provide dermatologists with the right data set, not just in terms of short-term but long-term efficacy and safety, to make informed treatment decisions.

Q: What specific aspects of ESK-001's safety and efficacy are you most focused on evaluating in the phase 3 trials?

A: We believe there are 3 key components. One is certainly the PASI scores. The second is PGA scores. The third is to make sure we have patient-reported outcomes. How does this really affect the patients? Those are all very standard measurements. Given that we're a precision immunology company, we have identified a proprietary biomarker, but given the high response rate, we don't believe that ultimately that plays a key role. We are conducting additional work around biomarkers, and especially our proprietary biomarker, to find out if there is a better response in a subset of patients.

Q: Could you elaborate on the long-term extension trial, ONWARD3, and its role in assessing the durability and maintenance of response to ESK-001?

A: The ONWARD program consists of 3 trials: ONWARD 1 and 2, which are 2 identical trials that we're running on a global level, and then ONWARD 3, which will provide 16-week placebo control data. These trials will also provide 24-week active control efficacy data. The ONWARD 3 program is basically the extension that will provide durability data, maintenance data, and also long-term efficacy data. We also have the STRIDE open-label extension program running in parallel, which will provide 2 and 3-year data potentially by the time that ESK-001 is going to launch. We will have long-term data and safety data in about 100 to 150 patients out to 3 years by the time we launch ESK-001.

Q: How does ESK-001's profile compare with the therapeutic landscape for moderate-to-severe plaque psoriasis?

A: We have an oral pill with a mechanism shown in genomic analysis to be very safe. There's a mutation in about 3% to 5% of the global Caucasian population, which mimics largely what we're doing pharmacologically with ESK-001. It turns out that most people with this mutation don't even know that they have it because there is no associated pathology. We believe we have a mechanism that should be very safe, and we want to make sure that we can demonstrate that safety through our ongoing clinical trials of an orally administered medication. The end goal for patients is to take a pill once a day to keep their psoriasis under control.

From an efficacy standpoint, our data to date show we have reached levels of PASI75, PASI90, and even sPGA, that are above and beyond what has been seen with oral therapies today. These results have to be confirmed in the phase 3 trial, and our hope is to replicate a similar outcome. The differentiation is that ESK-001 has potentially enhanced efficacy over current oral molecules, similar to what some of the biologics can achieve, with a favorable safety profile, and offers the convenience of the oral pill. On all 3 of those aspects, we hope that we'll be able to differentiate from current therapies.

Q: What are the next steps for Alumis following the initiation of the ONWARD phase 3 trials, and what milestones are you most looking forward to?

A: There are several key upcoming milestones and readouts. We look forward to seeing how well ESK-001 performs in our psoriasis clinical trials, reading out clinical data from our lupus program, and exploring additional indications to pursue. We are also advancing our second molecule, A-005 in a phase 1 trial to understand how well we're getting into the brain. Lastly, we have ongoing research programs with the goal of advancing additional molecules into the clinic. There will likely be additional opportunities for rheumatology, and also for autoimmune diseases.

Q: Is there anything else that you feel is important for dermatology clinicians to know?

A: I think the most important thing is that we've done significant analysis of TYK2 as a target, especially from the genomic side. The fact that a very significant group of individuals has a very similar mutation to the TYK2 mechanism that we're pursuing without any associated pathology gives us confidence that this mechanism should be very safe. So favorable safety, combined with a molecule that, now for the first time, is able to maximally inhibit this target, presents a truly exciting and differentiated product profile. There have been other TYK2 inhibitors in development, but one of their shortcomings is an inability to fully inhibit the target. Our data has proven to date that we have developed the only TYK2 inhibitor that can maximally inhibit the target. That's where we believe that additional efficacy comes from, especially in the open-label extension study.

Reference

1. Alumis initiates ONWARD phase 3 clinical program evaluating ESK-001, an oral TYK2 inhibitor, in moderate-to-severe plaque psoriasis. News release. Alumis Inc. July 29, 2024. Accessed August 5, 2024. https://investors.alumis.com/news-releases/news-release-details/alumis-initiates-onward-phase-3-clinical-program-evaluating-esk