Regeneron left the American Society for Hematology meeting in San Diego this week with a pair of trial aces, notching a head-to-head win against a rare disease blockbuster and a potential best-in-class performance in the crowded lymphoma market.
For Dr. L. Andres Sirulnik, senior vice president of translational and clinical sciences in hematology, the achievements come down to the company’s long-haul scientific efforts. Regeneron, despite playing catch-up in several disease markets, has a thriving pipeline that Sirulnik believes will disrupt treatment paradigms in a big way.
“We are very excited with what we have at hand, and I’m super busy,” Sirulnik said.
In a late-stage, head-to-head trial against Alexion Pharmaceuticals’ standard-of-care medicine Ultomiris, Regeneron showed that its combination of the antibody Veopoz with an investigative siRNA drug developed with Alnylam Pharmaceuticals achieved better disease control among patients with the rare blood disorder paroxysmal nocturnal hemoglobinuria.
And in follicular lymphoma, Regeneron’s phase 3 study of a bispecific antibody Ordspono led to a complete response in 12 out of 12 patients who had been previously untreated. The result sets Ordspono up for its own head-to-head against lymphoma treatments including chemotherapy and checkpoint inhibitors.
"That’s how we take new technologies and bring them to the table — we go where the science takes us."
Dr. Andres Sirulnik
Senior vice president of translational and clinical sciences in hematology, Regeneron
Here, Sirulnik discusses the important questions Regeneron considers before taking on a drug development endeavor, the implications of these two successful studies and why a disease-based approach has been critical for the company.
This interview has been edited for brevity and style.
PHARMAVOICE: Before we dig into your ASH data, can you tell me a little about Regeneron’s overall approach in hematology?
DR. ANDRES SIRULNIK: Regeneron is a truly science-driven company. We tackle difficult-to-treat problems, but we’re not focused on the platforms, technologies or modalities we use — we’re focused on addressing and understanding the biology and using whatever tools we have on hand to bring new medicines and treatments to patients. Hematology is an outstanding example of how we use different methodologies to address problems. Regeneron is probably one of the greatest companies to work in antibodies, but we have branched from that to bring new tools to address problems in hematology.
What we’ve done with complement inhibitors, for example, is to use an antibody coupled with an siRNA [developed with Alnylam Pharmaceuticals] to bring a differentiated approach and potential improvement on what’s out there for [the rare autoimmune disease paroxysmal nocturnal hemoglobinuria, or PNH]. In that case, we use this RNA to inhibit the synthesis of the protein in the liver that brings down the burden that the antibody needs to tackle — the antibody then has very little left in circulation to inhibit. So this has a more constant, deeper and prolonged inhibition of the protein that you cannot achieve with an antibody alone.
Another example is, in hereditary amyloidosis, we use CRISPR technology in vivo to shut down the production of a protein in the liver. This was the first example of in vivo gene editing using CRISPR. That’s how we take new technologies and bring them to the table — we go where the science takes us.
As you said, the siRNA-antibody combination is synergistic against PNH. How did you go about finding a combo worth pursuing?
The problem is a classic one. What is the problem we’re trying to solve? We have a very abundant target that requires a very significant amount of antibody to inhibit it. And in the case of complement activation, all you need is a minor, minute amount of [the] C5 [protein] to rev up the disease. The advantage we sought was how to decrease the protein, and we do that by inhibiting the synthesis of that C5 protein, knowing that there will be some circulating C5 left because it’s very difficult to have 100% inhibition of the synthesis. So we believe combining the inhibition of the synthesis and activation will provide uninterrupted inhibition coupled with easy administration.
The data has been very encouraging. Versus the standard-of-care long-acting C5 inhibitor [Ultomiris], a larger proportion of patients in the combination achieved disease control. More importantly, what I think is the power of this technology, for five patients who never achieved control on [Ultomiris], four of them achieved immediate disease control. Currently, we’re enrolling a pivotal study where we’re comparing not to [Ultomiris] but to the gold standard [Soliris] in this disease.
Alexion has had a hold on the PNH market for a long time. Where does Regeneron’s option fit into that space?
We bring a lot of value to the table. In terms of the market, we will come with a potentially better drug, a potentially more convenient way of administration. And we have other drugs in the pipeline that we haven’t disclosed yet going into PNH next year that I think will have the potential to disrupt the PNH market.
Switching gears to lymphoma, tell me about the results for the bispecific Ordspono that you’re presenting at ASH. And what are the challenges moving forward?
We’re addressing scientific questions that could potentially change the treatment paradigm in lymphoma — the level of efficacy we have observed overall, and specifically in follicular lymphoma, has been remarkable. When you look at Ordspono in the last line [of treatment] for follicular lymphoma, we saw 80% objective response rate, with 73% achieving complete remission. In first-line, out of 12 patients [who] got the full dose, all of them had a complete response. That is potentially best in class, and we truly believe that level of efficacy affords an option for patients [who] are chemotherapy free.
Safety is a challenge — if you move a bispecific to earlier lines of therapy, you have an intact immune system. In the last line, after tons of immunosuppressive therapy and chemotherapy and so forth, there is weakness in the immune system, and we saw cytokine release syndrome. But we are seeing better permeability and less cytokine release with a single agent in earlier lines.
Another challenge is that the market is crowded, but based on what we saw in late lines of therapy, we think we have potentially a best-in-class [treatment] in follicular lymphoma.
