ASH: Pfizer, swimming in crowded waters, eyes wide impact for sickle cell, hemophilia assets

Novo Nordisk and Pfizer are not going head-to-head in hemophilia. But they are, at least, racing side-by-side to bring an anti-tissue factor pathway inhibitor to market to provide a better treatment experience for patients.

While Novo’s efforts hit a roadblock earlier this year, Pfizer is striding ahead with its full data at the American Society of Hematology's annual meeting, with marstacimab showing a significant reduction in annualized bleeding rates among patients without inhibitors who had prior prophylaxis or on-demand therapies.

Pfizer previously reported a 92% reduction in bleeds in its phase 3 BASIS trial, with patients who received on-demand factor replacement intravenous therapy and then switched to marstacimab. The picture hasn't changed from the top-line results released in May, but the presentation at ASH provides a more in-depth illustration of the trial, including its safety data.

The phase 3 BASIS trial is complex, to say the least. Even Pfizer VP Greg Dirusso, M.D., development head for hematology, admitted that with four cohorts, it can be confusing. But the overall goal is to provide a new treatment option for all patients with hemophilia.

BASIS includes patients with hemophilia A and B with or without inhibitors—the four main groups—and then within those groups, the patients were either previously on prophylaxis or on-demand therapy.

Dirusso said in an interview with Fierce Biotech that the data “warrants evaluation of the regulatory authorities.” He said he's satisfied in the overall profile of the med.

“We believe that marstacimab … could be a top treatment for a broad range of patients,” Dirusso said.

The need is particularly great in hemophilia B, where patients currently do not have a subcutaneous option for treatment. Patients without inhibitors on prophylaxis have to take intravenous therapy as frequently as every week, and sometimes more often. Dirusso said that marstacimab is dosed once weekly subcutaneously using "flat dosing," so the amount does not change depending on weight. That has allowed Pfizer to plan for an auto-injector device to further ease the patient's burden. 

The therapy did not meet a secondary goal measuring hemophilia quality-of-life indicators. In the on-demand population, superiority was not met but the data showed a point estimate favoring marstacimab. The trial did claim non-inferiority in the routine prophylaxis group, but Pfizer’s drug was not better than existing treatments.

Dirusso said data on that endpoint will not be the focus of the ASH presentation, and that more details will be available later.

There were no deaths or thrombotic events in patients with hemophilia and no suggestion of consumptive coagulopathy, where the blood forms clots inside vessels. The safety data were also consistent with earlier phase 1 and 2 results, Dirusso said.

Speaking to the competitive pressure from Novo Nordisk, Dirusso was cautious but pointed to dosing and safety as key attributes that could put Pfizer’s program ahead.

“We want to be very cautious about any comparisons with regard to data or results because there was no head-to-head study,” he said.

Detailed in the ASH presentation is the demographic breakdown of the study. The BASIS trial’s 128 patients were 50% white and 47% Asian. There was one Black patient in the routine prophylaxis group—Dirusso acknowledged that there is likely an under-representation of Black patients relative to the disease burden in the trial. He says the study began enrolling during COVID, which meant they had to recruit based on availability of the sites.

Speaking to the challenges of recruiting during that timeframe, Dirusso said, “there was a time when many of us who do clinical trials for a living, were not really sure if it was ever going to be the same again.”

The New York pharma is still waiting for data on the inhibitor cohort, which is the indication where Novo’s asset was rejected by the FDA. Dirusso said Pfizer’s version is fully enrolled and data will be available next year.

Sickle cell

Pfizer is also showcasing the sickle cell medicine GBT601 at ASH. The therapy was part of its 2022 acquisition of Global Blood Therapeutics. GBT601 is a sickle hemoglobin polymerization inhibitor being tested in a phase 2/3 trial. The preliminary results were for 35 patients from the first two doses tested, 100 mg and 150 mg. The primary endpoint is hemoglobin change from baseline.

GBT601 led to a 2.7 gram per deciliter increase in hemoglobin in the 100 mg group and a 3.2 gram change for the 150 mg dose at week 12.

Safetywise, 63% of patients, or 22 out of 35, experienced a treatment-emergent adverse event of some kind, with the most common being sickle cell anemia with crisis. Three patients reported this event in the 100 mg group and two in the 150 mg arm.

There was one death in the study, but it was deemed to be unrelated to the study drug. Dirusso said the patient had a history of stroke and seizure heading into the trial. The other main adverse events reported were headache, upper respiratory tract infection and diarrhea.

“The issue is that this is a highly morbid disease. And so events like headache and diarrhea, abdominal discomfort, even seizure, unfortunately, are relatively common events in this patient population. So the profile that we're seeing we feel is typical of the population and reflects, you know, a generally well-tolerated intervention,” Dirusso said.

Sickle cell is another space where Pfizer is wading into some crowded competitive waters. CRISPR Therapeutics, Vertex Pharmaceuticals, bluebird bio, Intellia Therapeutics and many others are all working on treatments. Dirusso is not dismayed by the crowd.

“That's a good thing, I have to say. I think it's an area where it's been underserved. I think there's a tremendous amount of unmet medical need,” he said. He said Pfizer recognized the need when executing the acquisition of GBT, and that he's happy that patients will soon have many options to choose from.

“What we're recognizing is in a disease where there's been insufficient development, there are opportunities to address the disease from different angles,” Dirusso said.

GBT601, as well as Pfizer’s approved sickle cell disease treatment Oxbryta, address the red blood cells by stabilizing hemoglobin in the oxygenated state. In other words, Pfizer is hoping to shut down the process that causes the cell to form sickle shapes in the first place.

Other ways to tackle the disease include going after the vaso-occlusive crises and end-organ damage. Pfizer also has inclacumab, which also came from GBT,  in its pipeline to target that phase of the disease.

GBT, long before Pfizer came along, once touted GBT601 as a “functional cure” for sickle cell disease. Dirusso said he is not comfortable with that language at this point in the development timeline.

“That's aspirational at this time. With 12-week data, I think it would be preliminary in my cautious opinion,” Dirusso said. “The data are very encouraging, and they're consistent with what we had hoped to see.”

But Pfizer is hopeful that GBT601 will start to look a lot like Oxbryta—another asset claimed from GBT—in terms of modifying the disease as patients are followed for a longer period of time in the follow-up portion of the trial.

Currently, Pfizer is working with regulatory authorities around the world and considering a registrational study. The pharma is also “looking at these data internally to make a decision about next steps,” Dirusso said.