Bristol Myers Squibb and J&J’s Janssen look to move forward with a Phase III of their factor XIa drug in preventing secondary stroke despite missing the goalpost on a composite endpoint, the companies said Sunday morning at the European Society of Cardiology Congress.
During the same session, factor XIa competitor Bayer also announced it had missed the composite endpoint in a mid-stage stroke trial.
While not clearing the hurdle on the primary endpoint combining events of symptomatic ischemic stroke and brain infarctions observed by MRI, BMS and J&J duo thinks a relative 30% reduction observed in the former, as compared to placebo, will propel the factor XIa inhibitor into a large Phase III later this year.
Also supporting the pharmas’ confidence is a sign the drug led to very few bleeding events, a concern that has plagued anti-coagulants from being used in this patient population.
“This profile of milvexian holds as something that’s very efficacious for preventing life-threatening blood clots without having the same level of bleeding liability as current agents,” James List, Janssen’s global lead for cardiovascular, told Endpoints News ahead of the AXIOMATIC-SSP trial data presentation at the European Society of Cardiology Congress on Sunday.
The drug is seen as a future growth driver at Bristol Myers and is one of the main factor XIa inhibitors being closely observed by the industry, along with Bayer’s asundexian, which also came out with data Sunday morning.
Some figures of the BMS-J&J trial: 2,366 patients were randomized to the global Phase II. Of those, 691 patients were on placebo and 1,635 were on the study drug; 162 patients in the placebo group dropped out (82 cited an adverse event) and 412 in the investigational treatment cohort discontinued treatment (264 due to an AE).
All patients had a stroke within 48 hours prior to randomization and were given clopidogrel (an anti-platelet med) and aspirin for the first few weeks. From day 22 to day 90, they remained on aspirin and were given either placebo or milvexian.
In the placebo group, 16.6% of patients had a composite endpoint, meaning either they experienced a symptomatic ischemic stroke at any point during the study or a brain infarction observed by MRI at day 90, the end of the treatment period. That figure was 16.2% for the 25 mg once-daily cohort. For the twice-daily groups, the figures were: 18.5% for 25 mg, 14.1% for 50 mg, 14.8% for 100 mg and 16.4% for the 200 mg arm.
But the company honed in on the symptomatic ischemic stroke portion of the combined primary endpoint. When broken down, 6.1% of the patients on placebo were reported to have symptomatic ischemic stroke. But that percentage was lower across four of the five cohorts of the oral drug:
4.9% of the once-daily 25 mg arm
4.2% of the twice-daily 25 mg
4.2% of the 50 mg
4.0% of the 100 mg
The company said those figures represent “approximately 30%” relative risk reduction for symptomatic ischemic stroke in three of the milvexian cohorts. About 8.5% of the 200mg group experienced a symptomatic ischemic stroke, with List characterizing that arm as an “anomaly,” noting the companies are sifting through the data “in great detail” to understand why the group experienced more stroke events.
“This sort of efficacy, to see a 30% reduction in actual strokes, this is sort of unheard of today,” said Puneet Mohan, Bristol Myers’ VP for milvexian’s clinical development, in a joint interview with List a couple kilometers from the conference, near the FC Barcelona stadium. “That’s why we’re so excited to see this in Phase II.”
List said the companies had “healthy internal debate” about whether to use the composite endpoint. Mohan noted the MRI portion of the endpoint isn’t an accepted surrogate by the FDA and had never been included in an acute stroke population prior to their trial — “so that was also like an experiment within an experiment.”
“Nevertheless, it seems from first principles that it should track with clinical strokes, but in fact, the history of looking at these, it hasn’t always tracked,” List said of the MRI-observed brain infarction endpoint.
Bayer, a competitor in the factor XIa inhibitor field, also said it didn’t expect to see higher rates of MRI-determined brain infarctions in a Phase IIb study, PACIFIC-STROKE, for which results were presented minutes ahead of BMS and J&J.
“The flare imaging is not as predictive when it comes to looking at an effect of the intervention as we thought it would be, meaning the flare imaging is actually not as good as a biomarker for real stroke as was hypothesized,” Bayer’s pharma clinical development leader, Christoph Koenen, told Endpoints ahead of the Sunday presentation.
BMS’ Mohan noted the AXIOMATIC-SSP data will “add to the scientific knowledge” and further contribute to the debate of whether it should be used to measure stroke events.
“We weren’t expecting to see a 30% reduction. That’s why we needed more endpoints,” List said. “We would have been very happy with a lesser reduction, but you can imagine if this reduction were something like 15%, we’d be scratching our heads and saying, ‘We wish we had more data points to be sure of it.’”
The drug led to no fatal bleeding, the companies said, and there were low instances of so-called BARC type 3C bleeding, which is characterized by intracranial hemorrhage. There were two of those in the placebo group, three in the 50 mg arm and one in the 200 mg cohort, the companies said.
Overall, 9.7% of the placebo group cited bleeding as an adverse event. In the milvexian arms, those figures were: 9.5% in the once-daily 25mg group, 8.6% in the 25mg twice-daily cohort, 14.8% for 50mg, 13.4% for 100mg and 12.2% for 200mg.
In genetic studies dating back decades, factor XI has been seen as a potential target because of observations in Ashkenazi Jewish people, who were observed to have decreased rates of strokes and didn’t suffer from spontaneous bleeding because of deficiencies of factor XI, Mohan said.
“This is in a way confirming what I said to you in the genetic model. People say, ‘Oh yeah, these people have less strokes but they don’t seem to bleed spontaneously,’ and saying, ‘OK, so we’re mimicking exactly that situation here,’” Mohan said.
In a different patient population last November, the drug passed a Phase II trial in preventing blood clots in patients who had total knee replacement surgery. No patients in the milvexian arms reported major bleeds in that study.
The potential late-stage trial in preventing secondary strokes will be bigger and will likely go beyond a 90-day treatment period, Mohan and List said. The risk of stroke, albeit not as steep, is still there after 90 days as is the risk of bleeding, they noted.
“This is a drug which we really think is going to be useful long term like a chronic treatment,” Mohan said, “so we need to find a duration where we can sit comfortably and say, ‘In Phase III, should we test a longer duration?’ And the answer is yes.”
Mohan previously led clinical development of BMS’ apixaban, sold as Eliquis, a factor Xa inhibitor for treating and preventing blood clots and stroke in people with nonvalvular atrial fibrillation.
People always ask him, “‘Why didn’t you test in this population?’” Mohan says, referring to secondary stroke prevention.
“Because of the fear of bleeding,” Mohan responds.
With that in mind, List said “there’s nothing incremental about” the data out of AXIOMATIC-SSP.
“This is something that we’ve been wishing for our collective careers to find a way to treat patients,” List said.
“It’s changing the pattern, to be honest,” Mohan cut in.
“Without making them bleed,” List concluded.
The percent of serious adverse events ranged from 11.4% to 15.7% in the milvexian groups and 13.8% for the placebo group. There were five deaths recorded in the treatment arms and none in the placebo group.
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