SerpinPC eases joint involvement in severe hemophilia: Trial data

The ongoing clinical trial has been conducted in six separate stages

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Almost three years of treatment with SerpinPC was associated with a nearly complete resolution of bleeds and a reduction in the number of affected joints among men with severe hemophilia A or B who participated in a Phase 1/2a clinical trial.

The findings, presented by developer Centessa Pharmaceuticals at the recent 17th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD), support ongoing registrational trials that would be expected to buttress future regulatory applications.

“The compelling data from the ongoing Phase 2a study further demonstrate the potential for SerpinPC to be a convenient subcutaneous [under-the-skin] treatment with a differentiated safety profile for people living with hemophilia,” Saurabh Saha, MD, PhD, CEO of Centessa, said in a company press release. “These data also reinforce our confidence in SerpinPC’s novel mechanism of action as we continue to advance the registrational studies with the goal of bringing a new therapy option to patients and physicians.”

These include PRESent-2 (NCT05789524), which is evaluating SerpinPC in up to 120 people with moderate to severe hemophilia B without inhibitors and severe hemophilia A with or without inhibitors, and PRESent-3 (NCT05789537), which is enrolling about 12 hemophilia B patients with inhibitors. Both are seeking male patients, ages 12-65, at sites globally.

Also ongoing is PRESent-5 (NCT05605678), an observational feeder trial that’s enrolling around 200 patients at sites worldwide. Its goal is to collect bleed data while patients are on standard therapies before they enroll in PRESent-2 or PRESent-3.

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How does SerpinPC work?

Blood clotting, or coagulation, involves the serial activation of a number of different blood clotting factors. In each type of hemophilia, one of these factors is missing or dysfunctional, making a person susceptible to excessive, prolonged, or spontaneous bleeding.

Replacement therapies that provide patients with the clotting protein they lack are the standard treatment for hemophilia. Some people develop inhibitors, or neutralizing antibodies, against the delivered clotting factors, however, reducing their effectiveness.

SerpinPC reduces levels of activated protein C (APC), which normally controls coagulation by limiting the generation of thrombin, an enzyme involved in the final stages of blood clotting. In doing so, SerpinPC helps increase thrombin production, facilitating blood clotting. The therapy should be effective for hemophilia patients regardless of disease severity or inhibitor status, and may be used in other bleeding disorders too, according to Centessa.

The open-label Phase 1/2 AP-0101 clinical trial (NCT04073498) is investigating the safety and efficacy of SerpinPC via subcutaneous injections at various dosing regimens.

It’s being conducted in six parts. The first established the safety of single ascending doses in healthy men and men with severe hemophilia A or B (with or without inhibitors).

For parts 2 through 6, which make up the Phase 2 portion, 23 other patients with severe hemophilia were enrolled. In part 2, they received SerpinPC at a dose of 0.3, 0.6, or 1.2 mg/kg once every four weeks for 24 weeks, or about six months.

Those who remained in the trial then received a flat dose of SerpinPC (60 mg) every four weeks for another year (part 3), followed by a dose of 1.2 mg/kg every two weeks for another six months (part 4).

The results generally indicated SerpinPC was safe and led to significant reductions in overall and spontaneous bleed rates over pretrial (baseline) rates.

After 2.8 years of treatment

The presentation, titled “SerpinPC in persons with severe haemophilia (PwH): updated results from a multicentre multi-part, first-in-human study,” concerned data from part 5, where participants continued to receive SerpinPC at the same dose as in part 4 for another year.

The period from the start of part 2 to the end of part 5 amounted to 2.8 years of SerpinPC treatment. Twenty hemophilia patients remained enrolled at the start of part 5.

As reported, total annualized bleed rates declined by 96%, from 35.6 yearly bleeds at the baseline to one per year by the end of part 5. Spontaneous bleed rates declined by 95%, from 30.3 at baseline to one a year in part 5.

All the participants had target joints — specific joints where bleeding was recurrent — at baseline, whereas only two had them by the end of part 5. The median number of target joints per patient dropped by 100%, from three at baseline to zero at the end of part 5.

SerpinPC was well tolerated and no side effects related to the treatment were seen. There were no unexplained elevations in D-dimer, an indicator of excessive thrombin generation, across all parts of the trial. Only one person developed antibodies against the therapy, but they weren’t associated with a decrease in SerpinPC’s effectiveness.

Sixteen patients completed part 5 and entered part 6, where they’ll receive a flat dose of 60 mg, once every two weeks for another year.

SerpinPC has been granted orphan and fast track designations in the U.S. for hemophilia B, to expedite its clinical development.