SerpinPC for Severe Hemophilia

(PRESent-2 Trial)

Recruiting at 58 trial locations

Overseen By Centessa Pharmaceuticals

Age: Any Age

Sex: Male

Trial Phase: Phase 2

Sponsor: ApcinteX Ltd

Must not be taking: Emicizumab, Anticoagulants, Antiplatelets

Disqualifiers: Thrombophilia, Cancer, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new injection called SerpinPC to prevent bleeding in people with severe hemophilia A or B. It aims to see if SerpinPC is safe and effective, especially for those who don't respond well to other treatments. SerpinPC works by helping the blood clot better. Serpins are being explored as potential treatments for hemophilia by rebalancing coagulation.

Do I have to stop taking my current medications for the trial?

If you are currently in a prophylaxis program, you must stop prophylaxis before the first dose of SerpinPC. The protocol does not specify about other medications, but you cannot use emicizumab 24 weeks before the trial or be on anticoagulant or antiplatelet drugs.

Will I have to stop taking my current medications?

Participants currently in a prophylaxis program must stop their prophylaxis before starting SerpinPC. The protocol does not specify other medication restrictions, but you should discuss your current medications with the study team.

What data supports the idea that SerpinPC for Severe Hemophilia is an effective treatment?

The available research does not provide specific data on SerpinPC for Severe Hemophilia. However, it highlights the importance of early diagnosis and long-term preventive treatment to improve quality of life and prevent complications in severe hemophilia. Other treatments, like prophylactic therapy, are shown to be more effective than treating bleeding episodes as they occur, although they can be costly. This suggests that consistent preventive approaches are beneficial in managing severe hemophilia. ^{1 2 3 4 5}

What safety data is available for SerpinPC in treating severe hemophilia?

The provided research does not specifically mention SerpinPC or its safety data. The studies focus on inhibitor development and adverse reactions related to various clotting factor concentrates used in hemophilia treatment, but do not provide information on SerpinPC. Therefore, no specific safety data for SerpinPC is available in the given research. ^{6 7 8 9 10}

Is the drug SerpinPC a promising treatment for severe hemophilia?

Yes, SerpinPC is a promising drug for severe hemophilia because it targets natural proteins in the body to help balance blood clotting, which can reduce bleeding. ^{11 12 13 14 15}

How is the drug SerpinPC different from other treatments for severe hemophilia?

SerpinPC is unique because it targets and inhibits natural anticoagulant proteins, like activated protein C, to help restore the balance between bleeding and clotting, unlike traditional treatments that replace missing clotting factors. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for males aged 12-65 with severe Hemophilia A or moderately severe to severe Hemophilia B, without inhibitors. Participants must have a history of bleeding episodes and be on or willing to commit to a prophylaxis program. Adolescents can join after safety assessments in adults.

Inclusion Criteria

At least 12 weeks of prospective documentation of bleeding episodes in the AP-0105 non-interventional study before SerpinPC dosing for Part 1, or willing to complete a 12-week observational period in AP-0102

Able to use a diary to document bleeding events and medication usage

Capable of providing written informed consent (adolescent assent and parental/guardian/legal representative consent when appropriate)

Exclusion Criteria

History of intolerance to SC injections

History of recent alcohol or drug abuse in the 12 months before Screening

I weigh more than 150 kg or my BMI is over 40.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Prospective Observation

Participants undergo a minimum of 12 weeks of observation before treatment

12 weeks

Dose-justification Phase

Participants receive SerpinPC at varying doses to justify the appropriate dose

24 weeks

Dose-confirmatory Phase

Participants receive SerpinPC at a confirmed dose to evaluate efficacy and safety

24 weeks

Extension Phase

Participants continue treatment with SerpinPC at the selected dose from Part 2

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• SerpinPC

Trial Overview The study tests SerpinPC's effectiveness and safety when given subcutaneously as a preventive treatment for hemophilia. It has three phases: dose justification, confirmation, and an extension phase for ongoing evaluation.

Participant Groups

Group I: Part 3 - SerpinPC (Extension phase) Experimental Treatment 1 Intervention

After completion of dosing in Part 1 or Part 2, participants will continue treatment with SerpinPC at the dose of SerpinPC selected for Part 2 in a 24-week extension phase (Part 3).

Group II: Part 2 - SerpinPC (Dose-confirmatory phase) Experimental Treatment 1 Intervention

After a minimum of 24 weeks of prospective observation, participants will receive SerpinPC at dose of 1.2 mg/kg Q2W for 24 weeks in Part 2, unless the Interim Analysis (IA) shows a greater benefit-risk profile with either the 1.2 mg/kg QW or Q4W treatment regimens.

Group III: Part 1 - Cohort 3: SerpinPC Experimental Treatment 1 Intervention

Participants will receive SerpinPC 1.2 mg/kg SC Injection Q4W for 24 weeks after a minimum of 12 weeks of a prospective observation period.

Group IV: Part 1 - Cohort 2: SerpinPC Experimental Treatment 1 Intervention

Participants will receive SerpinPC 1.2 mg/kg SC Injection Q2W for 24 weeks after a minimum of 12 weeks of a prospective observation period.

Group V: Part 1 - Cohort 1: SerpinPC Experimental Treatment 1 Intervention

Participants will receive SerpinPC 1.2 mg/kg SC Injection QW for 24 weeks after a minimum of 12 weeks of a prospective observation period.

Who Is Running the Clinical Trial?

ApcinteX Ltd

Lead Sponsor

Trials

5

Recruited

230+

Centessa Pharmaceuticals plc

Industry Sponsor

Trials

10

Recruited

370+

Findings from Research

Early diagnosis and multidisciplinary care for severe hemophilia are crucial for improving patient outcomes, emphasizing the importance of pediatric involvement from birth to facilitate acceptance and management of the disease.

Long-term prophylaxis is the current gold standard treatment to prevent complications like hemophilic arthropathy, while ongoing research aims to better understand inhibitors and improve treatment regimens for young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Relevance of early paediatric care for boys with severe haemophilia]. Chambost, H., Meunier, S.[2006]

A tailored prophylaxis approach for 25 boys with severe hemophilia A resulted in low bleeding rates and good joint function, using significantly less clotting factor (3656 IU kg(-1) year(-1)) compared to traditional methods.

Over a median follow-up of 4.1 years, most participants experienced minimal joint bleeds (1.2 per person-year) and normal joint examination scores, indicating effective management of their condition with reduced factor use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. Feldman, BM., Pai, M., Rivard, GE., et al.[2023]

About 10% of patients with severe hemophilia show reduced bleeding and joint damage, indicating a wide range of clinical outcomes despite similar low clotting factor levels.

The variability in bleeding patterns among these patients is influenced by multiple factors, including the balance of coagulation factors, lifestyle, and the pharmacokinetics of treatments, suggesting that personalized approaches to management could improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic heterogeneity of hemostasis in severe hemophilia. Nogami, K., Shima, M.[2015]

The Phase 3 A-LONG study showed that rFVIIIFc is highly effective for treating acute bleeding episodes in severe hemophilia A, with 98% of episodes resolving after one or two infusions.

Among subjects receiving prophylactic treatment, a significant number (60% in individualized prophylaxis) did not experience target joint bleeds, highlighting the potential of rFVIIIFc to prevent bleeding complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A. Shapiro, AD., Mahlangu, JN., Perry, D., et al.[2017]

In a study of 65 boys with severe hemophilia A, those receiving regular prophylactic infusions of recombinant factor VIII showed significantly better joint health, with 93% having normal joint structure by age 6, compared to only 55% in the episodic therapy group.

Prophylaxis not only prevented joint damage but also resulted in fewer joint and total hemorrhages compared to episodic therapy, highlighting its efficacy in managing severe hemophilia A.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. Manco-Johnson, MJ., Abshire, TC., Shapiro, AD., et al.[2022]

In a study monitoring inhibitor development in severe hemophilia A and B, 26% of previously untreated patients (PUPs) with severe hemophilia A developed inhibitors, while only 7% of PUPs with severe hemophilia B did, indicating a higher risk in hemophilia A.

The study found no significant differences in inhibitor development rates between different clotting factor concentrates, whether plasma-derived or recombinant, suggesting that the choice of product may not impact the risk of inhibitor formation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. Fischer, K., Lassila, R., Peyvandi, F., et al.[2015]

Recent advancements in treatment for inherited coagulation disorders, particularly through improved purification and recombinant DNA technology, have significantly increased life expectancy for hemophiliacs, making it comparable to that of the general male population.

A systematic review of studies over the last 20 years found that severe and mild adverse reactions to coagulation factor concentrates are rare, with allergic reactions being the most common, confirming the high safety profile of both plasma-derived and recombinant products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies. Franchini, M., Makris, M., Santagostino, E., et al.[2018]

Inhibitors, which are a serious side effect of hemophilia treatment, occur in 25-30% of patients with severe hemophilia A, highlighting the need for careful monitoring and management.

The actual impact of specific clotting products on inhibitor development remains unclear due to conflicting data and the need for larger, well-defined studies, suggesting that early prophylaxis and collaboration among stakeholders could help reduce inhibitor risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different impact of factor VIII products on inhibitor development? van den Berg, HM.[2020]

In a comprehensive study of inhibitor development among patients treated with Recombinate rAHF recombinant factor VIII, the incidence of inhibitors was found to be significantly higher in previously untreated or minimally treated patients (PUPs) at 11.9%, compared to just 0.123% in previously treated patients (PTPs).

The study indicates that while inhibitor development is infrequent in PTPs receiving Recombinate rAHF/Bioclate, the true incidence may be underestimated, as data from clinical trials suggest it could be approximately twice the rate observed in this pharmacovigilance study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study. Ewenstein, BM., Gomperts, ED., Pearson, S., et al.[2018]

In a study of 138 patients with mild/moderate hemophilia A, the Arg593Cys mutation was found in 38% of patients and was associated with a 10-fold increased risk of developing inhibitors against factor VIII (FVIII).

Intensive peri-operative use of FVIII, particularly through continuous infusion, significantly raised the risk of inhibitor development, with a relative risk of 186 for those with specific mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. Eckhardt, CL., Menke, LA., van Ommen, CH., et al.[2023]

A multicenter study involving nine patients with inherited protein C deficiency demonstrated that a purified plasma-derived protein C concentrate is both safe and effective, with 19 out of 23 treatment courses resulting in complete recovery without any long-term complications.

The treatment showed excellent safety during 914 infusions, with no abnormal bleeding reported, even at high doses and during surgical procedures, indicating a strong safety profile for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of inherited protein C deficiency by replacement therapy with the French purified plasma-derived protein C concentrate (PROTEXEL). Dreyfus, M., Ladouzi, A., Chambost, H., et al.[2007]

In a study of 23 severe hemophilia A patients with high levels of factor VIII inhibitors, 78% of those with type I inhibitor kinetics did not respond to high doses of FVIII therapy, indicating a potential challenge in treatment efficacy.

The study suggests a possible link between the kinetics behavior of inhibitors and treatment response, which could help in predicting how patients might respond to therapies, although the results were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kinetics of factor VIII:C inhibitors and treatment response in severe hemophilia A patients. Luna-Záizar, H., Esparza-Flores, MA., López-Guido, B., et al.[2009]

Recent strategies for treating hemophilia A and B focus on blocking natural anticoagulant proteins, such as serpins, to restore the balance between procoagulant and anticoagulant systems, which could reduce bleeding episodes.

Studies have shown that targeting specific serpins like antithrombin and modifying α1-antitrypsin can effectively rebalance coagulation in hemophilia, suggesting a promising new therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serpins, New Therapeutic Targets for Hemophilia. Aymonnier, K., Kawecki, C., Arocas, V., et al.[2021]

In a study of 94 pediatric patients with purpura fulminans treated with protein C concentrate, 79.8% showed recovery or improvement, indicating that protein C treatment may significantly enhance patient outcomes.

The treatment was associated with a low incidence of severe adverse events, and patients who survived had higher protein C plasma levels, suggesting that timely administration of protein C could be crucial for improving survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients. Veldman, A., Fischer, D., Wong, FY., et al.[2021]

Engineered serpins that selectively inhibit activated protein C (APC) have been developed, showing promise in restoring blood clotting in hemophilia B mice by promoting thrombin generation and normalizing bleeding after injury.

This innovative approach targets the protein C anticoagulant system, demonstrating that it can effectively improve hemostasis in vivo, which could lead to new treatments for hemophilia that avoid the complications of traditional factor replacement therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and characterization of an APC-specific serpin for the treatment of hemophilia. Polderdijk, SG., Adams, TE., Ivanciu, L., et al.[2021]

References

1. France pubmed.ncbi.nlm.nih.gov

[Relevance of early paediatric care for boys with severe haemophilia]. [2006]

2. England pubmed.ncbi.nlm.nih.gov

Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Phenotypic heterogeneity of hemostasis in severe hemophilia. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Treatment of bleeding episodes with recombinant factor VIII Fc fusion protein in A-LONG study subjects with severe haemophilia A. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Inhibitor development in haemophilia according to concentrate. Four-year results from the European HAemophilia Safety Surveillance (EUHASS) project. [2015]

7. England pubmed.ncbi.nlm.nih.gov

Non-thrombotic-, non-inhibitor-associated adverse reactions to coagulation factor concentrates for treatment of patients with hemophilia and von Willebrand's disease: a systematic review of prospective studies. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Different impact of factor VIII products on inhibitor development? [2020]

9. England pubmed.ncbi.nlm.nih.gov

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Treatment of inherited protein C deficiency by replacement therapy with the French purified plasma-derived protein C concentrate (PROTEXEL). [2007]

12. England pubmed.ncbi.nlm.nih.gov

Kinetics of factor VIII:C inhibitors and treatment response in severe hemophilia A patients. [2009]

13. Germany pubmed.ncbi.nlm.nih.gov

Serpins, New Therapeutic Targets for Hemophilia. [2021]

14. England pubmed.ncbi.nlm.nih.gov

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients. [2021]

15. United States pubmed.ncbi.nlm.nih.gov

Design and characterization of an APC-specific serpin for the treatment of hemophilia. [2021]