Evaluation of Pegcetacoplan Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety in Transplant-associated Thrombotic Microangiopathy Post-Hematopoietic Stem Cell Transplantation

Trial ID: 2023-510443-37-00
Protocol: Sobi.PEGCET-201
Sponsor: Swedish Orphan Biovitrum AB (publ)

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Diseases & Conditions

Thrombotic microangiopathy

Objectives

The primary objective of this study is to evaluate the **pharmacokinetics** (PK), safety, and tolerability of pegcetacoplan in patients with Transplant-associated Thrombotic Microangiopathy (TA-TMA). This is clinically relevant as understanding the PK profile and safety of pegcetacoplan is crucial for determining appropriate dosing regimens and ensuring patient safety in this population, which is at risk due to the severe nature of TA-TMA following hematopoietic stem cell transplantation.

Secondary objectives include: - Evaluating the **pharmacodynamics** (PD) of pegcetacoplan in patients with TA-TMA, which will provide insights into the drug's biological effects and mechanism of action in this specific condition. - Assessing the efficacy of pegcetacoplan in patients with TA-TMA, which is essential for determining the therapeutic potential and clinical benefits of the treatment in improving patient outcomes.

Participants

The clinical trial involves a total of **3 participants** diagnosed with **Transplant-associated Thrombotic Microangiopathy (TA-TMA)**. The study population includes both male and female patients aged 18 years and older. Participants have received an allogeneic hematopoietic stem cell transplant (HSCT) from either a related or unrelated donor, with human leukocyte antigen-matched or mismatched donors being acceptable. Eligible stem cell sources include granulocyte colony-stimulating factor mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The trial population was selected based on specific laboratory markers indicating TA-TMA, such as thrombocytopenia, elevated lactate dehydrogenase (LDH), and additional clinical criteria. Participants are required to have a persistent diagnosis of TA-TMA despite initial management of any triggering condition. Lifestyle considerations such as diet and physical activity are not specified. The trial includes vulnerable populations, and both genders are represented. Participants must be capable of providing informed consent, and women of childbearing potential must adhere to specific contraceptive measures during the study.

Plans and Procedures

The clinical trial is designed to evaluate the **pharmacokinetics**, safety, and tolerability of pegcetacoplan in patients diagnosed with **transplant-associated thrombotic microangiopathy** (TA-TMA) following hematopoietic stem cell transplantation (HSCT). This is an open-label, single-arm, multicenter pilot study. The trial is expected to commence on February 1, 2022, and conclude by July 19, 2025. Participants will be involved in the study for a duration that includes multiple visits, with the primary endpoint being the assessment of pegcetacoplan PK parameters such as AUC0-tau, Cmax, Tmax, and Ctrough.

The study begins with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, previous HSCT, and a confirmed diagnosis of TA-TMA. Following the screening, participants will undergo regular follow-up visits to monitor safety, efficacy, and pharmacokinetic parameters. These visits will include assessments of laboratory markers and clinical status, with key evaluations at Week 12 and Week 24. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. Such conditions include the use of prohibited medications, withdrawal of consent, or any adverse events that compromise participant safety. The study aims to provide comprehensive data on the clinical response and overall survival, with secondary endpoints including the time to clinical and TMA response, duration of response, and relapse rates at Week 24.

Treatment

The clinical trial involves the administration of the experimental medication **pegcetacoplan**, also known by its descriptive name **APL-2**. Pegcetacoplan is a protein-based therapeutic agent classified under the category "Protein - Other." The pharmaceutical form, dosage, route, and frequency of administration are not specified in the provided data. The medication is not formulated for pediatric use and is not designated as an orphan drug. The trial aims to evaluate the pharmacokinetics, safety, and tolerability of pegcetacoplan in patients with transplant-associated thrombotic microangiopathy (TA-TMA) following hematopoietic stem cell transplantation (HSCT).

In this open-label, single-arm, multicenter pilot study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The study focuses solely on the effects and safety profile of pegcetacoplan. Details regarding dosing schedules, participant compliance monitoring, and additional drug administration information are not provided in the available data. The trial is conducted under the authorization numbers IMP12181/00001, UK MIA(IMP) 20377, and 5.9.1-2021-101141, ensuring compliance with regulatory standards.

Efficacy

Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint focuses on the pharmacokinetic (PK) parameters of **pegcetacoplan**, including AUC0-tau, Cmax, Tmax, and Ctrough. These parameters will be measured to evaluate the drug's absorption, distribution, metabolism, and excretion in patients with transplant-associated thrombotic microangiopathy (TA-TMA) following hematopoietic stem cell transplantation (HSCT).

Secondary endpoints will include pharmacodynamic (PD) measures and clinical responses. PD endpoints will assess absolute levels, changes from baseline, and percentage changes from baseline to Week 24 in biomarkers of complement activation, such as sC5b-9, C3a, C3, Bb, C4a, and functional assays for classical and alternative complement pathways. Clinical response at Week 24 will be defined by improvements in laboratory markers and clinical status, including renal, pulmonary, gastrointestinal, neurological responses, freedom from transfusion, cardiovascular, and serositis responses. TMA response at Week 24 will be determined by improvements in laboratory markers, specifically LDH levels, platelet count, and reduction in rUPCR. Additional secondary endpoints include overall survival at Day 100 from TA-TMA diagnosis and at Week 24 from treatment start, time to clinical and TMA response, duration of clinical and TMA response, TA-TMA relapse at Week 24, and clinical and TMA response at Week 12.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male and female patients aged ≥ 18 years at the time of informed consent form (ICF) signature.
Received allogeneic HSCT from a related or unrelated, human leukocyte antigen-matched or mismatched donor. Patients having received any of the following stem cell sources are eligible: granulocyte colony stimulating factor mobilized peripheral blood stem cells, bone marrow, umbilical cord blood.
Diagnosis of TA-TMA established as per the laboratory markers below, indicating TMA: a. De novo or progressing thrombocytopenia (platelet count < 50 x 109 /L or > 50 % decrease in platelet count from the highest value achieved after transplantation). AND b. Elevated LDH (> 1.5 x ULN). AND at least 2 additional laboratory/clinical criteria among the following: c. Presence of schistocytes on the peripheral blood smear (≥ 2 per hpf) or histologic evidence of microangiopathy in any biopsied organ. OR d. De novo anemia (hemoglobin < LLN or anemia requiring PRBC transfusion support as per local institutional standard). OR e. Proteinuria (random urinalysis protein concentration ≥ 30 mg/dL). OR f. Elevated plasma concentration of sC5b-9 above ULN. OR g. Arterial hypertension, defined by systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg.
Have a diagnosis of TA-TMA that persists despite initial management of any triggering condition.
Have rUPCR ≥ 1 mg/mg
Women of childbearing potential, defined as any women who have experienced menarche and who are NOT permanently sterile or postmenopausal, must have a negative serum pregnancy test at screening and agree to use protocol-defined methods of contraception for the duration of the study and 8 weeks after their last IMP dose. Note: Postmenopausal is defined as having had 12 consecutive months with no menses without an alternative medical cause.
Men must agree to the following for the duration of the study and 8 weeks after their last dose of IMP: a. Avoid fathering a child. b. Use protocol-defined methods of contraception. c. Refrain from donating sperm.
Patient and/or legally authorized representative must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF.

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Exclusion Criteria

Positive direct Coombs test.
Known familial or acquired ADAMTS13 deficiency.
Known Shiga toxin-related hemolytic uremic syndrome.
Known bone marrow or graft failure.
Diagnosis of disseminated intravascular coagulation.
Diagnosis of veno-occlusive disease (VOD).
Active GI bleeding (hematemesis or hematochezia) at baseline
Body weight < 30 kg and > 100 kg.
Uncontrolled systemic bacterial or fungal infection, presence or suspicion of sepsis.
Previously or currently treated with a complement inhibitor (approved or investigational).
Pregnancy or breastfeeding
Positive human immunodeficiency virus antibody at screening or documented in pre-HSCT medical record.
Hepatitis C virus detectable by polymerase chain reaction at screening or documented in pre-HSCT medical record.
Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at screening or documented in pre-HSCT medical record. Eligible patients who are chronic active carriers (≤ 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine) according to local country guidelines
Known or suspected hereditary fructose intolerance.
Hypersensitivity to pegcetacoplan or any of its excipients.
Inability to cooperate with study procedures or any condition that, in the opinion of the investigator, could increase the patient’s risk by participating in the study or confound the outcome of the study.