Phase 2 Evaluation of Narsoplimab in Pediatric Patients with High-Risk Hematopoietic Stem Cell Transplant-Associated Thrombotic Microangiopathy

Trial ID: 2023-509710-11-00
Protocol: OMS721-HCT-002
Sponsor: Omeros Corp.

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Diseases & Conditions

Thrombotic microangiopathy

Objectives

The primary objective of this Phase 2 study is to describe the 100-day **survival rate** following the diagnosis of high-risk **Haematopoietic Stem Cell Transplant Thrombotic Microangiopathy** (HSCT-TMA) in pediatric patients. This objective is clinically relevant as it provides critical insights into the short-term survival outcomes of patients undergoing treatment for this severe condition, which can inform future therapeutic strategies and improve patient management.

Secondary objectives include:

Evaluating the safety and tolerability of intravenous (IV) administration of **narsoplimab**.
Describing the efficacy of narsoplimab by responder rate, survival at 52 weeks, and mean, median, and overall survival rates.
Evaluating peak and trough pharmacokinetics (PK) of IV narsoplimab.
Assessing immunogenicity.
Summarizing and evaluating anti-drug antibody (ADA) responses by treatment group.

These secondary objectives aim to provide a comprehensive understanding of the drug's safety profile, pharmacokinetics, immunogenicity, and overall efficacy, which are essential for determining the therapeutic potential and optimizing the clinical use of narsoplimab in this patient population.

Participants

The clinical trial involves a total of **13 participants** diagnosed with **Haematopoietic Stem Cell Transplant Thrombotic Microangiopathy** (HSCT-TMA). The study population comprises both male and female subjects, aged at least 28 days and less than 18 years, who have undergone an allogeneic haematopoietic stem cell transplant for either non-malignant or malignant diseases. Participants were selected based on specific criteria, including a diagnosis of high-risk HSCT-TMA, characterized by a platelet count of less than 50,000/µL or a significant decrease in platelet count, alongside evidence of microangiopathic hemolysis. The trial includes a vulnerable population, requiring informed consent from a parent or legal guardian, and assent from the patients themselves, as per local regulations. Lifestyle considerations such as sexual activity are addressed, with requirements for effective birth control methods for females of childbearing potential and precautions for male participants to avoid fathering children during and after the study period. The selection process ensures that participants meet the high-risk criteria for HSCT-TMA, including persistent TMA or associated complications, to evaluate the 100-day survival rate following diagnosis.

Plans and Procedures

The clinical trial is a **Phase II** study designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of **narsoplimab** in pediatric patients with high-risk **haematopoietic stem cell transplant thrombotic microangiopathy** (HSCT-TMA). The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial is from May 2023 to July 2026, with participant involvement expected to last up to 52 weeks from the date of HSCT-TMA diagnosis.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, informed consent, and diagnosis of high-risk HSCT-TMA. Following the screening, participants will receive the study drug, administered as a **solution for injection** via the **intravenous** route. The maximum daily dose is 4 mg/kg, with a total dose not exceeding 370 mg over a treatment period of up to 2 weeks. Follow-up visits will be scheduled to monitor the primary endpoint, which is the 100-day survival rate from the date of HSCT-TMA diagnosis, as well as secondary endpoints, including survival at 52 weeks, pharmacokinetic parameters, safety assessments, and anti-drug antibody response.

The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the overall outcomes of the treatment. Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial aims to provide comprehensive data on the therapeutic potential of narsoplimab in this patient population, contributing to the understanding and management of HSCT-TMA.

Treatment

The clinical trial involves the administration of **narsoplimab**, an experimental medication developed by Omeros Corporation. Narsoplimab is classified under the ATC code L03AX, which denotes it as part of the "Other Cytokines and Immunomodulators" category. The pharmaceutical form of narsoplimab is a **solution for injection**, and it is administered intravenously. The dosing regimen specifies a maximum daily dose of 4 mg/kg, with a total maximum dose of 370 mg over the treatment period. The maximum treatment period is set at 2 weeks. Narsoplimab is not formulated specifically for pediatric use, although the trial includes pediatric patients aged 28 days to 18 years. The active substance in narsoplimab is a protein of other origin, and it has been designated as an orphan drug under the designation number EU/3/18/2067.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of narsoplimab in pediatric patients with high-risk hematopoietic stem cell transplant thrombotic microangiopathy (HSCT-TMA). Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the specified regimen. The trial aims to describe the 100-day survival rate following the diagnosis of high-risk HSCT-TMA.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **100-day survival rate** following the diagnosis of high-risk **Haematopoietic Stem Cell Transplant Thrombotic Microangiopathy (HSCT-TMA)**. This primary endpoint will provide a direct measure of the treatment's impact on patient survival within the specified timeframe. Secondary endpoints include survival at 52 weeks, as well as median, mean, and overall survival from the date of TMA diagnosis. These endpoints will offer additional insights into the long-term efficacy of the treatment.

Further efficacy assessments will involve the evaluation of **narsoplimab** pharmacokinetics, specifically peak and trough levels, and the activation of the lectin pathway, which will be measured using an ex vivo assay. The responder rate, based on clinical response criteria, will also be determined to assess the proportion of patients achieving a predefined level of clinical improvement. The collection and analysis of these parameters will be conducted at specified intervals throughout the trial to ensure comprehensive evaluation of the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age at least 28 days and less than 18 years prior to informed consent (Visit 0).
Have informed consent from at least one parent or legal guardian as required by local laws and regulations. Patient informed consent will be required if the patient has reached the local legal age of majority.
Assent from patients as required by local laws and regulations.
Have received an allogeneic HSCT for the treatment of non-malignant or malignant disease. All donor cell sources are allowed (i.e., matched, mismatched, and haploidentical; related and unrelated; bone marrow, peripheral blood stem cells, and umbilical cord blood).
Have a diagnosis of HSCT-TMA defined as having both of the following: a. Platelet count < 50,000/μL or a decrease in platelet count > 50% from the highest value obtained following transplant or are platelet transfusion dependent b. Evidence of microangiopathic hemolysis (presence of schistocytes, serum lactate dehydrogenase [LDH] > upper limit of normal [ULN], or haptoglobin < lower limit of normal [LLN])
Have at least one of the following HSCT-TMA high-risk criteria: a. Spot protein/creatinine ratio > 1 mg/mg b. TMA-related serum creatinine > 2 x the creatinine level prior to TMA development (sustained elevation for at least 48 hours) or a 50% decline in the estimated or measured glomerular filtration rate using either serum creatinine or cystatin C c. Biopsy-proven gastrointestinal TMA d. TMA-related neurological abnormality (e.g., confusion, stroke, transient ischemic attack [TIA], or seizures) e. Pericardial or pleural effusion without alternative explanation f. Pulmonary hypertension without alternative explanation g. Concurrent Grade II, III, or IV graft versus host disease (GVHD) h. Concurrent bacterial or viral infection i. Concurrent gastrointestinal bleeding j. Concurrent diffuse alveolar hemorrhage or need for positive-pressure ventilation (noninvasive or invasive) for ≥ 24 hours in the absence of alternative definite etiology k. Have elevated serum C5b-9 (>ULN) l. Peak LDH ≥ 2 x ULN
If sexually active and of childbearing potential (for female paediatric patients, defined as starting at onset of menses), must agree to practice a highly effective method of birth control throughout the study drug treatment and for at least 12 weeks after the last dose of study drug, such method of birth control defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence (abstinence is acceptable when it is in line with the patient’s preferred and usual lifestyle and is defined as complete abstinence of sexual intercourse, not periodic abstinence or withdrawal), or vasectomized partner.
Male patients must be willing to avoid fathering children during study treatment and for at least 12 weeks following the last dose of study medication.

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Exclusion Criteria

Use of a complement inhibitor (e.g. eculizumab or ravulizumab) within 3 months prior to screening, except: a. Failure of the therapy for the current episode of HSCT-TMA can be documented (including if the patient had completed prior therapy within the period and relapsed subsequently after completing therapy) b. Therapy was for another indication (e.g., paroxysmal nocturnal hemoglobinuria for which patient underwent HSCT) and the HSCT-TMA developed on or after discontinuing the therapy Note - Patients may not be on another complement inhibitor for any indication at the time of first narsoplimab dosing, i.e., prior therapy must have been discontinued.
Patients or their parents or legal guardians are an employee of Omeros, Clinical Research Organization (CRO), an Investigator, a study staff member, or an immediate family member.
Have a known hypersensitivity to any constituent of the product.
Presence of any condition that the Investigator believes would put the patient at risk.
Use of defibrotide within 3 months prior to screening, except: a. Therapy was for veno-occlusive disease (VOD) prophylaxis and the HSCT-TMA developed after having started defibrotide therapy. b. Therapy was for VOD treatment, the VOD is stable (not worsened) or improving, and the HSCT-TMA developed after having started defibrotide therapy. Note - Patients on defibrotide for one of the above reasons may remain on defibrotide during the study.
Have ADAMTS13 activity < 10%. Test results obtained within 28 days prior to informed consent may be used. Test result may be pending (must have been obtained) at time of first dose if patient requires urgent treatment.
Have a severe, uncontrolled systemic bacterial or fungal infection requiring antimicrobial therapy, or a severe uncontrolled viral infection (as determined by the investigator); prophylactic antimicrobial therapy administered as standard of care is allowed.
Due to conditions other than HSCT-TMA, have a poor prognosis with a life expectancy of less than 3 months in the opinion of the Investigator.
If pregnant or lactating
Have received treatment with an investigational drug or device within 4 weeks of entering study, except: a. Investigational usage of an approved drug substance or a dietary supplement may be allowable; contact the medical monitor for approval prior to enrollment. b. Other investigational agents, not for the treatment of HSCT-TMA, may be allowable; contact the medical monitor for approval prior to enrollment.
Have abnormal liver function tests defined as alanine aminotransferase (ALT) > 10 times ULN at time of informed consent through prior to the first dose.
Have a positive test by antigen, antibody, or polymerase chain reaction (PCR) for human immunodeficiency virus (HIV); if previously negative from time of transplant evaluation up to informed consent, the test does not need to be repeated.