Clinical trial NCT05684159: Study of NM8074 in Patients with AHUS with Evidence of Ongoing Thrombotic Microangiopathy
Official title: A Phase II, Open-Label Study of NM8074 in Patients with Atypical Hemolytic Uremic Syndrome (aHUS)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: AHUS - Atypical Hemolytic Uremic Syndrome
Lead sponsor: NovelMed Therapeutics
Sponsor class: INDUSTRY
First posted: 2023-01-13
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The study will enroll a planned total of 12 patients as subjects for the trial, with extra enrollment if needed, at the discretion of the Investigator. All subjects will be assigned to either Cohort 1 or Cohort 2. Enrollment in Cohort 2 will occur after at least three patients in Cohort 1 have been evaluated for safety for 3 days after the first dose. No more than three patients will be dosed in a day. Safety data will be assessed and reviewed by the Sponsor and Study Investigators for dosed subjects prior to dosing of the rest of the study subjects. In Cohort 1, all 6 subjects will be administered 20 mg/kg of NM8074 intravenously every two weeks for a total of 7 doses. All 6 patients in Cohort 2 will receive weekly doses of 10 mg/kg for a total of 4 doses followed by biweekly doses at 20 mg/kg for a total of 5 doses.
Primary purpose: TREATMENT

Brief summary: This is a Phase II, open-label study designed to determine if intravenously administered NM8074 results in remission from TMA in treatment-naïve aHUS patients.

Detailed description: The proposed study, NM8074-aHUS-401,will initially assign six (6) patients per cohort in a 2-cohort trial. In the first cohort, we will evaluate a biweekly dosing regimen whereas in the second cohort, we will evaluate a weekly dose (10 mg/kg) followed by the biweekly dose (20 mg/kg) over a 3-month period. These studies will determine if NM8074 results in remission from TMA in aHUS patients. If the study shows efficacy in aHUS, additional patients may be added per cohort.

Eligibility criteria: Inclusion Criteria:

* Patients ≥ 18 years at the time of consent
* Patients with evidence of resistant or relapsed complement-mediated aHUS with symptoms of Thrombocytopenia, hemolysis, ongoing Thrombotic Microangiopathy and acute kidney injury.
* Evidence of ongoing Thrombotic Microangiopathy which includes Haptoglobin \<LLN or undetectable and/or presence of schistocytes
* Acute kidney injury (proteinuria/creatinuria \> ULN and/or reduced eGFR)
* Platelets less than 150,000 per microliter (Thrombocytopenia)
* Anemia (Hemoglobin ≤10 g/dL) due to hemolysis
* Lactate dehydrogenase (LDH) level ≥ 1.5 times the upper limit of normal (xULN) during Screening
* All patients must be vaccinated prior to dosing with MenACWY Menactra® polysaccharide diphtheria toxoid conjugate vaccination against Neisseria meningitidis serogroups A, C, Y, and W-135 and MenB meningococcal serogroup B vaccine (Bexsero®). If the window of vaccination is short, then patients will be prophylactically treated with appropriate antibiotics
* Willing and able to understand and complete informed consent procedures, including signing and dating the informed consent form (ICF), and comply with the study visit schedule.
* Male patients and partners of child-bearing potential must agree to use contraceptives and male patients must agree to refrain from donating sperm for the duration of the study.
* Female partners of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must have a negative pregnancy test at screening and must agree to use highly effective methods of contraception during dosing and for 1 month after stopping the investigational drug.

Exclusion Criteria:

* History of bone marrow, hematopoietic stem cell, or solid organ transplantation
* Treatment with complement blockers
* Patients with infections
* HUS due to ADAMTS-13 deficiency (\<5%)
* Kidney disease other than aHUS
* Chronic dialysis (hemo or peritoneal)
* Liver disease or other major autoimmune diseases
* Typical HUS (Shiga toxin +)
* Known Systemic Lupus Erythematosus (SLE), Systemic Sclerosis, or antiphospholipid antibody positivity or syndrome
* History of currently active primary or secondary immunodeficiency
* Currently active systemic infection or suspicion of active bacterial, viral, or fungal infection within 2 weeks prior to first dose, or history of unexplained, recurrent bacterial infections
* Has a currently active or known history of meningococcal disease or N. meningitidis infection
* Severe concurrent co-morbidities not amenable to active treatment, e.g., patients with severe kidney disease (CKD stage 4, chronic dialysis)
* Females who have a positive pregnancy test result at Screening or on Day 1.
* Pregnant, planning to become pregnant, or nursing female subjects.

Primary outcomes:
measure: Normalization of platelet count (≥150 x 10^9/L)
timeFrame: Up to Study Day 120
measure: Normalization of LDH levels to below ULN
timeFrame: Up to Study Day 120
measure: Normalization of Schistocyte levels (<1%)
timeFrame: Up to Study Day 120
measure: Change from Baseline or Percent Change from Baseline in renal function
timeFrame: Up to Study Day 120
measure: Change from Baseline or Percent Change from Baseline in Haptoglobin
timeFrame: Up to Study Day 120
measure: Change from Baseline or Percent Change from Baseline in Hemoglobin
timeFrame: Up to Study Day 120
measure: Change from Baseline or Percent Change from Baseline in proteinuria/creatininuria
timeFrame: Up to Study Day 120
Secondary outcomes:
measure: Time to achieve complete TMA response
timeFrame: Baseline through Study Day 120
measure: Time to achieve higher hemoglobin from baseline
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in blood clots
timeFrame: Up to Study Day 120
measure: Change from Baseline or Percent Change from Baseline in the total number of plasma infusions or exchanges
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in eGFR (estimated glomerular filtration rate)
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in dialysis requirement
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in quality of life (QoL) Assessed via the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale, Version 4.
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in Quality of Life (QoL) Assessed via the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Scale (QLQ- C30), Version 3.0
timeFrame: Baseline through Study Day 120
Other outcomes:
measure: Change from Baseline or Percent Change from Baseline in CP modulation
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in Factor B levels
timeFrame: Baseline through Study Day 120
measure: Change from Baseline or Percent Change from Baseline in plasma concentration of NM8074
timeFrame: Baseline through Study Day 120
measure: Maximum plasma concentration (Cmax)
timeFrame: Baseline through Study Day 120
measure: Time corresponding to Cmax (tmax)
timeFrame: Baseline through Study Day 120
measure: Area under the drug concentration-time curves (AUC0-t)
timeFrame: Baseline through Study Day 120
Locations:
Study officials:
References:
citation: Barbour T, Scully M, Ariceta G, Cataland S, Garlo K, Heyne N, Luque Y, Menne J, Miyakawa Y, Yoon SS, Kavanagh D; 311 Study Group Members. Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults. Kidney Int Rep. 2021 Mar 24;6(6):1603-1613. doi: 10.1016/j.ekir.2021.03.884. eCollection 2021 Jun.
citation: Cammett TJ, Garlo K, Millman EE, Rice K, Toste CM, Faas SJ. Exploratory Prognostic Biomarkers of Complement-Mediated Thrombotic Microangiopathy (CM-TMA) in Adults with Atypical Hemolytic Uremic Syndrome (aHUS): Analysis of a Phase III Study of Ravulizumab. Mol Diagn Ther. 2023 Jan;27(1):61-74. doi: 10.1007/s40291-022-00620-3. Epub 2022 Nov 4.
citation: Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, Bedrosian CL, Faas SJ. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood. 2015 May 21;125(21):3253-62. doi: 10.1182/blood-2014-09-600411. Epub 2015 Apr 1.
citation: Pugh D, O'Sullivan ED, Duthie FA, Masson P, Kavanagh D. Interventions for atypical haemolytic uraemic syndrome. Cochrane Database Syst Rev. 2021 Mar 23;3(3):CD012862. doi: 10.1002/14651858.CD012862.pub2.