Weight-Based Dosing With Narsoplimab Is Recommended in HSCT-TMA

April 7, 2021
Jessica Hergert
Jessica Hergert

Assistant Editor, OncLive®
Jessica joined the company in August 2019 and is one of the point contacts for the OncLive On Air™ podcast. She is a Rider University alumna and holds a degree in journalism and biology. Prior to joining MJH Life Sciences, she interned with the Ireland-based social media monitoring agency Olytico and served as a copy editor and writer for The Rider News. Email: jhergert@onclive.com

Pharmacodynamic and pharmacokinetic modeling of the investigational MASP-2 inhibitor narsoplimab supported a weight-based dosing method for patients with hematopoietic stem cell transplant–associated thrombotic microangiopathy.

Pharmacodynamic and pharmacokinetic modeling of the investigational MASP-2 inhibitor narsoplimab (OMS721) supported a weight-based dosing method for patients with hematopoietic stem cell transplant–associated thrombotic microangiopathy (HSCT-TMA), according to findings from an analysis presented during the Virtual 47th Annual Meeting of the EBMT.1

Moreover, the findings demonstrated favorable exposure-response relationships between serum concentrations of narsoplimab and C4d inhibition for HSCT-TMA treatment responder and non-responder populations.

HSCT-TMA is a life-threatening complication, which results from endothelial injury associated with HSCT. The endothelial injury occurs after the lectin pathway of complement is activated.

Narsoplimab, a fully human IgG4 monoclonal antibody, inhibits MASP-2, which is an effector enzyme of the lectin pathway. MASP-2 also activates the coagulation cascade.

On January 19, 2021, the FDA granted a priority review designation to a biologics license application for narsoplimab for the treatment of patients with HSCT-TMA; the FDA is expected to make a decision regarding the approval of narsoplimab by July 17, 2021.2

The analysis utilized data from 4 clinical trials to evaluate the pharmacodynamic effect of narsoplimab on lectin pathway activation. The trials included a pivotal, phase 2 study (NCT02222545), an ongoing phase 2 trial (NCT02682407), and 2 phase 1 healthy volunteer studies. In the phase 2 trials, sparse pharmacokinetics sampling was performed; however, intense sampling was conducted in the healthy volunteers.

Afterward, a population pharmacokinetic/pharmacodynamic model was built based on the subset of single and multiple intravenous (IV) narsoplimab dosing regimens utilized in the 4 clinical trials.

The dataset analyzed included 5031 records including pharmacokinetic observations (n = 3439), infusion events (n = 1567), and C4d inhibition without pharmacokinetics (n = 25).

Of the 110 subjects included in the analysis, 37% were female. Additionally, 23% of patients had atypical hemolytic uremic syndrome, 25% had HSCT-TMA, 15% had IgA nephropathy, and 14% had other diseases. The remaining 23% of participants comprised healthy volunteers.

Regarding pharmacokinetics, minimal accumulation was observed at 2 mg/kg of narsoplimab when given in 6 once-weekly doses. Moderate accumulation was observed at 4 mg/kg.

Narsoplimab appeared to be distributed in the blood and hydrophilic extravascular space because critical parameters for central volume and peripheral volume were consistent with monoclonal antibodies.

Total clearance was concentration-dependent and ranged from 0.1146 to 0.1286 L/h for individual patients. The estimated Michaelis-Menten constant was approximately 5.7 µg/mL.

Additionally, the estimated terminal half-life of narsoplimab was about 198 hours in healthy volunteers who received 6 weekly IV doses at 4 mg/kg.

Covariates that affected the disposition of narsoplimab included albumin level, patient status, body weight, dose, and the presence of anti-drug antibodies (ADA), which were observed in 11% of patients with HSCT-TMA. Patients with ADA positivity had a higher maximum elimination velocity, but only a slightly lower overall exposure.

Taken collectively, the findings support that body weight is a significant covariate of narsoplimab dosing. Linear clearance increased with body weight, so weight-based dosing with narsoplimab is recommended. Conversely, age, race, and sex were not found to significantly affect the disposition of narsoplimab, so dose-adjustment based on any baseline patient characteristic beyond weight is not supported.

Regarding the exposure-response relationship, the EC50 and EC90 values of a direct-link mixed effects Emax model demonstrated that the concentrations of narsoplimab were maintained at levels greater than EC50 throughout the dosing interval.

Additionally, narsoplimab concentrations achieved in patients with HSCT-TMA induced clinically meaningful C4d inhibition and improved clinical response rate. Moreover, the modeling suggested that no residual pharmacodynamic effect was likely to be observed on C4d production 6 weeks after the last dose of narsoplimab.

Also presented during the 2021 EBMT meeting were findings from a pivotal phase 2 trial of narsoplimab (NCT02222545), which demonstrated high response rates and a significant improvement in laboratory markers and organ function irrespective of subgroup in patients with HSCT-TMA.3

Narsoplimab is currently being evaluated in phase 3 trials that are evaluating the agent’s use in other lectin pathway–associated diseases and other endothelial injury syndromes, including IgA nephropathy (NCT03608033) and atypical hemolytic uremic syndrome (NCT03205995).4,5

References

  1. Pullman W, Facius A, Lahu G, et al. Clinical pharmacology and population pharmacokinetic/pharmacodynamic modeling of lectin pathway inhibition by narsoplimab (OMS721). Presented at: 47th Annual Meeting of the EBMT; March 14-17, 2021; virtual. Abstract P168.
  2. Biologics license application for narsoplimab in HSCT-TMA accepted for priority review by U.S. FDA. News release. Omeros Corporation. January 19, 2021. Accessed March 24, 2021. http://bit.ly/2NncWTb.
  3. Rambaldi A, Claes K, Goh YT, et al. Narsoplimab (OMS721), a MASP-2 inhibitor, for the treatment of adult hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA): subgroup analyses. Presented at: 47th Annual Meeting of the EBMT; March 14-17, 2021; virtual. Abstract OS4-2.
  4. Study of the safety and efficacy of OMS721 in patients with immunoglobulin A (IgA) nephropathy. ClinicalTrials.gov. Posted July 31, 2018. Updated May 30, 2019. Accessed March 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03608033.
  5. Safety and efficacy study of OMS721 in patients with atypical hemolytic uremic syndrome (aHUS). ClinicalTrials.gov. Posted July 2, 2017. Updated October 18, 2018. Accessed March 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03205995.

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