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

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.