YARTEMLEA Solution for injection Ref.[116145] Active ingredients: Narsoplimab

The effect of YARTEMLEA on lectin pathway activity, assessed using inhibition of C4d deposition, was investigated in healthy subjects and patients with TA-TMA (TA-TMA Study). YARTEMLEA concentration levels achieved in patients with TA-TMA resulted in >80% inhibition of lectin pathway activity. Based on pharmacokinetic/pharmacodynamic (PK/PD) modeling, a wash-out period of 6 weeks is sufficient to reduce YARTEMLEA concentrations to below pharmacologically active levels.

The PK profile of narsoplimab-wuug has been characterized in healthy subjects and in patients. PK of narsoplimab-wuug is less than dose-proportional for 2 and 4 mg/kg weekly IV dosing, with an accumulation ratio ranging from 1.02 to 1.75 at 4 mg/kg IV weekly dosing. Narsoplimab-wuug steady state (measured at day 36) geometric mean C_max is 36.9 µg/mL, with geometric mean AUC_0-tau of 2314 µg·h/mL following 4 mg/kg administered intravenously in healthy subjects. Narsoplimab-wuug steady state is reached after three once-weekly IV doses (day 15) of 4 mg/kg in healthy subjects.

Absorption

After intravenous administration, peak plasma concentrations of narsoplimab-wuug occur approximately at the end of each infusion.

Distribution

Narsoplimab-wuug is distributed in the blood and hydrophilic extravascular space with an average (CV%) volume of distribution of 10.9 L (65%) in patients.

Elimination

Total clearance of narsoplimab-wuug is concentration-dependent, with an estimated mean (CV%) value of 0.12 L/hour (68%) in patients. The mean (CV%) terminal elimination half-life was estimated to be 209 hours (73%) in patients.

Metabolism

Narsoplimab-wuug is expected to be metabolized into small peptides and amino acids by catabolic pathways.

Excretion

No biotransformation or excretion studies have been conducted.

Specific Populations

Body weight was a significant covariate affecting the PK of narsoplimab-wuug. No clinically significant differences in PK of narsoplimab-wuug were observed based on race or sex.

Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.

A fertility study of narsoplimab-wuug in male and female mice produced no adverse effects on reproductive parameters, although a transient decrease in mean body-weight gain in females (premating) and a slight increase in mean percentage of sperm with abnormal morphology in males were observed in the highest dose groups. These effects were noted at exposures corresponding to 21-fold the exposure expected at the MRHD (based on AUC). In the absence of any functional effects on mating, fertility, or reproductive organ weight, these effects on sperm morphology were not considered adverse.

The efficacy of YARTEMLEA was assessed in (i) a single-arm, open-label study (TA-TMA Study) that enrolled 28 adult patients who developed TA-TMA following hematopoietic stemcell transplantation (HCT) and (ii) 19 adult and pediatric patients with TA-TMA with evaluable patient-level response data enrolled in an expanded access program (EAP). In the TA-TMA Study, 24 patients received YARTEMLEA 4 mg/kg intravenously once weekly and 4 patients received YARTEMLEA 370 mg intravenously once weekly. The median number of YARTEMLEA administrations received by the 28 TA-TMA Study patients plus the 19 EAP patients was 8 (range: 2-34), and the median duration of therapy was 8 weeks (range: 2-16 weeks).

Baseline demographic and disease-related characteristics are shown in Table 3. The TA-TMA Study patients had a confirmed diagnosis of TA-TMA per the diagnostic criteria as follows: platelet count <150,000/µL, evidence of microangiopathic hemolysis (presence of schistocytes, serum LDH greater than the upper limit of normal [ULN] and/or haptoglobin less than the lower limit of normal [LLN]), and renal dysfunction. Patients in the EAP were similarly thrombocytopenic with evidence of microangiopathic hemolytic anemia.

Table 3. Characteristics of TA-TMA Patients Treated with YARTEMLEA in the TA-TMA Study and Expanded Access Program:

^a Includes patients from EAP with available patient-level data. The entire EAP consisted of 221 patients; patientlevel response data were available in 13 adult and 6 pediatric patients.
^b Race and ethnicity data were not available for the 19 patients in the EAP.

Among patients in the TA-TMA Study, the median time from HCT to TMA diagnosis was 73.5 days (range: 21–436) and the median time from TMA diagnosis to first dose of narsoplimab was 13.5 days (range: 4–196). Among the 19 adult and pediatric patients in the EAP, the median time from HCT to TMA diagnosis was 81 days (range: 24–452) and the median time from TMA diagnosis to first dose of narsoplimab was 3 days (range: 0–52).

The primary efficacy assessment of YARTEMLEA was based on TMA response defined as improvement in both of two laboratory TMA markers (LDH and platelet counts) and either improvement in organ function or independence from transfusions. The same response criteria were applied to both the TA-TMA Study and EAP patients.

Improvement in platelet count was defined as follows:

• For baseline platelet count ≤20,000/μL: (i) ≥3-fold increase in platelet count, (ii) postbaseline platelet count >30,000/μL, and (iii) receipt of no platelet transfusions within 2 days prior to the platelet count assessment.
• For baseline platelet count >20,000/μL: (i) ≥50% increase in platelet count, (ii) platelet count >75,000/μL, and (iii) receipt of no platelet transfusions within 2 days prior to the platelet count assessment.

To meet LDH improvement criteria, LDH levels were required to be <1.5x ULN.

In the TA-TMA Study and the EAP, TA-TMA response was achieved in 17/28 (60.7%) and 13/19 (68.4%) patients, respectively (Table 4).

Table 4. Efficacy Results for TA-TMA Study and Expanded Access Program:

^a Confidence intervals were calculated using the exact (Clopper–Pearson) method.
^b These component findings are based on the number of patients with evaluable data.
^c Defined as no transfusions for at least 4 weeks from the last transfusion; only evaluated in patients who received transfusions within the 2 weeks prior to or on the first narsoplimab dose date.

In the TA-TMA Study, the 100-day survival from time of TMA diagnosis was 73.4% (95% CI: 52.2, 86.4). In the EAP cohort (N=19), 100-day survival from time of TMA diagnosis was 73.7% (95% CI: 47.9, 88.1).