KRESLADI Suspension for infusion Ref.[116648] Active ingredients: Marnetegragene autotemcel

In Study RP-L201-0318, Neutrophil CD18 and CD11a surface expression after KRESLADI administration were evaluated [see Clinical Studies (14)].

The nature of KRESLADI is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

No carcinogenicity studies have been performed with KRESLADI.

Intravenous administration of KRESLADI in a mouse model of LAD-I and intravenous administration of KRESLADI manufactured from healthy donors in immunodeficient mice showed no evidence of toxicity, genotoxicity, or oncogenesis (tumorigenicity).

No studies have been conducted to evaluate the effects of KRESLADI on fertility.

The efficacy of KRESLADI was evaluated in one open-label, single-arm, multicenter study (RP-L201-0318; NCT03812263) in 9 pediatric patients with molecularly confirmed ITGB2-associated severe leukocyte adhesion deficiency-I (LAD-I). Severe LAD-I was defined as having neutrophil CD18 expression <2% or CD11a and/or CD11b expression <2% (if neutrophil CD18 expression ≥2%), documented biallelic ITGB2 mutations, and clinical history consistent with severe LAD-I or a known family history. Patients with an available HLA-identical sibling donor for allogeneic hematopoietic stem cell transplant (HSCT) were excluded.

All patients underwent mobilization with G-CSF and plerixafor followed by apheresis. Three patients underwent a third day of apheresis collection, and one patient required a second mobilization and apheresis cycle to obtain sufficient cells for manufacturing. Eight patients received a subcutaneous dose of ustekinumab 0.75 mg/kg approximately 2 weeks prior to mobilization and at least one dose between mobilization and KRESLADI infusion. Busulfan was administered every 12 hours for 8 doses over 4 days, with pharmacokinetic-guided dosing to achieve a cumulative target AUC of 65,000 ng/mL per hour in the first 3 patients, and 75,000 ng/mL per hour in the remaining patients. Patients received infection prophylaxis and anti-seizure, anti-emetic, and analgesic treatment per institutional guidelines. KRESLADI was administered 25 to 69 hours after the final busulfan dose.

All patients received KRESLADI as a single intravenous infusion with a median dose of 4.3 × 10⁶ CD34+ cells/kg (range: 2.8 to 10 × 10⁶ CD34+ cells/kg). One patient required two cycles of mobilization and apheresis and received two KRESLADI infusions.

The population characteristics were as follows: median age 42 months (range: 9.8 to 117 months), 5 patients (56%) were female, 6 patients (67%) were white, 2 patients (22%) were Asian, and race was not reported for 1 patient (11%). Three of the 9 patients were siblings carrying the same pathogenic ITGB2 variant. No patients had a history of prior allogeneic HSCT. Seven out of 9 patients had baseline CD18 expression <2% and all patients had baseline neutrophil CD11a expression <2%.

The surrogate endpoints for efficacy included improvement in CD18 and CD11a surface expression in neutrophils at Month 12 and sustained expression through Month 24 post-infusion.

Seven out of nine patients had baseline neutrophil CD18 expression <2% and thus were evaluable for post-treatment CD18 assessment. CD18 expression increased in all seven patients after KRESLADI infusion with median CD18 surface expression at Month 12 and Month 24 post-infusion of 54% (range: 20% to 87%) and 50% (range: 16% to 82%), respectively. Neutrophil CD18 expression was sustained through at least Month 42 post-infusion in all seven patients.

Neutrophil CD11a surface expression increased after KRESLADI infusion in all 9 patients. Median CD11a surface expression at Month 12 and Month 24 post-infusion were 45% (range: 18% to 75%) and 39% (range: 17% to 65%), respectively. Neutrophil CD11a surface expression was sustained through at least Month 42 post-infusion in all 9 patients.

None of the 9 treated patients received allogeneic HSCT after product administration. The median duration of follow-up after KRESLADI administration was 4.2 years (range: 3.6 to 5.7 years).