High-Cost Therapy Profile

February 14, 2024

Detailed information about Marnetegragene autotemcel Intravenous (IV)

High-Cost Therapy Profile

Gene Therapy/Immunology

Marnetegragene autotemcel Intravenous (IV)

Rocket

Proposed indications

Severe leukocyte adhesion deficiency type I (LAD-I)

FDA approval timeline

June 30, 2024

  • Fast track
  • Orphan drug
  • Priority review
  • Rare pediatric disease (RPD)
  • Regenerative Medicine Advanced Therapy (RMAT)

Place in therapy

Marnetegragene autotemcel is a gene therapy that uses a lentiviral vector (LVV) to encode a functional copy of the integrin subunit beta 2 (ITGB2) gene into a patient’s own hematopoietic stem cells. The ITGB2 gene encodes for the cluster of differentiation 18 (CD18) subunit of β2-integrins, which allows for leukocyte migration in response to bacterial and fungal infections. Defective β2-integrin expression prevents leukocyte adherance to the endothelium and extravasation to infected areas, resulting in an insufficient innate immune response and wound healing.

  • If approved, marnetegragene autotemcel will be the only gene therapy approved to treat patients with LAD-1 and the first approved treatment alternative to allogeneic hematopoietic stem cell transplant (HSCT).
  • Marnetegragene autotemcel will provide a therapeutic alternative for patients who do not have a human leukocyte antigen (HLA)-identical sibling donor or if HLA-matched sibling donor is unable to donate stem cells (e.g., mobilization and apheresis are not feasible).
  • Patients with severe LAD-1 will receive the one-time gene therapy that is potentially curative and will address a high unmet need.
  • In a phase 2 clinical trial, after treatment, patients did not have any significant disease related infections or inflammatory skin lesions; disease-related skin rash was resolved and wound repair capability was restored, and with a favorable safety profile (no serious treatment related adverse events).

Understanding your data

The inflammatory process involves the migration of leukocytes from the blood vessels to sites of infection. This process requires leukocyte adhesion to the endothelium to enable CD18 extravasation from blood vessels to fight infections. In patients with LAD-I, this step is impaired due to mutations in the ITGB2 gene that encodes the beta-2 integrin subunit, CD18. Marnetegragene autotemcel is a gene therapy that uses autologous hematopoietic stem cells that have been genetically modified using a LVV to deliver a functional copy of the ITGB2 gene. Clinical trials evaluating marnetegragene autotemcel in LAD-I are limited and include the following:

  • NCT03812263: Gene therapy for LAD-I: A phase 1/2 clinical trial to evaluate the safety and efficacy of the infusion of autologous hematopoietic stem cells transduced with a LVV encoding the ITGB2

Identification of patients would reflect the clinical trial criteria listed in the study above, as well as diagnosis codes identified from claims data requiring among others:

Common measurable inclusion criteria:

  • Age: ≥ 3 months old
  • ICD-10 for genetic anomalies of leukocytes (note: not a condition specific ICD-10 code)

Common measurable exclusion criteria:

  • ICD-10 for: HIV, congestive heart failure, or arterial thromboembolic events

Appendix

CATEGORY PROCEDURE CODES
Genetic anomalies of leukocytes ICD-10: D72.0
HIV ICD-10: B20, Z21
Congestive heart failure ICD-10: I50.20, I50.21, I50.22, I50.23, I50.30, I50.31, I50.32, I50.33, I50.40, I50.41, I50.42, I50.43
Arterial thromboembolic events Stroke:

ICD10: G43.601, G43.609, G43.611, G43.619, I63.00, I63.011, I63.012, I63.013, I63.019, I63.02, I63.031, I63.032, I63.033, I63.039, I63.09, I63.10, I63.111, I63.112, I63.113, I63.119, I63.12, I63.131, I63.132, I63.133, I63.139, I63.19, I63.20, I63.211, I63.212, I63.213, I63.219, I63.22, I63.231, I63.232, I63.233, I63.239, I63.29, I63.30, I63.311, I63.312, I63.319, I63.313, I63.321, I63.322, I63.323, I63.329, I63.331, I63.332, I63.333, I63.339, I63.341, I63.342, I63.343, I63.349, I63.39, I63.40, I63.411, I63.412, I63.413, I63.419, I63.421, I63.422, I63.423, I63.429, I63.431, I63.432, I63.433, I63.439, I63.441, I63.442, I63.443, I63.449, I63.49, I63.50, I63.511, I63.512, I63.513, I63.519, I63.521, I63.522, I63.523, I63.529, I63.531, I63.532, I63.533, I63.539, I63.541, I63.542, I63.543, I63.549, I63.59, I63.6, I63.8, I63.81, I63.89, I63.9

Myocardial Infarction:

ICD10: I21.01, I21.02, I21.09, I21.11, I21.19, I21.21, I21.29, I21.3, I21.4, I21.9, I21.A1, I21.A9, I22.0, I22.1, I22.2, I22.8, I22.9

Clinical deep dive

Disease state overview

Leukocyte adhesion deficiency (LAD) is a rare genetic disorder of the immune system (B cell and T cell immunodeficiency). LAD-I is caused by mutations in the ITGB2 gene that encodes for the beta chain-2 protein, also known as CD18. The CD18 protein plays a key role in fighting infections by facilitating leukocyte migration to infection sites where they kill invading microbes. Pediatric patients with LAD-I are predisposed to recurrent and fatal bacterial and fungal infections and present with infections immediately after birth. LAD-I is an immune disorder that is invariably fatal in childhood without an allogeneic hematopoietic stem cell transplant (HSCT). If patients with LAD-1 survive past infancy, they suffer recurrent severe infections, such as gingival ulcers, necrotic skin ulcers, pneumonia, and septicemia; survival beyond childhood is uncommon. The hallmark sign of LAD-I is delayed umbilical cord stump detachment and lack of pus formation at the infection site.

Epidemiology

The exact prevalence of LAD is unknown, possibly due to difficulty in diagnosing LAD. Prevalence has been estimated based on less than 350 cases being reported in literature. LAD-I is estimated to impact 1 in 1,000,000 persons annually.

Treatment

Currently, the only treatment option for patients with severe LAD-1 is allogeneic HSCT; however, finding a matched donor may not occur in a timely manner, and without HSCT, death usually occurs by 2 years of age. Other treatments for severe LAD-1 focus on controlling and preventing the infections with the use of antimicrobial agents, as well as white blood cell (WBC) transfusions for life-threatening infections.

Drug and clinical trial overview

In a global phase 1/2 study, the efficacy and safety of marnetegragene autotemcel were evaluated in patients (n=9) with severe LAD-1, ages 3 months and older who did not have availability of a medically eligible human leukocyte antigen (HLA)-identical sibling donor transplant. The primary end points (phase 2) were the proportion of patients alive at least one year after treatment with marnetegragene autotemcel without allogeneic HSCT and the proportion of patients alive at age 2 years without allogeneic HSCT, if they were < 1 year old at the beginning of the study. Interim analysis reported that all primary and secondary end points (e.g., post infusion CD18 expression, genetic correction, incidence of infection) were met. At data cut-off, marnetegragene autotemcel demonstrated 100% overall survival at 12 months after infusion for all patients with 12 to 24 months of available follow-up. Those patients also demonstrated significant reductions in all-cause hospitalizations and severe infections. When compared to pre-treatment history, data showed restoration of wound repair capabilities and large decreases in the incidence of significant infections and skin lesions. Marnetegragene autotemcel was well tolerated, with no severe treatment related adverse events.

Treatment with marnetegragene autotemcel involves a lengthy process including pre-collection preparation; CD34+ hematopoietic stem and progenitor cell (HSPC) mobilization, and apheresis. This is followed by ex vivo transduction of autologous hematopoietic cells with the lentiviral vector encoding the ITGB2 gene. Patients also receive myeloablative conditioning followed by a one-time IV infusion of edited HSPCs.

Pipeline (late-stage development)

NAME MANUFACTURER ROUTE OF ADMINISTRATION MECHANISM OF ACTION PROPOSED/STUDIED

INDICATION

STATUS
Interferon Gamma National Institute of Allergy and Infectious Diseases (NIAID) IV/SC Interferon LAD-1 Phase 2
Modified Allogeneic Stem Cell Transplantation NIAID IV Stem Cell Transplant LAD Phase 2

 

Ustekinumab NIAID SC Anti-IL-12 and 23 monoclonal antibody LAD-1

(minimize inflammation)

Phase 1/2

 

References
  1. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136(5): 1186-1205.e1-78. DOI: 10.1016/j.jaci.2015.04.049.
  2. Johnson V. Rocket’s LAD-I gene therapy BLA accepted for priority review. October 2, 2023. Available at: https://www.cgtlive.com/view/rocket-lad-i-gene-therapy-bla-rp-l201-priority-review. Access December 28, 2023.
  3. Leukocyte adhesion deficiency (LAD). Immune Deficiency Foundation. Available at: https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi/leukocyte-adhesion-deficiency-lad#:~:text=LAD1%20is%20by%20far%20the,mainly%20from%20the%20Middle%20East. Accessed December 28, 2023.
  4. Leukocyte adhesion deficiency. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2968. Accessed December 28, 2023.
  5. Mesa-Núñez C, Damián C, Fernández-García M, et al. Preclinical safety and efficacy of lentiviral-mediated gene therapy for leukocyte adhesion deficiency type I. Mol Ther Methods Clin Dev. 2022; 26: 459-470. DOI: 10.1016/j.omtm.2022.07.015.
  6. NCT03812263. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/. Accessed December 20, 2023
  7. Rocket pharmaceuticals announces FDA acceptance of biologics license application with priority review for RP-L201 (marnetegragene autotemcel) for the treatment of severe leukocyte adhesion deficiency-I (LAD-I). October 2, 2023. Available at: https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-fda-acceptance-biologics. Accessed December 18, 2023.
  8. Justiz Vaillant AA and Ahmad F. Leukocyte adhesion deficiency. July 3, 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK539770/. Accessed December 18, 2023.

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