Rocket Pharmaceuticals: RP-L201 Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I)

About Leukocyte Adhesion Deficiency-I

Severe Leukocyte Adhesion Deficiency-I (LAD-I) is a rare, autosomal recessive pediatric disease caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18. CD18 is a key protein that facilitates leukocyte adhesion and extravasation from blood vessels to combat infections. As a result, children with severe LAD-I are often affected immediately after birth. During infancy, they suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2, and survival beyond the age of 5 is uncommon. There is a high unmet medical need for patients with severe LAD-I.

Phase I/II Clinical Study Title: 
A Clinical Trial to Evaluate the Safety and Efficacy of RP-L201 in Subjects With Leukocyte Adhesion Deficiency-I

Brief Summary:

The primary purpose of the Phase I portion of the study is to assess the therapeutic safety and preliminary efficacy of a hematopoietic cell-based gene therapy consisting of autologous CD34+ enriched cells transduced with the therapeutic lentiviral vector, Chim-CD18-WPRE, RP-L201. 
The primary objectives of the Phase II portion of the study are evaluation of survival, as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post-infusion without allogeneic hematopoietic stem cell transplant (HSCT) and characterization of the safety and toxicity associated with the infusion.

Study Design

Study Type:                     Interventional (Clinical Trial)
Estimated Enrollment:    9 participants
Allocation:                      N/A
Intervention Model:        Single Group Assignment
Masking:                         None (Open Label)
Primary Purpose:            Treatment
Official Title: Gene Therapy for Leukocyte Adhesion Deficiency-I (LAD-I): A Phase I/II Clinical Trial to Evaluate the Safety and Efficacy of the Infusion of Autologous Hematopoietic Stem Cells Transduced With a Lentiviral Vector Encoding the ITGB2 Gene

Experimental Drug: RP-L201

RP-L201 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic cells transduced with Chim-CD18-WPRE lentiviral vector administered as a single intravenous infusion

Primary Outcome Measures :

  • Phase I: Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 [ Time Frame: 2 years ]. Evaluation of safety associated with treatment with RP-L201
  • Phase II: Survival following infusion of RP-L201 [ Time Frame: 2 years ]. Evaluation of survival as determined by the proportion of subjects alive at age 2 (24 months) and at least 1-year post infusion without allogeneic hematopoietic stem cell transplant
  • Phase II: Number of participants with treatment-related adverse events as assessed by CTCAE v.5.0 [ Time Frame: 2 years ]. Evaluation of safety associated with treatment with RP-L201

Secondary Outcome Measures :

  • CD18 expression after infusion of RP-L201 [ Time Frame: 2 years ]. Determination of the percentage of subjects in whom infusion of RP-L201 results in a change in the percentage of neutrophils expressing CD18 to at least 10%
  • Genetic correction after infusion of RP-L201 [ Time Frame: 2 years ]. Determination of the percentage of subjects in whom infusion of RP-L201 results in at least 10% of peripheral blood neutrophils carrying the therapeutic Chim-CD18-WPRE lentiviral vector provirus at 6 months post-infusion
  • Incidence of infections after infusion of RP-L201 [ Time Frame: 2 years ]. Determination of the incidence and severity of bacterial or other infections (subsequent to hematopoietic reconstitution)
  • Assessment of LAD-I-associated neutrophilia after infusion of RP-L201 [ Time Frame: 2 years ].  Evaluation of change to partially normal or to normal levels of LAD-I-associated neutrophilia
  • Assessment of skin rash or periodontal abnormalities after infusion of RP-L201 [ Time Frame: 2 years ].  Evaluation of resolution (partial or complete) of any underlying skin rash or periodontal abnormalities
  • Assessment of overall survival after infusion of RP-L201 [ Time Frame: 2 years ]. Evaluation of overall survival (beyond age 24 months and beyond the initial year subsequent to investigational therapy)

Results from Phase I/II clinical Studies (Presented at ASH2020)

The data presented are from three pediatric patients with severe LAD-I, as defined by CD18 expression of less than 2%. Key highlights from the presentation include:
  • RP-L201 was well tolerated, no safety issues reported with infusion or post-treatment
  • All patients achieved hematopoietic reconstitution within 5-weeks
  • Peripheral blood VCN and neutrophil CD18-expression were assessed post-treatment to evaluate engraftment and phenotypic correction:
  • 12 months post-treatment, Patient L201-003-1001 demonstrated durable CD18 expression of approximately 40%, peripheral blood VCN levels of 1.2, resolution of skin lesions
  • 6-months post-treatment, Patient L201-003-1004 demonstrated CD18 expression of 23% and peripheral blood VCN kinetics similar to those of the first patient
  • 2-months post-treatment, Patient L201-003-2006 demonstrated CD18 expression of 76% and peripheral blood VCN kinetics similar to those of the first patient

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