Rocket Pharmaceuticals: RP-A501 Gene Therapy for Danon Disease (AAV9.LAMP2B)

- Danon Disease is caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2)
- RP-A501 is an investigational gene therapy product consisting of a rAAV9 capsid containing the human LAMP2B transgene 
- Preliminary Results from the Phase 1 study showed Positive Increases in Cardiac Protein Expression in low dose cohort
-Decreases in Cardiac Biomarker BNP of >50% and Stabilization of Clinical Biomarkers CK-MB and Transaminases in Two Patients—
- Low Dose Cohort Generally Well-Tolerated with Manageable Safety
- Safety Assessment in Two Adult Patients Treated in Higher Dose Cohort Ongoing
- One Drug Product-Related Serious Adverse Event Resolved Following Intensified Immunosuppressive Therapy

About Danon Disease
Danon Disease is caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2), an important mediator of autophagy. The genetic mutations in the LAMP2 gene result in the accumulation of autophagosomes and glycogen, particularly in cardiac muscle and other tissues, which ultimately leads to severe and frequently fatal cardiomyopathy. It is estimated to have a prevalence of 15,000 to 30,000 patients in the U.S. and the European Union. 
Cardiomyopathy in Dann Disease
(Maron et al, 2012)

The disease is often fatal in male patients in the second or third decade of life due to rapidly progressive heart failure. Available therapies for Danon Disease include cardiac transplantation, which is associated with substantial complications and is not considered curative. There are no specific therapies available for the treatment of Danon Disease.

Regulatory Status: N/A

Study Title for Phase I study: 

Evaluation of RP-A501 in pediatric patients (ages 8-14) at either dose level will commence only pending determination of safety in the older (adult and age ≥15 and generally capable of providing assent) population

Brief Summary:
This is a non-randomized open-label Phase 1 study to evaluate the safety and toxicity of gene therapy using a recombinant adeno-associated virus serotype 9 (AAV9) containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B) transgene (investigational product (IP), RP-A501) in male patients with Danon Disease (DD).

Study Design
Study Type: Interventional (Clinical Trial)
Estimated Enrollment: 24 participants
Intervention Model: Sequential Assignment
Intervention Model Description:
Subjects will receive RP-A501 according to a 3+3 dose escalation design as follows:
    Cohort 1: Age 15 years and older: Low Dose (n=3-6 subjects)
    Cohort 2: Age 15 years and older: High Dose (n=3-6 subjects)
    Cohort 3: Age 8-14 years: Low Dose (n=3-6 subjects)
    Cohort 4: Age 8-14 years: High Dose (n=3-6 subjects)
Masking: None (Open Label)

Experimental Drug: RP-A501
RP-A501 is a gene therapy product consisting of a rAAV9 capsid containing the human LAMP2B transgene which will be administered as a single intravenous (IV) infusion. Subjects will receive one of two dose levels depending on the cohort.

Primary Outcome Measures:
  • Number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE) [ Time Frame: 3 years ].  Evaluation of safety associated with RP-A501
  • Number of participants within each dose level cohort with treatment-related adverse events as assessed by United States (US) National Cancer Institute Common Terminology Criteria (NCI CTCAE) [ Time Frame: 3 years ]. Assessment of safety at both doses (single IV administration)
  • Detection of target tissue transduction following administration of RP-A501 [ Time Frame: 3 years ]. Assessment of target tissue transduction by gene expression
  • Evaluation of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy [ Time Frame: 3 years ]. Assessment of cardiomyocyte histologic correction following administration of RP-A501 via endomyocardial biopsy
  • Preliminary evaluation of clinical stabilization of cardiomyopathy following administration of RP-A501 via cardiopulmonary testing [ Time Frame: 3 years ]. Assessment of clinical stabilization of cardiomyopathy following infusion of RP-A501 via cardiopulmonary testing

Secondary Outcome Measures:
  • Determination of the percentage of patients in whom RP-A501 resulted in a sustained improvement or stabilization in cardiovascular pathophysiology [ Time Frame: 3 years ]. Evaluation of sustained improvement or stabilization in cardiovascular pathophysiology as assessed by medical evaluation, radiographic evaluation of cardiac structure and function, and cardiopulmonary exercise/physiologic parameters
  • Determination of the percentage of patients in whom cardiomyocytes corrected LAMP2B gene and/or protein [ Time Frame: 3 years ]. Evaluation of the percentage of patients in whom cardiomyocytes contain the corrected LAMP2B gene and/or protein and improvement in DD-associated histologic abnormalities and when feasible to quantify the extent of genetic and histologic correction in the myocardium.
  • Evaluation of serologic markers of muscle injury and congestive heart failure following administration of RP-A501 [ Time Frame: 3 years ]. Assessment of serologic markers (creatinine phosphokinase, brain natriuretic peptide, etc) will be performed as potential surrogates of clinical, structural and histologic modification of DD
  • Determination and characterization of immunologic response to RP-A501 [ Time Frame: 3 years ].  Assessment of potential immunogenicity to the components of the investigational product
  • Evaluation of patient-reported outcomes/quality-of-life (PRO/QOL) [ Time Frame: 3 years ]. Assessment of PRO/QOL will be performed via the Kansas City Cardiomyopathy Questionnaire
  • Assessment of PRO/QOL [ Time Frame: 3 years ]. Evaluation of PRO/QOL will be performed via the Pediatric Cardiac Quality of Life Inventory
  • Determination of the percentage of patients who require and/or receive treatment for heart failure following RP-A501 [ Time Frame: 3 years ]. Assessment of the percentage of patients who require and/or receive subsequent cardiac transplantation, left ventricular assist device (LVAD), implantable cardioverter-defibrillator or pacemaker placement, electrophysiologic ablative procedure for cardiac conduction aberrancy or subsequent hospitalizations for heart failure.
  • Evaluation of overall survival [ Time Frame: 3 years ]. Assessment of overall survival post RP-A501
  • Determination of the percentage of patients with stabilization in neuromuscular function via timed test of essential neuromuscular activities [ Time Frame: 3 years ]. Assessment of the percentage of patients with stabilization in neuromuscular function via timed test of essential neuromuscular activities. Determination of the percentage of patients with stabilization in ophthalmologic function via ophthalmologic examination [ Time Frame: 3 years ]. Assessment of the percentage of patients with stabilization in ophthalmologic function via ophthalmologic examination

Key Results from Phase 1 Clinical Study

Preliminary safety and efficacy results from the three patients treated with the low dose of 6.7×10^13 genome copies (gc)/kilogram (kg) and early safety information from the two patients treated with the higher dose of 1.1×10^14 gc/kg as of November 2020 are as follows:

Safety Results
  • RP-A501 showed a manageable safety profile in the three patients treated in the low dose cohort. No unexpected drug product related adverse events (AEs) or severe adverse events (SAEs) were observed. 
  • The most common adverse events were mild and were consistent with AEs caused by elevated transaminases observed post treatment. Elevation in transaminases were observed in all three low-dose patients and returned to baseline within the first one to two months post-treatment. These elevations were largely responsive to corticosteroids and other immunosuppressive therapies. 
  • All patients were given oral steroids to prevent or minimize potential immune-related events. At dose escalation, rituximab and tacrolimus were also added to the protocol as additional options to mitigate the immune response associated with RP-A501.
  • Upon dose escalation to 1.1×1014 gc/kg, one of the two treated patients, who received the highest total dose volume of AAV9 and had some degree of pre-existing anti-AAV9 immunity, experienced a non-persistent, immune-related event that was classified as a drug product related SAE. Rocket believes this event was likely due to complement activation, resulting in reversible thrombocytopenia and acute kidney injury requiring transient hemodialysis. This patient returned to baseline within three weeks and regained normal kidney function.

Gene Expression Results

  • All three low dose participants demonstrated evidence of cardiac LAMP2B expression by Western blot and/or immunohistochemistry.
  • In cardiac biopsies of patients treated at a systemic dose of 6.7x1013 gc/kg, LAMP2B gene expression was observed to be present in 68% of cells versus normal as determined by immunohistochemistry at month 9 in one patient, and at 92% of cells versus normal at month 12 in the other patient. 
  • Western blot assessment showed 61% of normal LAMP2B protein expression at month 9 in one patient. The 12-month Western blot data were still pending for all three patients as of the data cutoff.

Biomarker Results
  • Two of the three low dose patients demonstrated key clinical biomarker improvements consistent with improved cardiac function. Brain natriuretic peptide (BNP), a key marker of heart failure, improved in all three patients, including greater than 50% in the two patients with closely monitored immunosuppressive regimen compliance.
  •  Additionally, creatine kinase myocardial band (CPK-MB) either improved or stabilized in these two patients. Notably, all three patients showed visible improvements in autophagic vacuoles, a hallmark of Danon Disease pathology, as assessed by electron microscopy.
  • Two of the three low dose patients with closely monitored immunosuppressive regimen compliance demonstrated improvement in cardiac output as measured by invasive hemodynamics, including one patient who showed a 1.62-fold increase in cardiac output at month 12, and one patient who showed a 1.35-fold increase at month 9.
Source
https://clinicaltrials.gov/ct2/show/NCT03882437
https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-positive-gene-expression

Source

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