Evicenter
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RP-A501 (AAV9.LAMP2B)

Danon disease

Regulatory submission
BLA planned for late 2028
Last updated
300 sources

Product information and disease descriptionProduct descriptionProduct informationDosing and administration

Dosage

11 evidence topics · 14 sources

Dose levels and cohorts in the phase 1 trial

“In Phase 1, RP-A501 will be investigated in three treatment cohorts, as follows with a single cohort currently recruiting: Cohort 1: Adult and age 15-17: 6.7 × 10¹³ GC/kg (n=3-4) Cohort 2: Adult and age 15-17: 1.1 × 10¹⁴ GC/kg (n=2 [patients already treated; closed for current enrollment]) Cohort 1A: Pediatric age 8-14: 6.7 × 10¹³ GC/kg (n=2-4)” (opens the source at this quote in a new tab)

“Subjects will receive one of three dose levels depending on the cohort.” (opens the source at this quote in a new tab)

Dose levels and cohorts in the phase 2 trial

“Dose of RP-A501: Cohorts 1, 2 & 3 = 6.7 x10^13 genome copies (GC)/kg; Cohort 4 = 3.8 x10^13 GC/kg.” (opens the source at this quote in a new tab)

“Cohort 1: Adolescent/Adult males (age ≥ 15 years) [N=1 subject; enrollment closed] Cohort 2: Pediatric males (age 8 to 14 years) [N= 3 subjects; enrollment closed] Cohort 3: Males age ≥ 8 years receiving a pegcetacoplan-containing immunomodulatory regimen [N=2 subjects; enrollment closed] Cohort 4: Males age ≥ 8 years [N=12 subjects; enrolling]” (opens the source at this quote in a new tab)

Weight-based dosing and total administered dose in the first five phase 1 participants
ParticipantWeightCohort doseTotal dose
1001“52.2 kg”“6.7 x 10¹³ GC/kg”“3.25 x 10¹⁵ GC”
1002“89.1 kg”“6.7 x 10¹³ GC/kg”“5.97 x 10¹⁵ GC”
1005“97.8 kg”“6.7 x 10¹³ GC/kg”“6.08 x 10¹⁵ GC”
1006“82.7 kg”“1.1 x 10¹⁴ GC/kg”“9.10 x 10¹⁵ GC”
1007“96.7 kg”“1.1 x 10¹⁴ GC/kg”“1.06 x 10¹⁶ GC”
Highest dose permitted under the investigational new drug application

“1. IND enables doses up to 2.0 x 10¹⁴ GC/kg” (opens the source at this quote in a new tab)

Discontinuation of the 1.1 × 10¹⁴ GC/kg dose, August 2021

“Given the positive benefit/risk profile in the low dose, and additionally to mitigate safety concerns observed at the higher dose, in agreement with FDA we will no longer treat Danon patients with the higher dose (1.1e14).” (opens the source at this quote in a new tab)

“Rocket does not anticipate pursuing doses higher than 1.1x10¹⁴ moving forward.” (opens the source at this quote in a new tab)

“The high dose was discontinued after one of the two patients treated at this dose developed thrombotic microangiopathy[11].” (opens the source at this quote in a new tab)

Selection of 6.7 × 10¹³ GC/kg for the phase 2 trial

“Based on the initial efficacy observed in the low dose cohort and to mitigate complement-mediated safety concerns observed in the high dose cohort (related to thrombotic microangiopathy or TMA) and in agreement with the FDA, the Phase 2 study was initiated at the low dose (6.7e13 gc/kg).” (opens the source at this quote in a new tab)

“I am pleased to announce that following discussions with FDA, we anticipate proceeding with a dose of 6.7e13 GC/kg, and we anticipate utilizing a single arm open-label trial design with a robust natural history comparator, pursuant to the FDA’s acknowledgment of the challenges associated with executing a randomized controlled trial in Danon Disease,” (opens the source at this quote in a new tab)

Rationale for the recalibrated 3.8 × 10¹³ GC/kg dose: relation to the phase 1 doses associated with efficacy

“The FDA authorized the pivotal study to resume first with a recalibrated dose of 3.8 x 10¹³ GC/kg of RP-A501 in three patients, treated sequentially with a minimum four-week interval between each treatment. This adjusted dose aligns with the lower range of administered doses that were associated with efficacy across multiple biomarkers, echocardiographic and clinical endpoints in the Phase 1 study, and has been determined as most likely to confer the safety and efficacy identified in the low-dose Phase 1 cohorts.” (opens the source at this quote in a new tab)

Rationale for the recalibrated dose: full capsid content of the current drug product

“The recalibrated Phase 2 dose was selected with the expectation that it will deliver potency consistent with the dose at which RP-A501 demonstrated meaningful efficacy in patients in Phase 1” (opens the source at this quote in a new tab)

“This recalibration accounts for the higher proportion of full capsids in the current drug product in the setting of Danon disease and was developed in consultation with leading experts and the FDA.” (opens the source at this quote in a new tab)

“We anticipate that the dose will preserve RP-A501's therapeutic potential while optimizing its benefit-risk profile.” (opens the source at this quote in a new tab)

“Cohort 4 Updates and Rationale Dose recalibrated to account for the higher full-to-empty capsid ratio” (opens the source at this quote in a new tab)

“The recalibrated Phase 2 dose was selected to deliver a therapeutic profile consistent with the dose at which RP-A501 demonstrated meaningful efficacy in Phase 1 patients.” (opens the source at this quote in a new tab)

Rationale for the recalibrated dose: analytical characterization and nonclinical bridging

“The recalibrated dose was selected based on analytical characterization of the Phase 2 commercial-grade product, including its full-particle content, and is supported by nonclinical bridging data.” (opens the source at this quote in a new tab)

“The FDA also confirmed that the pivotal study population will include 12 male patients treated with RP-A501 at the recalibrated dose of 3.8 × 10¹³ genome copies per kilogram (GC/kg) using commercial-grade product.” (opens the source at this quote in a new tab)

Product change underlying the recalibration: full-particle content of the in-house material

“Superior specifications to Phase I material; allow for full dosing with lower total viral particles, potentially further improving safety profile” (opens the source at this quote in a new tab)

“Product Quality: Significant increase in full versus empty viral particles” (opens the source at this quote in a new tab)

Maximum dose and treatment duration recorded in the European Union application

“Max daily dose 67000000000000 Other Max total dose 67000000000000 Other Max treatment duration 1 Day(s)” (opens the source at this quote in a new tab)