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 informationPharmacology

Pharmacokinetics

15 evidence topics · 15 sources

Conventional pharmacokinetic characterization

No evidence found.

Preclinical biodistribution: vector genomes by tissue in the mouse

“The differential biodistribution of the vg in the three tissues shows that in both cohorts, the highest vg concentration was detected in the liver, followed by the heart, and the skeletal muscle (table S1), findings that are consistent with previous studies evalu- ating AAV9 transfection properties (28).” (opens the source at this quote in a new tab)

“In the 2-month-old cohort 24 weeks after injection, a dose-dependent difference in biodistribu- tion was observed in the three tissues (table S1).” (opens the source at this quote in a new tab)

“➢ Differential distribution of vector genomes (vg) was noted ➢ Highest levels of mRNA were measured in heart, which were stable between day 30 and 91 timepoints” (opens the source at this quote in a new tab)

Preclinical biodistribution: vector copy number and transcript by tissue in non-human primates

“➢ Differential distribution of vector genomes was observed, with highest VCN measured in liver and heart ➢ High levels of transduction (mRNA) were observed in the heart” (opens the source at this quote in a new tab)

“Specifically, VCNs in the ~10 range were about ten-fold higher in heart chambers versus skeletal muscle and most central nervous system tissues.” (opens the source at this quote in a new tab)

“On May 2, 2019, we presented additional preclinical data at the ASCGT annual meeting, indicating that high VCN, in Danon disease-relevant organs in both mice and non-human primates (“NHN’s”), with high concentrations in heart and liver tissue (for NHP, cardiac VCN was approximately 10 times higher on average than in skeletal muscle and central nervous system), which is consistent with reported results in several studies of heart tissue across different species.” (opens the source at this quote in a new tab)

Cardiac vector copy number in phase 1 participants, week 8 and month 12
Cohort and participantWeek 8Month 12
Adult low dose, 1001“0.5”“0.6”
Adult low dose, 1002“6.5”“1.5”
Adult low dose, 1005“2.5”“1.91”
Adult high dose, 1006“3.9”“1.1”
Adult high dose, 1007“5.9”“6.8 (RV)”

“VCN=Vector Copies per diploid nucleus” (opens the source at this quote in a new tab)

“1 Month 9 data 2 Explanted heart samples at Month 5” (opens the source at this quote in a new tab)

Cardiac vector copy number in an explanted heart five months after infusion

“Pre Dose Biopsy Week 8 Biopsy - IVS 5M Explant - RV 5M Explant - LV 0 2 4 6 8 10 0.00 5.85 6.77 9.15 Vector DNA Copies/diploid genome (VCN) Patient 1007 Heart VCN” (opens the source at this quote in a new tab)

Cardiac vector DNA by quantitative polymerase chain reaction through month 36

“Cardiac LAMP2 DNA by qPCR (vector copies per diploid nucleus)” (opens the source at this quote in a new tab)

ParticipantPredoseMonth 6Month 12Month 36
1001“0”“0.384”“0.197”“0.120”
1002“0”“ND”“0.575”“0.590”
1005“0”“0.583”“ND”“1.228”
1006“0”“2.693”“1.131”“-”
1008“0”“0.492”“-”“-”
Persistence of vector genomes and transcripts in myocardium through 60 months

“LAMP2B vector RNA and DNA (VCN) levels have persisted through 60 months of follow-up” (opens the source at this quote in a new tab)

Vector shedding in body fluids

No evidence found.

Pre-existing anti-AAV9 neutralizing antibodies: eligibility threshold in both trials

“Anti-AAV9 neutralizing antibody titer >1:40.” (opens the source at this quote in a new tab)

“Exclusion Criteria • Anti-AAV9 neutralizing antibody titer >1:40 • Cardiopulmonary instability • Prior organ transplantation • LVEF <40% • Implemented prior to pediatric cohort” (opens the source at this quote in a new tab)

Pre-existing anti-AAV9 immunity in a participant with a serious immune-related event

“At the higher dose administered (1.1×10¹⁴ gc/kg), one of the two treated patients, who received the higher absolute AAV9 dose 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 serious adverse event.” (opens the source at this quote in a new tab)

“Patient with enhanced risk due to high weight & vector dose and pre-existing AAV immunity” (opens the source at this quote in a new tab)

Post-dose antibody responses to the capsid and to the transgene in preclinical species

“Immune response ▪ Dose-dependent increase in neutralizing antibodies (NAbs) ▪ Characteristic strong total antibody (TAb) response to capsid ▪ No significant anti-drug antibody (ADA) response to transgene” (opens the source at this quote in a new tab)

“➢ NAbs to AAV9 capsid developed as expected ➢ Although robust TAb response to capsid was seen, mild ADA response to transgene was noted ➢ No significant T-cell response to capsid or transgene (ELISpot) was observed” (opens the source at this quote in a new tab)

Anti-LAMP2 antibody responses in the mouse model

“No anti-LAMP2 antibodies were detected in mice that received AAV9.LAMP2B.” (opens the source at this quote in a new tab)

“We also evaluated the development of antibody to the LAMP2 transgene. Unlike capsid antibodies, only 2 of 10 mice (1 in the 1 × 10¹⁴ vg/kg group and 1 in the 2 × 10¹⁴ vg/kg) developed antibodies against the transgene. These antibodies were much lower than those against the viral capsid (antibody titer log10 values, 1.7 to 2.0).” (opens the source at this quote in a new tab)

Immunogenicity assessment planned in the clinical program

“Determination and characterization of immunologic response to RP-A501 Assessment of potential immunogenicity to the components of the investigational product 3 years” (opens the source at this quote in a new tab)

Post-dose anti-AAV9 and anti-LAMP2 antibody titers in treated participants

No evidence found.

Antibody kinetics after systemic AAV9 with and without rituximab and sirolimus, including Danon disease participants

“Group 2 ( n = 15) received rituximab plus sirolimus as the IMR in addition to corticosteroids to prevent the formation of anti-capsid antibodies and included 2 participants (Group 2A) with SMA treated with Zolgensma, 11 participants (Group 2B) with GM1 gangliosidosis (GM1) receiving the investigational product from NCT03952637 (NIH), and 2 participants (Group 2C) with Danon disease receiving the investigational product RP-A501 ( NCT03882437 ).” (opens the source at this quote in a new tab)

“An increase in IgM level was first detected on day 5 after dosing and peaked on day 14. IgG was detectable by day 7 and continued to increase during the first 30 days after dosing. Group 2 participants received rituximab plus sirolimus IMR and there was no significant change in either IgM or IgG ( Figure 1 and Table 2 ).” (opens the source at this quote in a new tab)

Seroprevalence of anti-AAV9 neutralizing antibodies in a 10-country sample of adults and children

“We measured activity of NAbs against six clinically relevant AAV serotypes across 10 countries in adults ( n = 502) and children ( n = 50) using a highly sensitive transduction inhibition assay.” (opens the source at this quote in a new tab)

“In adult participants at the 1:1 serum dilution, the most prevalent AAV NAb activities were AAV1 (74.9% of evaluable participants had positive serum samples), AAV6 (70.1%), and AAV5 (63.9%), followed by AAV8 (60.4%), AAVRh74var (58.4%), and AAV9 (57.8%; Figure 1 A).” (opens the source at this quote in a new tab)

“NAb activity against AAV6, AAV8, AAV9, and AAVRh74var was intermediate, ranging from 51.6% to 55.4% at the 1:2 dilution and from 45.6% to 47.6% at the 1:4 dilution.” (opens the source at this quote in a new tab)

“Pediatric samples ( Figure 1 B) exhibited lower prevalence of anti-AAV NAbs compared with adult samples ( Figure 1 A), although the sample size was considerably smaller for the pediatric population ( n = 50 compared with n = 502 for adults).” (opens the source at this quote in a new tab)

“In the US, the prevalence of NAb positivity ranged considerably by AAV vector, from 48% for AAVRh74var and AAV9 to 86% for AAV1.” (opens the source at this quote in a new tab)

Variability of neutralizing antibody assays and eligibility cutoffs across programs

“Finally, assays to determine NAb levels are poorly standardized across studies and vary in methodology, cutoffs used to determine sample positivity, and cutoffs used to determine patient eligibility. 34 Consequently, the same patient may be deemed eligible for administration of AAV gene therapy in one trial but ineligible in another.” (opens the source at this quote in a new tab)

Pre-existing antibodies as a barrier to transduction, as stated in the preclinical report

“An additional limitation regarding translation of the preclinical studies described in this paper to patients with DD is the presence of preexisting AAV9 antibodies. It is well established that these neu- tralizing antibodies can prevent viral transduction (43).” (opens the source at this quote in a new tab)

“In these investigations, we did not observe evidence of relevant antibodies in mice, although the prevalence of AAV antibodi” (opens the source at this quote in a new tab)

“es may be as high as 30% in humans (43). Patients with such antibodies are not considered candidates for AAV9 therapies at present; however, substantial re- search is ongoing to address this limitation (44, 45).” (opens the source at this quote in a new tab)