Abstract: The Safety and Efficacy of Pre-Treatment with Imlifidase Prior to Adeno Associated Virus (AAV)-Based Gene Therapy in Non-Human Primates with Pre-Existing Anti-AAVrh74 Antibodies
Abstract from Sarepta's preclinical study with imlifidase as pretreatment to SRP-9001 on the link below (Oral presentation May 17)
https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=149
AdComm meeting held Friday voted positively on accelerated approval for Sarepta Therapeutics' investigational gene therapy SRP-9001 for the potential treatment of Duchenne muscular dystrophy (DMD) ahead of its PDUFA date May 29, 2023 https://www.cgtlive.com/view/fda-adcomm-leans-yes-on-sarepta-dmd-gene-therapi
The Safety and Efficacy of Pre-Treatment with Imlifidase Prior to Adeno Associated Virus (AAV)-Based Gene Therapy in Non-Human Primates with Pre-Existing Anti-AAVrh74 Antibodies
Type: Oral Abstract Session
Presentation Details
Session Title: AAV Vectors: Clinical and Non-Human Primate Studies
Location: Room 411
Start Time: 5/17/2023 16:00
End Time: 5/17/2023 16:15
Duchenne muscular dystrophy (DMD) is an X-linked, neuromuscular disease caused by mutations in the DMD gene that prevent the production of functional dystrophin protein. Delandistrogene moxeparvovec (SRP-9001) is a gene transfer therapy designed to compensate for missing dystrophin in DMD by delivering a transgene that utilizes an adeno-associated virus (AAV) vector-AAVrh74-and encodes SRP-9001 dystrophin, a shortened, engineered dystrophin protein that retains key functional domains of the wild-type protein. Despite generally low levels of pre-existing immunity to AAVrh74 in humans, anti-AAV antibodies do occur and can impact the safety and efficacy of gene therapies and preclude their use in otherwise eligible patients. Here, we assessed the ability of imlifidase, a unique endopeptidase that cleaves IgG, to lower anti-AAVrh74 antibodies as a potential means of overcoming or reducing pre-existing immunity.
This study of imlifidase in female cynomolgus monkeys was carried out in two parts with a reporter construct. Part 1 assessed a single (Day 1) or once-daily dose (Days 1-14) of prednisolone via oral gavage (1 mg/kg/day) as a standard immunosuppressive treatment and intravenous (IV) imlifidase (10 mg/kg/dose, Day 1) followed by IV AAVrh74.CMV.eGFP (1.33x1014 vg/kg/dose, Day 3) in both anti-AAVrh74 antibody-negative and -positive animals. Part 2 assessed once-daily prednisolone (Days 1-62 or Days 1-96) and single (Day 1) or repeated (Days 1 and 36) imlifidase or saline control and/or AAVrh74.CMV.eGFP (Day 3 or Days 3 and 38). Animals underwent an observation period of at least 59 days. We assessed biodistribution, expression of eGFP, immunological response (anti-AAVrh74 total antibodies using an enzyme-linked immunosorbent assay and T-cell response to AAVrh74 peptides using an enzyme-linked immunosorbent spot), histopathology, and pharmacokinetics/pharmacodynamics of imlifidase.
In brief, treatment with imlifidase prior to AAVrh74-eGFP in animals with pre-existing anti-AAVrh74 antibodies (titer range: 1:800-1:1600) led to a decreased anti-AAVrh74 antibody response. The decrease in anti-AAVrh74 antibodies observed in animals that received imlifidase prior to gene therapy resulted in efficient transduction (as measured by droplet digital polymerase chain reaction) and expression (as measured by immunofluorescent quantification) of AAVrh74.CMV.eGFP relative to animals with the same antibody titers that did not receive imlifidase. These results suggest that imlifidase can permit AAV transduction in seropositive animals. No adverse clinical events or mortality occurred subsequent to dosing with gene therapy, and no adverse immunotoxicological or histopathological findings related to imlifidase pre-treatment were found, including in the reproductive organs.
In this proof-of-concept study, imlifidase pre-treatment lowered anti-AAVrh74 total antibody titers, allowing for safe administration of AAV-based gene therapy in seropositive animals. These findings may help enable treatment in patients currently excluded due to pre-existing antibodies against AAVrh74.
This research was funded by Sarepta Therapeutics.
Rachael Potter1, Sohrab Khan1, John Snedeker1, Kaitlin Adegboye1, Alex Haile1, Behnam Sayanjali1, Nicole Pukos1, Kyle Cochran1, Jen Ahner1, Ting Su1, Nathalie Uzcátegui2, Yvonne Stenberg2, Catja Freiburghaus2, Lena Winstedt2, Louise Rodino-Klapac1
1Sarepta Therapeutics, Cambridge, MA,2Hansa Biopharma, Lund, Sweden
R. Potter: 1; Commercial Interest i.e. Company X; Sarepta Therapeutics. 1; What was received? i.e. Honorarium; Employment and stock options. 1; For what role? i.e. Speaker; Employee.
Abstract from Sarepta's preclinical study with imlifidase as pretreatment to SRP-9001 on the link below (Oral presentation May 17)
https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=149
AdComm meeting held Friday voted positively on accelerated approval for Sarepta Therapeutics' investigational gene therapy SRP-9001 for the potential treatment of Duchenne muscular dystrophy (DMD) ahead of its PDUFA date May 29, 2023 https://www.cgtlive.com/view/fda-adcomm-leans-yes-on-sarepta-dmd-gene-therapi
The Safety and Efficacy of Pre-Treatment with Imlifidase Prior to Adeno Associated Virus (AAV)-Based Gene Therapy in Non-Human Primates with Pre-Existing Anti-AAVrh74 Antibodies
Type: Oral Abstract Session
Presentation Details
Session Title: AAV Vectors: Clinical and Non-Human Primate Studies
Location: Room 411
Start Time: 5/17/2023 16:00
End Time: 5/17/2023 16:15
Duchenne muscular dystrophy (DMD) is an X-linked, neuromuscular disease caused by mutations in the DMD gene that prevent the production of functional dystrophin protein. Delandistrogene moxeparvovec (SRP-9001) is a gene transfer therapy designed to compensate for missing dystrophin in DMD by delivering a transgene that utilizes an adeno-associated virus (AAV) vector-AAVrh74-and encodes SRP-9001 dystrophin, a shortened, engineered dystrophin protein that retains key functional domains of the wild-type protein. Despite generally low levels of pre-existing immunity to AAVrh74 in humans, anti-AAV antibodies do occur and can impact the safety and efficacy of gene therapies and preclude their use in otherwise eligible patients. Here, we assessed the ability of imlifidase, a unique endopeptidase that cleaves IgG, to lower anti-AAVrh74 antibodies as a potential means of overcoming or reducing pre-existing immunity.
This study of imlifidase in female cynomolgus monkeys was carried out in two parts with a reporter construct. Part 1 assessed a single (Day 1) or once-daily dose (Days 1-14) of prednisolone via oral gavage (1 mg/kg/day) as a standard immunosuppressive treatment and intravenous (IV) imlifidase (10 mg/kg/dose, Day 1) followed by IV AAVrh74.CMV.eGFP (1.33x1014 vg/kg/dose, Day 3) in both anti-AAVrh74 antibody-negative and -positive animals. Part 2 assessed once-daily prednisolone (Days 1-62 or Days 1-96) and single (Day 1) or repeated (Days 1 and 36) imlifidase or saline control and/or AAVrh74.CMV.eGFP (Day 3 or Days 3 and 38). Animals underwent an observation period of at least 59 days. We assessed biodistribution, expression of eGFP, immunological response (anti-AAVrh74 total antibodies using an enzyme-linked immunosorbent assay and T-cell response to AAVrh74 peptides using an enzyme-linked immunosorbent spot), histopathology, and pharmacokinetics/pharmacodynamics of imlifidase.
In brief, treatment with imlifidase prior to AAVrh74-eGFP in animals with pre-existing anti-AAVrh74 antibodies (titer range: 1:800-1:1600) led to a decreased anti-AAVrh74 antibody response. The decrease in anti-AAVrh74 antibodies observed in animals that received imlifidase prior to gene therapy resulted in efficient transduction (as measured by droplet digital polymerase chain reaction) and expression (as measured by immunofluorescent quantification) of AAVrh74.CMV.eGFP relative to animals with the same antibody titers that did not receive imlifidase. These results suggest that imlifidase can permit AAV transduction in seropositive animals. No adverse clinical events or mortality occurred subsequent to dosing with gene therapy, and no adverse immunotoxicological or histopathological findings related to imlifidase pre-treatment were found, including in the reproductive organs.
In this proof-of-concept study, imlifidase pre-treatment lowered anti-AAVrh74 total antibody titers, allowing for safe administration of AAV-based gene therapy in seropositive animals. These findings may help enable treatment in patients currently excluded due to pre-existing antibodies against AAVrh74.
This research was funded by Sarepta Therapeutics.
Rachael Potter1, Sohrab Khan1, John Snedeker1, Kaitlin Adegboye1, Alex Haile1, Behnam Sayanjali1, Nicole Pukos1, Kyle Cochran1, Jen Ahner1, Ting Su1, Nathalie Uzcátegui2, Yvonne Stenberg2, Catja Freiburghaus2, Lena Winstedt2, Louise Rodino-Klapac1
1Sarepta Therapeutics, Cambridge, MA,2Hansa Biopharma, Lund, Sweden
R. Potter: 1; Commercial Interest i.e. Company X; Sarepta Therapeutics. 1; What was received? i.e. Honorarium; Employment and stock options. 1; For what role? i.e. Speaker; Employee.
16/5 2023 09:02 ProInvestorNEWS 5
112654 FDA panel narrowly backs approval of Sarepta's DMD gene therapy
Published: May 13, 2023
An FDA advisory panel that convened Friday to discuss the merits of Sarepta Therapeutics' SRP-9001 (delandistrogene moxeparvovec) for ambulatory patients with Duchenne muscular dystrophy (DMD) voted 8 to 6 recommending accelerated approval for the AAV vector-based gene therapy. The filing, granted a priority review late last year, has been assigned a target action date of May 29.
"If it were to receive an accelerated approval, it would need to have confirmatory data from a clinical trial to support continued approval," remarked Peter Marks, director of the FDA's Center for Biologics Evaluation and Research. He said the agency would take the advice into consideration and "do something that we have to do every day at FDA... We have to manage through the uncertainty here."
Earlier in the week, FDA staff scientists had laid out a number of concerns about Sarepta's application, ultimately concluding that clinical studies of SRP-9001 did "not provide unambiguous evidence" of benefit in ambulatory patients with DMD. It also poses a risk of patients not being able to receive other AAV vector-based gene therapies in the future if SRP-9001 turns out to be ineffective, they said. The agency's presentation on Friday continued in much the same vein, casting doubt on the structure of Sarepta's microdystrophin - a shortened form of dystrophin encoded by the therapy - as well as on preclinical testing, clinical trial results and manufacturing.
Another readout later this year
Panel member Nirali Shah, who voted against, said "I don't have any real concerns about the risk of therapy, I think it's well tolerated, but I do remain concerned about the actual benefit, and whether that has been adequately demonstrated without a study that is going to be using the commercialised product." She added that "coming from a field of gene therapy - the product is the process - and I think the confirmatory study needs to be completed." Meanwhile, Rajiv Ratan said he was not convinced that Sarepta's data package "provided plausibility that...the expression of the microdystrophin would predict a clinical outcome."
Caleb Alexander, another no voter, said he agreed that videos shown to the panel of boys who had been treated, and who appeared to achieve improved muscle function, were "compelling and there are good clinicians here that think this product works...but as we heard, accelerated approval is based on more than that, and the threshold of substantial evidence has to be met."
Sarepta's regulatory filing included mixed Phase II findings, where SRP-9001 succeeded on the main biological endpoint of microdystrophin protein expression, but showed no significant difference against placebo on a functional endpoint measured by the North Star Ambulatory Assessment (NSAA). The company is currently running the Phase III EMBARK trial, also known as Study 301, which is expected to read out by year end. "The decision the FDA has to make doesn't just affect the patients in Study 301; it affects the entire field of drug development for Duchenne," Alexander said, adding "the totality of evidence...simply doesn't rise to the threshold that's required for accelerated approval."
Erring on the side of access
Meanwhile, among those who voted yes were Donald Kohn, who said "giving accelerated approval will give patients access to this over the next year, while the results from the definitive study are being analysed... We need to err on the side of patients being given the benefit of access." Raymond Roos suggested "the downside of the gene therapy here is relatively small compared to whether it really helps the patient, and for this reason, I voted yes," while panelist John Chiorini said "waiting is not going to be beneficial to the patients."
https://firstwordpharma.com/story/5739648
Published: May 13, 2023
An FDA advisory panel that convened Friday to discuss the merits of Sarepta Therapeutics' SRP-9001 (delandistrogene moxeparvovec) for ambulatory patients with Duchenne muscular dystrophy (DMD) voted 8 to 6 recommending accelerated approval for the AAV vector-based gene therapy. The filing, granted a priority review late last year, has been assigned a target action date of May 29.
"If it were to receive an accelerated approval, it would need to have confirmatory data from a clinical trial to support continued approval," remarked Peter Marks, director of the FDA's Center for Biologics Evaluation and Research. He said the agency would take the advice into consideration and "do something that we have to do every day at FDA... We have to manage through the uncertainty here."
Earlier in the week, FDA staff scientists had laid out a number of concerns about Sarepta's application, ultimately concluding that clinical studies of SRP-9001 did "not provide unambiguous evidence" of benefit in ambulatory patients with DMD. It also poses a risk of patients not being able to receive other AAV vector-based gene therapies in the future if SRP-9001 turns out to be ineffective, they said. The agency's presentation on Friday continued in much the same vein, casting doubt on the structure of Sarepta's microdystrophin - a shortened form of dystrophin encoded by the therapy - as well as on preclinical testing, clinical trial results and manufacturing.
Another readout later this year
Panel member Nirali Shah, who voted against, said "I don't have any real concerns about the risk of therapy, I think it's well tolerated, but I do remain concerned about the actual benefit, and whether that has been adequately demonstrated without a study that is going to be using the commercialised product." She added that "coming from a field of gene therapy - the product is the process - and I think the confirmatory study needs to be completed." Meanwhile, Rajiv Ratan said he was not convinced that Sarepta's data package "provided plausibility that...the expression of the microdystrophin would predict a clinical outcome."
Caleb Alexander, another no voter, said he agreed that videos shown to the panel of boys who had been treated, and who appeared to achieve improved muscle function, were "compelling and there are good clinicians here that think this product works...but as we heard, accelerated approval is based on more than that, and the threshold of substantial evidence has to be met."
Sarepta's regulatory filing included mixed Phase II findings, where SRP-9001 succeeded on the main biological endpoint of microdystrophin protein expression, but showed no significant difference against placebo on a functional endpoint measured by the North Star Ambulatory Assessment (NSAA). The company is currently running the Phase III EMBARK trial, also known as Study 301, which is expected to read out by year end. "The decision the FDA has to make doesn't just affect the patients in Study 301; it affects the entire field of drug development for Duchenne," Alexander said, adding "the totality of evidence...simply doesn't rise to the threshold that's required for accelerated approval."
Erring on the side of access
Meanwhile, among those who voted yes were Donald Kohn, who said "giving accelerated approval will give patients access to this over the next year, while the results from the definitive study are being analysed... We need to err on the side of patients being given the benefit of access." Raymond Roos suggested "the downside of the gene therapy here is relatively small compared to whether it really helps the patient, and for this reason, I voted yes," while panelist John Chiorini said "waiting is not going to be beneficial to the patients."
https://firstwordpharma.com/story/5739648
16/5 2023 09:03 ProInvestorNEWS 4112655 74th Cellular, Tissue, and Gene Therapies Advisory Committee
19/5 2023 08:20 B.Andersen 2112691 "Partner news from Sarepta on pipeline project in Gene Therapy!!!
Shares in Hansa Biopharma and Sarepta are up more than 5 and 30 percent respectively - yesterday, following a surprise decision by an FDA advisor panel on Friday to recommend FDA to grant accelerated approval of gene therapy product SRP-9001 from Hansa Biopharma's partner Sarepta Therapeutics at an upcoming FDA meeting late May. Hansa Biopharma's enzyme cleaving technology imlifidase may potentially be used as a pre-treatment to SRP-9001 in up to 14% of the DMD patient population and if successful in both DMD and LGMD Hansa Biopharma will be eligible to receive up to USD 400 million in milestones from Sarepta Therapeutics plus up to midteens in royalty payments and sales of imlifidase . According to Fierce Biotech, expectations in DMD are high with SRP-9001 potentially be one of the biggest biotech product launches in 2023 with annual sales of more than USD 2 billion in less than five years.
The decision to recommend SRP-9001 for accelerated approval came after FDA last week released documents send to the advisors that raised concerns regarding efficacy, safety etc. of SRP-900, but among other things the advisory panel instead put weight on the high need for treatment options becoming available to patients as well as convincing testimonials from clinicians that SRP-9001has shown good results for individual patients. That said, the vote in favor to recommend approval was very narrow and the smallest possible with 8 members voting in favor and 6 against. Also, FDA does not have to follow a positive recommendation from the advisory panel, but until the FDA decision meeting in late May, the pendulum has swung back in favor Sarepta Theraputics and Hansa Biopharma".
Kilde og disclaimer: HC Andersen Capital receives payment from Hansa Biopharma for a Digital"
Shares in Hansa Biopharma and Sarepta are up more than 5 and 30 percent respectively - yesterday, following a surprise decision by an FDA advisor panel on Friday to recommend FDA to grant accelerated approval of gene therapy product SRP-9001 from Hansa Biopharma's partner Sarepta Therapeutics at an upcoming FDA meeting late May. Hansa Biopharma's enzyme cleaving technology imlifidase may potentially be used as a pre-treatment to SRP-9001 in up to 14% of the DMD patient population and if successful in both DMD and LGMD Hansa Biopharma will be eligible to receive up to USD 400 million in milestones from Sarepta Therapeutics plus up to midteens in royalty payments and sales of imlifidase . According to Fierce Biotech, expectations in DMD are high with SRP-9001 potentially be one of the biggest biotech product launches in 2023 with annual sales of more than USD 2 billion in less than five years.
The decision to recommend SRP-9001 for accelerated approval came after FDA last week released documents send to the advisors that raised concerns regarding efficacy, safety etc. of SRP-900, but among other things the advisory panel instead put weight on the high need for treatment options becoming available to patients as well as convincing testimonials from clinicians that SRP-9001has shown good results for individual patients. That said, the vote in favor to recommend approval was very narrow and the smallest possible with 8 members voting in favor and 6 against. Also, FDA does not have to follow a positive recommendation from the advisory panel, but until the FDA decision meeting in late May, the pendulum has swung back in favor Sarepta Theraputics and Hansa Biopharma".
Kilde og disclaimer: HC Andersen Capital receives payment from Hansa Biopharma for a Digital"
