Advanced Therapy Medicinal Products: Recent US Approvals, Upcoming Guidance
Advanced Therapy Medicinal Products (ATMPs) offer new and potentially curative opportunities for the treatment of disease or injury, but the tactical, procedural, and logistic considerations for their development are complex. New guidance documents have been released and workshops and forums organized to foster more proficient development of ATMPs, but harmonization is still needed to efficiently bring these products to market.
This article will examine the 2022-2023 approvals of ATMPs by the Center for Biologics Evaluation and Review (CBER) and OTP, formerly known as the Office of Tissues and Advanced Therapies (OTAT). It will also look at how finalized FDA guidances will shape ATMP development and how town hall meeting discussion can help minimize challenges and maximize opportunities for future ATMP development.
It should be noted that in September 2022, the FDA announced the reorganization of the OTAT to the “super office” structure and renamed it the Office of Therapeutic Products (OTP) within CBER.1 The notice stated, “Due to the substantial growth in innovative, novel products as well as the need to address an ever-changing landscape of potential health threats, CBER is currently facing scientific, medical, and regulatory challenges that require changes to its structure.”1 The new structures were approved in August 2022 and became effective on 16 September 2022.1 Structural and increased staff changes are anticipated to improve functional alignment, increase review capabilities, and enhance expertise on new cell and gene therapies.2
Four ATMPs classified as cell and gene therapy products were approved in 2022.
Carvykti (ciltacabtagene autoleucel).3 Janssen Biotech’s chimeric antigen receptor T-cell (CAR-T) therapy, featuring two B-cell maturation antigen targeting single domain antibodies, was approved by the FDA on 28 February 2022, for treating adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy – including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody – have proven no longer effective. The biologics license application (BLA) for the therapy, also known as cilta-cel, was submitted on 31 March 2021 and underwent a priority review with the Prescription Drug User Fee Act (PDUFA) on 28 February 2022. Carvykti previously received orphan drug and breakthrough therapy designations from the FDA.
The approval of Carvykti was based on results from the Study CARTITUDE-1, a Phase 1b/2, single-arm, open-label multicenter study in adults with refractory multiple myeloma after three or more lines of prior therapy to include an immunomodulatory drug, proteasome inhibitor and an anti-CD38 antibody. The primary endpoint of CARTITUDE-1 was overall response rate. In the study, a one-time treatment with cilta-cel resulted in 98% overall response rate.
Carvykti comes with a boxed warning of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias. Despite those warnings, the benefit-risk ratio profile of Carvykti was considered favorable in the target patient population and is available only under the implementation of a risk mitigation and evaluation strategy program.
Zyntelo (betibeglogene autotemcel). 4 Bluebird Bio’s autologous CD34+ hematopoietic stem cells transduced with lentiviral vector, BB305 LVV, encoding the human βA-T87Q -globin gene was approved by the FDA on 17 August 2022 as the first gene therapy for treating adult and pediatric patients with β thalassemia who require regular red blood cell transfusions. The BLA was submitted on 20 September 2021, underwent a priority review, and also received a priority review voucher upon approval. Zyntelo previously received both orphan drug and breakthrough therapy designations from the FDA.
The approval of Zyntelo was based on data from multiple clinical trials, including two Phase 3 trials (HGB-207/Northstar-2 and HGB-212/Northstar-3) and one long-term followup study (LTF-303). The two Phase 3 studies were similar in design but enrolled two age cohorts (≥12 years of age and <12 years of age) and had different genotype eligibility. Enrollment and treatment in both the single-arm, open-label, 24-month Phase 3 studies have been completed; followup is ongoing in HBG-212. After being on either of the Phase 3 studies, patients were enrolled in the followup study for up to 15 years from the time of gene therapy administration. The primary endpoint of these studies was the proportion of subjects gaining transfusion independence. Patients on these studies who achieved transfusion independence remained transfusion-free.
Skysona (elivaldogene autotemcel).5 Bluebird Bio’s autologous hematopoietic stem cell-based gene therapy, also known as eli-cel, was approved by the FDA on 16 September 2022, to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). The BLA was submitted on 18 October 2021, and underwent a priority review, and Bluebird Bio received a rare pediatric priority review voucher upon approval. Skysona previously received orphan drug designation, rare pediatric disease designation, and breakthrough therapy designations from the FDA.
The approval of Skysona was based on data from two single-arm studies, a Phase 2/3 study (ALD-102/Starbeam) and a Phase 3 study (ALD-104). Even though the efficacy of Skysona was compared to a natural history population, there were challenges in making this comparison. The Phase 2/3 study did not meet its event-free survival primary outcome measure, but Skysona eventually received accelerated approval based on the identification of a subgroup of patients who were free of major functional disability two years from the time they had symptoms. As a condition of Skysona’s accelerated approval, Bluebird Bio has agreed to provide confirmatory long-term clinical data to the FDA which will likely include data from their ongoing long-term follow-up study (LTF-304), which follows patients treated in clinical trials for 15 years.
Skysona comes with a boxed warning of hematologic malignancy, due to the integration of the lentiviral vector, Lenti-D, in proto-oncogenes.
Hemgenix (etranacogene dezaparvovec-drlb).6 CSL Behring’s adeno-associated virus vector-based gene therapy was approved by the FDA on 22 November 2022 for the treatment of adults with hemophilia B (congenital Factor IX deficiency). The BLA was submitted on 24 March 2022 and underwent priority review. Hemgenix previously received orphan drug and breakthrough therapy designations from the FDA.
The approval of Hemgenix was based on a single, adequate, and well controlled study, Study CT-AMT-061-02, which was a Phase 3, open-label, single dose, multicenter, multinational trial studying Hemgenix in adult patients with severe or moderately severe hemophilia B. The endpoint of the study was annualized bleeding rate during months 7-18 after treatment compared with during the lead-in period. Approval of Hemgenix was supported by an earlier safety study, Study CT-AMT-061-01, a Phase 2b, open label, single-dose, single-arm, multicenter trial, which was a safety study conducted to confirm the activity level of the adeno-associated viral vector containing a codon-optimized human Factor IX gene administered to three adult patients with severe or moderately severe hemophilia B.
2023 to date
As of June 2023, one ATMP classified as cell and gene therapy products has been approved.
Vyjuvek (beremegene geperpavec-svdt.)7 Krystal Biotech’s herpes-simplex virus type 1 (HSV-1) vector-based gene therapy was approved by the FDA on 19 May 2023 for treating wounds in patients aged 6 months or older with dystrophic epidermolysis bullosa (DEB) with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene. The BLA was submitted on 20 June 2022, underwent a priority review, and received a rare pediatric disease priority review voucher on approval. Vyjuvek previously received orphan drug, regenerative medicine advanced therapy (RMAT) and fast track designations from the FDA.
The approval of Vyjuvek was based on a randomized, double-blinded, placebo-controlled study with 31 subjects with DEB, of which 30 had recessive dystrophic epidermolysis bullosa (RDEB) and 1 had dominant dystrophic epidermolysis bullosa (DDEB). Results showed improved wound healing, defined as the difference in the proportion of confirmed complete (100%) wound closure between the Vyjuvek-treated and the placebo-treated wounds at 24 weeks. In all, 65% of the Vyjuvek-treated wounds completely closed while only 26% of the placebo-treated wound completely closed. Vyjuvek is the first FDA-approved gene therapy treatment for DEB, a rare and serious genetic skin disorder
Anticipated regulatory decisions in 2023
The FDA is expected to decide on 22 June whether to grant approval to the first gene therapy for Duchenne muscular dystrophy, a genetic disorder that affects about 1 in 3,500 boys. This therapy known as SRP-9001, made by Sarepta Therapeutics, would be the first to treat this disorder, in which affected children are unable to make a protein called dystrophin, resulting in progressive muscle degeneration and death in their twenties due to heart or respiratory failure. This approval will also be the first gene therapy to go through the accelerated approval mechanism, which relies on surrogate endpoints to demonstrate clinically meaningful benefits.
Other possible regulatory actions in 2023 for gene therapy products include:
- Roctavian, indicated for hemophilia A (BioMarin)
- BB1111, indicated for sickle cell disease (Bluebird Bio)
- CTX001, indicated for sickle cell disease, beta-thalassemia (Vertex and CRISPR Therapeutics)
Similarities and differences among the approvals
These approvals represent first-in-class approvals for serious diseases, as defined in the FDA’s 2014 guidance on expedited programs7 for drugs and biologics for serious, previously untreated conditions. These examples involve a one-time administration that may enhance a patient’s quality of life. All these products were granted expedited designations (orphan, fast track, RMAT and breakthrough) by the FDA.
Only one of these approved products, Skysona, received approval under the accelerated approval pathway. Skysona did not meet its primary endpoint of event-free survival in the Phase 2/3 study. However, the FDA review team identified outcomes that were not consistent with the natural history of CALD that resulted in identification of major-functional disability‒free survival as an endpoint that is reasonably likely to predict clinical benefit, while considering the severity and rarity of CALD and the lack of alternative therapies.
Carvykti is the only approved product that comes with a boxed warning and is available only under the implementation of a risk mitigation and evaluation strategy program. Since multiple myeloma is an incurable blood cancer, and despite the fact that there are additional treatment options that have been developed in recent years, most patients with this cancer experience disease progression, even after a rigorous treatment schedule including three different therapy classes (an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody). The approval of Carvykti provided hope to the many patients suffering from this cancer.
Vyjuvek is the first topical gene therapy to be approved, the first drug to treat DEB, and the first readily redosable gene therapy. This approval provides new hope to patients with this rare, often debilitating skin disease.
Two draft guidances were issued in March 2022:
- Considerations for the development of human gene therapy products incorporating genome editing,8 and
- Considerations for the development of CAR-T therapies.)9
These two guidance documents provide the agency’s current thinking on multiple functional areas by providing guidance on quality and manufacturing, pharmacology, toxicology, clinical development, and study design considerations.
In strategy discussions with sponsors, these guidance documents often serve as the playbook and foundation for future FDA interaction(s), such as INTERACT meetings; Type B, pre-investigational new drug (IND) application, or Type C meetings; or by an alternative mechanism (i.e., request for comments and advice submitted to an active IND application). As sponsors review the guidances, they should align their product development program to the FDA’s current expectations. Areas in which alignment is not possible or where sponsors may be prevented from meeting the FDA’s expectations, warrant an FDA interaction. This exercise should result in a list of questions to seek FDA feedback regarding the alternative proposals anticipated to meet the FDA’s expectations.
Other noteworthy 2022 activities include the finalization of guidance of human gene therapy for neurodegenerative diseases10 and on studying multiple versions of cellular or gene therapy product in early-phase clinical trial.11
On 30 January 2023, CBER posted the guidance agenda for 2023. Included in this list under Tissues and Advanced Therapies was the release of draft guidance on manufacturing changes and comparability for human cellular and gene therapy products.12 Cell and gene therapy sponsors are likely anticipating this guidance document as most cell and gene therapy programs undergo manufacturing changes and optimization between the initial IND application and planned BLA. Sponsors must have a clear understanding of these manufacturing and process changes and optimizations to enable the design of a successful comparability study or studies. Most manufacturing changes and optimizations are typically not customized, therefore, guidance providing the FDA’s expectations on methods toward establishing comparability may contribute to a more efficient, harmonized approach.
In addition to the pending manufacturing changes and comparability guidance, the current gene therapy product definition needs to be reviewed, given the number of innovative RNA therapies (i.e., mRNA, viral RNA, iRNA, etc.) encapsulated in lipid nanoparticles or other novel delivery mechanisms. More guidance from the FDA on how and why in vitro transcribed RNA therapies are subject to the current gene therapy guidance and regulations may aid ATMP developers with research and development planning and activities.
OTP town hall meetings
OTP launched its virtual town hall series to engage with product development stakeholders and discuss topics related to OTP-regulated products. The town halls have a question-and-answer format with the goal of providing regulatory information to stakeholders to advance drug development. Thus far, there have been three OTP town halls specific to cell and gene therapy product development:
- Gene therapy chemistry, manufacturing, and controls;13
- Cell therapy chemistry, manufacturing, and controls;14 and
- Clinical development of gene therapy product for rare diseases.15
The OTP town halls have allowed the opportunity for ATMP cell and gene therapy product developers to hear feedback directly from CBER OTP reviewers on key product development topics outside of a formal meeting interaction. These events have transcripts, and recordings are available for reference on demand. These meeting transcripts and recordings, in addition to available FDA guidance documents and regulations, serve as resources for ATMP developers.
PDUFA VII and OTP
The reauthorization of PDUFA VII from 2023 through 2027 was signed into law on 30 September 2022. The PDUFA VII goals letter contained several commitments and initiatives planned by the FDA, many of which directly impact CBER and OTP. There was a restructuring within CBER to result in enhanced capacity, primarily to respond to the number of cell and gene therapy programs the division is encountering. One of the first initiatives is to strengthen staff capacity and capabilities to meet the demands of the innovative therapies under development. The FDA will also continue to organize and manage the cell and gene therapy program to streamline and harmonize the program’s procedures, processes, and interactions.1
Another FDA commitment is the expansion of INTERACT meetings and the introduction of the new Type D meeting.16 INTERACT meetings were first introduced in 2018 to give sponsors an informal platform to gain pre‒pre-IND advice, primarily on innovative products with unprecedented challenges. The FDA has now expanded the C in INTERACT from CBER to now include CDER, thereby expanding the scope of this meeting format.
These meetings may help sponsors get agency feedback early in development and lead to fewer questions during the pre-IND phase. PDUFA VII also introduced a new meeting type – the Type D meeting. This type of meeting will be available when the feedback needed is focused on a narrow set of questions to no more than two topics and questions that require input from no more than three disciplines or divisions. Another addition to the goals letter is the “request for clarification.” This will give sponsors the opportunity to ask for clarification to the agency’s feedback through written response or within meeting minutes issued by the agency. At the time of publication, this request should be submitted by a sponsor within 20 calendar days of receipt of the meeting minutes or written response only, and the FDA committed to responding to such requests within 20 days.
There has been advancement of ATMPs impacting human health by bringing benefit to patients, their families, and caregivers, and ATMP development will continue during 2023. Clear communication, collaboration, and knowledge sharing will enable more ATMP therapeutics to have an impact on patient lives.
ATMP, advanced therapy medicinal product; FDA, [US] Food and Drug Administration; OTP, Office of Therapeutic Products; CBER, Center for Biologics Evaluation and Review; OTAT, Office of Tissues and Advanced Therapies; BLA, biologics license application; PDUFA, Prescription Drug User Fee Act; CALD, cerebral adrenoleukodystrophy; IND, investigational new drug.
About the authors
Nicole Gallo, RAC, is a principal consultant in regulatory affairs at Halloran Consulting Group. She has more than 15 years of regulatory affairs and drug development experience, covering cell and gene therapies, small molecules, and therapeutic biologics, with an emphasis on diseases of the central nervous system and immuno-oncology, oncology, and rare diseases. She has a bachelor of science degree in molecular and cellular developmental biology and holds the RAPS Regulatory Affairs Certification. Gallo can be reached at email@example.com
Mamta Puri-Lechner, PhD, is a lead consultant in regulatory affairs at Halloran Consulting Group. She has more than five years of regulatory strategy and regulatory affairs experience. Puri-Lechner has developed regulatory strategies to align with global and regional requirements. She has a bachelor of science degree in life sciences/biochemistry, a master of science degree in biotechnology, and a doctorate in cell/cellular biology and microbiology. She can be reached at firstname.lastname@example.org
Citation Gallo N, Mamta Puri-Lechner. Advanced therapy medicinal products: Recent US approvals, upcoming guidance. Regulatory Focus. Published online 13 June 2023. https://www.raps.org/news-and-articles/news-articles/2023/6/advanced-therapy-medicinal-products-recent-us-appr
All references were accessed and/or verified on 5 June 2023.
- [US] Food and Drug Administration. Statement of organization, functions, and delegations of authority. Federal Register. Dated 28 September 2022. https://www.federalregister.gov/documents/2022/09/28/2022-20997/statement-of-organization-functions-and-delegations-of-authority
- Eglovitch J. FDA elevates OTAT to ‘super office’ within CBER. Regulatory Focus. Published online 30 September 2022. https://www.raps.org/news-and-articles/news-articles/2022/9/fda-elevates-otat-to-super-office-within-cber
- [FDA] Office of Tissues and Advanced Therapies. Summary basis for regulatory action for Carvykti (ciltacabtagene autoleucel). Dated 28 February 2022. https://www.fda.gov/media/156999/download
- [FDA] Office of Tissues and Advanced Therapies. Summary basis for regulatory action for Zynteglo (betibeglogene autotemcel). Dated 17 August 2022. https://www.fda.gov/media/161472/download
- [FDA] Office of Tissues and Advanced Therapies. Summary basis for regulatory action for Skysona (elivaldogene autotemcel). Not dated. https://www.fda.gov/media/162098/download
- [FDA] Office of Tissues and Advanced Therapies. Summary basis for regulatory action for Hemgenix (etranacogene dezaparvovec-drlb). Dated 22 November 2022. https://www.fda.gov/media/164094/download
- Vyjuvek [prescribing information]. Krystal Biotech; 2023. https://www.fda.gov/media/168350/download
- [US] Food and Drug Administration. Expedited programs for serious conditions – Drugs and biologics [guidance]. Dated May 2014. Accessed 5 June 2023. https://www.fda.gov/media/86377/download
- [US] Food and Drug Administration. Human gene therapy products incorporating human genome editing [draft guidance]. Dated March 2022. https://www.fda.gov/media/156894/download
- [US] Food and Drug Administration. Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products [draft guidance]. Dated March 2022. https://www.fda.gov/media/156896/download
- [US] Food and Drug Administration [US]. Human gene therapy for neurodegenerative diseases [guidance]. Dated October 2022. https://www.fda.gov/media/144886/download
- [US] Food and Drug Administration [US]. Studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial [guidance]. Dated November 2022. https://www.fda.gov/media/152536/download
- [FDA] Center for Biologics Evaluation and Research. Guidance agenda: Guidance documents CBER is planning to publish during calendar year 2023. Dated January 2023. https://www.fda.gov/media/120341/download
- [US] Food and Drug Administration. Gene therapy chemistry, manufacturing, and controls. OTAT [OTP] town hall, 29 September 2022. https://www.fda.gov/news-events/otat-town-hall-gene-therapy-chemistry-manufacturing-and-controls-09292022
- [US] Food and Drug Administration. Clinical development of gene therapy products for rare diseases. OTAT [OTP] town hall, 3 February 2023. https://www.fda.gov/news-events/otat-town-hall-cell-therapy-chemistry-manufacturing-and-controls-12072022
- [US] Food and Drug Administration. Clinical development of gene therapy products for rare diseases. OTAT [OTP] town hall,7 February 2023. https://www.fda.gov/news-events/otat-town-hall-clinical-development-gene-therapy-products-rare-diseases-02072023
- [US] Food and Drug Administration. PDUFA reauthorization performance goals and procedures fiscal years 2023 through 2027. Current as of 22 February 2023. https://www.fda.gov/media/151712/download