Michelle Hudson1 and Kasey Kime2
1Clinical Trials Practice Educator, Parkville Cancer Clinical Trials Unit, Australia
2Director of Regulatory Affairs, Thermo Fisher Scientific, New Zealand
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NEW CELL AND GENE THERAPIES APPROVED INTERNATIONALLY:
The Therapeutic Goods Administration approved the use of Janssen’s CAR-T cell therapy CARVYKTI® (Ciltacabtagene Autoleucel) as a fourth-line treatment for people with multiple myeloma on 7th Jun 2023 (1). This follows on from preceding approvals from the FDA, EMA and Japan's Ministry of Health, Labour, and Welfare (MHLW) in 2022, which were covered in the Australia and New Zealand Legal and Regulatory Affairs Watchdog Update April 2023.
Previously, the Australian Medical Services Advisory Committee (MSAC) did not support public funding for Ciltacabtagene Autoleucel (Cilta-cel) at its consideration on 28-29 July 2022. MSAC found the evidence base in the proposal as insufficient for determining the comparative safety and effectiveness. Janssen Australia expressed disagreement with this, noting that single-arm clinical trials have been the accepted evidence base for all previously approved CAR-T therapies considered by MSAC (2).
In a related development, Janssen has presented the results of the CARTITUDE-4 study at the American Society of Clinical Oncology annual meeting (ASCO), the European Hematology Association (EHA) annual meeting, and published in the New England Journal of Medicine, all in early June 2023. The CARTITUDE-4 study compared Janssen’s Ciltacabtagene Autoleucel (Cilta-Cel) CAR T-cell therapy to standard of care in heavily pretreated patients with relapsed or refractory multiple myeloma. The Phase III clinical trial in 419 patients showed that those who received the Cilta-cell CAR-T cell treatment were more likely to show a complete response – 73% compared to 22% in standard of care. After a year, progression-free survival in the group who received CAR-T was 76% compared to 49% for standard of care (3)
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Gamida Cell’s Omidubicel Approved by FDA
.On April 17, 2023, the Food and Drug Administration approved omidubicel-onlv (Omisirge, Gamida Cell Ltd.) for use in adult and pediatric patients (12 years and older) with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection.
This application was granted priority review, breakthrough designation and orphan drug designation (4).
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Krystal Biotech Vyjuvek (formerly B-VEC) Approved by FDA
.A topical, redosable gene therapy, B-VEC (Vyjuvek) has been approved by the FDA for the treatment of dystrophic epidermolysis bullosa, a rare skin blistering disorder with currently no targeted approved treatment (5).
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WATCH THIS SPACE:
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FDA grants IND Clearance to Australian Company Imugene to commence onCARlytics first-in-class phase 1 clinical trials for patients with solid tumours.
“A Phase I, Dose Escalation and Dose Expansion, Safety and Tolerability Study of onCARlytics (CF33-CD19), Administered Intravenously or Intratumorally in Combination with Blinatumomab in Adults with Advanced or Metastatic Solid Tumors (OASIS).”
CF33-CD19 (onCARlytics, HOV4) is a live, attenuated oncolytic orthopox (vaccinia) virus engineered to encode a truncated human CD19 (Cluster of Differentiation 19) transgene, resulting in expression of de novo CD19 at the tumour cell surface before virus-mediated tumour cell lysis (6).
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APPLICATIONS AND APPROVALS:
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Landmark ZUMA-7 Study OS Data Reach Maturity Per Protocol, 5 Years After 1st Patient Randomized
.Kite’s Yescarta® CAR T-cell Therapy Demonstrates a statistically significant Improvement in overall survival for initial treatment of relapsed/refractory Large B-cell Lymphoma – first and only treatment in nearly 30 years to show statistically significant improvement in OS for treatment of R/R LBCL patients vs standard of care in curative setting (7, 8).
In an application to the Medical Services Advisory Committee* (MSAC) from Gilead Sciences Pty Limited it is proposed that the current availability of Axicabtagene Ciloleucel, which permits use of Axicabtagene Ciloleucel as a third-line agent, be modified to also permit use of Axicabtagene ciloleucel in the second line setting (9).
*MSAC appraises new medical services proposed for public funding and provides advice to Government on whether a new medical service should be publicly funded. See more information about MSAC here: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/about-msac
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CSL Granted OGTR License for Hemgenix
CSL was granted an OGTR licence on 5 April 2023 for the supply of etranacogene dezaparvovec (Hemgenix) for the treatment of haemophilia B (7). Hemgenix is the first US Food & Drug Administration approved gene therapy for haemophilia B (10). It is under evaluation by the Therapeutic Goods Administration (TGA).
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REGULATORY INTELLIGENCE UPDATES:
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TGA GMP Forum Update
On 21 March 2023, The TGA held the GMP Forum in Sydney to provide industry stakeholders with a unique opportunity to connect with and learn from regulators and subject matter experts from across the TGA. There were seven sessions in total with helpful advice on GMP obligations for sponsors vs contract manufacturers and updates on the TGA’s adoption of the latest PIC/s guidelines (PE009-16). There was also a breakout session on GMP for ATMPs with a focus on aseptic processing and contamination control strategy. The full presentations are available on the TGA website (11).
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Alliance for Regenerative Medicine Workforce Report – Gap Analysis for the Cell and Gene Therapy Sector March 2023
The Alliance for Regenerative Medicine released its Workforce Report in March 2023 (12). The report provides a landscape overview and gap analysis of the workforce needed for sustainable biomanufacturing in the USA. Positions most in demand were manufacturing, analytical development and testing, and quality control.
The issues of attracting, training and retaining skilled workers in the USA are likely to reflect the same issues we will face in the APAC region. The problem is likely to get worse before it gets better, as manufacturing techniques become more scalable.
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The International Pharmaceutical Regulators Programme released their Cell and Gene therapy raw materials reflection paper on 16th March 2023.
.The cell and gene therapy working groups at IPRP published a succinct reflection paper on raw material quality and safety considerations from the perspective of the regulators (103). While there is nothing new in the reflection paper, it provides a handy summary of the key considerations for selection of appropriate raw materials in clinical manufacturing. The TGA is an observing member of IPRP Gene Therapy Working Group.
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New Independent White Paper: CAR T-cell therapy: Is Australia ready, willing and able?
Evohealth recommends how Australia can prepare to deliver CAR T-cell therapy for patients at scale. The evidence-based recommendations of the white paper ‘CAR T-cell therapy: Is Australia ready, willing and able?’ are supported by an expert advisory committee of patients, policy makers and clinicians (14).
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Australian Government Health Technology Assessment (HTA) Policy and Methods Review Committee – Consultation #1 open
The Committee consults on and reports findings which inform federal government decisions to fund and subsidise health technologies including cell and gene therapies through programs and schemes such as the PBS, MBS, and life-saving drugs program.
There is an acknowledged need to consult with consumers, industry, academic and advisory bodies within the rapidly changing health technology sector, with the key goals of:
- Improving Access to breakthrough new medicines
- Improving delivery of robust and uninterrupted supply of medicines and treatments
- Reducing time access new health technologies for Australians
- Maintaining the attractiveness of Australia as a first-launch country
Public consultations from key stakeholders including consumers, industry, advisory bodies is open from 11th April to 6th June 2023 (15).
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REFERENCES
1. https://www.tga.gov.au/resources/artg/410143
2. MSAC, 1690 – Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell to treat refractory or relapsed multiple myeloma, http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1690-public, updated 7 November 2022, accessed 20 March 2023
3. San-Miguel J, Dhakal B, Yong K et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma N Engl J Med. Published online June 5, 2023, DOI: 10.1056/NEJMoa2303379
4. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-omidubicel-reduce-time-neutrophil-recovery-and-infection-patients-hematologic
5. https://www.fda.gov/news-events/press-announcements/fda-approves-first-topical-gene-therapy-treatment-wounds-patients-dystrophic-epidermolysis-bullosa
6. Park A, Fong Y, Kim SI, Yang M, Murad JP, Lu J, et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci Transl Med. 2020 Sep 2;12(559)
7. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
8. Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, et al. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. New England Journal of Medicine [Internet]. 2023 Jun 5; Available from: http://www.nejm.org/doi/10.1056/NEJMoa2301665
9. http://www.msac.gov.au/internet/msac/publishing.nsf/Content/1722-public
10. https://www.ogtr.gov.au/what-weve-approved/dealings-not-involving-intentional-release-dnir
11. https://www.tga.gov.au/sites/default/files/2023-04/presentation-gmp-gmp-advanced-therapeutic-medicinal-products.pdf
12. ARM Workforce Report: Gap Analysis for the Cell and Gene Therapy Sector https://alliancerm.org/sector-report/workforce/
13. https://admin.iprp.global/sites/default/files/2023-03/IPRP_CTWG-GTWG_RawMaterialsReflectionPaper_2023_0215_0.pdf
14. https://evohealth.com.au/media/reports/2023_CAR-T_Ready_Willing_Able.pdf
15. https://www.health.gov.au/our-work/health-technology-assessment-policy-and-methods-review
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