CASGEVY™ (gene editing)
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Product Information
Scientific name: exa-cel (exagamglogene autotemcel)
Brand name: CASGEVY™
RESPONSIBLE: Vertex Pharmaceuticals and CRISPR Therapeutics collaboration -
Clinical Trial/Study Information
CLIMB-121
Trial Name: CLIMB-121
Code: NCT03745287
Phase: 1/2/3
Eligible patient diagnosis: SCD (adult & paediatric/adolescent; ages 12 – 35)
No. of Patients enrolled: 35 (Last update: 10/6/2023)
Study Sites: 17 Sites per countryAnticipated completion date: October 2024
Scope of the Study / Aim: No VOCs for at least 12 consecutive months15 Years Follow-up Study
Trial Name: Long-term follow-up study (CLIMB-131)
Code: NCT04208529
Phase: Long-term follow-up study of CLIMB-111 (TDT) & CLIMB-121 (SCD)
Eligible patient diagnosis: TDT patients who participated in CLIMB-121 (ages 2 and older)
No. of Patients enrolled: 114 [total anticipated] (Last update: 30/6/2023)
Study Sites: 15 Sites per countryAnticipated completion date: September 2039
Scope of the Study / Aim: After completing the parent clinical study, patients will be followed for 15 years post infusion. Monitoring for malignancies, new or worsening haematologic disorders, serious adverse events, mortality.CLIMB-161
Trial Name: CLIMB-161
Code: NCT05477563
Phase: 3
Eligible patient diagnosis: TDT – all genotypes & SCD (adult & paediatric/adolescent; ages 12 – 35)
No. of Patients enrolled: 18 [total anticipated] (Last update: 7/7/2023)
Study Sites: 5 Sites per countryCompletion date: February 2025
Scope of the Study / Aim: Concentration of Total (Hb) and Fetal (HbF) for up to 12 months after infusion
VX21-CTX001-151
Trial Name: VX21-CTX001-151
Code: NCT05329649
Phase: 3
Eligible patient diagnosis: : SCD (paediatric; ages 2 -11)
No. of Patients enrolled: 15 [anticipated] (Last update: 31/5/2023)
Study Sites: 7 Sites Sites per countryCompletion date: May 2026
Scope of the Study / Aim: Safety & efficacy in children with SCD (no VOCs for at least 12 consecutive months) -
Regulatory Information
Status: Not Authorised
Additional notable points:
- EMA: Orphan Drug Designation (2020), Priority Medicines (PRIME) designation (2020 – SCD) ; CHMP Positive Opinion for conditional approval (Dec 2023) – conditional marketing authorisation for SCD and TDT patients 12 years and older (Feb 2024)
- FDA: Fast Track Designation (2019), Regenerative Medicine Advanced Therapy (RMAT) designation (2020), Orphan Drug Designation (2020) ; BLA submission accepted for TDT & SCD (Jun 2023) – Priority Review PDUFA Target Date: 8 December 2023 ; Approved for the treatment of sickle cell disease (SCD) in patients 12 years of age and older (Dec 2023) and TDT (Jan 2024)
- MHRA: Granted Innovation Passport (2023), Marketing Authorisation Application submitted in Jan. 2023 – Under review, Conditional approval for SCD and TDT in patients 12 years of age and older (Nov 2023)
- NHRA (Bahrain): Approved for the treatment of SCD and TDT (Dec 2023)
- SFDA (Saudi Arabia): Approved for the treatment of SCD and TDT in patients 12 years and older (Jan 2024)
- Canada: Approved for the treatment of TDT and SCD (Sep 2024)
- Switzerland: Approved for the treatment of SCD and TDT (Nov 2024)
Update: 19 December 2024
- Planned submissions in the UAE and Kuwait
- 45 authorised treatment centres have been activated (mid-October 2024)
- 40 patients have had a first cell collection to-date (Dec 2024)
- Early Access Programme approved for TDT and SCD in Italy (4 November 2024)
- Commercial discussions with NHS England for access for patients with SCD
New data:
Data presented at the 66th ASH Annual Congress (7 – 10 December 2024) in San Diego (USA) showed that:
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- A total of 46 patients were infused at the cut-off (May 2024).
- Median follow up of 29.9 months, 31 patients completed 2 years of follow up.
- 90% were VOC-free for more than 12 consecutive months post-infusion ; mean VOC-free duration was 29.3 months.
- 95% were hospitalisation-free for more than 12 consecutive months post-infusion.
- All patients maintained increased levels of Hb (mean total Hb 11.9g/dL from Month 3).
Sources: https://news.vrtx.com/news-releases/news-release-details/vertex-presents-positive-long-term-data-casgevytm-0
https://news.vrtx.com/news-releases/news-release-details/vertex-reports-third-quarter-2024-financial-results
Durable Clinical Benefits with Exagamglogene Autotemcel for Severe Sickle Cell Disease
Update: 30 September 2024
- 35 authorised treatment centres (ATCs) have been activated globally
- Early Access Programmes for TDT and SCD implemented by French National Health Authority (HAS)
Update: 30 June 2024
Data presented at the 29th EHA Annual Congress (13 – 16 June 2024) in Madrid (Spain) from the CLIMB SCD-121 phase 3 trial showed that:
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- A total of 46 patients with SCD had received exa-cel by the cut-off date of 18 September 2023.
- The median follow-up was 22.3 months, with 17 patients completing 2 years follow-up, and enrolling in the long-term follow-up study (CLIMB-131) involving 15 years follow up.
- Of the 31 patients evaluable,
- 29 (93.5%) were VOC free for ≥12 consecutive months
- 31 (100%) were free from VOC hospitalisations for ≥12 consecutive months.
Source: Exagamglogene Autotemcel for Severe Sickle Cell Disease
Update: 31 March 2024
- SFDA (Saudi Arabia): Approved for SCD and TDT in patients 12 years and older (Jan 2024)
- 1st authorised treatment centre has been activated (Ministry of National Guard Health Affairs). The company is working to qualify additional hospitals (e.g. King Faisal Specialist Hospital).
- EMA: conditional marketing authorisation for SCD and TDT patients 12 years and older (Feb 2024)
- Patient eligibility is determined by recurrent VOCs (SCD) and suitability for HSCT for whom a matched donor is not available (TDT).
- It is estimated that approx. 8,000 patients will potentially be eligible for treatment in the EU.
- Draft guidance, published on 14 March 2024, said the NICE committee considered the cost-effectiveness estimate for Casgevy to be higher than what NICE normally considers to be an acceptable use of NHS resources.
- Authorised Treatment Centres: 12 in the US, 3 in EU and 1 in KSA are activated. Goal: 50 in the US, 25 in Europe and 2 in KSA.
- Enrolment in phase 3 studies for patients with SCD and TDT aged 5 – 11 years is complete.
Sources: https://news.vrtx.com/news-releases/news-release-details/vertex-announces-approval-first-crisprcas9-gene-edited-therapy
https://pharmaceutical-journal.com/article/news/gene-editing-sickle-cell-drug-not-approved-for-nhs-use-in-draft-nice-guidance
https://www.businesswire.com/news/home/20240109040535/en/Vertex-Announces-Approval-of-First-CRISPRCas9-Gene-Edited-Therapy-CASGEVY%E2%84%A2-for-the-Treatment-of-Sickle-Cell-Disease-SCD-and-Transfusion-Dependent-Beta-Thalassemia-TDT-in-Kingdom-of-Saudi-Arabia
https://news.vrtx.com/news-releases/news-release-details/european-commission-approves-first-crisprcas9-gene-edited
https://news.vrtx.com/news-releases/news-release-details/vertex-reports-fourth-quarter-and-full-year-2023-financial
Update: 20 December 2023
- CHMP Positive Opinion for conditional approval (Dec 2023) – awaiting European Commission approval for Marketing Authorisation (estimated for Feb. 2024)
- MHRA (UK): Conditional approval for SCD and TDT in patients 12 years and older (Nov 2023)
- FDA: Approved for the treatment of sickle cell disease (SCD) in patients aged 12 years and older (Dec 2023)
- NHRA (Bahrain): Approved for the treatment of SCD and TDT (Dec 2023)
- A list price of $2.2 million in the USA has been announced.
New data
- Data presented at the 65th ASH Annual Congress (9–12 December 2023) in San Diego (USA) showed that:
- The CLIMB SCD-121 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to elimination of VOCs in 95% of pts, elimination of inpatient hospitalization for VOCs in 100% of pts and improved QOL. Safety profile of exa‑cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation.
- A total of 42 patients with SCD had received exa-cel by the cut-off date of 10 February 2023.
- Of the evaluable patients:
- 19/20 (95.0%) were free of VOCs for ≥12 consecutive months with an average VOC-free period of 21.8 months
- 20/20 (100%) were free from hospitalizations for VOCsfor ≥12 consecutive months
- 29/30 (96.7%) were free ofVOCs for ≥9 consecutive months
- For all patients, total Hb was 12.1 g/dL at Month 3 and was maintained at ≥11.0 g/dL from Month 6 onward; HbF was 36.0% at Month 3 and was generally maintained at ≥ 40.0% from Month 6 onward
- 36/39 pts with ≥60 days follow-up after last RBC transfusion (including those not yet evaluable) remained VOC free (up to 41.4 months). Quality-of-life (QOL) measures showed clinically significant improvements.
Sources: https://www.reuters.com/business/healthcare-pharmaceuticals/vertexcrispr-price-sickle-cell-disease-gene-therapy-22-mln-2023-12-08/
https://news.vrtx.com/news-releases/news-release-details/vertex-receives-chmp-positive-opinion-first-crisprcas9-gene
https://news.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-authorization-first
https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
https://www.globenewswire.com/news-release/2023/12/02/2789644/0/en/CASGEVY-Gets-Bahrain-approval-for-treatment-marking-it-second-country-in-the-world.html
https://news.vrtx.com/news-releases/news-release-details/positive-results-pivotal-trials-casgevytm-exagamglogene
https://ash.confex.com/ash/2023/webprogram/Paper190139.html
Update: 30 September 2023
- FDA plans to hold an advisory committee meeting for exa-cel (date to be confirmed).
- Investigation in gentler conditioning for exa-cel is underway.
- The Institute for Clinical and Economic Review (ICER) determined that lovo-cel will be cost-effective if priced between $1.35M to $2.05M. ICER has made recommendations to encourage companies to set prices toward lower end of this range to facilitate access and affordability across all insurance systems (in the USA).
Sources: https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2023-financial-results
https://icer.org/news-insights/press-releases/icer-publishes-final-evidence-report-on-gene-therapies-for-sickle-cell-disease/
Update: 30 June 2023
FDA Submission
• BLA application submitted to FDA (3 April 2023) for exa-cel for patients with SCD and TDT. The submission is based on the results of the ongoing Phase 3 studies, CLIMB-111 and CLIMB-121, as well as an ongoing long-term follow-up study, CLIMB-131.
• FDA has accepted Priority Review for BLA submission and set a PDUFA (the date by which the FDA must respond to the application) target date of 8 December 2023.
Trial Progress
• Dosing in the Phase 1/2/3 CLIMB-111 and CLIMB-121 studies continues, as does the CLIMB-131 long-term follow-up study in patients 12 years of age and older.
• Two additional Phase 3 studies of exa-cel continue to enroll patients 5 to 11 years of age with TDT or SCD.
New data
Data presented at the 28th EHA Annual Congress (9 – 11 June 2023) in Frankfurt (Germany) showed that:
• Of the 35 patients with SCD who had received exa-cel at the time of the analysis, 17 patients were evaluable for the primary and key secondary endpoint at the time of the data cut.
• 16/17 (94.1%) were VOC-free for at least 12 consecutive months
• Mean duration of VOC-free was 18.7 months, with a maximum of 36.5 months.
• 17/17 (100%) did not need hospitalisation for VOCs for at least 12 consecutive months
• All patients who received exa-cel, mean fetal hemoglobin was more than 30% of total hemoglobin by Month 3 and was then maintained at approximately 40.0% through follow-up, with pancellular distribution.
Sources: https://www.businesswire.com/news/home/20230402005036/en/
https://investors.vrtx.com/news-releases/news-release-details/vertex-and-crisprtherapeutics-complete-submission-rolling
https://investors.vrtx.com/news-releases/news-release-details/fda-accepts-biologicslicense-applications-exagamglogene
https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-firstquarter-2023-financial-results
https://investors.vrtx.com/news-releases/news-release-details/positive-resultspivotal-trials-exa-cel-transfusion-dependent
Update: 31 March 2023
- The Phase 1/2/3 CLIMB-111 and CLIMB-121 studies and the CLIMB-131 long-term follow-up study are ongoing in patients 12 years of age and older.
- Two additional Phase 3 studies of exa-cel in pediatric patients with TDT and SCD continue to enroll patients.