February 29th marks Rare Disease Day. While rare diseases themselves are rare, collectively they are not; more than 3 million people in the UK live with a rare disease (1). Given the proportion of people affected, rare diseases have been of great interest to many nations, as they seek to support and improve the care available to their patients. For example, the UK developed a rare disease strategy, putting a national plan in place in 2013 and a rare diseases framework in 2021 (2); making several commitments that require collaborative efforts across patient organisations, health and social care providers and industry. Research and drug development within the life science and pharmaceutical industries are a big part of fulfilling some of these commitments (1), and as such, these areas continue to witness increased investments through the years. Many mergers and acquisitions worth billions have occurred in the last few years to change the treatment landscape narrative; examples include Amgen’s acquisition of Horizon Therapeutics for its TEPEZZA® (3), AstraZeneca's acquisition of Alexion and its Soliris® (4), as well as Vertex’s deal with CRISPR Therapeutics to develop CASGEVY™ (a therapy for sickle cell disease) (5).

This blog post is focused on sickle cell disease (SCD), its impact on patients; and the use of real-world evidence (RWE) studies to understand burden of disease and changes in the treatment landscape with the use of new CRISPR technologies to potentially revolutionise treatment. SCD is a rare genetic disorder characterised by the expression of abnormal sickle haemoglobin, which leads to a variety of acute and chronic complications. SCD is associated with vaso-occlusive crises (VOCs) which are severe painful events often requiring emergency hospitalisation, leading to organ complications and increased mortality (6). The 2019/20 annual National Hemoglobinopathy Registry (NHR) report identified over 7,000 patients with SCD in England (7). Among those patients, the majority were of African and Caribbean ethnicity. Between 2011 and 2019, patients with SCD experienced just over 500 acute chest syndrome events (one of the painful events contributing to VOCs) and more than 200 patients died (7). Current treatments which include hydroxyurea, transfusions, antibiotics and painkillers aim to reduce the frequency and severity of pain crises and prevent infections in patients with severe SCD (8–11). Additionally, hematopoietic stem cell transplant (HSCT) is also available as an alternative treatment; however, this is limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GvHD) (12). Despite advances in therapy increasing life expectancy, serious, lifelong complications and death remain high in patients with severe SCD.

In a recent study, conducted by IQVIA and Vertex, identifying SCD with recurrent vaso-occlusive crises (VOCs) and evaluating the SCD related complications, 1,117 patients were identified between July 2008 and June 2018, using the primary care data (Clinical Practice Research Datalink [CPRD]) linked with secondary care data (Hospital Episode Statistics [HES]) in England. In this study, VOCs were defined as any of one of the following events: SCD with crisis, priapism and acute chest syndrome. Among these patients, 30% had cardiopulmonary complications, 26% had bone/joint problems, 19% had retinopathy, 16% had mental health complications, and 15% had chronic pain (13). In addition, healthcare resource use was higher in patients with SCD with recurrent VOCs compared to the general population (average of ~22 vs ~3 hospital visits [accident and emergency, inpatient and outpatient] per patient per year, respectively) (14). This means that despite the access of current treatment and care, patients still experience significant SCD related clinical complications and elevated healthcare resource utilisation (HCRU).

CRISPR Cas9 technology allows for targeted genome editing and has the potential to transform the landscape for gene therapy in the following years (15). Gene therapy technology works by selective modification of sections of DNA. Modifications vary depending on what is needed to be achieved i.e., whether it be disruption, correction or replacement of DNA to provide a therapeutic benefit (15,16). CRISPR technology takes advantage of the immune defence system in bacteria that works by detecting foreign DNA from invading viruses and informs an enzyme to abolish the viral genome (17). This system can be programmed to edit mammalian genomes with more precision than has previously been possible from other gene editing technologies (18). Several pharmaceutical companies are investing in the use of CRISPR to develop gene therapies for genetic diseases (19). This is wide ranging from inherited neurological diseases, diseases causing blindness, cancer and blood disorders (20). Vertex pharmaceuticals has made history by developing the first gene therapy using CRISPR technology to be approved for clinical use in the UK by the MHRA, the EU by the EMA and in the US by the FDA at the end of 2023 (21–23). The treatment, named Casgevy, can treat eligible patients with SCD.(24). This is an exciting advancement in medicine, and one that will be monitored closely to capture any downstream effects of Casgevy-treated patients.

In conclusion, rare diseases, such as SCD, have a significant impact on individuals, necessitating comprehensive strategies and collaborative efforts for improved patient care and outcomes (6). The recent acquisitions and investments in the life sciences industry signify a promising shift in the treatment landscape, with gene editing technology such as CRISPR Cas9 poised to revolutionise SCD treatment (22). Rare diseases which are often complex and require high healthcare resource utilisation can benefit from RWE studies to better  understand the disease burden and evaluate the impact of new treatments, ultimately aiming to enhance the quality of life for patients living with rare diseases (25). IQVIA, with its vast data assets, data source partnerships and scientific expertise can offer robust support in developing the scientific evidence required in the complex landscape of rare diseases.

1. GOV.UK [Internet]. [cited 2024 Feb 6]. Rare diseases strategy. Available from: https://www.gov.uk/government/publications/rare-diseases-strategy

2. GOV.UK [Internet]. [cited 2024 Feb 6]. UK Rare Diseases Framework. Available from: https://www.gov.uk/government/publications/uk-rare-diseases-framework

3. Amgen [Internet]. [cited 2024 Feb 6]. AMGEN COMPLETES ACQUISITION OF HORIZON THERAPEUTICS PLC. Available from: https://www.amgen.com/newsroom/press-releases/2023/10/amgen-completes-acquisition-of-horizon-therapeutics-plc

4. AstraZeneca expands global footprint in rare disease with availability of first Alexion rare disease therapy for patients in China [Internet]. 2022 [cited 2024 Feb 6]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2022/astrazeneca-expands-global-footprint-in-rare-disease-with-availability-of-first-alexion-rare-disease-therapy-for-patients-in-china.html

5. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVYTM (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia | Vertex Pharmaceuticals Newsroom [Internet]. [cited 2024 Feb 6]. Available from: https://news.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-authorization-first

6. Piel FB, Jobanputra M, Gallagher M, Weber J, Laird SG, McGahan M. Co-morbidities and mortality in patients with sickle cell disease in England: A 10-year cohort analysis using hospital episodes statistics (HES) data. Blood Cells Mol Dis. 2021 Jul 1;89:102567.

7. NHR – Home [Internet]. [cited 2024 Feb 6]. Available from: https://nhr.mdsas.com/

8. BSH [Internet]. [cited 2024 Feb 6]. Guidelines for the use of hydroxycarbamide in children and adults with sickle cell disease. Available from: https://b-s-h.org.uk/guidelines/guidelines/guidelines-for-the-use-of-hydroxycarbamide-in-children-and-adults-with-sickle-cell-disease

9. Davis BA, Allard S, Qureshi A, Porter JB, Pancham S, Win N, et al. Guidelines on red cell transfusion in sickle cell disease Part II: indications for transfusion. Br J Haematol. 2017 Jan;176(2):192–209.

10. Davis BA, Allard S, Qureshi A, Porter JB, Pancham S, Win N, et al. Guidelines on red cell transfusion in sickle cell disease. Part I: principles and laboratory aspects. Br J Haematol. 2017 Jan;176(2):179–91.

11. Nevitt SJ, Jones AP, Howard J. Hydroxyurea (hydroxycarbamide) for sickle cell disease. Cochrane Database Syst Rev. 2017 Apr 20;4(4):CD002202.

12. Bhalla N, Bhargav A, Yadav SK, Singh AK. Allogeneic hematopoietic stem cell transplantation to cure sickle cell disease: A review. Front Med [Internet]. 2023 [cited 2024 Feb 7];10. Available from: https://www.frontiersin.org/articles/10.3389/fmed.2023.1036939

13. BSH 2023 Poster Abstract Book. Br J Haematol. 2023;201(S1):31–118.

14. Udeze C, Ly NF, Ingleby FC, Fleming SD, Conner S, Howard J, et al. Sickle Cell Disease With Recurrent Vaso-Occlusive Crises in England.

15. Uddin F, Rudin CM, Sen T. CRISPR Gene Therapy: Applications, Limitations, and Implications for the Future. Front Oncol. 2020 Aug 7;10:1387.

16. Humbert O, Davis L, Maizels N. Targeted gene therapies: tools, applications, optimization. Crit Rev Biochem Mol Biol. 2012;47(3):264–81.

17. Asmamaw M, Zawdie B. Mechanism and Applications of CRISPR/Cas-9-Mediated Genome Editing. Biol Targets Ther. 2021 Aug 21;15:353–61.

18. Mani I, Arazoe T, Singh V. CRISPR-Cas systems for genome editing of mammalian cells. Prog Mol Biol Transl Sci. 2021;181:15–30.

19. Vara V. Who are the leading innovators in CRISPR vectors for the pharmaceutical industry? [Internet]. Pharmaceutical Technology. 2023 [cited 2024 Feb 6]. Available from: https://www.pharmaceutical-technology.com/data-insights/innovators-crispr-vectors-pharmaceutical/

20. Fernández CR. Eight diseases CRISPR technology could cure [Internet]. Labiotech.eu. 2021 [cited 2024 Feb 6]. Available from: https://www.labiotech.eu/best-biotech/crispr-technology-cure-disease/

21. Commissioner O of the. FDA. 2023 [cited 2024 Feb 6]. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

22. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVYTM (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia [Internet]. 2023 [cited 2024 Feb 6]. Available from: https://www.businesswire.com/news/home/20231115290500/en/%C2%A0Vertex-and-CRISPR-Therapeutics-Announce-Authorization-of-the-First-CRISPRCas9-Gene-Edited-Therapy-CASGEVY%E2%84%A2-exagamglogene-autotemcel-by-the-United-Kingdom-MHRA-for-the-Treatment-of-Sickle-Cell-Disease-and-Transfusion-Dependent-Beta-Thalassemia

23. Casgevy | European Medicines Agency [Internet]. [cited 2024 Feb 8]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/casgevy

24. Commissioner O of the. FDA. 2023 [cited 2024 Feb 6]. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

25. Using RWE in rare disease drug development: effective innovations with historical controls. Eur Pharm Rev [Internet]. [cited 2024 Feb 6]; Available from: https://www.europeanpharmaceuticalreview.com/article/174498/using-rwe-in-rare-disease-drug-development-effective-innovations-with-historical-controls/