Introduction
The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing approval for Vertex & CRISPR Therapeutics' Casgevy to treat Sickle Cell Disease (SCD) and transfusion-dependent beta thalassemia on November 16, 2023. [Pai, 2023]
The day before the announcement:
- CRISPR Therapeutics AG (CRSP) was trading at $56.23.
- Vertex Pharmaceuticals Inc (VRTX) was trading at $349.34
The day after the announcement:
- CRISPR Therapeutics AG (CRSP) closed at $67.89 on November 17, 2023, which is an increase of approximately 20.74%.
- Vertex Pharmaceuticals Inc (VRTX) closed at $350.50 on November 17, 2023, which is an increase of approximately 0.33%.
Casgevy is a genetically modified autologous CD34+ cell enriched population, featuring human hematopoietic stem and progenitor cells that have undergone ex vivo editing by CRISPR/Cas9. This editing specifically targets the erythroid-specific enhancer region of the BCL11A gene.
What the Data Say
In two global clinical trials of CASGEVY (Genetically Modified Autologous CD34+ Cell Enriched Population) in Sickle Cell Disease (SCD) and Transfusion-Dependent Thalassemia (TDT), specifically, CLIMB-111 and CLIMB-121, the trials successfully achieved their respective primary outcomes. Participants became free from severe Vaso-Occlusive Crises (VOCs) or achieved transfusion independence for at least 12 consecutive months. Once these benefits are realized, they are anticipated to provide potential life-long advantages.
The safety profile observed in 97 SCD and TDT patients treated with CASGEVY in these ongoing studies was generally equivalent to the safety considerations associated with myeloablative conditioning using busulfan and hematopoietic stem cell transplant.
Casgevy is currently undergoing additional evaluations by the European Medicines Agency, the Saudi Food and Drug Authority, and the U.S. Food and Drug Administration (FDA). For Sickle Cell Disease (SCD), the FDA has accorded Priority Review, while for Transfusion-Dependent Thalassemia (TDT), a Standard Review is in progress.
The Potential of Gene Editing
Gene editing has the potential to correct rare genetic diseases, such as SCD and Thalassemia prompting the development of several technologies to achieve this including Transcription Activator-Like Effector Nuclease (TALEN) and Zinc Finger Nuclease (ZFN), but none had achieved market approval until now. [Zhu, 2022] Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing technology has certain usability advantages that helped it win conditional regulatory approval in the UK, a world first for the technology. [Le Page, 2021] [Tong, 2023] CRISPR was not invented, rather it was found naturally occurring in some bacteria and most archaea (the third domain of life) and then later modified for use as biotechnology. [Ishino, 1987] [Jinek, 2012]
CRISPR in the Wild
CRISPR systems consist of an operon of CRISPR-associated (cas) genes and a CRISPR array. This array is made up of a leader sequence followed by a series of short, identical direct repeats (DRs) interspaced by unique spacer sequences. [Jinek, 2012] The spacers originate from mobile genetic elements, which were memorized upon an initial infection with phage or archaeal viruses. In turn, they enable the recognition of invading viral elements during subsequent infections. Thus, CRISPR is a type of prokaryotic adaptive immune system.
Classification of CRISPR Systems
There are two classes and five types of CRISPR/Cas systems. [Makarova, 2015] Precursor CRISPR RNAs (pre-crRNAs) are formed after the transcription of the CRISPR locus. Each type of system exhibits distinct characteristics in its mechanisms of pre-crRNA processing and differ in their roles in recognizing and cleaving nucleic acids. [Charpentier, 2015]
Class I - Multisubunit Effector Complexes
Type I, III, and IV systems have common features including specialized Cas endonucleases that process the pre-crRNAs. Each crRNA matures and combines into a large multi-Cas protein complex. The Cas complex is capable of recognizing and cleaving nucleic acids complementary to the crRNA...
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