Last year saw a landmark approval in precision medicine for the first therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR associated protein 9 (Cas9) genome editing. Little more than a decade after the initial publications on the technology, Casgevy (exagamglogene autotemcel or exa-cel) from Vertex Pharmaceuticals and CRISPR Therapeutics is now marketed for the treatment of sickle cell disease and beta-thalassemia.
The ex vivo cell therapy is created using a CRISPR–Cas9 nuclease to inactivate the gene coding for B cell lymphoma/leukemia 11A (BCL11A), a repressor of the fetal hemoglobin gene, in hematopoietic stem and progenitor cells that have been harvested from patients. Transplantation of modified blood cells back to patients leads to the production of fetal hemoglobin, addressing the deficiencies in adult hemoglobin function that cause the two diseases.
Building on this breakthrough, large biopharma companies have recently entered collaborations with companies that have developed various technologies harnessing CRISPR systems, with the aim of expanding the range of diseases that can be treated as well as addressing challenges for the first-generation platforms such as delivery of the therapeutics.
Exa-cel originated from a collaboration that began in 2015 between Vertex and CRISPR Therapeutics, one of the first companies to be founded to harness CRISPR systems to develop therapies. Since then, the two companies have signed further deals, including one in March 2023 worth up to $330 million to use CRISPR–Cas9 genome editing to develop hypoimmune insulin-producing islet cells for the treatment of patients with type 1 diabetes (see deal snapshot below).
A key issue with the broad applicability of exa-cel for sickle cell disease and beta-thalassemia is the need for patients to undergo bone-marrow ablation—a high-risk process that involves weeks in hospital—to remove dysfunctional blood cells before transplantation of the edited cells. Multiple companies are working on genome-editing therapeutic candidates for disorders such as sickle cell disease that make genome edits in vivo instead, with the aim of avoiding this process.
One such company, Scribe Therapeutics, signed a deal with Sanofi in July 2023 worth up to $1.24 billion (see deal snapshot below). The companies will collaborate to combine Scribe’s engineered Cas endonucleases, which have higher activity, specificity and deliverability than Cas9, with Sanofi’s non-viral delivery technologies to develop in vivo therapies for sickle cell disease and other disorders.
This was the second major deal signed by Scribe last year, following on from one with Eli Lilly’s Prevail Therapeutics in May (see deal snapshot above). Prevail agreed then to pay $75 million upfront, including an equity investment, and more than $1.5 billion in potential milestones to use Scribe’s technologies for the development of in vivo therapies directed against targets known to cause serious neurological and neuromuscular diseases.
Base-editing therapeutics
First-generation genome editors such as exa-cel make double-stranded breaks in DNA. This may raise safety concerns related to off-target effects, particularly for therapeutics that make edits in vivo rather than ex vivo, as with exa-cel. CRISPR-based technologies such as base editing that can make precise changes to genes without creating double-stranded breaks have been developed by companies including Beam Therapeutics.
In October 2023, Lilly signed a deal that could be worth up to $600 million to acquire opt-in rights from Beam to programs for base-editing therapeutics being developed by Verve Therapeutics for cardiovascular disease (see deal snapshot above). Verve’s lead candidate, known as VERVE-101, is a base editor in phase 1 trials that targets the gene coding for the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9). VERVE-101 is designed to alter a single base in PCSK9 to reduce the production of the encoded protein and thereby durably decrease levels of low-density lipoprotein cholesterol, a long-known cardiovascular disease risk factor. In contrast to exa-cel, VERVE-101 makes this alteration in vivo using a lipid nanoparticle delivery vehicle.
Lilly made another deal last year with Verve around a program focused on lipoprotein(a), elevated levels of which also increase the risk of cardiovascular disease independently of low-density lipoprotein cholesterol. In June, Lilly agreed to pay Verve $60 million consisting of an upfront payment and equity investment, and up to $465 million in milestones, as well as royalties on the sales of resultant products.
Multiple companies are now pursuing cardiovascular disease targets such as PCSK9 and lipoprotein(a) with various therapeutic modalities including monoclonal antibodies, antisense oligonucleotides and small interfering RNAs (siRNAs)—some of which are already on the market1. So, a key question for genome-editing therapeutics aimed at the same targets will be if their potential for a ‘one-and-done’ treatment will enable them to compete effectively.
