Finding the right words to encapsulate the significance of Friday's FDA approval of Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exa-cel) for sickle cell disease (SCD) proves challenging. This long-awaited therapeutic breakthrough represents a potential cure for the life-threatening disorder, impacting over 100,000 individuals in the United States.
Casgevy not only marks a historic moment in treating SCD but also stands as the first therapy utilizing the revolutionary CRISPR gene-editing system. This groundbreaking technology, acknowledged with a Nobel Prize in 2020, holds immense promise to address diseases lacking any viable treatment. The approval signifies a transformative leap toward novel solutions for previously incurable conditions.
Timed surprisingly, the FDA also granted approval to bluebird bio's gene therapy, Lyfgenia (lovo-cel), for the treatment of patients aged 12 and above suffering from SCD and a history of vaso-occlusive events (VOEs), a type of painful episodes.
The nearly simultaneous approval Casgevy sets the stage for a compelling competition between two distinct gene therapies. The race is officially underway, marking a pivotal moment in the evolution of SCD treatment options.
Lyfgenia employs a lentiviral vector to introduce genetic modifications into the patient's blood stem cells, prompting the production of a specific type of hemoglobin A to replace dysfunctional counterparts. The gene therapy comes with a hefty $3.1 milion price tag.
In contrast, Casgevy harnesses CRISPR technology to edit blood stem cells, enhancing the production of fetal hemoglobin, being priced at $2.2 million, setting the stage for a competitive gene therapy race. The Institute for Clinical and Economic Review (ICER) had suggested cost-effectiveness up to $2.05 million after discounts for both therapies. In a single study, Lyfgenia demonstrated great efficacy, with 90.9% of patients achieving resolution of vaso-occlusive events (VOEs), and 97% experiencing no severe VOEs. Casgevy showed comparable efficacy, with 93.5% of patients free from severe vaso-occlusive crises for at least 12 consecutive months.
New Wave of CRISPR-based Systems
High-Level Landscape
With the first-generation CRISPR-Cas9 therapy Casgevy showing remarkable potential, a new wave of CRISPR-based systems is emerging, offering greater precision and versatility. These advanced techniques, set to surpass the initial limitations, are poised to redefine the landscape of genome editing, building on the regulatory groundwork laid by the classical CRISPR-Cas9 approval. A summarized landscape of the evolving CRISPR-technologies is shown here:
Base Editing
High Precision | Low Flexibility
As CRISPR-Cas9 is better at destroying than fixing, base editing was explored by many, a method that changes individual DNA letters, allowing for precise modifications like converting A to G or C to T. Unlike traditional CRISPR-Cas9, base editing usually avoids cutting both DNA strands, enhancing precision. Despite its remarkable accuracy, base editing has limitations, such as its inability to insert DNA chunks into the genome. Nonetheless, it shows promise in early clinical trials for conditions like high cholesterol and certain types of leukemia. Here, Verve Therapeutix explores VERVE-101 targeting PCSK9 for heterozygous familial hypercholestolemia in a Phase I trial. Beam Therapeutix is another interesting base editing player with clinical Phase I development of BEAM-101 for sickle cell disease and BEAM-201 for T-cell lymphoma.
Prime Editing
More Flexible & Versatile
Introduced in 2019, prime editing offers versatile genome editing by changing DNA bases and inserting or deleting stretches, potentially enabling to exchange entire copies of a defective gene. While complex, it addresses previous limitations. Researchers have improved its efficiency, and Prime Medicine (currently in IND-enabling phase) plans a clinical trial for chronic granulomatous disease. Advancements aim to insert larger DNA pieces into the genome, potentially revolutionizing therapies. KOLs envision a universal therapy for genetic disorders like cystic fibrosis. The pursuit of diverse approaches continues to unlock genome editing's potential for widespread treatments.
Epigenome Editing
Potentially Safer | Still Immature
CRISPR systems not only alter gene sequences but can also impact gene expression through epigenome modifications. Recent breakthroughs challenge misconceptions about the lasting effects of epigenome edits during cell division. In May, Tune Therapeutics demonstrated long-lasting gene shutdown in non-human primates by adding methyl groups to DNA. This method's effects persisted for at least 11 months, presenting an advantage over some RNA-based medicines. Importantly, it doesn't involve changing DNA, addressing safety concerns associated with traditional CRISPR-Cas9 approaches. This breakthrough exemplifies how an enhanced understanding of the epigenome could advance treatments, such as Tune's approach to develop TUNE-401 addressing hepatitis B virus infections.
In this pivotal moment for CRISPR-based editing, recent regulatory approvals for applications distinct from the first CRISPR-Cas9 medicine signal a noteworthy advance. KOLs highlight the significance, noting that these endorsements help solidify CRISPR-based editing as a viable avenue for treating diseases. The anticipation of increased interest in epigenome editing follows, marking a transformative phase for the pharmaceutical landscape. The monumental impact of the current approvals might allow for fast-track developments for CRISPR-based innovations in the near future.
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