First CRISPR therapy seeks landmark approval

Vertex and CRISPR Therapeutics’s first-in-modality genome-editor exa-cel, for the treatment of two haemoglobinopathies, has entered the regulatory spotlight.

• Katie Kingwell

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Credit: S. Harris/Springer Nature Limited

Vertex and CRISPR Therapeutics have submitted their CRISPR-based ex vivo cell therapy exagamglogene autotemcel (exa-cel) for FDA approval, for sickle cell disease (SCD) and beta-thalassemia. A regulatory decision on the gene-editing candidate is expected within 8 to 12 months. The companies have also filed for approval in Europe and the UK.

“This is an incredible validation for a technology that 10 years ago was a paper,” says Bastiano Sanna, chief of cell and genetic therapies at Vertex, which partnered with CRISPR Therapeutics in 2015 to develop exa-cel, formerly called CTX-001. “It was like opening a bottle: when the right tool came, suddenly we could use all the science that the [haemoglobinopathy] field had stored up for so many years,” says Sanna.

“It’s astounding,” agrees Jennifer Doudna, one of the scientists who showed in 2012 that the CRISPR–Cas system could be used to edit genomes. “It was clear that having the ability to edit genomes was a powerful tool, but I don't think any of us could have imagined how fast the field would move.” Doudna co-founded the genome-editing companies Editas and Intellia, while Emmanuelle Charpentier, a co-author of the 2012 paper, co-founded CRISPR Therapeutics. Doudna and Charpentier shared a Nobel Prize in 2020 for their ground-breaking work.

Beta-haemoglobinopathies are a popular testing ground for gene-targeted approaches, because the underlying genetic drivers are well understood and tractable. The target cells can also be modified ex vivo and returned to patients, sidestepping some delivery hurdles. Bluebird bio recently secured FDA approved of its lentiviral gene therapy betibeglogene autotemcel (beti-cel) in this setting. But with the competitive landscape maturing, some contenders are now retreating (Table 1).

Table 1 | Selected beta-haemoglobinopathy therapies in development

HBB, beta-globin gene; HbF, fetal haemoglobin; HBG, gamma-globin gene; HBS, sickle haemoglobin gene variant; HSPCs, haematopoietic stem and progenitor cells.

Exa-cel data, from 75 patients in ongoing open-label studies, helps set the bar.

“It’s been spectacular, and beyond anybody's expectations,” says Martin Steinberg, a haematologist at Boston University and a member of Vertex’s steering committee for exa-cel’s development.

Vertex’s gene-editing therapy stopped painful vaso-occlusive crises in SCD, and led to transfusion-independence in 90% of patients with beta-thalassemia over 1.2 to 37.2 months, the company has reported.

This is a step change over pharmacological therapies for SCD, such as the standard-of-care haemoglobin-boosting agent hydroxyurea, and more recently approved options such as GBT/Pfizer’s anti-sickling agent voxelotor and Novartis’s P-selectin-blocking antibody crizanlizumab. “Hydroxyurea is extremely useful, but it never cured anybody,” says Steinberg. “The idea behind exa-cel is a curative intent.”

So far, exa-cel’s efficacy looks similar to that of lentiviral approaches, including Bluebird’s investigational lentiviral gene therapy for SCD, Steinberg adds.

A 15-year follow-up trial of exa-cel is ongoing to assess its durability and longer-term safety. Concerns linger about the theoretical and practical possibilities of both on-target and off-target editing with CRISPR–Cas-based drugs.

The treatment regimen is also onerous, and is likely to be expensive. Because the majority of haemoglobinopathy patients live in under-resourced countries in Africa and elsewhere, access and affordability will remain huge hurdles. “I see it as a biological breakthrough. But, in the context of things, it’s a small first step to making these types of gene therapies applicable to most people who need them,” says Steinberg.

While an approval would buoy the rapidly evolving field of CRISPR–Cas therapeutics, more work is needed to improve the delivery and expand the therapeutic potential of the modality. “The two axes along which people are pushing forward are to improve delivery across organ systems, and to develop the technology so you can make gene corrections at higher efficiency,” says Samarth Kulkarni, CEO of CRISPR Therapeutics.

Getting to the point

Beta-haemoglobinopathies are caused by mutations in the beta-subunit of haemoglobin, the protein that enables red blood cells to carry oxygen. In beta-thalassemia, a lack of the protein leaves patients with little or no oxygen-carrying capacity. In SCD, the mutation causes sickling and clumping of red blood cells, triggering painful inflammatory vaso-occlusive crises, and drives haemolysis, bursting of red blood cells that leads to anaemia and chronic organ damage.

Treatment for beta-thalassemia involves blood transfusions, as often as every month in severe cases. For SCD, existing small-molecule drugs reduce, but do not prevent, the pain, morbidity and mortality of the disease.

The point mutation that causes SCD was the first genetic cause of a disease to be identified, over 65 years ago. “It’s interesting that the latest tool is going be applied to the oldest genetic disease described in science,” notes Sanna.

With exa-cel, Vertex and its partner use the precise DNA-cutting ability of a CRISPR–Cas9 nuclease to silence BCL11A, a repressor of the fetal haemoglobin gene, in haematopoietic stem and progenitor cells (HSPCs) that have been harvested from patients. Fetal haemoglobin is usually silenced in the months following birth, but the re-activation of the gene produces protein that can compensate for defective beta-globin in both beta-haemoglobinopathies.

As with other ex vivo gene-targeted approaches, exa-cel treatment amounts to a bone marrow transplantation with a patient’s own, modified cells. HSPCs are mobilized from the bone marrow, collected and edited ex vivo. Patients then receive bone marrow ablation therapy to remove dysfunctional blood cells, and the edited HSPCs are re-infused.

“Myeloablative conditioning is harsh,” says Steinberg. “20 years from now people are going to look back at this and laugh that we could possibly do something so crude.” Patients are vulnerable to infections, bleeding and other complications for about 2 months, until the edited HSPCs engraft in the bone marrow, he explains.

But the effects of treatment are compelling. Vertex and CRISPR Therapeutics reported the latest data on 75 patients in two ongoing phase I/II/III trials at the European Hematology Association Congress last year. Treatment with exa-cel led to independence from transfusion in 42 of 44 patients with severe beta-thalassemia (mean follow-up 12.3 months). It also prevented vaso-occlusive crises in all 31 patients with SCD (mean follow-up 9.6 months). In the 2 years prior to gene editing, these SCD patients experienced about 4 crises per year on average.

“It just shows you the power of CRISPR — the ability to precisely treat at the genetic level and bring about cures that have eluded big pharma,” says Kulkarni.

Treatment also increased the mean proportion of fetal haemoglobin to 40% and boosted mean haemoglobin levels to over 11 g/dL. These effects are comparable to those produced by Bluebird’s lentiviral gene therapy lovotibeglogene autotemcel (lovo-cel), which adds an anti-sickling haemoglobin variant gene ex vivo into patient HSPCs. Bluebird is preparing to submit a BLA for lovo-cel soon.

“With the results so far, there’s not that much to distinguish them,” says Steinberg.

For both approaches, the durability of effects remains to be seen. The proportions of edited BCL11A alleles in bone marrow and in peripheral blood mononuclear cells remained stable more than 1 year after treatment with exa-cel. Follow-up studies over many years are needed to confirm if exa-cel is truly a one-time therapy, says Steinberg.

More data are also needed to see if exa-cel will differentiate in other ways from gene replacement approaches like beti-cel and lovo-cel. Vertex expects, however, that the therapeutic’s ability to precisely switch on an existing gene, rather than insert an exogenous gene into the genome at a random location, may make it more appealing to patients and physicians.

An approval for exa-cel would also validate the newer gene-editing technology as a therapeutic contender.

Whereas the leading gene-targeting approaches prevent vaso-occlusive crises in SCD, the jury is still out on whether they can address the haemolysis component of the disease. Lovo-cel did not reduce haemolysis and Vertex has not reported such data for exa-cel. “Vaso-occlusive crises are what bothers patients most, but it’s the intensity of the haemolytic anaemia that is most closely associated with mortality. Both parts of the pathophysiology have to be addressed,” says Steinberg.

This leaves room for other drugs such as voxelotor, a major driver of Pfizer’s US$5.4 billion buyout of GBT last year. In the pivotal phase III trial of voxelotor, the small-molecule drug cut markers of haemolysis and increased haemoglobin levels, but did not reduce the rate of vaso-occlusive crises.

Scrutinizing safety

Because of exa-cel’s status as a leading gene editor, its safety will be of paramount concern for regulators.

Of 75 treated patients, 2 experienced severe adverse events (SAEs) including thrombocytopenia and haemophagocytic lymphohistiocytosis. The SAEs were thought to be related to exa-cel and the bone marrow ablation regimen, and resolved.

The mechanism of the CRISPR–Cas editing could, in theory, cause safety issues though.

To achieve gene silencing, the Cas nuclease makes double-stranded DNA breaks that are then mis-repaired by the cell. However, this can lead to large genomic rearrangements and translocations in vitro, as well as complete loss of the target chromosome through a process called chromothripsis. These effects have not been reported in treated patients so far, and could well cause affected cells to die before they are even re-infused into patients, says Annarita Miccio, a scientist who studies genetic therapies for beta-haemoglobinopathies at the Imagine Institute of Genetic Diseases in Paris. But these editing events still raise the spectre of oncogenic and other serious risks. “This is still a concern,” says Miccio.

Genome editing technologies such as base editing and prime editing, which are at earlier stages of development, do not make double-stranded DNA breaks and might side-step this issue.

Another potential risk stems from the possibility that the editor’s guide RNA can direct the Cas nuclease to cut similar, non-target, sites — resulting in off-target editing. Researchers have made good inroads in predicting and mitigating these liabilities, however, through deep sequencing to screen for genomic sites that might match the guide RNA, and by selecting Cas nucleases with more stringent editing windows, says Kulkarni.

Miccio also wonders about the consequences of raising fetal haemoglobin levels in women who later get pregnant. Fetal haemoglobin has a higher affinity for oxygen than does the adult form of the protein, and this balance ensures oxygen flows to the foetus across the placenta. Might fetal haemoglobin in the mother’s blood disrupt this equilibrium? Available evidence “strongly suggests” induction of fetal haemoglobin to levels of 40% will not impact fetal development, said a spokesperson from Vertex.

As a potential first-in-modality treatment, exa-cel could warrant an FDA advisory committee meeting to further review these and other aspects of the drug’s efficacy and safety profile.

Counting costs

If the gene-editing therapy is approved, pricing and access considerations will come into play. Vertex and CRISPR Therapeutics have yet to comment on pricing plans for exa-cel, but expectations are for it to be high. Beti-cel costs $2.8 million in the USA. Although Bluebird secured an approval for this gene therapy in Europe in 2019, it subsequently withdrew the product from that market after failing to strike a deal with payers on a proposed $1.8 million price-tag.

“The meaning to patients of an approval [for exa-cel] depends on the price,” says Miccio. “After the Bluebird retreat [from Europe], that’s what we are scared of.”

Vertex estimates that 32,000 patients have severe SCD or transfusion-dependent beta-thalassemia in the US and Europe. Analysts at Evaluate Pharma predict the therapy could achieve $1.6 billion in sales by 2028.

But treating patients in under-resourced countries will require a different paradigm, adds Steinberg. Oral fetal haemoglobin inducers that can work synergistically with hydroxyurea would be game-changers. “But the pipeline is sort of constricted,” he says. The FDA recently placed a hold on the phase Ib trial of Fulcrum Therapeutics’ oral small-molecule fetal haemoglobin inducer FTX-6058, owing to safety signals in animal studies.

The cutting edge

The CRISPR–Cas nuclease pipeline is also beginning to advance into new therapeutic territories.

Drug developers are keen to apply the technology to achieve in vivo editing, addressing genetic drivers of disease in other organs and cell types. The liver is a clear starting point, because intravenously delivered drugs readily traffic there. Intellia’s CRISPR–Cas9 candidates NTLA-2001 and NTLA-2002, for example, are editing liver cells for the respective treatment of transthyretin amyloidosis and hereditary angioedema. Last year, Verve advanced its PCSK9-base-editing programme into the clinic, targeting liver cells for the treatment of cardiovascular disease.

Vertex and CRISPR Therapeutics are also co-developing a muscle-targeted gene-editing therapy for Duchenne muscular dystrophy. Their preclinical programme uses an AAV-vectored approach to snip out a small fragment of the mutant dystrophin gene in muscle cells, realigning the gene’s reading frame and re-enabling the production of nearly full-length protein.

CRISPR Therapeutics is also partnering with AAV-specialist biotech Capsida to develop CNS-targeted CRISPR–Cas drugs. New delivery vectors could further expand the range of organs available for in vivo editing. Engineered virus-like particles, developed by David Liu at the Broad Institute and others, use viral coat proteins as a DNA-free delivery vehicle. Feng Zhang, also at The Broad Institute, recently launched Aera Therapeutics to advance another platform, using retrovirus-like proteins encoded in the human genome to deliver genome-editing payloads.

“What we're seeing right now in the field is that in addition to advancing the actual tools for editing DNA, we're also advancing the ways that those tools are delivered into cells. Those go hand in hand, because if you can't efficiently deliver the editor into the tissue where it’s necessary then it’s kind of moot,” says Doudna.

Gene correction is another frontier. Rather than using a nuclease to just cut and silence a gene, some next-generation editors harness a DNA template to rewrite a gene at a cut site, using either the cell’s own machinery or through more experimental gene-editing approaches such as prime editing.

“The opportunity there obviously is huge if this becomes a more generalizable way of correcting mutations that cause disease,” says Doudna.

One of the most advanced gene correction programmes recently suffered a major setback. In January, Graphite Bio halted the clinical trial of its gene-corrected autologous HSPC therapy for SCD, when the first patient experienced a serious case of pancytopenia. It has since discontinued the programme. Graphite has yet to disclose further details about the cause of the adverse event, but Miccio speculates that the manipulations to the HSPCs might have been too toxic to the cells.