CRISPR Therapies Heading to the Clinic

In a much-anticipated move, US regulators have approved two new gene therapies for sickle cell disease. On December 8, the Food and Drug Administration (FDA) gave the green light to Casgevy, a CRISPR-based therapy from Vertex Pharmaceuticals and CRISPR Therapeutics (co-founded by Emmanuelle Charpentier) and to Lyfgenia, a lentiviral-based gene therapy from bluebird bio that does not use gene editing.

Casgevy’s approval was the first in the US of a therapy using the CRISPR gene editing tool; it followed the treatment’s approval in the UK by a few weeks. These milestone approvals occurred a mere 11 years after researchers first hypothesized that CRISPR could be used to engineer DNA in humans.

The approvals represent a breakthrough for treatment of sickle cell disease, after decades of neglect and poor treatment of patients who, in the US, are overwhelmingly African American. The therapies, intended to be one-time treatments approaching a cure, were very effective in clinical trials. In the Vertex clinical trial, 29 out of 30 patients were free of pain crises for at least one year, many for almost two years. The first person treated, Victoria Gray, has been free of pain crises for four years. One person who participated in the clinical trials described his symptoms “virtually disappearing overnight.”

But these are grueling treatments requiring hospital stays of several weeks to months, with the potential for side effects including severe infections and infertility. As a result, only those with the most severe symptoms are likely to consider them.

Many patients and their doctors may take a wait-and-see approach, especially given how new the treatments are and how few participants were involved in the clinical trials (around 60, across trials for both treatments). Vertex has estimated that 25,000 people in the US and Europe, mainly those with more serious disease, would be good candidates for Casgevy. The FDA’s Peter Marks has put the number of people in the US who would be eligible for either therapy at around 20,000.

The price tag

Even patients eager to undergo the treatments will find that barriers to access are considerable. First and foremost, they are eye-poppingly expensive. Casgevy will cost $2.2 million, and Bluebird priced Lyfgenia even higher, at $3.1 million (one of several mis-steps that sent the company’s stock price sliding). Those prices are just for the gene editing product itself — they do not include hospital stays or other aspects of the protocol.

Access is therefore likely to be very limited in the US and around the world. How will Medicaid, which funds treatment for around half of adults with sickle cell disease in the US, afford it? And what about patients living in states that have not expanded access to their Medicaid programs? Are these the kind of “extreme and unjustified” prices that would prompt Joe Biden to use newly proposed “march-in” rights?  

In sub-Saharan Africa, where millions of people with sickle cell live, these treatments won’t be available at all, due both to their high cost and the lack of medical infrastructure to support the bone marrow transplant-like procedure. According to the New York Times:

Vertex has been prioritizing winning approval in six wealthy countries — the United States, Italy, Britain, France, Germany and Saudi Arabia — that, by one estimate, are home to 2 percent of the global sickle cell population. Three-quarters of the world’s sickle cell patients are in sub-Saharan Africa. Several million of them are believed to be sick enough that they would be eligible for the new therapies, compared with some 20,000 in the United States.

For comparison, neither newborn screening for sickle cell disease nor the current standard treatment, hydroxyurea — which costs about $7 per month — are widely available in many African countries. This is also the case in India, a point made by both civil society and patient advocates at the Third International Summit on Human Genome Editing.

The New York Times quotes a source at Vertex who says they are working on treatments that would be more accessible in countries without medical infrastructure and resources, but these would likely be a long way off. A Bluebird spokesperson is quoted lamenting the “unfortunate reality” that much of the world would not have access to the treatment and promised investments that “may support global access in the future.”

The approval of Casgevy may also initiate a new round of the CRISPR patent battle, since the Broad Institute holds the US patent on the CRISPR technology used in Vertex’s therapy, which it licensed exclusively to its own spin-off company, Editas. This could further impact cost and availability of the therapies.

Remaining questions and what’s next

Questions about the safety and effectiveness of the therapies remain: Will the treatments' dramatic benefits be durable over time? Will adverse side effects, like increased risk of blood cancer, emerge later? Findings of increased cancer risk in several recent studies suggest that this may be the case. In fact, Lyfgenia carries a black box warning from the FDA advising about the possibility of developing blood cancer and that patients should be monitored long-term for that risk.

The recent death of Terry Horgan in the so-called “N of 1” gene therapy trial for Duchenne muscular dystrophy signals reason for concern. Horgan suffered a previously unseen immune reaction to the delivery method, demonstrating that new risks could emerge as trials proceed or treatments make their way to more people.

Other CRISPR-based gene therapies, including some using base and prime editing, are moving through clinical trials now. Among those making their way toward the clinic are additional therapies for sickle cell from Editas and Kamau, the company newly launched by Stanford scientist Mathew Porteus to revive development of a therapy that was halted after adverse effects in the first clinical trial patient.

The approval of Casgevy in the UK happened to come just a week before the fifth anniversary of He Jiankui’s announcement of the first “CRISPR babies.” This coincidence juxtaposes the promise of CRISPR to provide much-needed treatments for existing patients with the grave risks to individuals and society posed by the prospect of heritable genome editing. Surprisingly, the anniversary generated almost no media discussion. The approval of the first CRISPR gene therapy is a good time to reiterate that we can support responsible development of gene editing treatments for patients — as long as they are safe, effective, and accessible — while protecting our prospects for a fair and inclusive future by keeping heritable genome editing off limits.