NEW YORK – After the US Food and Drug Administration's approval last week of the first-ever gene therapies for sickle cell disease, including the first-ever CRISPR drug, Vertex Pharmaceuticals and Bluebird Bio are ramping up commercialization and manufacturing of their competing products, while physicians are trying to figure out how this scientific and medical milestone will fit into the clinic.
The FDA last Friday simultaneously approved Vertex and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) and Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel). The drugmakers say their gene therapies are one-time and potentially curative treatments for sickle cell disease, a rare, inherited blood disorder due to abnormalities in genes that encode the hemoglobin protein and cause red blood cells to have a "sickle" shape. The misshapen cells inhibit oxygen delivery throughout the body and can cause severely painful episodes, called vaso-occlusive crises (VOCs).
While Casgevy and Lyfgenia undoubtedly represent major scientific and medical feats, the treatments come with sky-high price tags.
Vertex has priced Casgevy at $2.2 million, while Bluebird's Lyfgenia carries a $3.1 million price tag — slightly less than the $3.5 million price of CSL Behring's hemophilia B gene therapy, Hemgenix (etranacogene dezaparvovec), which is often called the most expensive drug in the world. The prices of both sickle cell gene therapies exceed the $1.35 million to $2.05 million range the Institute for Clinical and Economic Review (ICER), a nonprofit that conducts independent value assessments of healthcare interventions, had suggested would be cost-effective.
Without clarity into pricing plans or insurance coverage, doctors are wondering how accessible these multimillion-dollar treatments will be for their patients.
"The adoption of these expensive therapies is still not clear, as payors have not weighed in completely on how widely they will make these treatments available for patients," said Roger Hajjar, director of Mass General Brigham's Gene and Cell Therapy Institute. Hajjar noted that while Bluebird's Lyfgenia is more expensive, it has more long-term follow-up data, just one of many considerations physicians and patients will need to weigh.
Need for differentiation
Casgevy and Lyfgenia both have shown durable efficacy in reducing VOCs. And on paper, the treatments look very similar: Both are one-time infusions created from patients' own hematopoietic stem and progenitor cells (HSPC) and are approved for patients at least 12 years of age with sickle cell disease and a history of VOCs.
The FDA reviewed data from single-arm trials to approve both drugs. In these studies, 28 of 32 patients on Lyfgenia achieved complete resolution of VOCs between six and 18 months after treatment, and 29 of 31 patients on Casgevy were free of severe VOCs for at least 12 consecutive months during the follow-up period.
As the companies launch their gene therapies and compete for market share, they'll have to differentiate their products and have plenty of opportunity to do so given the treatments' distinct mechanisms of action, their different adverse event profiles, and how much long-term follow-up data they have.
In terms of how the drugs are designed to work, Casgevy involves editing the BCL11A gene in patients' autologous CD34-positive HSPCs ex vivo with CRISPR-Cas9, in an effort to increase production of fetal hemoglobin to facilitate oxygen delivery. Bluebird's Lyfgenia, by comparison, involves genetically modifying a patient's autologous HSPCs ex vivo by using lentiviral vectors to deliver a functional copy of a modified beta-globin gene designed to produce anti-sickling hemoglobin HbAT87Q, which the company says functions similarly to normal adult hemoglobin.
One disadvantage for Lyfgenia is that the FDA added a black box warning to its label cautioning that patients should be monitored lifelong for hematologic malignancies, which led to the death of two patients in clinical trials. According to safety information about the gene therapy in the label, mobilization, conditioning, and infusion of Lyfgenia could lead to additional hematopoietic stress and increase risk of hematologic malignancy.
An advantage for Bluebird, however, is that it has more long-term follow-up data on Lyfgenia than there is available for Casgevy. Over the weekend, researchers at the American Society of Hematology's annual meeting in San Diego presented long-term efficacy and safety data from sickle cell patients who were enrolled in a Phase I/II and Phase III trial of Lyfgenia. Patients in these studies were followed for a median of 35.5 months and for as long as 61 months, or just over five years.
In Vertex's favor is the fact that "CRISPR" is now in the vernacular. CRISPR's use in drug development has rapidly taken hold. The gene-editing technique, based on the immune system of bacteria, was discovered by Jennifer Doudna and Emmanuelle Charpentier just a decade ago in 2012 and earned them the Nobel Prize in chemistry in 2020. In 2013, researchers at the Broad Institute led by Feng Zhang published the first example of using CRISPR to edit genes in mouse and human cells.
"This is encouraging news for CRISPR-based companies, and more generally, for base editing and prime editing," Hajjar said of Casgevy's approval. "The next frontier for CRISPR-based therapies will be in vivo delivery."
There are a handful of other programs in clinical development, including treatments for cardiovascular disease, diabetes, and cancer by CRISPR Therapeutics. Sickle cell also remains an area of interest for gene editing, with another CRISPR therapy being pursued by Editas Medicine, while Beam Therapeutics is advancing a gene therapy candidate that uses a different editing technology called base editing. Excision BioTherapeutics is testing a gene-editing therapy for treating a type of HIV, and Intellia Therapeutics is exploring candidates for in vivo gene editing, including one for transthyretin amyloidosis under development with Regeneron and another for hereditary angioedema.
From market approval to patients
While cost, follow-up data, and other concerns are important to consider, according to Hajjar, adoption could come down to which company has the most robust infrastructure in place to administer the treatments.
As the supply backlogs with marketed autologous cell therapies have shown, making and getting highly individualized drugs to patients requires advanced technologies, experts, and novel manufacturing, supply, and delivery considerations. In light of this, Vertex and Bluebird are both establishing their own national networks of treatment centers in the US, where clinicians are trained to administer the respective gene therapies.
As of Friday, Vertex said its network comprises nine hospitals, including children's and cancer hospitals, that are ready to begin treating patients, and it plans to add more centers to the network in coming weeks. Bluebird has tapped 29 treatment centers to administer its gene therapy so far and is onboarding more, drawing on an existing network of centers that offer its other gene therapies, a Bluebird spokesperson said in an email. The company expects Lyfgenia to be available through its full network of about 50 centers in early 2024.
Vertex, in having treatment centers ready to dispense its gene-editing therapy on the approval date Friday, could enable it to "swiftly initiate [Casgevy's] commercial launch" and give it a leg up in the market, analysts from Goldman Sachs wrote in an equity research report released over the weekend. On top of that, Casgevy's $2.2 million price tag is "meaningfully below" Lyfgenia's $3.1 million, which might provide the CRISPR therapy with a competitive advantage despite being slightly above ICER's suggested cost-effectiveness range, they added.
Despite Casgevy's lower cost, Vertex has yet to share specifics about its strategy with payors. The company has suggested it may consider flexible arrangements, such as outcomes-based contracts, or provide rebates for patients who don’t derive benefit. "We await further details on this front," the Goldman Sachs analysts wrote.
Bluebird, on the other hand, has been far more forthcoming about its reimbursement strategy. In a public statement last Friday, immediately following the approval, the company said it will offer outcomes-based contracting options to payors that are tied to VOC-related hospitalizations. Bluebird also justified the $3.1 million price for Lyfgenia based on the "estimated lifetime impact that reducing or eliminating [vaso-occlusive events] may have on patients' healthcare utilization, future earnings, and life opportunities."
A Bluebird spokesperson on Thursday said the company has signed its first outcomes-based agreement with an unnamed payor that represents 100 million covered lives in the US. She added that the outcomes-based pricing approach, which the company uses for two other FDA-approved gene therapies it sells, "puts our money where our mouth is."
"We can stand behind our therapy in this way because our data show transformative benefits sustained through five years — something no one else in the field can say," the spokesperson said, referring to the follow-up data from the company's Phase I/II and Phase III trials.
The Centers for Medicare & Medicaid Services has not announced the extent to which it will cover either gene therapy, but in September, it highlighted a Cell & Gene Therapy Access model, in which the agency said it will partner with pharmaceutical companies and state Medicaid agencies to test outcomes-based agreements for covering new treatments, including gene therapies for sickle cell disease. In the announcement, the CMS said most sickle cell disease patients with health insurance are covered by Medicaid, the Children's Health Insurance Program, or Medicare.
In an email to GenomeWeb, a Vertex spokesperson similarly said that when setting the price for its gene therapy, the company considered the "lifetime clinical benefit of Casgevy as a one-time potential transformative therapy, reduced economic impact of lifelong healthcare expenses, long-term value delivered across healthcare ecosystems and society, and investment required for ongoing discovery and development of new medicines."
Still, Lyfgenia's higher price, paired with the FDA's requirement for a black box warning about hematologic malignancies, could lead physicians to favor Casgevy, said Katy Spink, chief operating officer and managing partner at Dark Horse Consulting, a firm that advises life sciences companies on cell and gene therapy development. Ultimately, in her view, it will come down to payor policies and what patients will be expected to pay out of pocket.
A "challenge for adoption of these therapies will be that, as with all gene therapy products, our medical system is not really designed for one-time therapies that deliver a long-lasting benefit," she said. "It will be interesting to see if Bluebird’s outcomes-based reimbursement policy, designed to address this challenge, helps them overcome the higher price and black box warning."
Unsurprisingly, the excitement over the approval of these therapies in the healthcare sector has been tempered by worries that these expensive treatments could widen existing healthcare disparities. About 100,000 people in the US have sickle cell disease, according to the US Centers for Disease Control and Prevention, and it's most common in Black Americans, a population in which the disease is estimated to occur in one out of every 365 births. Black Americans have also been shown to often have poor healthcare access.
Beyond that, globally, most patients with sickle cell disease live in low- and middle-income countries, said Christopher McKinney, director of the pediatric sickle cell and hemoglobinopathy program at Children's Hospital Colorado. Unfortunately, that limits "the reach of these therapies to some of the people who need them most," he said.
What physicians are thinking
McKinney said he will likely offer both Casgevy and Lyfgenia to his patients, although for now, neither will be his first-choice treatment. For patients with available donor matches, stem cell transplants from healthy donors will continue to be standard care as a known curative option for the disease. "We have over 40 years of experience with this [treatment] and excellent long-term outcomes," he said.
In cases where that's not possible, he said there will be a lot of information to discuss, including details in Lyfgenia's labeling like the black box warning and a risk of anemia in patients with two copies of a certain mutation in the HBA1 gene that's associated with alpha-thalassemia. On the other hand, Lyfgenia also has more follow-up data, including evidence of the gene therapy reducing risk of stroke in some patients, which could provide some reassurance.
"Ultimately, I anticipate engaging in shared decision-making after educating patients about each of the products," he said. "Some patients may feel more comfortable with a CRISPR-based therapy and the lack of a black box warning and prefer Casgevy, while other patients may feel more confident in the duration of follow-up with Lyfgenia."
A Bluebird spokesperson emphasized in an email that the two patients who died from hematologic malignancies were treated with an earlier version of the gene therapy that used a different manufacturing process and transplant procedure. "The safety profile of Lyfgenia is extremely well characterized and well understood by clinicians," the spokesperson said. "The boxed warning is an important tool for transparency for a community where trust is critical."
Julie Kanter, codirector of the Lifespan Comprehensive Sickle Cell Center and a professor in the hematology and oncology division at the University of Alabama at Birmingham, said she thinks Vertex and Bluebird Bio's products both should have been given black box warnings.
"These individuals may be at increased risk of [myelodysplastic syndrome] at baseline, and there is a risk when you take out those cells and manufacture them, regardless of which therapy you're using," she said during a press conference at ASH. Kanter was an investigator in studies of Lyfgenia but specified that she wasn't speaking on behalf of Bluebird.
She also said she'd like to see head-to-head comparisons of the two gene therapies, which could help doctors determine which is most appropriate for a particular patient.
Lyfgenia's black box warning is a cause for caution, according to Athena Pefkarou, a pediatric hematologist/oncologist in the sickle cell anemia program at Nicklaus Children's Hospital in Miami, though she said she will discuss the therapy with patients. If a patient has exhausted other treatments and is suffering from complications, Lyfgenia could be an option.
"Once [patients] are given the information, it's going to be their choice if they want to take risks," Pefkarou said.
For now, Pefkarou said she's most likely to refer older patients with serious complications from sickle cell disease to receive a gene therapy. She is hopeful for the day when she will be able to offer a one-time curative gene therapy to all her patients with this disease, which could be possible if, over time, these treatments become less expensive, as other procedures like bone marrow transplants have, and as there is more evidence about long-term outcomes and side effects.
According to post-marketing requirements stipulated by the FDA, Vertex and Bluebird must follow the patients who receive their gene therapies for 15 years in observational studies, so they can better characterize the treatments' safety and effectiveness and learn more about the risk of secondary malignancies. These post-marketing studies must enroll 250 subjects.
"This is the first CRISPR-based gene therapy approval, so the FDA clearly wants to gather as much data about safety as possible," Hajjar said, referring to the Vertex treatment.
The FDA also mandated that Vertex study off-target effects of Casgevy, a topic the agency has expressed concerns about and sought feedback on from its advisory committee.
For now, despite having two companies with two innovative therapies entering the market and competing for the same patient population, "there's a lot of room in this sandbox," Kanter said. And there's still a need for other sickle cell disease treatments, since patients will have different ways of weighing risks associated with gene therapy and the stem cell procedure, and different ability to access the treatments.
"There are so many individuals that need this care," Kanter said. "There is plenty of room to do multiple different gene therapies."