By Kevin Davies, PhD

In a truly historic decision today, the U.S. Food and Drug Administration (FDA) has, as expected, approved Casgevy, the groundbreaking CRISPR-based gene editing therapy for sickle cell disease (SCD), sponsored by Vertex Pharmaceuticals.

It is ironic that the first approved CRISPR therapy—a technology barely ten years old— should be for the genetic disorder that Linus Pauling famously dubbed “the first molecular disease” almost 75 years ago.

The FDA also announced approval of Bluebird Bio’s lentiviral SCD gene therapy, Lyfgenia. That approval comes with a black box warning on the label given the occurrence of rare instances of blood cancers in patients.

The FDA decision comes two weeks after regulatory authorities in the U.K. became the first country to approve Casgevy. (Bahrain followed suit a week later.) That news drew enthusiastic reactions from many scientists and stakeholders, including the CRISPR gene editing Nobel laureates, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD.

“Going from the lab to an approved [CRISPR] therapy in just 11 years is a truly remarkable achievement,” Doudna said, adding she was especially pleased that the approval helps patients with “a disease that has long been neglected by the medical establishment.”

The Vertex exa-cel clinical trial officially launched under the auspices of its partner, CRISPR Therapeutics, co-founded by Charpentier, in 2018. In July 2019, Victoria Gray became the first American SCD patient to be treated, by Haydar Frangoul, MD, and his team at the Sarah Cannon Research Institute in Nashville. (Gray’s journey has been featured in an exclusive series of interviews on National Public Radio over the past four years.)

The Casgevy therapy involves the use of CRISPR-Cas9 to inactivate BCL11A expression in the precursors of red blood cells, thus releasing the handbrake on fetal globin expression, which in turn compensates for the SCD mutation in the beta-globin gene. [F. Urnov/The CRISPR Journal]
The Vertex strategy, which is being followed by several other groups, is to compensate for the SCD mutation β-globin by restoring expression of fetal hemoglobin (HbF), which is expressed in utero and switched off shortly after birth. The CRISPR scissors is applied in patients’ harvested stem cells to target the key regulator of HbF expression before the edited cells are restored to the patient.

“It is very exciting to witness how our foundational research, conducted 15 years ago, which established BCL11A as a key suppressor of fetal hemoglobin, has paved the way for numerous subsequent breakthroughs and insights. This progress has ultimately led to the successful development and approval of exa-cel today,” said Vijay Sankaran, MD, PhD, Lodish Family Chair in the Division of Hematology/Oncology at Boston Children’s Hospital, whose genomic studies in 2008 (along with those of Swee Lay Thein, MD, chief of the sickle cell branch at NIH) pinpointed BCL11A as the key regulator of HbF expression.

“This experience underscores a critical lesson—the indispensable role of fundamental discovery science. Without such studies, many of these pivotal advances would remain beyond our reach.”

Among other notable reactions to the FDA news was a comment from Victoria Gray, who posted on LinkedIn: “I am crying real tears of joy and I can’t stop shaking!!… To all my fellow Sickle Cell Warriors help is here! We will never forget the warriors who we lost along the way!… our prayers were not in vain! This is only the beginning!!!”

In Tanzania, Julie Makani, MD, PhD, a leading SCD physician-scientist, hailed the news as “a momentous milestone” for SCD, one that would have “a major impact on our approach” to SCD therapeutic interventions. On the launch of a local sickle cell program 20 years ago, she said, “the message to patients was that there is no cure for SCD… Today, we can tell patients that gene therapy is available for treatment of SCD in the USA and U.K.” The Sickle in Africa consortium has enrolled more than 30,000 patients in its registry and efforts are growing to make gene-based therapies available in Africa. “The message has changed,” Makani said. “This is truly an example of translation of science to improve health.”

Thein, the NIH SCD expert, told GEN: “This is a major triumph for translational science and a major step towards curative treatment for patients with sickle cell disease… But let’s not forget the rest of the patients; we still need more small molecule disease-modifying drugs for patients with sickle cell disease.”

120 Years of hurt

A baby is born with SCD every two minutes. The disease affects some 100,000 people in the United States, the vast majority African Americans, and millions more worldwide. A point mutation in the β-globin gene—which NIH researchers deduced originally arose some 7,000 years ago in sub-Saharan Africa—results in the polymerization of the oxygen-carrying hemoglobin protein that in turn warps the shape of the beautiful, biconcave red blood cells, leading to excruciating pain crises and the risk of organ damage.

As Siddhartha Mukherjee, MD, wrote in his best-selling book The Gene, SCD is “a Rube Goldberg disease. A change in the sequence of a gene caused the change in the sequence of a protein that warped its shape; that shrank a cell; that clogged a vein; that jammed the flow; that racked the body (that genes built).”

Throughout the 20th century, the study of SCD symbolized the bleeding edge of biomedical progress. In 1910, Chicago physician James Herrick, MD, belatedly published a case report of an unnamed 20-year-old dental student from the Caribbean island of Grenada, who had first been treated in 1904 by a resident, Ernest Irons, MD. Herrick noted the presence of peculiar “pear-shaped” red blood cells. Following a few additional case reports over the next decade, Johns Hopkins resident Verne Mason, MD, coined the term “sickle cell anemia” in 1922.

Herrick’s patient was identified only decades later by historian Todd Savitt, PhD, as one Walter Clement Noel, who arrived in Chicago in 1904 to enroll in dental school. He returned to Grenada to set up his own dental practice in the capital, St. George’s, in 1907, and was probably unaware of the 1910 publication. Noel died in 1916 and is buried in a family grave on Leapers Hill, a famous landmark on the north coast of the island, in a Catholic church cemetery overlooking the ocean.

Walter Clement Noel from Grenada was the first recorded SCD patient in the medical literature. He died in 1916, six years after his peculiar blood cells were published. He is buried in a cemetery in Sauteurs, Grenada. On the left, a plaque outside the cemetery entrance; on the right, the family grave where Noel is buried with seven relatives. [ Kevin Davies.]
In 1948, a Brooklyn pediatrician named Janet Watson, MD, observed that the presence of sickle cells in patients increases as their fetal hemoglobin switches off—a discovery that laid the foundation for the strategy of upregulating HbF as exemplified by Casgevy. A year later, Linus Pauling, PhD, demonstrated that SCD was a recessively inherited disease caused by an alteration in hemoglobin.

Seven years later, Vernon Ingram, PhD, working in the same Cavendish Laboratory where Crick and Watson assembled the double helix model of DNA, identified the precise amino-acid substitution in beta-globin. Around the same time, epidemiological studies in East Africa by Anthony Allison, MD, proved that the incidence of SCD coincided with rates of malaria—a vivid example of heterozygous advantage. In the late 1970s, hematologist Y.W. Kan, MD, and Andree Dozy performed the first prenatal DNA diagnosis on an SCD pregnancy.

But despite these scientific milestones, the experience of SCD patients has not advanced to the same degree. As the late science journalist Sharon Begley put it plainly: “The U.S. healthcare system is killing adults with sickle cell disease.” And while FDA approval of Casgevy is a moment for celebration, this approach won’t help the vast majority of patients worldwide. As Dhruv Khullar wrote in the New Yorker: “If we truly want to cure sickle-cell disease, editing genomes will only get us so far. We’ll need to rewrite our medical system, too.

SCD patients are routinely profiled and denied urgently needed pain medications by hospital staff. “There may be no population of patients whose health care and outcomes are more affected by racism” than those with SCD, hematologists Alexandra Power-Hays, MD, and Patrick McGann, MD, wrote in the New England Journal. “Patients with SCD are too often marginalized and dismissed while seeking medical care when their bodies hurt and they cannot breathe.” Making matters worse, many SCD patients lack basic information and/or access to generic drugs and screening tools that could ward off disease complications.

There is no good reason why fewer than one in five children with SCD are prescribed antibiotics, or the generic anti-cancer drug hydroxyurea, which boosts levels of fetal hemoglobin, is not more widely offered. “To have teenage patients who never heard the word hydroxyurea—that’s preposterous,” says McGann. Former NIH director Francis Collins acknowledges that the plight of SCD patients is indicative that “we do not have equity in our country.” There isn’t even a national registry of SCD patients, so no-one can say precisely how many individuals are affected.

More than 50 years ago, President Nixon signed the Sickle Cell Control Act, creating new treatment centers and increased funding. But SCD has not enjoyed the billion-dollar stimulus funding of the cancer moonshot or the philanthropic boost of the ALS Ice Bucket Challenge. In a study published in 2020, Duke University hematologist John J. Strouse, MD, and colleagues argued that by many metrics, including federal funding, philanthropic support and new drug approvals, support for SCD lags that afforded cystic fibrosis (CF), even though CF affects roughly one third of the number of patients in the U.S. as SCD.

A new hope

Until recently, the FDA had only approved four drugs for SCD, including hydroxyurea, which boosts HbF levels (although the mechanism is unclear). But hope is on the horizon. In August 2022, Pfizer acquired Bay Area biotech Global Blood Therapeutics (GBT) for $5.4 billion. GBT’s lead drug, Oxbryta, attacks the disease at its source, binding to β-globin and preventing polymerization. GBT’s former CEO Ted Love, MD, defended the drug’s list price of $10,000/month, insisting the company needed to invest in R&D to develop more efficacious drug candidates.

New hope for SCD patients is emerging in gene therapy and genome editing. NIH hematologist John Tisdale, MD, has been treating SCD patients with Bluebird Bio’s Lyfgenia™ (lovotibeglogene autotemcel), a form of gene therapy that uses a lentiviral vector and was formerly known as “lovo-cel.”

“This looks like a cure,” Collins told 60 Minutes two years ago in an episode that profiled patients in Tisdale’s care. The FDA also approved Bluebird’s lovo-cel therapy (Lyfgenia) today.

Today, nearly two weeks ahead of its scheduled target decision date of December 20, Lyfgenia won FDA approval as well. Lyfgenia is a one-time gene therapy custom-designed to treat the underlying cause of sickle cell disease. The therapy is indicated for patients ages 12 and older who have a history of vaso-occlusive events (VOEs), which Lyfgenia has the potential to resolve.

However, Lyfgenia was approved with the FDA’s highest safety-related warning that a medication can have. According to the boxed warning on Lyfgenia’s label, incidents of blood cancers have occurred in patients treated with the heme therapy.

“Although the approval of Lyfgenia makes it the company’s third approved product, we see several factors that could limit its commercial potential, particularly given the announcement of CRISPR/Vertex’s Casgevy,” Sami Corwin, PhD, a healthcare analyst focused on biotechnology at William Blair, and colleagues observed today in a research note.

Those factors include:

  • The boxed warning, which Casgevy does not have.
  • A list price that is $900,000 more than Casgevy.
  • Casgevy’s broader regulatory acceptance, with approvals in the U.K. and Bahrain; Lyfgenia will be commercialized only in the U.S.

Meanwhile, Beam Therapeutics and Editas Medicine are also targeting pursuing SCD among their lead clinical gene editing programs. At Boston Children’s Hospital, David Williams, MD, and Erica Esrick, MD, have published promising clinical data treating SCD patients using a short hairpin RNA approach.

But for now, all eyes are on Casgevy. Taking over the exa-cel program launched by CRISPR Therapeutics, Vertex published the initial exa-cel results in the New England Journal of Medicine in 2021. These represented not only a huge advance in treating SCD but also a crucial early validation of the clinical promise of CRISPR. Fyodor Urnov, PhD (Innovative Genomics Institute) hailed the results as “borderline utopian.”

Writing in The CRISPR Journal, Urnov, who literally coined the term “genome editing” in 2005, proposed that Gray be added to “the pantheon of names inscribed in golden letters in the history of biomedicine”—a list that includes James Phipps (the boy vaccinated by Edward Jenner), Albert Alexander (Florey treated with penicillin), Louise Brown (the first test tube baby) and Emily Whitehead, the pioneering CAR-T patient.

David Altshuler, MD PhD, Vertex Pharmaceuticals’ Executive VP, Global Research and Chief Science Officer. (Vertex Pharmaceuticals)

Utopian or not, the positive Vertex trial results have been extended to dozens of SCD patients, with no reported serious adverse events, although a couple of patients have continued to experience some vaso-occlusive events. The sponsors, regulators, competitors and other observers will be closely monitoring these patients for years to come. Five weeks ago, an FDA advisory committee meeting assembled a panel of experts to consider not the efficacy of the exa-cel clinical trial, which is not in doubt, but the issue of off-target effects, a theoretical concern with any use of the CRISPR-Cas9 “genetic scissors”. The Vertex investigators, led by chief science officer David Altshuler, MD PhD, appeared to satisfy most of the panel’s lingering concerns about off-target editing and the plan to monitor the long-term health of the exa-cel trial volunteers.

Not all gene editing efforts have fared as well as Casgevy. In August 2022, Graphite Bio, a Bay Area gene editing company co-founded by another pioneer in the field, Stanford University physician-scientist Matthew Porteus, MD, PhD, launched its own “find and replace” SCD gene editing trial. But five months later, the company voluntarily paused the trial after its first patient developed complications. Graphite subsequently halted the trial completely, shed 75% of its workforce (including the CEO), and recently agreed to a reverse merger with LENZ, a biotech company developing ocular therapies.

Long road ahead

In one respect, this progress is astonishing. If the inspiring story of Victoria Gray is the medical equivalent of the Lindbergh flight across the Atlantic, the next challenge, as Urnov says, is to develop the equivalent of “routine, scalable, safe, and reasonably priced affordable air travel in a Dreamliner.” Urnov has been championing initiatives and regulatory changes to realize the clinical potential of gene editing in a New York Times commentary and in a recent video interview with GEN’s Jonathan Grinstein, PhD.

Despite Casgevy’s FDA approval, an ex vivo genome editing strategy that involves toxic chemotherapy, weeks in hospital, and stem cell transfusions is not going to be easily affordable or scalable. Vertex announced that the list price of Casgevy, a one-and-done therapy, would be set at $2.2 million. Bluebird has priced Lyfgenia at $3.1 million.Vertex and CRISPR Therapeutics have set a $2.2 million list price for the one-and-done Casgevy, placing it within the same roughly $2 million range as other recently approved gene therapies such as Novartis’ Zolgensma® (onasemnogene abeparvovec-xioi) and Bluebird’s Zynteglo® (betibeglogene autotemcel).

How will these therapeutic advances be translated to the millions of SCD patients living in Africa, Asia and beyond? Speaking at GEN’s “The State of Biotech” virtual event in 2022, Doudna predicted that a one-time in vivo delivery approach—without ex vivo manipulation and bone marrow transplantation—would ultimately be achievable. “Is that going to be possible? My answer is yes,” she said. “Is it possible today? No.”

For SCD patients suffering from “the most famous point mutation in genetics”, as Beam’s CEO John Evans calls it, Casgevy is not the end of the journey, merely a long-awaited beginning.

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