1st gene-editing therapy for SCD, called Casgevy, approved in UK

CRISPR-based treatment for patients eligible for transplant but lacking a donor

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The U.K. Medicines and Healthcare products Regulatory Agency (MHRA) has conditionally approved the gene-editing therapy exa-cel (exagamglogene autotemcel), under the brand name Casgevy, for people with sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT).

The authorization covers adults and children, ages 12 and older, with SCD and experiencing recurrent vaso-occlusive crises (VOCs) or with TDT. Patients also must be eligible for a stem cell transplant, but have no available donor.

“I am pleased to announce that we have authorized an innovative and first-of-its-kind gene-editing treatment called Casgevy, which in trials has been found to restore healthy hemoglobin production in the majority of participants with [SCD] and [TDT], relieving the symptoms of disease,” Julian Beach, interim executive director of MHRA’s Healthcare Quality and Access, said in a press release.

Exa-cel is under review in the U.S., European Union, and Saudi Arabia. In the U.S., the therapy was granted priority review for SCD, with an expected decision by Dec. 8. A decision on its use for TDT is set for March 30, 2024.

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Casgevy now is the first gene-editing therapy for sickle cell disease

“Sickle cell disorder is an incredibly debilitating condition, causing significant pain for the people who live with it and potentially leading to early mortality,” said John James, chief executive of the Sickle Cell Society. “There are limited medicines currently available to patients, so I welcome today’s news that a new treatment has been judged safe and effective.”

An estimated 2,000 SCD and TDT patients in the U.K. will be eligible for the treatment, according to Casgevy’s developers, Vertex Pharmaceuticals and CRISPR Therapeutics.

“Today is a historic day in science and medicine: this authorization of Casgevy in Great Britain is the first regulatory authorization of a CRISPR-based therapy in the world,” Reshma Kewalramani, MD, Vertex’s CEO and president, said in a joint company press release.

CRISPR technology — whose developers won the 2020 Nobel Prize in chemistry — is a gene-editing tool adapted from natural defense mechanisms in bacteria.

While Casgevy now can be marketed in the U.K., its conditional approval means that additional trial results will be needed before the treatment can earn full approval. This type of clearance is granted for medications that may fulfill an unmet medical need for serious or life-threatening diseases.

“The MHRA will continue to closely monitor the safety and effectiveness of Casgevy, through real-world safety data and post-authorization safety studies being carried out by the manufacturer,” Beach said.

Like the inherited blood disorder TDT, sickle cell disease is characterized by problems with hemoglobin, the protein in red blood cells that helps them carry oxygen throughout the body. SCD patients carry a faulty version of hemoglobin, while TDT patients don’t make enough of it.

Both conditions can be treated with a stem cell transplant, where patients undergo a round of chemotherapy to clear faulty cells before receiving healthy blood cell precursors (hematopoietic stem cells) from a donor, which work to repopulate the blood with healthy cells, including red blood cells.

However, a suitable donor must match the recipient for certain immune markers to prevent the recipient having an unwanted immune response against the donated cells.

Casgevy works by editing a person’s own hematopoietic stem cells to increase production of fetal hemoglobin, the version of the protein produced before birth that is more effective at carrying oxygen than its adult counterpart. SCD-causing mutations only affect adult hemoglobin, whose production begins shortly after birth.

The therapy employs the CRISPR technology to edit a part of the gene that encodes BCL11A, a protein responsible for turning off fetal hemoglobin. This prevents BCL11A production, allowing more fetal hemoglobin to be produced.

For the treatment, a patient’s cells are collected, edited in the lab, and then returned via a stem cell transplant after a round of chemotherapy.

Findings in 2 ongoing clinical trials supported the conditional approval

Two ongoing Phase 1/2/3 trials — CLIMB-121 (NCT03745287) in SCD patients and CLIMB–111 (NCT03655678) in TDT patients — mainly supported the regulatory applications. These studies are due to conclude next year.

Data from CLIMB-121, which enrolled patients with severe SCD, ages 12-35, indicated that a single infusion of the therapy prevented painful VOCs for at least a year in 29 of 30 evaluated patients, meeting the trial’s main goal. It also successfully boosted fetal hemoglobin levels after about three months, and they were sustained over time.

Casgevy’s side effect profile across nearly 100 treated patients has been consistent with the known side effects of a commonly used chemotherapy agent and of stem cell transplant, according to the companies.

Its long-term safety will continue to be assessed in the CLIMB-131 extension study (NCT04208529), where CLIMB-121 and CLIMB-111 participants are being monitored for up to 15 years.

“This authorization offers a new option for eligible patients who are waiting for innovative therapies and I look forward to patients having access to this therapy as quickly as possible,” said Josu de la Fuente, MD, PhD, principal investigator for the U.K. part of the ongoing clinical trials, a consultant hematologist at Imperial College Healthcare NHS Trust, and a professor at Imperial College London.

Scientists hope that this first clearance of a CRISPR-based therapy will open doors for the technology to treat other diseases with a known genetic cause.

“I hope this represents the first of many applications of this Nobel Prize winning technology to benefit eligible patients with serious diseases,” said Samarth Kulkarni, PhD, chairman and CEO of CRISPR Therapeutics.