questions about historic approval of a CRISPR-based medicine

Four questions about the historic approval of a CRISPR-based medicine

Victoria Gray lies in her hospital bed at Sarah Cannon Research Institute in Nashville, Tennessee, praying the bone marrow transplant will finally stop the pain. Her younger brother is a match, and the procedure is planned for the following days. But Dr Haydar Frangoul enters the room to bring some news. Gray could be a good candidate to test a genome editing technology for the first time in humans. If it works, Gray could be free from the agony of living with sickle cell disease.

Gray is the first person in the world to receive a CRISPR therapy to treat sickle cell disease. This rare genetic condition causes blood cells to stiffen and bend, leading to clotting and unbearable aches. But scientists, using CRISPR, have now figured out how to fix the typos in the genome that cause the. “I can dream again,” says Gray.

In the United States, sickle cell disease affects approximately 100,000 Americans. Australia has a comparatively low incidence of sickle cell disease, with only around 400 people thought to have been affected. Yet, Australia’s sickle cell disease drug market size was around $1.1m in 2022 and is projected to reach $2.6m in 2030.

In November last year, the UK was the first to approve a therapy that uses the CRISPR gene editing tool to treat sickle cell disease and β-thalassaemia. The US Food and Drug Administration (FDA) followed suit in December, and the Saudi Food and Drug Authority (SFDA) granted Marketing Authorization in January.

What is sickle cell disease?

Sickle cell disease (SCD) is a genetic disorder affecting red blood cells. It is inherited in an autosomal recessive manner, meaning both parents must pass on a specific gene mutation for a child to have the disease.

The primary feature of sickle cell disease is the presence of abnormal haemoglobin in the red blood cells. Haemoglobin is a protein that carries oxygen from the lungs to the rest of the body. In individuals with sickle cell disease, abnormal haemoglobin causes the red blood cells to become rigid, sticky, and shaped like crescent moons or sickles.

These abnormally shaped red blood cells can get stuck in small blood vessels, reducing blood flow. This can cause various symptoms and complications, including pain, anaemia, organ damage, and a higher infection susceptibility. The pain episodes, known as “sickle cell crises,” can be severe and require medical attention.

There are several types of the disease, with the most common being sickle cell anaemia.

There is currently no cure, but various treatments can help manage symptoms and complications. These may include medications, regular blood transfusions, and, in some cases, stem cell transplantation.

CRISPR and the human immune system

How does Casgevy work?

CRISPR therapy, marketed as Casgevy by Vertex, manipulates the patient’s blood stem cells. The goal is to stimulate the production of foetal haemoglobin, the healthy variant crucial during fetal development.

The first step is collecting stem cells responsible for blood production from the patient. These cells are then edited using CRISPR in a laboratory, with Casgevy precisely targeting the BCL11A gene. This gene edit acts as a key, disabling a molecular brake on the production of fetal haemoglobin, which typically diminishes after birth. The edited stem cells are then delivered back to the patient. The company says it can take up to 6 months from the time cells are collected to manufacture and test CASGEVY before it is sent back to the healthcare provider.

While the injection of Casgevy-treated cells is swift, the treatment journey is far from straightforward. Patients undergo a preparatory phase with chemotherapy that eradicates any remaining native stem cells in the bone marrow. This creates space for the functional, CRISPR-edited cells to engraft and grow.

The chemotherapy treatment comes with potentially severe side effects, including an increased risk of infection, and patients must remain in the hospital until their immune system rebounds.

Compared to existing bone marrow transplants, a one-time therapy option that has been available over the past three decades, the Casgevy treatment eliminates the challenges associated with finding a compatible donor.

Why is it so expensive?

The promising cure comes with a jaw-dropping price tag. “A US$2 million cure is not a cure,” says Fyodor Urnov, Professor of Molecular Therapeutics at the University of California, Berkeley, and Scientific Director at the Innovative Genomics Institute.

Fyodor Urnov

There are four major issues that drive prices and hinder accessibility. 

First, getting a drug to market is a lengthy and expensive process. Developing a gene therapy can cost an estimated $5 billion. This is more than five times the average cost of developing traditional drugs. In addition to the costs of research, manufacturing and distribution, these biological therapeutics are subjected to multiple regulatory structures, which result in a long and expensive route to approval. When you factor in the limited number of eligible patients, the motivation behind pricing becomes clear.

Second, the United States healthcare and pharmaceutical industries have an outsize effect on the cost of medical therapies. Currently, the US market funds the majority of the global pharmaceutical industry—roughly 75%—and prices for drugs are significantly higher in the US compared to other countries. For example, Novartis sells a gene-editing drug to treat spinal muscular atrophy for $2m a patient.

The market dynamics in the US shape the availability of medicines and therapies for the world. But even in wealthy European nations, pharmaceutical and therapeutic companies find they cannot obtain similar payments and thus either accept a price cut or leave the market. For example, Bluebird Bio’s Zynteglo, the first gene therapy for people with beta-thalassemia who require regular transfusions, costs $2.8 million in the US. Bluebird Bio priced Zynteglo at $1.8 million in Europe. Yet, in 2021, the company wound down its operations in Europe, citing “challenges of achieving appropriate value recognition and market access in Europe”.

Third, infrastructure and know-how to develop genetic therapies do not exist in the parts of the world with the most need. Without specialised facilities, these medicines cannot even be delivered. In addition, low-income countries do not have the luxury of dedicating millions to one patient when basic healthcare gasps for funding. 

The fourth issue is that most of the world’s genetic diseases are not currently the focus of biotech companies because they just don’t see how they will make a profit.

The pathway towards what Urnov calls “health justice in the CRISPR revolution” requires taking a global lens through a not-for-profit pathway. 

Cost efficiencies might be gained by building research platforms that look at rare diseases as a whole rather than looking at them one at a time. It means making screening and data collection widely available across the world, and increasing worldwide coordination of clinical trials, reducing costs and time while increasing participants’ diversity. It means rethinking and streamlining the regulatory processes and building worldwide platforms so that while every country will maintain its standards, applications need to be done once only.

When will it arrive in Australia?

Typically, costly cell and gene therapies of this type arrive in Australia around 12 months after they are launched in the US and Europe, explains David Gottlieb, a Professor of Haematology at The University of Sydney, Director of the Blood Transplant & Cell Therapies Program at Westmead Hospital, Sydney, and Head of Westmead T-Cell Therapies Group, Westmead Institute for Medical Research. Vertex hasn’t yet announced its plans for an Australian launch.

The approval pathway involves registration by the TGA for the relevant indication. “Normally, the TGA would review all the clinical trial data available and closely examine the safety information,” said Gottlieb. “However, they will be very influenced by the FDA and European approvals.”

Once approved, the regulators will then negotiate an arrangement for joint federal and state funding to cover the high cost of the therapy. “It is highly unlikely that private insurers will be involved in reimbursement based on the cost of the product though they may be asked to foot the bill for the hospital admission associated with the treatment for those patients with private insurance.”

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