The First Crispr Medicine Just Got Approved

[bnew]

I received the new gene-editing drug for sickle cell disease. It changed my life.

As a patient enrolled in a clinical trial for Vertex’s new exa-cel treatment, I was among the first to experience CRISPR’s transformative effects.

www.technologyreview.com

I received the new gene-editing drug for sickle cell disease. It changed my life.​

As a patient enrolled in a clinical trial for Vertex’s new exa-cel treatment, I was among the first to experience CRISPR’s transformative effects.

By

• Jimi Olaghere archive page

December 4, 2023

MATT ODOM

On a picturesque fall day a few years ago, I opened the mailbox and took out an envelope as thick as a Bible that would change my life. The package was from Vertex Pharmaceuticals, and it contained a consent form to participate in a clinical trial for a new gene-editing drug to treat sickle cell disease.

A week prior, my wife and I had talked on the phone with Haydar Frangoul, an oncologist and hematologist in Nashville, Tennessee, and the lead researcher of the trial. He gave us an overview of what the trial entailed and how the early participants were faring. Before we knew it, my wife and I were flying to the study site in Nashville to enroll me and begin treatment. At the time, she was pregnant with our first child.

I’d lived with sickle cell my whole life—experiencing chronic pain, organ damage, and hopelessness. To me, this opportunity meant finally taking control of my life and having the opportunity to be a present father.

The drug I received, called exa-cel, could soon become the first CRISPR-based treatment to win approval from the US Food and Drug Administration, following the UK’s approval in mid-November. I’m one of only a few dozen patients who have ever taken it. In late October, I testified in favor of approval to the FDA’s advisory group as it met to evaluate the evidence. The agency will make its decision about exa-cel no later than December 8.

Related Story​

The first CRISPR cure might kickstart the next big patent battle


Vertex Pharmaceuticals plans to sell a gene-editing treatment for sickle-cell disease. A patent on CRISPR could stand in the way.

I’m very aware of how privileged I am to have been an early recipient and to reap the benefits of this groundbreaking new treatment. People with sickle cell disease don’t produce healthy hemoglobin, a protein that red blood cells use to transport oxygen in the body. As a result, they develop misshapen red blood cells that can block blood vessels, causing intense bouts of pain and sometimes organ failure. They often die decades younger than those without the disease.

After I received exa-cel, I started to experience things I had only dreamt of: boundless energy and the ability to recover by merely sleeping. My physical symptoms—including a yellowish tint in my eyes caused by the rapid breakdown of malfunctioning red blood cells—virtually disappeared overnight. Most significantly, I gained the confidence that sickle cell disease won’t take me away from my family, and a sense of control over my own destiny.

Today, several other gene therapies to treat sickle cell disease are in the pipeline from biotech startups such as Bluebird Bio, Editas Medicine, and Beam Therapeutics as well as big pharma companies including Pfizer and Novartis—all to treat the worst-suffering among an estimated US patient population of about 100,000, most of whom are Black Americans.

But many people who need these treatments may never receive them. Even though I benefited greatly from gene editing, I worry that not enough others will have that opportunity. And though I’m grateful for my treatment, I see real barriers to making these life-changing medicines available to more people.

A grueling process​

I feel very fortunate to have received exa-cel, but undergoing the treatment itself was an intense, monthslong journey. Doctors extracted stem cells from my own bone marrow and used CRISPR to edit them so that they would produce healthy hemoglobin. Then they injected those edited stem cells back into me.

It was an arduous process, from collecting the stem cells, to conditioning my body to receive the edited cells, to the eventual transplant. The collection process alone can take up to eight hours. For each collection, I sat next to an apheresis machine that vigorously separated my red blood cells from my stem cells, leaving me weakened. In my case, I needed blood transfusions after every collection—and I needed four collections to finally amass enough stem cells for the medical team to edit.

The conditioning regimen that prepared my body to receive the edited cells was a whole different challenge. I underwent weeks of chemotherapy to clear out old, faulty stem cells from my body and make room for the newly edited ones. That meant dealing with nausea, weakness, hair loss, debilitating mouth sores, and the risk of exacerbating the underlying condition.

MATT ODOM

My transplant day was in September 2020. In a matter of minutes, a doctor transferred the edited stem cells into me using three small syringes filled with clear fluid. Of course, the care team did a lot to try and make it a special day, but for me that moment was honestly deflating.

However, the days and months since have been enriching. I’ve escaped from the clutch of fear that comes from thinking every occasion could be my last. Noise and laughter from my 2-year-old twin daughters and 4-year-old son echo through my home, and I’ve gained immense confidence from achieving my goal of being a father.

It’s clear to me from my experience that this treatment is not made for everyone, though. To receive exa-cel, I spent a total of 17 weeks in the hospital. Not everyone will want to subject themselves to such a grueling process or be able to take time away from family obligations or work. And my treatment was free as part of the trial—if approved, exa-cel could cost millions of dollars per patient.

Another potential barrier is that some people become enmeshed with their chronic disease. In many ways, your disease becomes part of your identity and way of life. The community of people with sickle cell disease—we call ourselves warriors—is a source of strength and support for many. Even the promise of a better life from a novel technology may not be strong enough to break that bond.

From few, to many​

Other challenges are society-wide. In advancing new treatments, the US medical industrial complex has too often left a trail of systemic racism and unethical medical practices in its wake. As a result, many Black Americans mistrust the medical system, which could further suppress turnout for new gene therapies.

Related Story​

Three people were gene-edited in an effort to cure their HIV. The result is unknown.



CRISPR is being used in an experimental effort to eliminate the virus that causes AIDS.

Global accessibility has also not been a priority for most of the companies developing these new treatments, which I feel is a mistake. Some have cited the lack of health-care infrastructure in sub-Saharan Africa, which houses about 80% of all sickle cell disease cases globally. But that just sounds to me like a convenient excuse.

The options for treating sickle cell disease are very limited. Denying access to such a powerful and transformative treatment based on someone’s ability to pay, or where they happen to live, strikes me as unethical. I believe patients and health-care providers everywhere deserve to know that the treatment will be available to those who need it.

Conducting gene therapy research and clinical trials in African populations could allow for a more comprehensive understanding of the genetic diversity of sickle cell disease. This knowledge may even contribute to the development of more effective and tailored therapies—not only for Africans, but also for people of African descent living in other regions.

Even as a direct beneficiary of gene therapy, I often struggle with not knowing the full consequences of my actions. I fundamentally, at a cellular level, changed who I am. Where do we draw the line at playing God? And how do we make the benefits of a God-like technology such as this more widely available?

Jimi Olaghere is a patient advocate and tech entrepreneur.

 

[null]

GEN-Vertex




a bit earlier than i expected.

i thought crispr was still accidentally snipping people's nads off

 

[bnew]

FDA approves cure for sickle cell disease, the first treatment to use CRISPR

The groundbreaking approval has been eagerly anticipated by patients and doctors alike. The treatment is priced at $2.2 million per person.

www.nbcnews.com

FDA approves cure for sickle cell disease, the first treatment to use gene-editing tool CRISPR​

The groundbreaking approval has been eagerly anticipated by patients and doctors alike. The treatment is priced at $2.2 million per person.


Dec. 8, 2023, 11:19 AM EST / Updated Dec. 8, 2023, 1:19 PM EST

By Berkeley Lovelace Jr. and Marina Kopf

The Food and Drug Administration on Friday approved a powerful treatment for sickle cell disease, a devastating illness that affects more than 100,000 Americans, the majority of whom are Black.

The therapy, called Casgevy, from Vertex Pharmaceuticals and CRISPR Therapeutics, is the first medicine to be approved in the United States that uses the gene-editing tool CRISPR, which won its inventors the Nobel Prize in chemistry in 2020.

“I think this is a pivotal moment in the field,” said Dr. Alexis Thompson, chief of the division of hematology at Children’s Hospital of Philadelphia, who has previously consulted for Vertex. “It’s been really remarkable how quickly we went from the actual discovery of CRISPR, the awarding of a Nobel Prize, and now actually seeing it being an approved product.”

The approval marks the first of two potential breakthroughs for the inherited blood disorder. The FDA on Friday also approved a second treatment for sickle cell disease, called Lyfgenia, a gene therapy from drugmaker Bluebird Bio. Both treatments work by genetically modifying a patient’s own stem cells.

Until now, the only known cure for sickle cell disease was a bone marrow transplant from a donor, which carries the risk of rejection by the immune system, in addition to the difficult process of finding a matching donor.

Casgevy, which was approved for people ages 12 and older, removes the need for a donor. Using CRISPR, it edits the DNA found in a patient’s stem cells to remove the gene that causes the disease.

“The patient is their own donor,” Thompson said.

“It’s a game-changer,” said Dr. Asmaa Ferdjallah, a pediatric hematologist and bone marrow transplant physician at the Mayo Clinic in Rochester, Minnesota. “To really reimagine and re-discuss sickle cell disease as a curable disease and not as this painful and debilitating chronic disease is hope enough with this news.”

Still, the new therapy is extremely expensive — $2.2 million per patient, Vertex said. The pricing strategy, experts argue, may place it out of reach for many families. What’s more, that price doesn’t include the cost of care associated with the treatment, like a stay in the hospital or chemotherapy.

“We really have to make sure that it is accessible,” said Dr. Rabi Hanna, a pediatric hematologist-oncologist at the Cleveland Clinic who has previously served on the advisory board for Vertex. “This could be an equalizer for people with sickle cell because many patients cannot pursue career options” because of the illness.

“It’s something families have been aware of in the early research stage, and they’ve been very patiently waiting for years,” Ferdjallah said. “It’s been eagerly awaited by patients and families, but also by providers and physicians.”

How Casgevy works​

In patients with sickle cell disease, red blood cells, which are usually disk-shaped, take on a crescent or sickle shape. This change can cause cells to clump together, leading to clots and blockages in the blood vessels, starving tissues of oxygen. Patients can experience excruciating pain, breathing problems and stroke.

Casgevy works by editing the DNA in a patient’s stem cells — which are responsible for making the body’s blood cells — so that they no longer produce sickle-shaped cells.

While technically a one-time treatment, a number of steps that span months are required before the patient actually gets the modified stem cells. It begins with a series of blood transfusions over three to four months, after which the stem cells are extracted from the patient’s bone marrow and sent off to a lab where they are edited, Hanna said.

Before they can be reinfused into the patient, however, doctors need to make sure no flawed stem cells remain in the body. To do so, chemotherapy is used to destroy the patient’s bone marrow.

Only then can the edited stem cells be reinfused into the patient, followed by another month or two in the hospital to allow the cells to grow and the patient to recover.

Hanna said he’s always “cautious” when telling families and patients about the one-time treatment because they may have unrealistic expectations.

“There are multiple phases of this journey,” he said.

The clinical trial included 46 people in the U.S. and abroad, 30 of whom had at least 18 months of follow-up care after the treatment. Of those, the treatment has been successful in 29.

LaRae Morning, 29, of Phoenix, was among the trial patients whose treatment was successful.

Her doctors did not expect her to live past the age of 11. Her mother lost several jobs when Morning was a child and a teenager because of her frequent hospital visits.

In April 2021, Morning joined the clinical trial at Sarah Cannon Research Institute and HCA Healthcare’s The Children’s Hospital at TriStar Centennial in Nashville, Tennessee, a decision she initially regretted. Living in Phoenix, she had to fly to Nashville once a month for treatment. It included several blood transfusions, which lasted eight hours each, and taking a medication, called plerixafor, which she recalled causing her intense stomachaches. When she started chemotherapy, her hair began to fall out and her skin changed color, resembling the appearance of a chemical burn. She also experienced nausea.

It took about six to seven months for her to feel back to normal following the CRISPR treatment. Now, she said, she’s feeling the benefits, going out to coffee shops, spending time with her friends and finishing her first semester of law school in Washington, D.C.

“Now that I’m here, I’m so happy that I did it,” she said of the trial. “I’m just like a regular person. I wake up and do a 5K. I lift weights. If I wanted to swim, I can swim. I’m still trying to know how far I can stretch it, like what are all the things I can do.”

That’s been the experience for several other patients in the trial as well, according to Dr. Monica Bhatia, chief of pediatric stem cell transplantation at NewYork-Presbyterian/Columbia University Irving Medical Center. Bhatia is a principal investigator at one of the clinical trial sites in New York City.

Following the treatment, most patients were going back to school, going to the gym or resuming other activities — “things that a lot of people take for granted,” she said — after about three to four months.

“They’re really able to live life without restrictions,” Bhatia said.

Dr. Haydar Frangoul, medical director of pediatric hematology-oncology for the Sarah Cannon Research Institute, said he is hopeful the therapy will provide relief to more patients.

“I think this is a huge moment for patients with sickle cell disease,” said Frangoul, who was the lead investigator on the clinical trial and treated Morning.

Long-term questions ​

Although Casgevy has been shown to be effective, experts still don’t know about potential long-term effects, since the trial is only set to run for two years.

During a meeting in October, an FDA advisory committee discussed the risk of “off-target” effects, which refers to when the gene-editing tool makes cuts to other stretches of DNA other than the intended target and how the FDA should consider those risks moving forward.

It’s unclear what effects an off-target edit would have on a patient, but the fear is that it could result in unintended health consequences down the road, Thompson said. “To date, there do not appear to be measurable consequences.”

The FDA did, however, add a boxed warning — the strongest safety warning label— to Bluebird Bio’s Lyfgenia, noting that in rare cases the treatment can cause certain blood cancers.

Dr. Nicole Verdun, director of the Office of Therapeutic Products in the FDA's Center for Biologics Evaluation and Research, said Lyfgenia was given the warning after two patients who got the therapy in a clinical trial died from a form of leukemia.

It's unclear whether the gene therapy itself or another part of the treatment process, such as the chemotherapy, caused the cancer, but Verdun said the agency thought the deaths "rose to the level of a black-box warning." No cases were seen in the Vertex clinical trial, she said.

Bhatia is following the patients for 15 years as part of a post-approval study for Casgevy and will be monitoring for signs of long-term effects.

“Long-term follow-up is still going to be so crucial,” she said.

Christopher Vega, 31, of Allentown, Pa., on Dec. 7, 2020, the day he got his infusion of CRISPR-edited stem cells.Courtesy Christopher Vega

Christopher Vega, 31, from Allentown, Pennsylvania, said the possibility of long-term effects aren’t a concern for him; he is happy to be living a life free of chronic pain.

He joined the clinical trial at the Children’s Hospital of Philadelphia in late 2020. He had suffered from chronic fatigue since he was a young child and would end up in the hospital every year with a pain crisis.

“When I was younger, my mom used to always tell me things happen for a reason. And I had so much trouble believing that, because I always thought, ‘Why me?’” he said.

While the treatment process was not always easy — Vega temporarily lost his hair, felt weak and nauseous and developed skin rashes — he said it was worth it.

“I am a whole different person,” said Vega, who is now attending the Los Angeles Film School online for visual effects while taking care of his 5-year-old daughter.

“Sometimes I would get small moments of anxiety that I would have a crisis,” he said. “And after going years now, I’m slowly coming to terms with, I’m OK, and I know I’m going to be here, present.”