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Msg  61 of 70  at  11/11/2023 1:07:03 PM  by


Is This Miracle Cure Worth the Risk?

Bloomberg businessweek (Online)

Is This Miracle Cure Worth the Risk?

By: Smith, Gerry, Bloomberg Businessweek, 00077135, 11/6/2023, Issue 4803

The FDA will soon decide if Crispr's Nobel Prize-winning gene-editing technique is safe for use on real patients

Over the ages, scientists have devised medicines to successfully treat thousands of illnesses, but eliminating rare and deadly maladies altogether is a Holy Grail. Treatments for inherited conditions such as sickle cell disease have offered mere stopgaps that still leave patients to live sickly, pain-filled lives. The gene-editing technology Crispr, whose researchers were awarded the 2020 Nobel Prize in chemistry, could change that. It's been heralded for its potential not only to treat such diseases, but also to cure them by changing a person's genetic code.

Now, for the first time, a therapy that harnesses Crispr's power is poised to make its way to market. That is, if it can clear one last hurdle: regulators.

The US Food and Drug Administration is considering a Crispr treatment that could offer a cure for the blood disorder sickle cell disease, a condition that affects some 100,000 Americans, most of whom are Black. In late October, FDA staff raised concerns about some of the safety data submitted by two companies seeking approval for the therapy, dubbed exa-cel. A panel of FDA medical advisers convened on Oct. 31 to ask questions about the treatment. By early December, regulators will decide whether to give it a stamp of approval.

It's a major test for a technology that, since its discovery more than a decade ago, has been expected to bring about a revolution in medicine. Crispr's innovation is the ability to cut and paste DNA with far more ease and precision than ever before—necessary, for example, to address the mutation to a single letter of genetic code that causes sickle cell disease. Instead of treating the disease, Crispr essentially rewrites the code for what's causing the malady. But regulators have viewed it with caution, worried about the risks of making permanent changes to the body's instruction manual. Advocates also say they fear the one-time sickle cell disease treatment, which is expected to cost at least $1 million, will be far too expensive for many patients.

Two companies, Vertex Pharmaceuticals Inc. and Crispr Therapeutics AG, are seeking approval to edit the genes of people with sickle cell disease so that they make a different form of hemoglobin, the molecule that carries oxygen throughout the body. Sickle cell disease is caused by a mutation of just one of the 3 billion letters that make up a person's DNA. That mutation causes red blood cells to bend in a crescent shape instead of a round one, making it harder for essential oxygen to reach tissues and organs. The companies want to extract blood stem cells and edit them in a lab, then return them to patients' bodies.

The results so far have been promising. A clinical trial conducted by the companies found that more than 90% of sickle cell disease patients were free of pain crises for at least 12 months. Hank Greely, a law professor at Stanford University who wrote a book on the science and ethics of Crispr, called the study's results "tremendous."

But researchers have studied patients treated with Crispr for only a few years, and no one knows what will happen to them over their lifetimes. "That will be an ongoing question for any clinical application of genome editing: What are the longterm effects, and are they truly predictable?" says Jennifer Doudna, a Crispr pioneer, biochemist at University of California at Berkeley and founder of the Innovative Genomics Institute. "If they are, that bodes well for opening up the pipeline to other diseases in the future."

There are other potential safety concerns. Crispr is more precise than previous gene-editing technologies, but it's not perfect. The wrong gene could accidentally be edited. Researchers started studying its use in blood disorders in part because it's less risky. They can remove blood stem cells and edit them in a lab "ex vivo," or outside the body, making sure they hit their target before returning them. But for Crispr to reach its full potential and cure other diseases that affect the brain, heart, lungs and other organs, researchers will need to safely edit genes "in vivo," inside the body, through an injection or a pill.

"You can't take lungs outside the body and make edits and put them back," Greely says. "That's going to be trickier."

In 2012, Doudna and her research partner, Emmanuelle Charpentier, published work on Crispr that eight years later won them the Nobel Prize in chemistry. Both went on to start biotech companies that aim to use Crispr to treat different diseases. Charpentier co-founded Crispr Therapeutics, one of the two companies applying for FDA approval. The two researchers are part of a group that's been in a legal battle with another group of researchers—which includes another Crispr pioneer, Feng Zhang—over who owns the potentially lucrative patent for the gene-editing technology. Zhang also co-founded gene-editing companies, including Editas Medicine and Beam Therapeutics.

Today, companies are only looking to do what's called somatic cell gene therapy—editing cells that affect a living person but don't affect eggs or sperm that could pass changes on to future generations. The idea of changing DNA that affects future generations, called germline editing, has raised moral and ethical questions because it could lead to people not just curing diseases but making their descendants smarter or taller or faster. In 2018 a Chinese scientist was widely condemned after revealing that he'd used the technology to edit human embryos that became twin girls.

For decades, sickle cell disease didn't get as much attention or funding as diseases that mostly affected White people, like cystic fibrosis, largely because the medical community has historically overlooked Black people. Recently, biotech companies have started to develop new treatments for the blood disorder. But for now, the only approved cure is a bone marrow transplant from a matched sibling, which is hard to find.

Before participating in the clinical trial, Jimi Olaghere, 38, said his life with sickle cell disease was "pretty bleak." He was always tired. He has suffered from heart attacks, organ damage and bouts of pneumonia. He moved his family from New Jersey to the South because the cold winters made his blood cells thicker, exacerbating his pain.

"For most of my adult life, I never really had control," says Olaghere, who lives in the Atlanta metro area. "The disease really dominates every facet of your life."

After receiving the Crispr treatment in September 2020, Olaghere wakes up energized. He says he can now "be the father that I wanted to be." And he's pain-free. "This therapy has allowed me to choose my own destiny," he says.

For Vertex, getting approval from regulators would help it move beyond its core business of cystic fibrosis treatments. The biotech company initially expects to treat some 20,000 patients with severe sickle cell disease. But the rollout will be slow because the treatment process takes several months. Vertex would split the profits with its partner, Crispr Therapeutics. Goldman Sachs analysts estimate the gene-editing treatment for sickle cell disease will generate peak global sales of $3.9 billion between the two companies.

Stifel analyst Paul Matteis says investors are more focused on Vertex's trials on a non-opioid drug for acute pain, and there's debate on Wall Street about how many sickle cell disease patients will choose to get the gene-editing treatment, in part because of the harsh cancer drugs they must take beforehand. "The expectation is it will be pretty niche at first," Matteis says.

Unlike many FDA expert panel hearings, there was no vote at the end of the seven-hour hearing on Oct. 31 on whether to recommend that the agency approve the treatment. But some panelists said the benefits of the therapy appeared to outweigh the risks. "We want to be careful to not let the perfect be the enemy of the good," said Scot Wolfe, a professor in the department of molecular, cell and cancer biology at UMass Chan Medical School.

FDA approval would also be good news for other gene-editing companies that hope to hit the market someday. They include Intellia Therapeutics Inc., which is studying a gene-editing treatment for a rare swelling disorder, and Verve Therapeutics Inc., which wants to target cholesterol-raising genes and prevent heart attacks.

The effects of an FDA blessing would reverberate far beyond Wall Street. It could usher in a new chapter in health care, bringing hope to patients who are desperate for cures to debilitating diseases. "It would signal a paradigm shift for how we think about medicine," says Samarth Kulkarni, chief executive officer of Crispr Therapeutics. "We'd be going from chronic pills or injections to a one-time procedure or therapy that can be potentially curative for life."

Even if a Crispr drug were to make it to market, it's not clear how many people would be able to afford it. Vertex and Crispr Therapeutics haven't said how much they plan to charge. But in August, a nonprofit research group, the Institute for Clinical and Economic Review, said they might charge up to $2 million for a single patient. Gene therapy treatments for other diseases can cost more than $3 million.

Industry executives say such steep prices are justified because the treatments can cure or dramatically reduce the damage from rare diseases that can sometimes cost millions of dollars to treat over a patient's lifetime. The companies say they are in talks with insurers and are optimistic that the treatment will get covered. Others aren't so sure. Many people with sickle cell disease are on Medicaid. And many live in Southern states that haven't expanded their Medicaid programs, raising doubts that the high-cost therapy will be covered. "It seems so inaccessible to the average person with sickle cell disease," says Melissa Creary, an assistant professor of health management and policy at the University of Michigan who has done research on the blood disorder for over 20 years.

Olaghere, the clinical trial participant, says having his genes edited wasn't easy. Before the procedure, he drove four hours every three weeks to a hospital to get blood transfusions. More than once, he sat next to a machine that collected his blood cells for eight hours a day. He went through chemotherapy to get his body ready for the infusion of edited cells, causing him to lose his hair and develop painful mouth sores. The process took about a year.

But it was worth it, Olaghere says. "I looked at it as an investment in my future," he says. "It's been quite life-changing." —Gerry Smith

THE BOTTOM LINE Scientists have developed treatments for thousands of diseases. Now gene editing could allow them to cure inherited illnesses such as sickle cell, if regulators approve.

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