At #JPM20, two CEOs, two radically different therapies, and a fight to chase down sickle cell

Friday, January 17, 2020

Source: Endpoints News

Few CEOs tell a story better than bluebird’s Nick Leschly.

He cuts a Jeff Bezos figure on stage at the Colonial Room, the JP Morgan presentation hall for A-list biotechs: lean and bald, fast-talking and vest-wearing. He explains in simple language, apologizing when he has to brush on the data. It helps that he has a good story to tell.

“We treated them one time,” Leschly tells a packed crowd, gesturing to the slide behind him. “Look what happened.”

The slide shows 9 horizontal bars studded with diamonds. Each bar, he explained, represented a sickle cell patient, and each diamond represented a severe medical event, such as a pain crisis. The diamonds stud one side – before the therapy – and vanish on the other, afterward.

“A 99% reduction in these events — this is a functional cure for sickle cell disease,” Leschly says. “This is unprecedented data.”

Upstairs and an hour later, Ted Love stands before a narrow conference room in his suit and polka-dot tie. Love, the CEO of Global Blood Therapeutics, is a 60-year-old physician, and the story he tells is less compelling. There are no cured patients.

“This is the first drug that addresses the root cause of sickle cell disease,” Love says, speaking in front of a slide showing a white pill bottle for GBT’s new drug Oxbryta. “Right in the label, it says that this drug inhibits polymerization.”

In the 60 years after scientists discovered the cause of sickle cell, almost no treatments emerged, even as the condition debilitated hundreds of thousands of Americans, most of them black or Hispanic. But the last few years have seen a resurgence of interest as new technologies have made the disease seem newly beatable.

Most of that interest has focused on gene therapy. Leschly’s company, bluebird bio, is gunning to get the first such therapy approved by the FDA in 2022. The transformation seen in the handful of patients to receive it — the disease all-but gone after a single injection — have spurred headlines, including a 60 Minutes documentary on bluebird’s therapy and last week’s New York Times video profile of a 16-year-old girl whose pain events vanished after she received a rival gene therapy. (Vertex and CRISPR also have a third program).

But at JP Morgan, Ted Love quietly laid out the case against gene therapy: It will likely work, he said, but it will come with such risks and require such resources that few will use it. He noted a cure already exists for sickle cell: About a quarter of patients have a match for a bone-marrow transplant, yet the drawbacks are such only several hundred get one each year.

“Gene therapy brings those same issues,” Love told investors in a Q&A. “We don’t expect it to be a material competitor.”

His solution for sickle? A pill that, though welcomed by doctors, has yet to show any clinical benefit: Oxbryta.

Gene therapy — it should be noted — and Oxbryta are not direct competitors. Both have been welcomed by sickle cell researchers, and by Love and Leschly.

“They’re quite different,” Alexis Thompson, a former president of the American Society of Hematology who has consulted with bluebird, told Endpoints News. “And the patients who access them are quite different.”

Gene therapy is an exhaustive and dangerous process, akin to a bone marrow transplant. The patient has to spend weeks in the hospital as doctors administer myeloablative chemotherapy to clear out the bone marrow and make space for the genetically modified cells. The chemo can have serious long-term effects. The genetic changes and the virus used to deliver those changes are also thought to potentially cause adverse effects, although those haven’t been seen in patients.

That means gene therapy, though widely regarded as all-but curative, won’t be an option for many, experts who have worked with bluebird and GBT said. That includes patients who don’t want or can’t handle the chemotherapy regimen and those who lack access to the medical infrastructure. There are also those who are too healthy to want the risk.

So far that’s meant young patients have received it, particularly ones whose disease is bad enough to make the risk worth the cure.

“An older patient with severe sickle cell – they’re not a candidate for gene therapy,” Michael DeBaun, a sickle cell expert at Vanderbilt who has worked on Oxbryta trials and consulted with GBT, told Endpoints. “We’ve already eliminated more than half the population.”

Leschly said in an email that though many patients won’t want intensive therapy, “we believe the lion’s share of SCD patients are in the more severe category and will be open to considering such options as they become available.”

“The hype is a double-edged sword”

Both Love and Leschly talk a lot about access.

Bluebird has yet to announce a price for the sickle cell treatment, but it unveiled a unique pricing mechanism for its beta-thalassemia gene therapy, Zynteglo, now sanctioned by the EU. Under the Zynteglo scheme, the company would charge $315,000 per year over 5 years. After the initial payment, each annual bill only comes if the therapy is working. (Others have not agreed with bluebird on its affordability).

Leschly has also spoken at length about working with patients who have grown distrustful of the medical system, echoing concerns from clinicians about a long-running dearth of sickle cell research and from patients who speak, for instance, about ER doctors who don’t believe they’re in pain and accuse them of being addicts. He has talked about how these efforts, coupled with his gene therapy, will radically change life for most sickle cell patients.

“The average life expectancy in the US for all sickle cell disease is 44 years old. That’s not good enough,” Leschly said at JPM. “Be 21 and be in mid-life? No, not good enough. This has the possibility of changing that.”

Outside experts, though, suggest the broad impact will be far smaller. The procedure is too intense.

“It cannot offer much benefit in a public health sense, though it is obviously of great benefit to those who are treated,” Stuart Orkin, a longtime sickle cell researcher at Harvard Medical school, wrote in an email to Endpoints. (Bluebird noted in an email that Leschly acknowledged in the presentation bluebird “has a ways to go.”)

Mark Walters, a marrow and blood transplant specialist at the University of California San Francisco, has worked with bluebird on trials for sickle cell and another inherited blood disorder, beta-thalassemia. He said he often meets families who don’t know there’s long been a bone marrow transplant cure, and all the media attention around bluebird has helped educate them. But he said it could leave patients with a false impression that there’s an easy fix out there.

“The hype is a double-edged sword,” Walters told Endpoints. “What it really requires is a clear discussion from an open-minded physician who really presents the options.”

Love tells a similar story of access, although with a longer history. He made a name at Genentech and Onyx, but before that he did his medical training at two prestigious institutions, where he saw the discrimination experts say have kept research back and directly harmed patients.

“As an African-American physician at Yale and Harvard, it was embarrasing to see how sickle cell patients were treated,” Love told Endpoints in an interview Monday.

Love said he came out of retirement to address that initial injustice. The result, after five years, was approval for a voxelotor pill this past year, branded as Oxbryta.

“The simpler the therapy”

Physiologically, sickle cell is caused by a mutant form of hemoglobin forming polymers on red blood cells, giving them the sickle shape. As a result, the cells can’t carry enough oxygen, leading to the highly painful crises that afflict some patients and also cause long-term organ damage and even stroke.

“They basically age 30 or 40 years earlier,” Elliot Vichinsky, who led the pivotal Phase III voxelotor trial and is the hematology director at UCSF, told Endpoints.

While hydroxyurea, approved in 1998, and Novartis’ new drug Adakveo limit the pain crises, Oxbryta is the first drug to stop polymerization and increase the level of hemoglobin – and thus oxygen – in the blood. In theory, then it should prevent organ damage and improve long-term health. It is also dramatically safer and easier to administer than gene therapy.

GBT has faced its own pricing criticisms – the drug costs over $100,000 per year and patients would take it for their entire lives – but they say an oral drug will be more accessible and are working on expanding coverage. That includes in countries outside the US and Europe, where the vast majority of sickle cell patients live and where the infrastructure is unlikely to allow for a gene therapy.

“The simpler the therapy, the more embraced it is,” Love told Endpoints. “We’re trying to come up with simple approaches that you could give your child in the bottle and they never get sick.”

“We don’t know”

Oxbryta has its detractors, though. There’s a simple problem: There’s no evidence it affects patients lives.

“Does it improve patients’ pain crises, which is the hallmark of the disease?” Walters, the USCF researcher and bluebird investigator, said. “We don’t know.”

The trials for Oxbryta did not show the drug reduced pain crises or improved any other clinical measure. Love said that’s because the studies weren’t designed to.

GBT was trying to stop the systemic cause of sickle cell and thus improve long-term outcomes, he said. They didn’t want a pivotal pain trial because they said that would lead to the drug being indicated for and given only to pain patients, and not the many sickle cell patients who don’t have crises. And they couldn’t wait the decades it would require to prove that the drug will extend lives, though he and some other researchers are confident, based on its biological effects, that it will.

Love compares it to the advent of HIV drugs that didn’t cure the disease but turned the viral load to zero.

“This would literally be like you are an HIV patient and I’ve come along with this drug where I can make the virus undetectable in your blood,” Love said. “Do you want that drug or not? Or are you going to say no, no, no, don’t give me that drug until you showed survival benefit?”

Most clinicians Endpoints spoke to believe the drug will help patients but wouldn’t make a similar claim.

“Yes, the drug may lessen the severity of the disease but I think the big question is how much of a reduction in severity does this agent provide?” Orkin said. “In HIV therapy, the viral load can be near zero and the patients are essentially free of HIV (though not cured). With the data shown thus far, Oxbryta doesn’t appear to be as effective.”

“Absolutely thrilled to have choices”

Alexis Thompson spoke to Endpoints as she returned from treating a gene therapy patient. He’s at year 4 now, she said. No relapses. No pain.

Thompson said she wishes she had a tool: one that could sample a child’s blood and tell her if they would suffer from years of pain crises; or have occasional pain and silent organ damage but live mostly healthy lives; or be one of the sliver of patients who have sickle cell but, for reasons still unclear to researchers, live virtually unimpeded lives. Then she could doll out therapies accordingly: gene therapy for the kids who have it worst and Oxbryta for those who just need some more oxygen and for whom the risks of gene therapy aren’t worth the benefit.

“I don’t have that tool,” she said. Instead, if a gene therapy is approved, she’ll have to make choices with her patients.

But those choices might get easier. Thompson and other physicians think ways of giving gene therapy will improve. Researchers at universities and new biotechs are working on antibodies that get around the need for chemotherapy, and thus the worst of the potential side effects, including a higher risk of leukemia.

They’ll be watching to see how the first gene therapy will be indicated; the clinical trials were reserved for the most critical patients but the label may allow more to use it if they choose.

They’ll also be watching the post-approval trials from Global Blood Therapeutics, which will show better if the drug improves oxygen flow to the brain and thus decreases the risk of stroke.

And there’s a new venture with another potential cure. GBT recently teamed with Syros to advance a decades-old idea. Babies don’t develop the disease for months because fetal hemoglobin doesn’t sickle; if you can make the body keep producing fetal hemoglobin, you could, in theory, cure the disease.

Orkin had wanted funding for that idea for decades. He couldn’t get $5 million to advance research. Now hundreds of millions of dollars are flowing into the field, and that’s a good thing, Thompson said.

Doctors will be able to decide with patients the best of a list of treatments – the same versatility that’s led to advances in fields such as cancer and diabetes.

“I’m absolutely thrilled to have choices,” Thompson said. “We’ve not had that in sickle cell.”

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