When multimillion-dollar curative gene therapies started hitting the market a few years ago, the big question was how we were going to pay for all of them.

• But so far, very few patients are taking some of them — even as few as four or five people.

Why it matters: The slow rollout illustrates the potential disconnect between cutting-edge science and patient benefit.

• There's plenty of optimism that gene therapies' launch kinks will get worked out.
• But it serves as a reality check as the U.S. faces a pipeline chock-full of novel drugs and devices that the health system isn't used to incorporating — and patients may not immediately be comfortable with using.

"They've just begun to enter the health care system, which was designed decades ago. So changing the status quo takes time, and this is just the first chapter in a long story," said Stephen Majors, head of communications at the Alliance for Regenerative Medicine.

Driving the news: Second-quarter earnings calls over the last few weeks have shed light on the commercial progress — or lack thereof — made by some gene therapies, including new treatments for sickle cell disease and hemophilia.

• Bluebird Bio, which has three gene therapies on the market, reported that 27 patients total have begun treatment with their products so far this calendar year, and it anticipates 85 starts by the end of the year.
• Of those 27, 19 initiated treatment with Zynteglo, a beta thalassemia treatment. Four patients each began treatment with Skysona, which treats cerebral adrenoleukodystrophy, and Lyfgenia, one of two sickle cell gene therapies the FDA approved late last year.

The other newly approved sickle cell treatment, Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy — which is also approved to treat beta thalassemia — has begun the treatment process with 20 patients.

• BioMarin Pharmaceutical announced it was narrowing its efforts to the U.S., Germany and Italy after only treating five patients — three in the U.S. and two in Italy — with Roctavian, its hemophilia A gene therapy, during Q2. That equated to $7 million in revenue.
• Roche reported revenues of only about $12 million during the first half of 2024 for Luxturna, which was approved in 2017 to treat an inherited form of vision loss.

By the numbers: CVS has previously estimated that 8,000 U.S. adults would be candidates for Roctavian and 42,500 patients with sickle cell would be eligible for Vertex's Casgevy and Bluebird's Lyfgenia.

• In other words, the drugs' approval didn't exactly open the floodgates for patients to immediately begin receiving them.
• "This ramp is in retrospect, I think, easy to understand. Of course, everyone was hoping there would be thousands and thousands of sickle cell patients being treated in the first six months," said Mark Trusheim, strategic director of Tufts' New Drug Development Paradigms initiative.
• "But I think if you looked at the facilities that were qualified to do this and how many doctors and nurses they have, I think that was probably an unreasonable expectation."

What's happening: Receiving many of the gene therapies is a very long and intensive process, which involves harvesting a patients' cells, modifying them in a lab and then reinfusing them back into the patient.

• Even before that can happen, pharma companies have to negotiate payment rates with insurers and establish relationships with hospitals capable of performing the collection and infusion processes.
• At launch, "you may only have a dozen hospitals across the country that are ready from both a skill standpoint and an infrastructure standpoint to deliver the therapies," Trusheim said.
• Some of the companies touted insurance coverage agreements or the expansion of treatment centers as markers of progress on their earnings announcements.

And, of course, patients have to be willing to go through all of this.

• "This is gene editing. This is gene therapy. This is something that patients are understandably going to have questions about," Majors said.
• A reluctance to shake up their existing treatment may be an especially big factor among hemophilia patients, Stat reported earlier this year.

But let's look on the bright side ...

Some gene therapies are doing much better than others. For example ...

• Novartis announced that its gene therapy, Zolgensma, generated $644 million in net sales the first half of 2024. Zolgensma, which treats spinal muscular atrophy in children, was among the first FDA-approved gene therapies and has been on the market since 2019.
• Sarepta Therapeutics reported that its gene therapy, Elevidys — which is used to treat Duchenne muscular dystrophy and was only approved last summer — brought in $121.7 million in net Q2 revenue.

And slow starts aren't necessarily being read as predictions of failure.

• Stuart Arbuckle, executive vice president of Vertex, said on its earnings call that the company's sickle cell treatment "will help large numbers of patients around the world and represent a multibillion-dollar opportunity."
• Tufts' Trusheim said he and his colleagues' estimate of patient uptake of the new sickle cell treatments adjusted to the slow rollout by increasing the amount of time it will take, but still projects the same number of patients will receive the therapies.
• "I think the major lesson learned, which some of the pioneers have always said … is you have to start preparing for patient access for these therapies much earlier than the traditional drug launch, where you can almost wait until the FDA approves," Trusheim said.

Between the lines: Not all gene therapies are created equal. Some involve more intensive processes than others, and the size of the potential markets for the diseases being treated varies significantly.

• There's also a very interesting tradeoff that may exist between market size and patient uptake: Rarer diseases — which inherently have less revenue potential — are less likely to have existing treatments, whereas more common ones, including sickle cell and hemophilia, often have existing management regimens and more options still in the development pipeline.
• "It's like asking, is a chain restaurant better than a boutique local restaurant?" Trusheim said. "Both are successful business models, but they're different."

The big picture: Investors and biotechs don't seem to be throwing in the towel, and more than a dozen additional gene therapies could be approved through 2027, according to CVS.

• More than $11 billion has already been invested into the sector so far in 2024, nearly the total amount invested all of last year, according to the Alliance for Regenerative Medicine.

The bottom line: No one is declaring the gene therapy market nonviable (yet). But it's making a great case study of how difficult it can be for our old health system to absorb a categorically new — and expensive — product, no matter how promising it is.

I recently Zoomed with Lou Reese, executive chairman and co-founder of Vaxxinity, a biotech focused on developing medicines that train a patient's immune system to target chronic diseases like Alzheimer's and Parkinson's. He was chatting from Costa Rica's Osa Peninsula, while I (sadly) was just in Arlington, Virginia.

• If you follow biotech news closely, then you already know that Vaxxinity voluntarily delisted from Nasdaq earlier this year, a decision that Reese attributed to the state of the biotech market and the mismatch between the company's value and its stock price.
• Earlier this summer, after the delisting, promising results from a small phase 1 study testing one of Vaxxinity's drug candidates against Parkinson's — which currently has no treatment available on the market — were published in Nature.
• "Of any drug ever, we're the only one that changed and altered the course of the disease," he said.

A very fun fact about Reese: He's not Vaxxinity's CEO, which is the position I've typically been interviewing for these Q&As. But he's married to her!

• "The part that's amazing is you get to kind of double down on the kids, because you know each other's schedule intimately so there isn't an explanation component," he told me.

Without further ado, here's our (lightly edited) Q&A:

Q: What is transformative about what you are working on?

A: The idea [of] addressing the No. 1 cost to the global health care system in Alzheimer's, and the idea of addressing the fastest-growing neurodegenerative disease in Parkinson's — and doing it through an innovative platform.

• It's about democratizing health … and it's about a platform that we believe can get these to all the patients who need them and not just the 1%.

Q: One trend transforming health care that we're not paying enough attention to?

A: I think it's actually at the core of what we're doing. We're about health care and not sick care. … This is a healthy aging play at the time in society where it's most needed.

Q: Biggest challenge health care faces?

A: In the U.S., the biggest challenge is the burdens of the existing system, and what I mean by that are the structural layers between true innovation and the payer systems and the reimbursements thereof. All of those systems combined make a system where we pay 10 times as much for a drug here as in Canada.

Q: Biggest opportunity?

A: The math would say the biggest opportunity is within the longevity space and the healthy aging space. My heart says that it's within addressing the fundamental inequalities inherent in some of the technologies.

Q: Highlight and lowlight of working with your spouse?

A: The highlight is that no matter what the circumstance, no matter how good the news is or how bad the news is, we get to face it together. ...

• The worst part is that even the best moments are tinged with the constant burdens, pressures, responsibilities of carrying this level of potential global impact.

Q: What's the coolest place you've worked from?

A: During COVID we were in I want to say 60 countries or something. ... We worked out of the Maldives for a period of time in the only underwater hotel room in the world.

Q: Favorite piece of technology that you own?

A: I still write with a fountain pen. I like this fountain pen. It's retractable. ... I don't do email, I haven't in almost 20 years, I'm a text and Signal and phone call person. The first priority for me is to be in person.

1 fun prediction: Tell us something about what health care is going to be like in 5-10 years that's different from today.

A: I believe that in 5-10 years, with simple bloodwork and a remote doctor, so via digital health, you'll be able to have at-home active immunotherapies for these products in Alzheimer's, in Parkinson's ... that would be self-administered and would be as easy to administer as applying a sticker, and could be delivered to your house via drone.