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Sickle Cell Gene Therapy Fertility Risks Spur Calls for Changes Allowing Industry Support Services

A patient sits on a hospital bed alone

NEW YORK – It's been nearly six years since Tesha Samuels received gene therapy treatment for sickle cell disease.

Samuels is one of the 100,000 people in the US, and one of millions globally, who suffer from the genetic blood disorder. She said she was desperate for a cure — anything that could alleviate the persistent, often debilitating, pain and fatigue she had felt since she was 13 years old. "It was so unbearable at times," she reflected. "The pain was just so deep, and it was every day."

Samuels had been advocating for therapeutic advances since her early teen years, but she felt the sickle cell community was often overlooked. "I felt forgotten," she said. "And that no one cared."

When she got the chance in 2018 to join Bluebird Bio's clinical trial for the gene therapy lovotibeglogene autotemcel, now branded as Lyfgenia, she jumped at it.

Today, Lyfgenia is at the forefront of an emerging class of genetic treatments that hold the promise of the cure that sickle cell patients like Samuels had long hoped for. The US Food and Drug Administration late last year simultaneously approved Lyfgenia and Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) as the first-ever gene therapies for sickle cell disease. Casgevy in particular also marked a massive scientific milestone as the first medicine to hit the market incorporating CRISPR gene editing.

Sickle cell patients' red blood cells are C-shaped due to abnormalities in genes that encode hemoglobin. These misshapen red blood cells aren't able to adequately deliver oxygen throughout the body, resulting in severely painful episodes known as vaso-occlusive crises (VOCs). The condition is most common among Black Americans.

Casgevy and Lyfgenia are both designed to promote production of functional hemoglobin through one-time infusions of patients' own cells that are modified outside of the body, or ex vivo. Specifically, Casgevy involves editing the BCL11A gene to increase production of fetal hemoglobin, while Lyfgenia involves delivering a functional copy of a modified beta-globin gene to produce a form of anti-sickling hemoglobin, which functions similarly to normal adult hemoglobin.

For Samuels, that one-time infusion of Lyfgenia was life-changing, as it reduced VOCs. But the chance for a cure also came with risks and sacrifices, such as the possibility of infertility.

To prepare the body to receive genetically modified stem cells, patients undergo an intensive conditioning process that involves chemotherapy, which can reduce both female and male fertility. "That was a grieving process for me," she said, describing what it was like to come to terms with the reality that a cure that could open so many possibilities for her could also squelch the chance to have biological children in the future. "It was difficult."

As long as Samuels was in the Lyfgenia clinical trial, she had access to fertility preservation services and the option to freeze her eggs for five years at no cost. That five-year period expired earlier this year. Samuels, now 42 years old, couldn't afford to continue storing them.

'Still out of reach'

The approval of Casgevy and Lyfgenia last year was met with cheers from the healthcare and life sciences industry. But now that these landmark gene therapies are commercialized, patients in many cases won't have access to the fertility preservation services that were available and paid for by drugmakers during clinical trials. That's in part because of fraud and abuse laws like the federal Anti-Kickback Statute that prohibit companies from paying for such services for patients insured by government programs, including Medicaid and Medicare.

This challenge isn't unique to sickle cell gene therapies and is a point of consideration for any treatment that incorporates chemotherapy. In fact, as more cell and gene therapies enter the market, the medical establishment will need support managing the risks associated with them.

Patients shouldn't have to choose between having children and getting cured, said Haydar Frangoul, medical director of pediatric hematology/oncology at the Sarah Cannon Pediatric Transplant and Cellular Therapy Program at TriStar Centennial in Nashville, Tennessee. He's the first author of a paper on Casgevy published in the New England Journal of Medicine last week.

A long-term solution will hopefully involve cutting out chemotherapy altogether and finding another way for patients to accept modified stem cells without the associated side effects. "Now that we have established that these therapies work, a lot of groups are going to investigate other treatments that are less toxic than busulfan," Frangoul said, referring to the chemotherapy drug used in the conditioning regimens.

In the meantime, drug manufacturers are figuring out how they can offer fertility preservation services within insurance programs and not run afoul of the law.

Vertex has said it plans to offer fertility support to eligible commercially insured patients, but that it's prohibited from doing so for patients insured by government programs. "We recognize the potential fertility needs for this patient population," a spokesperson wrote in an email. "Unfortunately, the federal government has informed us that it will not issue a favorable advisory opinion for this program for patients insured by the government (e.g., Medicaid or Medicare), and as a result, we are not providing fertility support for them. We are working with urgency to resolve this, with the goal of providing equal support for all patients regardless of insurance."

The spokesperson, however, declined to comment on what specific services are available to patients and to what extent Vertex covers the cost. 

Bluebird Bio said it also has not included fertility preservation in its patient support services offerings due to regulatory uncertainty under the Anti-Kickback Statute for patients in government-sponsored health insurance programs, but that it is in the process of establishing a program for commercially insured patients. In an email, a company spokesperson said that Bluebird Bio in 2021 asked the US Department of Health and Human Services' Office of Inspector General, which polices fraud, waste, and abuse in HHS programs, to weigh in on whether gene therapy manufacturers can financially support fertility preservation services, but the OIG has not yet issued an opinion.

"At the heart of our approach is equitable access for patients, and our goal was to stand up a single offering for all eligible patients, irrespective of their insurance type," the spokesperson said. "We anticipate the OIG will ultimately rule that manufacturers cannot offer financial support for fertility preservation to patients who are federally insured. In light of OIG's anticipated guidance, we are moving forward to establish a compliant offering for commercially insured patients."

The Bluebird Bio spokesperson added that legislative or policy changes may be needed for manufacturers to set up compliant fertility preservation offerings. In the meantime, the company's patient navigation service provides information on fertility preservation and refers patients to potential third-party resources.

Sometimes, gene therapy feels like a carrot "being dangled in front of the people that I love … and it's still out of reach," said Samuels, who now serves as president of Journey to ExSCellence, a local Maryland nonprofit she founded last year to build awareness of sickle cell disease and create resources for patients and their caregivers.

Vertex has priced Casgevy at $2.2 million, while Bluebird's Lyfgenia carries a $3.1 million price tag. That's just the price of the treatments, without factoring in ancillary costs like those related to fertility preservation procedures, freezing and storage, and eventually in vitro fertilization (IVF). After adding on those costs, "I can't tell you one of my fellow warriors who would be able to sustain the cost," Samuels said.

Quality care or kickbacks?

The primary challenge isn't fertility preservation itself, for which there is an established medical procedure for most adult patients, said Lydia Pecker, director of the young adult clinic at the sickle cell center for adults at Johns Hopkins Medicine in Baltimore. It's the accessibility and expense of the services.

"If people's insurance don't cover that care, then it's a huge challenge to get them there," she said. If a patient needs fertility preservation and has insurance coverage, the next step is referring them to a reproductive endocrinology and infertility specialist. A different conversation takes place with uninsured or underinsured patients, focusing on the need to identify research or grant funding they might be eligible for that can cover these costs.

Pecker researches reproductive health in female patients with sickle cell disease and is involved with the Sickle Cell Reproductive Education Directive, a nonprofit founded in 2021 by Teonna Woolford, a sickle cell patient, to advocate for reproductive healthcare in this patient population. The organization also provides educational resources, and in partnership with the National Marrow Donor Program, launched a program that provides grants to sickle cell patients to offset the cost of fertility preservation.

Although drug manufacturers covered fertility preservation services for patients in clinical trials of Casgevy and Lyfgenia, now that these drugs are on the market, they must grapple with the Anti-Kickback Statute. The federal law prohibits compensating — or offering "kickbacks" — in exchange for patient referrals, or otherwise generating business for healthcare services that will be paid with money from state or federal government programs. That includes services billable to government programs like Medicaid or Medicare.

The law is meant to prevent overspending, unnecessary services, unfair competition, and skewed medical decision-making. In the absence of a specific exception or safe harbor, however, drugmakers must be careful not to run afoul of these fraud and abuse laws anytime they provide support services that can be associated with the sale of their products through government payor programs.

"The regulations prohibit, basically, incentivizing anyone from generating business for you," said Isabelle Bibet-Kalinyak, an attorney and vice chair of the healthcare practice group at the law firm Brach Eichler. "Every time there is an exchange of money or the write-off of something in healthcare, we have to analyze this."

That creates particular challenges for pharma-backed support services for sickle cell disease since 50 percent to 60 percent of patients in the US are enrolled in Medicaid, according to the CMS.

Fertility preservation, such as collection and storage of eggs and sperm, typically isn't covered by public or private health insurance. About one-third of US states require insurers to cover some degree of fertility preservation, according to RESOLVE: The National Infertility Association, although policies vary as to what qualifies a patient for coverage, what services are covered, and what types of insurance plans are required to cover them. Within these states that have some degree of coverage for fertility preservation, only a subset cover IVF.

Without insurance coverage, these services can cost thousands of dollars, especially for women. According to the Alliance for Fertility Preservation, egg freezing can cost up to $15,000 with up to $500 in storage costs per year, and sperm banking can cost up to $1,000 with storage costs of up to $400 per year.

A potential new approach in Medicaid 

There are some signs that the prohibition on drugmakers' fertility preservation programs could change.

The Center for Medicare and Medicaid Innovation (CMMI) at CMS, also called the Innovation Center, in January announced plans for a voluntary Cell and Gene Therapy (CGT) Access Model in an effort to improve access to new therapeutics for Medicaid patients with rare and severe illnesses, beginning with sickle cell disease. CMS will partner with state Medicaid programs and drug manufacturers, who will participate in outcomes-based agreements for sickle cell therapies and tie pricing for treatments to improved health outcomes. The CMS expects the model arrangement to launch next year, an agency spokesperson said in an email.

In a document released in March outlining initial requirements for participating manufacturers, CMS specified that companies must pay for certain supportive services to address barriers to receiving gene therapy, including fertility preservation.

CMS has the authority to establish such a safe harbor within the Innovation Center's model arrangements, but not permanently. Typically, establishing safe harbors is the purview of the HHS OIG.

Specifically, within the CGT Access Model, CMMI says manufacturers will be required to pay for services including egg and sperm collection, making those services free to patients with Medicaid coverage. Manufacturers will also be required to pay for patients to freeze and store eggs and sperm for between five and 15 years, and in some cases, reimburse patients for the travel and lodging necessary for receiving fertility preservation care. However, manufacturers are not allowed to pay for certain fertility services, such as IVF, within the model.

The aim with the access model is to balance the high upfront costs of these cell and gene therapies against their potential to reduce healthcare spending over time and ensure "taxpayer dollars are being used more effectively," CMS said in its announcement in January, estimating that sickle cell disease-related expenditures cost the US healthcare system nearly $3 billion each year.

"During and after the model test period, the model will be subject to a rigorous and independent evaluation," the CMS spokesperson said in an email. "Part of that evaluation will involve a comparison between states that participated in the model and states that did not participate in the model. CMS will use data generated under the model to evaluate the model and will disseminate quantitative results to states and to the public."

There's not a clear process for how a successful demonstration model expands beyond a CMMI program, said Seth Lundy, a partner within the life sciences practice at the law firm King & Spalding.

"OIG promulgated a broad safe harbor to the Anti-Kickback Statute to allow for innovative arrangements to be fostered through the CMMI," Lundy said. "But what it doesn't do is provide any suggestion as to how a successful program run through the Innovation Center would necessarily translate out, on its own, into the broader … healthcare space."

That is, just because a program proves successful within a CMMI model doesn't mean that it can be rolled out broadly. There will either need to be changes made to the program to bring it into compliance with existing fraud and abuse laws, or new safe harbor protections under the Anti-Kickback Statute will be needed that allow for this type of program to move forward. 

Still, biotech industry players are hoping to see such safe harbors extended outside of the demonstration model.

In response to the OIG's annual solicitation for proposals for new safe harbors, the Alliance for Regenerative Medicine in February issued a letter recommending the office adopt a safe harbor specifically to permit drug manufacturers or other entities to make payments for fertility preservation to patients in financial need. "Addressing fertility risks is critical to ensuring access to CGTs for vulnerable populations," the organization wrote.

A younger generation

There are additional concerns when offering gene therapy to the youngest eligible patients, who can be as young as 12 years of age. These patients may not have hit puberty yet, which comes with its own challenges, biologically and emotionally.

Even explaining fertility and reproduction to a 12-year-old, who may not have received sex education in school yet, adds another layer of complexity, said Lewis Hsu, director of the pediatric sickle cell center at the University of Illinois, Chicago. In cases involving minors, it's also imperative to present information for parents or other caregivers who will be making decisions on behalf of their child.

"They're making decisions about something theoretical," Hsu said of younger patients. "They have no idea what their expectations [about having children] might be."

It's also challenging to collect sperm or eggs in patients who have yet to go through puberty. In prepubescent girls, for example, fertility preservation involves a surgical procedure to collect and then freeze ovarian tissue with immature eggs. Prepubescent boys can undergo testicular tissue preservation, which is considered experimental.

Then, there's the cost of freezing and storage, which for younger patients can mean having to pay for those services for a decade or longer before they're ready to have children. Once they are ready to use the eggs or sperm they've saved, they are confronted with the high cost of IVF, which is not covered under the CMS access model and generally not covered by insurers outside of the model either.

"Even if we're seeing laws change that improve access to fertility preservation, we are not necessarily seeing the same improvements, yet, in access to IVF," Pecker said. "But, of course, this becomes a long-term care need."

Fertility issues can arise even without gene therapy, Pecker noted, and sickle cell itself comes with fertility risks for men and women, as do other available treatments. In men with sickle cell, for example, semen abnormalities are common. Women with sickle cell tend to have lower total egg supply than women generally, though it's unclear the extent to which that translates to infertility. And another cure for sickle cell, bone marrow transplant from a compatible donor, also involves chemotherapy and can cause infertility.

"Even before you introduce curative therapies to this picture, what we're increasingly aware of is that this is a population with infertility risk factors based on their disease and chronic therapies," Pecker said. She stressed that there's a need for additional population studies to better characterize infertility among sickle cell patients, since there are still many knowledge gaps.

What to do today

While the federal government and manufacturers work on ensuring the latest gene therapies and support services are accessible to sickle cell patients, physicians are tasked with ensuring patients are making informed decisions about whether to undergo gene therapy, and if they do, that they understand the supportive services they'll need. As it stands, information on reproductive health is lacking: In a small survey of male adolescents and young adults with sickle cell, many patients and caregivers didn't know that their condition or treatment might make it difficult to have a biological child in the future, according to results published in Blood Advances in 2022.

In light of the two gene therapies' approvals, the Sickle Cell Disease Association of America (SCDAA), which advocates for sickle cell patients and their caregivers, has been putting together an online library of educational materials about these treatments. "We are trying to get everybody ready for what's called 'shared decision-making,'" said Hsu, who, in addition to his role at UIC, also serves as the SCDAA's chief medical officer. Shared decision-making in this context means that patients and families are involved in care decisions and fully aware of their options and the potential risks and benefits.

The SCDAA's goal is to present educational information in multiple formats that are easy to understand and tailored to patients of different ages. Some patients, for example, might learn best through a discussion with their physician, while others might prefer receiving written information or watching videos. For younger patients, animations that break down concepts in an engaging way could be useful, Hsu said. Still others might prefer seeing perspectives presented from others in the sickle cell community, rather than a healthcare professional.

"Everybody has their own learning style, their own way of taking in information," he said. "And then, of course, there's people who want all of the above."

Patients and their families will also need enough time to make informed decisions about gene therapy and fertility preservation, without feeling rushed. Hsu suggested that clinical teams allow patients to make decisions over multiple appointments, with at least one appointment dedicated to providing information and time for patients to follow up with questions later. "Try not to have people make a decision in one session," he said. 

Of course, gene therapy won't be the answer for every sickle cell disease patient. Some patients won't be eligible, and some may not want it, especially given its costs and risks.

At TriStar Centennial, Frangoul said he'd like to see insurance companies or drugmakers cover fertility preservation as part of treatment. In the meantime, he said he discusses infertility risks openly with patients and tries to find grants that cover some of the costs of fertility preservation services if they need them.

Eventually, he hopes that ongoing research into gene therapies that don't require chemotherapy will remove this concern altogether. Researchers at the US National Institutes of Health, for example, are studying a novel conditioning agent that, based on testing in animals so far, doesn't appear as toxic and damaging to other organs as chemo.

"I'm hopeful that in my lifetime I will see therapies reaching the bedside that use treatments that do not increase the risk of infertility," Frangoul said.