CGT Space Faces Some Challenges, but There ‘Still Is a Place’ for Therapies

Reprinted with AIS Health permission from the March 2025 issue of Radar on Specialty Pharmacy.

The cell and gene therapy (CGT) space seems to be a bit of a mixed bag recently. While last year’s accomplishments included FDA approvals of two new first-in-class treatments for solid tumors and the first chimeric antigen receptor T cell (CAR-T) therapyF since 2022, on back-to-back days last month, the news was more downbeat.

On Feb. 20, reports that Pfizer Inc. was discontinuing its hemophilia B gene therapy Beqvez (fidanacogene elaparvovec) globally were first publicized and later confirmed by the drugmaker. The FDA had approved the single-dose $3.5 million treatment less than a year prior, on April 25, 2024.

The approval came amid sluggish uptake of the other two hemophilia gene therapies: CSL Behring LLC and uniQure Inc.’s Hemgenix (etranacogene dezaparvovec-drlb) for hemophilia B and BioMarin Pharmaceutical, Inc.’s Roctavian (valoctocogene roxaparvovec-rvox) for hemophilia A.

The company said that many reasons were behind the decision to discontinue Beqvez, “including the limited interest patients and their doctors have demonstrated in hemophilia gene therapies to date.” It said it planned to focus on other therapies that it thinks “will have the greatest impact on patients.”

Pfizer has been divesting itself of its gene therapy interests, most recently pulling out of a collaboration and license agreement with Sangamo Therapeutics, Inc. on hemophilia A candidate giroctocogene fitelparvovec earlier this year. Beqvez was the company’s last commercial or pipeline gene therapy.

Then Feb. 21 brought news about a company focused on gene therapies: bluebird bio, Inc. revealed that it had agreed to be acquired by investment firms Carlyle and SK Capital Partners, LP. The company’s board “determined this transaction is in the best interest of stockholders following a comprehensive review of strategic alternatives,” bluebird said.

In less than 16 months over 2022 and 2023, bluebird gained FDA approvals for three CGTs, starting with Zynteglo (betibeglogene autotemcel) on Aug. 17, 2022, indicated for the treatment of beta-thalassemia in adults and pediatric patients. Slightly less than a month later on Sept. 16, 2022, Skysona (elivaldogene autotemcel) was given accelerated approval to slow the progression of neurologic dysfunction in boys 4 to 17 years old with early, active cerebral adrenoleukodystrophy (CALD). The following year, on Dec. 8, 2023, the FDA approved Lyfgenia for the treatment of sickle cell disease in people at least 12 years old.

All three therapies come with high price tags: Zynteglo is $2.8 million per dose, Skysona is $3 million, and Lyfgenia is $3.1 million.

The company had been seeking a rare pediatric disease priority review voucher from the FDA for Lyfgenia, but the FDA turned it down a third time. Bluebird previously had sold two vouchers, one for $95 million and a second for $102 million, to generate funding. “Absent a significant infusion of capital, bluebird is at risk of defaulting on its loan covenants,” said the firm when unveiling the new agreement.

David Meek, former CEO of Mirati Therapeutics, Inc. and Ipsen Pharma, is expected to be bluebird’s new CEO after the transaction closes, which is expected to occur within the first half of the year.

According to Meek, “bluebird is built on an extraordinary legacy of scientific breakthroughs, and we are committed to unlocking its full potential for patients. With the backing of Carlyle and SK Capital, we will bring the capital and commercial capabilities needed to accelerate and expand patient access to bluebird’s life-changing gene therapies.”

The bluebird deal was unveiled only a few weeks before Bristol Myers Squibb entered into an agreement to purchase 2seventy bio, BMS’s partner on CAR-T therapy Abecma (idecabtagene vicleucel) — and a company that bluebird spun off in May 2021.

Challenges Exist in Development, Commercialization

Multiple reasons could have spurred Pfizer to pull back from developing gene therapies, says Angela Luong, Pharm.D., R.Ph., senior clinical consultant at Pharmaceutical Strategies Group (PSG), an EPIC company. “First, the investment in gene therapy and commercialization requires end-to-end process, including relationships with qualified treatment centers and commercialization/access. Even after approval of Beqvez, there was a delay for treatment centers to be certified.”

Another challenge is finding not only qualified patients for treatment but also ones who are willing to undergo it with new and innovative agents. And within hemophilia, effective treatments already exist, so “if the patients were well-controlled, they may be hesitant to change therapy or pursue a gene therapy treatment,” says Luong. “In relation to Beqvez in particular, we have seen limited uptake of gene therapies for hemophilia. The gene therapies were studied in patients who do not develop inhibitor status, which could happen as patients are exposed to factor product over longer periods of treatment and could be considered more severe.”

The hemophilia drug pipeline also has other potentially effective treatments expected to get FDA approval, she points out, so “providers and patients could be in a more wait-and-see approach with hemophilia.”

And specific to Pfizer, the FDA approved the drugmaker’s Hympavzi (marstacimab-hncq) on Oct. 11, 2024, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in people at least 12 years old with hemophilia A without factor VIII inhibitors or hemophilia B without factor IX inhibitors. It is the first FDA-approved once-weekly subcutaneous prophylactic treatment for hemophilia B and the first with agency approval to use a prefilled pen or prefilled syringe for administration for hemophilia A or B. “Supporting a gene therapy that is priced at $3 million could have interfered with other hemophilia treatment programs Pfizer is planning on deploying,” Luong tells AIS Health, a division of MMIT.

With respect to the bluebird acquisition, Luong points out that it values the company at about $30 million, “which is significantly lower than expected, considering the company was once valued at over $4 billion.”

It was challenging for the drugmaker to commercialize its therapies, both in the U.S. and the European Union, she says. The three gene therapies have “encountered barriers to patient access and provider adoption…includ[ing] high costs, uncertain long-term clinical benefits and concerns about the short and long-term safety profiles of the therapies,” she says. “Additionally, Skysona has had post-marketing safety concerns, which may cause hesitation among providers and caregivers when considering treatment.”

Asked if other CGT companies may take a similar approach, Luong replies, “We are observing a recurring trend among several manufacturers in the gene therapy space. The slow market uptake of these therapies appears to be a contributing factor. Notably, larger manufacturers have halted investments in targeted gene therapy development and clinical trials. This decision is influenced by the substantial long-term investment required and the potential for limited access and slow uptake even after FDA approval.”

Overall, says Luong, “the alignment of patients’ and caregivers’ readiness with providers and payers needs to happen for one gene therapy infusion to occur, which, although it seems simple, could get tricky considering all stakeholders.”

Different health care systems that operate in a variety of ways can complicate uptake of new innovative therapies, she says. “We’ve uncovered differences that need to be addressed, including provider training and certification, care management coordination and standard billing practices. It can be complicated to coordinate.”

Administration Process Is Burdensome

In addition, Luong note that “patient, caregiver and provider considerations along this journey are complicated and require a tremendous commitment from each patient and their caregivers. The process from start to finish could take months, involve travel to a certified treatment center and require inpatient stays pre- and post-administration.”

Some gene therapies, such as those for hemophilia, are launching into a space that already has effective therapies, while others are for ultra-rare conditions lacking any treatments. As an example, Luong points to Kyowa Kirin division Orchard Therapeutics plc’s $4.25 million Lenmeldy (atidarsagene autotemcel), approved March 18, 2024, for the treatment of children with early-onset metachromatic leukodystrophy. “However, many patients tested for treatment with Lenmeldy did not qualify as their symptoms were too severe,” she explains.

Finally, hesitation among payers around gene therapies can result in restrictive utilization management and even lack of coverage for some with accelerated approval. For example, earlier this year Independence Blue Cross implemented a policy saying that it will not cover certain therapies with accelerated approval for 18 months following that approval. One of the nine agents not covered is Sarepta Therapeutics, Inc.’s Elevidys (delandistrogene moxeparvovec-rokl). Excellus BlueCross BlueShield also excludes 40 therapies with accelerated approval, including a handful of CGTs.

“The magic crystal ball every payer wants to understand,” says Luong, is “where CGTs are heading in the next few years.”

“The CGT industry has had some growing pains,” she acknowledges. “This year, we’re seeing pharma react to some of the slow uptake by retracting investments in developing their pipeline around innovative CGTs or looking into other developments such as biosimilars or chronic conditions (GLP-1 agonists).”

Nevertheless, she maintains that “there still is a place for these innovative cell and gene therapies and an unmet need for them to help patients and families with rare and debilitating diseases. High cost is the biggest obstacle in determining value for all payers. It’s complicated, so it just may move a little slower or take a little more time with regard to the changing market dynamics of these CGTs.”

So what needs to happen to turn around the situation? “The value of CGT and evaluation of pricing of the CGT, clinical outcomes and cost-offset evaluations need to be reassessed in this new era of targeted genetic therapies,” Luong contends. “Personalized medicine could be a powerful tool in helping provide better patient care and potentially provide curative options for diseases that have few options. Affordability remains a key factor in the evaluation from our discussions with all stakeholders.”

It’s not all bad news for the space, however: “While there are concerns about the low adoption rates in the gene therapy space, it’s important to highlight that 2024 witnessed one of the most successful gene therapy launches to date with Elevidys.”

Elevidys was granted accelerated approval on June 22, 2023, for the treatment of ambulatory people ages 4 and 5 years with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene except for any deletion in exon 8 and/or exon 9 in that gene. Almost a year later, on June 20, 2024, the agency gave traditional approval for the treatment of people at least 4 years old who are ambulatory and who have a confirmed mutation in the DMD gene and accelerated approval for nonambulatory people at least 4 years old with a confirmed mutation in the DMD gene.

The drug’s price for a one-time infusion is $3.2 million.

When Sarepta reported third-quarter earnings on Nov. 6, 2024, it revealed that Elevidys reaped $181 million in net revenue in the U.S., up from $122 million in the second quarter and in excess of $160 million in prior guidance. When also considering royalty sales via Roche outside the U.S., total third-quarter revenue for the agent was more than $190 million.

“This success demonstrates that the market exists for certain diseases when pharmaceutical companies have the necessary infrastructure in place,” says Luong.

By Angela Maas