How Will Beqvez Fare in Challenging Market for Cell and Gene Therapies?

The FDA recently approved the second gene therapy for hemophilia B, Pfizer Inc.’s Beqvez (fidanacogene elaparvovec-dzkt). While the agent offers an additional treatment option with the potential for freedom from regular infusions of factor therapy, its price — which is equal to that of its competitor — may be too high for many payers, according to a Zitter Insights survey. Industry experts say that it may suffer from some of the challenges other cell and gene therapies have faced in gaining a foothold in the U.S. market.

On April 25, the FDA approved Beqvez for the treatment of adults with moderate to severe hemophilia B who use factor IX (FIX) prophylaxis therapy; have current or historical life-threatening hemorrhage; or have repeated, serious spontaneous bleeding episodes and do not have neutralizing antibodies to adeno-associated virus (AAV) serotype Rh74var (AAVRh74var) capsid as detected by an FDA-approved test. The manufacturer launched a warranty program for the intravenous infusion based on durability of patient response to treatment.

The price for the single-dose gene therapy is $3.5 million — the same price as the other AAV vector-based gene therapy for hemophilia B, CSL Behring LLC and uniQure Inc.’s Hemgenix (etranacogene dezaparvovec-drlb). That therapy was approved Nov. 22, 2022, for the treatment of people at least 18 years old with hemophilia B who currently use FIX prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.

According to CVS Health’s “Gene Therapy Report: Q1 2024-Q4 2026,” an estimated 1,300 U.S. adults are candidates for Beqvez.

For the Managed Care Biologics and Injectables Index: Q4 2023, from Nov. 20, 2023, to Dec. 31, 2023, Zitter Insights polled 36 commercial payers covering 116.1 million lives, 27 Medicare payers covering 43.4 million lives, 50 hematologists and 55 practice managers about their management of and prescribing for hemophilia. Half of all payers and 54% of hematologists said they have moderate satisfaction with the current treatments for the condition.

AIS Health and Zitter Insights are both divisions of MMIT.

Payers with 69% of commercial covered lives and 45% of Medicare lives, as well as 34% of hematologists, said that high or very high unmet need exists in treating hemophilia. Of those respondents, the top drivers of high/very high unmet need are the lack of effective therapies, poor adherence due to the route of administration and the need for safer treatments.

Payers with 41% of commercial lives and those covering 9% of Medicare lives said they are aggressive in their management of branded agents, meaning that they cover most agents, with some preferred over others through the use of tiering, step edits and/or prior authorization, and exclude other therapies.

Almost half — 47% — of payer respondents said they were somewhat or moderately aware of Beqvez compared with 40% of hematologists. Payers with 44% of Medicare lives and 38% of commercial lives rated their level of awareness as moderate.

Payer respondents said that an annualized net price of $2.17 million for Beqvez is too expensive, meaning that they would recommend that the product not be covered or that it be highly restricted.

Forty-one percent of hematologists said they expect the new gene therapy to have a moderate impact on their prescribing, meaning that they may change their treatment approach for a considerable portion of patients. Similarly, payers with 56% of commercial lives and 58% of Medicare lives expect that Beqvez will have a moderate approach on their coverage of treatments for hemophilia B (see chart).

The FDA’s approval of Beqvez “marks a significant milestone,” declares Mesfin Tegenu, CEO and chairman of RxParadigm, Inc. “It provides eligible patients with an additional treatment option that directly addresses the underlying cause of the condition…[and] enables patients to produce their own FIX, representing a major shift in treatment. Currently, the standard of care requires regular intravenous infusions of FIX, often administered multiple times a week. As a one-time treatment, Beqvez has the potential to reduce both the medical and treatment burden for patients. This approval underscores the transformational impact that gene therapy can have for patients with rare diseases that have limited treatment options.”

However, another industry expert has somewhat of a different take on the new agent.

“I am not really sure it can be said that there is any true significance to the approval of Beqvez,” says Winston Wong, Pharm.D., president of W-Squared Group, as it has “no true differentiation” from Hemgenix and has “similar limitations and monitoring.” Both agents’ durability remains in question, he adds, noting that people receiving Beqvez have been monitored for six years as opposed to two years of monitoring for those receiving Hemgenix.

“Payers will be hard pressed to pit one versus the other, as I suspect that product selection will be driven by provider familiarity and preference,” Wong tells AIS Health. “Location of the infusion centers may also play a part in the product selection.”

“At this point, I do not believe payers will be able to differentiate and select a preferred product,” he says. “Hemophilia B has an orphan designation, and as such, there are few patients. When either of these treatment options are decided, I am sure that one-off discussions will need to take place to determine a case-rate with the infusion center, much like what we have already seen with the CAR-T [chimeric antigen receptor T cell] therapies.”

Tegenu says he expects the “patient screening process will be strong, as defined by the prescribing information. I suspect, as with other gene therapies, reimbursement will be on a case-by-case basis with the infusion center.”

Beqvez and Hemgenix fall under the medical benefit, says Arash Sadeghi, Pharm.D., a clinical pharmacist at Optum Rx, and both will be used in patients who are failing FIX therapy and continue to have serious bleeding episodes. In the spring 2024 edition of the Optum Rx Drug Pipeline Insights Report, the PBM declares that the “biggest questions” for both Hemgenix and Beqvez are whether “their effects are durable, and if they are safe long term.”

Patient eligibility criteria from both therapies’ pivotal trials can help inform payers’ coverage decisions, states Tegenu. Both therapies’ indications are for similar patient populations, but “subtle differences” exist. For example, “in Hemgenix’s HOPE-B trial, patients with pre-existing anti-AAV5 neutralizing antibodies were not excluded. In contrast, Beqvez’s labeling requires testing to confirm the absence of pre-existing antibodies to AAVRh74var prior to treatment. The presence of these antibodies could potentially compromise treatment efficacy. Payers may take these differences into account when determining coverage or formulary tiering, such as preferred versus nonpreferred status. Additionally, the availability of a warranty program for Beqvez may be an important distinguishing factor to some payers when compared to Hemgenix.”

Uptake of Hemophilia Gene Therapies Has Been Slow

Wong points out that the $3.5 million one-time cost “is only for the FIX gene treatment. It does not include all the diagnostics and ancillary procedures and processes that must be put into place to even administer the infusion, as well as continuation of prophylactic treatment. One usually believes that a second agent in a therapeutic area means competition: however, I doubt that would be the case here. Even with a value-base reimbursement program in place, the uptake of the first agent has been well below expectations.”

While Hemgenix coverage has been growing — as of May 2023, payers covering about 60% of the U.S. population had medical policies in place for it — its uptake “has been slow,” says Tegenu, who cites its cost as the likely reason why and adds that with an identical price, Beqvez may experience “similar challenges.”

Indeed, uptake not only of Hemgenix but also of the only FDA-approved gene therapy for hemophilia A, BioMarin Pharmaceutical, Inc.’s Roctavian (valoctocogene roxaparvovec-rvox), “have been well below expectations,” says Wong. That agent has a one-time price of $2.9 million.

The FDA approved Roctavian on June 29, 2023, but only four people had been treated with it as of late April. During BioMarin’s April 24 call to discuss first-quarter 2024 earnings, CEO Alexander Hardy said that three options exist with Roctavian: staying the course if uptake improves, “rightsizing the level of investment across the organization” or divesting the therapy. Hardy said that the company would reveal its decision on its Sept. 4 Investor Day.

Considering the performances of Hemgenix and Roctavian, “I do not expect Beqvez to stimulate the market,” says Wong.

Will Warranty Program Help Uptake?

One aspect that could boost uptake of Beqvez is that Pfizer is offering a warranty program. Specifically, it is an “innovative warranty program based on durability of patient response to treatment,” the company said when announcing its approval. The offering’s goal “is to provide greater certainty to payers, maximize access for eligible patients who receive Beqvez, and offer financial protection by insuring against the risk of efficacy failure.”

“This innovative approach seeks to address concerns regarding efficacy and long-term outcomes, ultimately mitigating the risk associated with covering these therapies and ensuring broader accessibility to Beqvez,” declares Tegenu. The program “might help increase its adoption.”

However, says Wong, the program is “simply a marketing name for a value-based/outcomes-based contract. CSL also offered a value-based agreement, which has not seemed to ease payers, evident by its low uptake. The warranty program is said to remain in place even if the patient moves on to another insurer; however, this is only a viable solution for fully insured business. With 60% of today’s nonpublic commercial population being self-insured, following the financial routing and getting the warranty funds back to the proper entity is a difficult task.”

According to a recent white paper on paying for gene therapies from the Institute for Clinical and Economic Review (ICER) and Tufts Medical Center’s NEWDIGS, the following are advantages of upfront payments with warranties:

• They are allowed by Medicare and Medicaid,
• They usually don’t impact Medicaid Best Price, and
• They reduce the administrative burden on plan sponsors.

In addition, two disadvantages to warranties exist:

• Plan sponsors must pay the upfront full cost of the therapy, and
• The “warranty amount for incurred health care expenses due to treatment failure may not account for much of the initial price.”

Priced at $2.9 million for a one-time treatment, Roctavian also launched with an outcomes-based warranty guaranteeing reimbursement of up to 100% of the wholesale acquisition cost. The agreement is good for the first four years of treatment, and BioMarin will reimburse payers on a prorated basis for any patient who does not respond to the agent during that time frame.

Hemgenix also has a similar arrangement, with CSL Behring offering “a substantial rebate to payers” if a patient must use prophylactic FIX within three-and-a-half years of infusion with the therapy.

“To date, nearly all durable gene therapies have offered an innovative payment model when they launched,” ICER and NEWDIGS told Scrip. “Most of these have been some form [of] value-based contract such as milestone-based rebate or a warranty. We expect this emphasis to continue in the near future.”

AIS Health and Scrip are part of the same parent company, Norstella.

New models to manage budget impact are under discussion, the organizations added, “such as enhanced stop loss insurance, subscription models offered directly by manufacturers or even a new federal benefit for gene therapies,…but [those] will likely appear later, if at all.”

How Can Pfizer Differentiate Beqvez?

Asked if there are any lessons learned from Hemgenix that Pfizer can apply to Beqvez, Wong replies, “If anything, try to definitively determine what is driving the slow uptake.  I am pretty sure it is the high price, but that needs to be definitively determined.”

Tegenu responds that Pfizer understood “the need for innovative strategies,…especially given Hemgenix’s slow uptake, which faced challenges related to cost and durability.” Beqvez’s warranty program is “aimed at maximizing accessibility. In contrast, CSL Behring offers a value-based agreement for Hemgenix, tying reimbursement to specific patient outcomes. Pfizer’s warranty program is linked to the patient’s response to treatment and provides a safeguard against the risk of efficacy failure. Notably, Pfizer’s warranty program will continue to provide coverage for commercially insured patients if they change insurance after receiving treatment.”

In addition, he points to Pfizer’s GeneTogether program, which gives patients educational resources about gene therapy, details on insurance coverage and financial support options and offers various support services to health care professionals. “Additionally, Pfizer collaborates with treatment centers, payers and the hemophilia community to ensure broad access to Beqvez. By employing these strategies, Pfizer aims to maximize accessibility and facilitate the successful adoption of Beqvez within the health care system.”

Gene Therapies Have Had Slow Uptake So Far

It’s not just the hemophilia gene therapies that have had a slower-than-expected uptake but cell and gene therapies overall, points out Tegenu, citing logistical and cost challenges, as well as uncertain long-term outcomes.

“The logistics of bringing gene therapy administration out of a clinical trial setting and into a real-world setting has proven challenging,” he maintains. “Additionally, gene therapy requires a specialized infrastructure. Ensuring that treatment centers, hospitals, clinics and personnel have the necessary expertise, equipment and protocols is essential.”

The products’ high upfront costs “can hinder payer coverage and strain payer budgets,” he continues. “To address this, innovative pricing and reimbursement strategies are being pioneered, including outcomes-based agreements, risk-sharing models and installment payment options, aiming to improve accessibility for patients while mitigating financial risks.”

Finally, says Tegenu, “the lack of long-term efficacy and durability data raises concerns about the therapies’ long-term value and cost-effectiveness. Real-world evidence such as post-marketing surveillance, patient registries and data-sharing initiatives can help address these uncertainties and help build confidence among payers, patients and providers.”

According to Sadeghi, uncertainty around long-term durability and safety is “particularly noteworthy because these therapies function as one-time treatments with an extremely high price tag.”

In addition, he explains, “even with traditional therapies and drugs, we often see very slow early adoption since it takes time for providers and patients to become knowledgeable and comfortable about a new market entrant; this is magnified with gene therapy since it’s relatively new.” Another issue is that “some of these therapies essentially function as stem cell transplants, requiring a complex patient journey that can last six to 12 months.”

“The solution to some of the challenges associated with gene therapy is really going to be time — as more patients are treated and additional follow-up occurs, we’ll know more about these products and have a better understanding about the long-term benefit vs. risk,” he asserts.

As far as what’s next in hemophilia treatment, “novel subcutaneous nonfactor therapies are in the pipeline for the treatment of both hemophilia A and B,” explains Tegenu, and will provide an alternative to intravenously infused factor. “One of these agents is Pfizer’s marstacimab, which is currently awaiting FDA approval, with a decision expected in the fourth quarter of this year. If approved, marstacimab could become the first once-weekly subcutaneous treatment for people living with hemophilia B and the first treatment administered as a flat dose for people living with hemophilia A or B.”

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