For Pfizer, which has suffered a major setback in the field of gene therapy, the year 2025, which is about to end, has indeed been incredibly difficult. Now, the giant faces further troubles in the field of next-generation therapies, which are seen as potential successors.

On December 14, a patient who participated in the long-term extended study of Pfizer's new hemophilia drug Hympavzi died from cerebellar infarction followed by cerebral hemorrhage.

This patient, suffering from hemophilia A and on inhibitors, underwent minor surgery and was routinely using the experimental drug Hympavzi for prophylaxis, as well as recombinant coagulation factor VIIa for perioperative hemostasis management. Tragically, the incident occurred a few days later.

The exact reasons are still under investigation. Pfizer quickly initiated a review with researchers and an independent data monitoring committee, and notified regulatory agencies.

However, the patient's death is like a boulder thrown into a lake in the industry, and the chain reaction it has triggered is rapidly emerging.

It happened at an extremely delicate time: Pfizer's new drug Hympavzi, hailed as the "world's first non-coagulation factor therapy," had just received FDA approval in the United States in October 2024 and was approved for marketing in China in November 2025. Its commercial promotion had just begun when it encountered major safety concerns.

On a larger scale, several multinational pharmaceutical giants, including Pfizer, are collectively shifting their focus away from gene therapy, a field once considered promising. Hympavzi's " rebalancing therapy" is one such promising next-generation alternative.

TONACEA

01
What caused the death?

This was not an isolated adverse event with a simple cause. According to statements from the European Hemophilia Federation and Pfizer, there is a alarming link between the death and the drug's mechanism of action.

Hympavzi's mechanism of action is revolutionary—it does not directly replenish the clotting factors VIII or IX that hemophilia patients lack, but rather "awakens" and enhances the patient's own clotting ability by inhibiting the body's "tissue factor pathway inhibitor" (TFPI) , a process known as "clotting rebalancing."

However, it is precisely this "enhanced blood clotting" mechanism that harbors potential risks.

When this stimulated clotting function encounters recombinant coagulation factor VIIa used for perioperative hemostasis, it can produce an "excessive" clotting effect, ultimately leading to fatal thrombotic stroke. Industry reviews have long pointed out that thrombotic risk is a known and critical challenge for this type of "rebalancing therapy."

In its response, Pfizer emphasized that based on existing overall clinical data, it does not believe it will affect the safety of medication use in approved patients. However, a crucial question remains: why did previous clinical trials fail to adequately expose this risk?

The answer may lie in the gap between clinical trials and the complexities of the real world, which needs to be acknowledged.

The pivotal Phase III BASIS study and its extension demonstrated that Hympavzi was safe and effective in patients without inhibitors, with "no reported deaths or thromboembolic events." However, in the real world, patients face situations that are difficult to fully simulate in clinical trials, such as surgery, concomitant medications, and complex underlying diseases.

The patient who died in this case belonged to the more challenging subgroup of "with inhibitors," and Hympavzi's indication for this subgroup has not yet been approved and is still in the clinical research stage.

This incident serves as a wake-up call for all "rebalancing therapies": When innovative therapies move from relatively ideal experimental environments to more complex real-world medical scenarios, are our cognitive and management contingency plans adequately prepared?

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02
Behind the "Halo" of Innovation

Before the death, Hympavzi possessed an aura of innovation that was enough to excite the market.

In February 2025, the authoritative nursing journal *American Journal of Nursing* introduced it to the medical community as a new option for weekly subcutaneous injection. When it was approved in China in November, it was hailed by Pfizer and medical experts as a landmark drug with "triple innovative breakthroughs."

First, it is innovative in its mechanism. It breaks away from the decades-old approach of "supplementing what is lacking" in alternative therapies, and treats diseases by regulating the body's own anticoagulation system.

Secondly, it innovates the route of administration. Hympavzi frees patients from frequent intravenous injections, replacing them with a weekly subcutaneous injection.

Thirdly, it innovates in terms of target population. Industry experts consider Hympavzi to be an innovative product suitable for both hemophilia A and B patients.

Professor Yang Renchi of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, commented that it is "theoretically unaffected by inhibitors" and pointed out that "no thrombosis-related adverse events were observed" throughout the Phase III study. These positive evaluations based on clinical trials have led to high hopes for this drug in promoting a transformation in the diagnosis and treatment of hemophilia.

However, the deaths in December brought all of this to a standstill.

There exists a chasm that must be bridged between the perfection of theoretical models and the uncertainties of the complex human body. This is especially true for patients with "concomitant inhibitors," who are the most vulnerable group and in dire need of new treatment options. The path to new drugs requires not only scientific breakthroughs but also an extreme respect for and management of risks.

This new drug, which was expected to be commercially successful, now faces a reassessment of its market access pace and R&D strategy due to this tragedy.

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03
Pfizer, stumbling repeatedly

Hympavzi's security crisis occurred at an awkward "transitional" moment in Pfizer's R&D strategy.

In early 2025, Pfizer abruptly halted the development and commercialization of its gene therapy for hemophilia B, Beqvez. This "star product," which had just received FDA approval in April 2024 and was priced at a hefty $3.5 million, failed to attract any patients after its market launch and was ultimately withdrawn from the market.

Beqvez's collapse was not accidental; it was the culmination of a series of setbacks.

Previously, Pfizer's Phase III gene therapy for Duchenne muscular dystrophy failed, and its gene therapy for hemophilia A in collaboration with Sangamo was discontinued. A decade-long, costly gene therapy project was ultimately almost wiped out.

The collective predicament of giants in gene therapy stems from a difficult-to-solve "commercial deadlock": the exorbitant research and development and production costs force prices to reach millions of dollars, which in turn stifles the already limited market for rare disease patients, resulting in commercial returns falling far short of expectations and thus failing to support continued investment.

However, a huge unmet need remains in the field of hemophilia. When the "one-size-fits-all" gene therapy approach is blocked, the industry has turned its attention to another technological track—"rebalancing therapy" represented by Hympavzi.

"Rebalancing therapy" is seen as a more feasible and commercially viable next-generation solution due to its relatively controllable production costs and the potential for repeated dosing. Pfizer hoped to regain lost ground and rebuild its growth narrative in the field of hemophilia treatment with Hympavzi.

However, this death was like a sudden cold snap.

Pfizer has had to admit that even in an attempt to avoid the commercialization pitfalls of its predecessors, the next-generation therapies, seen as its "successors," may still harbor clinical risks that could potentially disrupt the entire industry. For this giant, this is tantamount to encountering another major technical glitch on a newly opened track.

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04
The way out

Pfizer's predicament is a microcosm of the collective difficulties currently facing the field of breakthrough therapies, represented by gene therapy and novel biologics. In 2025, this field seems to be entering a challenging period of headwinds.

Safety concerns have been raised in multiple locations around the world. In 2025, Sarepta's DMD gene therapy Elevidys reported a series of patient deaths; Rocket Pharmaceuticals' gene therapy clinical trials also saw deaths. These events have exacerbated the concerns of regulators, investors, and patients' families.

The deeper contradiction lies in the fundamental conflict between the high cost of innovation and the fragile ability to pay. More than 70% of hemophilia patients worldwide still cannot access adequate treatment, and the millions of dollars per injection are an unbearable burden for global health insurance systems.

However, the exploration did not stop. The industry is learning from setbacks to find a more solid path forward.

One direction is the diversification and iteration of technological approaches. Many companies are shifting their focus from traditional AAV viral vectors to non-viral delivery systems such as lipid nanoparticles, in order to achieve better safety and controllability.

Another direction is the refinement and integration of clinical strategies. For example, exploring the combined use of "rebalancing therapy" with traditional factor replacement therapy to achieve the best balance between efficacy and risk. At the same time, establishing a more refined patient risk management system, such as through thrombosis risk stratification and novel coagulation function monitoring, to achieve personalized treatment.

Innovation in regulatory and payment systems has also been put on the agenda.

Organizations such as the World Federation of Hemophilia are continuously promoting the systematic integration of the treatment of bleeding disorders into the global public health framework. Innovative payment models based on efficacy risk sharing and installment payments are becoming the focus of discussion in the industry, attempting to solve the accessibility problem of "sky-high priced drugs".

The road ahead still requires navigating through the fog. Perhaps only when the grand narrative of "curing with a single injection" gradually gives way to a careful consideration of efficacy, safety, and accessibility will a truly mature and sustainable era of medical innovation begin.

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