The king bomb turns into a discarded piece! Giants flee, CEOs resign, can the gene therapy track still work?

Global pioneers in gene therapy are experiencing a wave of turbulence.

• On February 24, BioMarin, which has been unable to find a buyer for its product, announced the withdrawal of its A-type hemophilia gene therapy Roctavian from the global market;

• On February 25, another star company in gene therapy, Sarepta, announced that Doug Ingram, who has served as CEO for nearly a decade, will resign.

These two companies, representing the "first tier" of global gene therapy, released a rather heavy signal almost simultaneously, bringing this billion-dollar golden track back into the spotlight.

Gene therapy has been one of the most imaginative technological revolutions in the past decade. During the most fervent phase of capital investment, from AAV vector platforms to CRISPR editing, and from rare diseases to common diseases, not only did biotech companies with advanced technologies emerge, but almost all major pharmaceutical companies were also making moves, with acquisitions and collaborations occurring frequently.

However, the golden period did not last long. As time progressed to around 2025, the atmosphere in the industry began to change significantly. The revolutionary track suffered severe blows, and many pioneers and benchmark companies found their clinical trials and post-market products constantly embroiled in safety crises and commercialization dilemmas. Those once highly anticipated "game-changing" new drugs are facing the difficult test of transitioning from technical proof of concept to market reality.

Safety Risks Looming

On February 25, Sarepta's CEO announced his resignation. The official reason was related to family matters, but at this time point, it is hard to completely dissociate it from the product safety risks and regulatory pressures that Sarepta has faced over the past year.

In the field of rare diseases, Sarepta has long been regarded as a pioneer in the treatment of Duchenne muscular dystrophy (DMD). Its core gene therapy, Elevidys, received FDA approval in 2023, becoming the first AAV gene therapy for DMD. For this fatal disease, it was once hoped to "change the progression of the disease in patients."

However, multiple severe liver injury incidents and patient death cases have drawn significant attention from global regulatory agencies towards Elevidys. The deaths of two patients receiving Elevidys treatment in 2025 have pushed the $3.2 million per injection Elevidys into the spotlight, also plunging Sarepta into an unprecedented safety and regulatory crisis.

Following the death incidents, the FDA urgently halted the use of Elevidys for non-outpatient patients, updated the therapy's label to include significant safety warnings, and imposed stricter restrictions on specific patient populations. For a therapy that emphasizes "curative potential," a black box warning signifies a clear tightening of the regulatory tolerance for risks. As a result, Elevidys sales have continued to decline, and Sarepta's stock price has dropped by 82% over the past year.

In fact, the safety concerns surrounding gene therapy are not limited to Elevidys but are challenges faced by AAV gene therapies in general. From a technical perspective, the immune responses, liver toxicity, and long-term expression stability brought about by AAV vectors remain difficult to overcome. Moreover, clinical trials for this type of therapy often focus on short-term efficacy in early clinical data, while the true risk curve needs to be revealed through larger-scale and longer-term follow-ups This is also why there have been frequent cases of patient deaths due to gene therapy in the past two years.

Whenever a safety incident occurs, public sentiment and regulatory attitudes change rapidly, affecting the entire sector and altering the logic of risk pricing.

In the past, both institutional investors and large pharmaceutical companies were willing to pay a high premium for "technological disruption"; however, the market has begun to become cautious. In the field of AAV gene therapy alone, MNCs including Johnson & Johnson, Novartis, Roche, Pfizer, Takeda, and BioMarin have abandoned ship and "fled."

As we enter 2026, safety concerns continue to loom over the gene therapy sector. In January of this year, the FDA urgently halted two core gene therapies from REGENXBIO due to severe adverse reactions leading to cancer in a five-year-old participant. This decision caused the company's stock price to plummet by 32%.

According to E Drug Manager's statistics based on public information, there will be an average of one participant death incident in the gene therapy field every three months throughout 2025, with safety issues becoming the biggest stumbling block for the advancement of gene therapy.

Commercialization Failure

If Sarepta and REGENXBIO represent the safety concerns at the technical level of gene therapy, then BioMarin reveals the real challenges of commercialization.

Roctavian received its first marketing approval in the European Union in August 2022. In June 2023, the U.S. FDA approved Roctavian for the treatment of patients with severe hemophilia A (with coagulation factor VIII [FVIII] activity < 1 IU/dL), confirming through FDA-approved testing that the patients did not have antibodies against adeno-associated virus 5 (AAV5). BioMarin stated that Roctavian is the first gene therapy approved by the FDA for treating severe hemophilia A patients.

With a star-studded reputation, but just three years after its launch, it faced the outcome of being forced to delist.

Before announcing its global delisting, BioMarin had made multiple attempts to save this product. Just a year after its U.S. launch, BioMarin initiated a cost-cutting plan in mid-2024, putting its gene therapy production facility on standby and focusing operations in the U.S., Germany, and Italy, where there are health insurance reimbursement policies. It also planned to reduce its annual direct spending to $60 million by 2025 and aimed to achieve profitability by the end of 2026.

However, contrary to expectations, the drug's global revenue in 2024 was only $26 million, far below market expectations, and sales were projected to increase to $36 million in 2025, still well short of the company's profitability expectations.

In addition to shrinking its market operations, in October 2025, BioMarin also attempted to find a way out by divesting this product line. At that time, its CEO stated that divesting Roctavian aligned with the company's pipeline strategy and could maximize the assurance of continuous medication for patients. Subsequently, BioMarin began searching for buyers, but until the announcement of its delisting, no buyer was found. In a difficult situation, on February 24 this year, BioMarin announced its withdrawal from the global market for the product and confirmed a loss of approximately $240 million in its financial report, including inventory write-downs and asset impairments.

A star therapy has declared its end within three years of its launch. If it’s not about the product's safety and efficacy, then where is the problem?

A major gap facing the entire gene therapy field is that no one is willing to pay. In other words, although the product has been approved, it is too expensive, and both doctors and patients are not interested.

Looking at hemophilia, this field has long been occupied by long-acting factor preparations and antibody therapies. Patients and doctors need to weigh long-term safety against proven efficacy when choosing new therapies. Once there is uncertainty about the duration of efficacy, market acceptance will quickly decline.

Furthermore, there is the issue of patient base. Gene therapies often target rare diseases, which also determines that the number of patients is small, and the market size is inherently limited. When the applicable population is further screened by immune conditions and age restrictions, the commercial space will narrow even further.

The fact that no one is willing to pay for exorbitantly priced gene therapies has even prompted major pharmaceutical companies like Pfizer to come forward and "speak out."

In February last year, Pfizer withdrew the AAV gene therapy Beqvez, used for treating hemophilia B. This product was only approved by the FDA for treating hemophilia B on April 26, 2024, with a price tag of up to $3.5 million. However, less than a year after its launch, due to weak market demand, no patients had accepted commercial treatment since its approval, leading Pfizer to abandon it directly.

Roche is also undergoing a "fundamental reorganization" of its gene therapy division Spark Therapeutics after 25 years. Similar to Pfizer's abandonment of Beqvez, Roche's reorganization is also linked to commercialization obstacles. As early as 2017, Spark's first global gene therapy for hereditary retinal diseases, Luxturna, was approved, but by 2023, its sales plummeted by 59%, with only about $20 million. Roche also stated that "Spark's future revenue and synergies cannot cover its book value."

The timely cut-off of losses by multinational corporations in the gene therapy field is not enough to cause significant damage, but for biotech companies focused on gene therapy, the situation is dire.

The most representative case is Bluebird Bio, a pioneer in the gene therapy field, which struggled to commercialize but still could not escape the fate of "pioneers becoming martyrs." This company, which once held three high-priced gene therapies—Zynteglo, Skysona, and Lyfgenia—and had a market value that once exceeded $30 billion, was a star during the gene therapy frenzy.

However, the long approval process, stringent reimbursement conditions, and numerous barriers at the payment end during the product launch process led its products to fall into the predicament of "getting praise but not sales" within the extremely narrow rare disease patient group, with total annual revenue from the three core therapies only reaching $29.1 million. Ultimately, Bluebird Bio, with its cash flow completely depleted, was acquired by a private equity fund for $29 million in early 2025, with a market value of less than 0.1% of its peak, and it quietly delisted. From industry star to being sold off at a low price, it took less than ten years Although gene therapy is currently facing setbacks, it does not mean that gene therapy has lost its scientific value. It remains one of the important technological pathways in the fields of rare diseases, genetic disorders, and other illnesses. With breakthroughs in technological pathways and new opportunities in exploring innovative payment models, companies that find a balance between safe technological pathways, sustainable business models, and clinical value will ultimately return to the spotlight.

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