Recently, AstraZeneca announced that the FDA rejected the full approval of its drug Andexxa.

It is worth mentioning that the drug was applied for listing in China in December last year. In 2018, Andexxa was approved by the FDA for accelerated listing in the United States, and the following year it won conditional approval from the European Union for the treatment of acute bleeding complications caused by apixaban and rivaroxaban. It is the first and only treatment method that can specifically reverse the activity of FXa inhibitors and achieve hemostasis. It can be said to be a "life-saving drug" in clinical practice.

In 2021, AstraZeneca acquired the rare disease giant Alexion for US$39 billion, and Andexxa became a drug under AstraZeneca. Last year, Andexxa contributed US$182 million in sales to AstraZeneca, a year-on-year increase of 23%.

In its reply letter, the FDA pointed out that the rejection was because the data provided by AstraZeneca revealed a "significant safety finding": Andexxa treatment doubled the incidence of thrombosis-related deaths compared with standard therapy.

In response, AstraZeneca said that Andexxa will not withdraw from the US market yet, and the company will further collect data on drug safety and efficacy to respond to FDA's questions. If favorable results cannot be given by then, Andexxa may be required to withdraw from the market.

This decision of the FDA may affect the fate of Andexxa in other markets. In December 2023, Andexxa applied for listing in China and is still waiting for further news. In March next year, Andexxa's conditional approval in the European Union will be renewed and may also be subject to stricter review.

▍"Shaban" antidote
Due to its better efficacy and safety in the prevention and treatment of thrombosis, Xa factor inhibitors led by rivaroxaban and apixaban have seen rapid sales growth after they were launched, and soon replaced the market of warfarin, becoming the first-line anticoagulant drug at home and abroad.

In 2019, the combined sales of rivaroxaban and apixaban reached $16.4 billion. In the same year, 25,000 lawsuits were filed for internal bleeding caused by rivaroxaban.

This is because "Xaban" drugs have the common disadvantages of anticoagulants and antithrombotic drugs: bleeding. Data show that after treatment with factor Xa inhibitors, 3%-5% of patients will experience severe bleeding. In 2016 alone, there were about 117,000 hospitalizations and nearly 2,000 deaths in the United States. Reports show that Bayer and Johnson & Johnson paid more than $770 million in compensation for this.

Andexxa is an antidote for "Xaban" drugs. Andexxa is a recombinant protein developed by Portola that can specifically bind to factor Xa inhibitors and quickly reverse their anticoagulant effects. Based on the effect of anti-factor Xa activity in healthy volunteers, Andexxa has obtained both U.S. orphan drug and FDA breakthrough therapy qualifications, and won FDA accelerated approval.

In 2020, rare disease giant Alexion acquired Portola for $1.4 billion and took Andexxa into its pocket. Less than a year later, with the sale of Alexion, Andexxa was taken into AstraZeneca's pocket.

Cardiovascular, renal and metabolic were originally AstraZeneca's second largest business after oncology drugs, and AstraZeneca attached great importance to Andexxa. After taking over, with the support of AstraZeneca's sales, Andexxa's sales grew rapidly, with global sales of $182 million in 2023, a year-on-year increase of 23%; in the first three quarters of this year, Andexxa's sales increased by 24% year-on-year.

Obviously, AstraZeneca expects Andexxa to realize greater potential, so it has been promoting its post-marketing clinical trials in order to obtain full approval. In December last year, the drug was applied for listing in China.

▍Continue to seek full approval
Some industry insiders believe that the FDA's rejection this time is somewhat unexpected.

In June 2023, the results of the ANNEXA-I trial came out, a Phase IV trial for patients treated with oral Factor Xa inhibitors and experiencing intracranial hemorrhage. It was found that Andexxa reached the clinical endpoint ahead of schedule, and its effect was shown earlier than expected in the study. As a result, AstraZeneca ended the clinical trial ahead of schedule to submit a full approval faster.

However, the FDA advisory committee found unfavorable evidence during the review: Although the drug achieved positive results in hemostasis, the safety of Andexxa was questionable. In the study, the incidence of thrombosis or coagulation in patients using Andexxa doubled to 14.6%, while that of patients receiving standard treatment was only 6.9%.

However, perhaps considering that Andexxa is currently the only treatment option for this part of patients, the FDA's attitude is not firm. Members of the advisory committee said that such results were related to the study population. The study recruited patients with acute intracranial hemorrhage, who are usually older and more seriously ill, and may be more susceptible to adverse events than other indications. Therefore, it is recommended to modify the indication, and some members also recommend modifying the dosage.

AstraZeneca plans to submit complete efficacy and safety results for presentation and publication at an upcoming medical conference. If the supplementary data is favorable to it, the fate of Andexxa may change.

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