Zynquista for Type 1 Diabetes Rejected Again by FDA; Lexicon to File Second Appeal

Compiled by Fan Dongdong

In March this year, the FDA rejected the application by Lexicon Pharmaceuticals and Sanofi for Zynquista (sotagliflozin), a dual SGLT1/2 inhibitor for lowering blood sugar, to be used in combination with insulin for adult patients with type 1 diabetes. Although the drug has already been approved for this indication in the European Union, the FDA's latest decision once again dashed the hopes of the two companies to expand the use of the drug to type 1 diabetes patients in the United States. Nine months later, Zynquista was once again rejected by the FDA.

In January this year, the FDA advisory panel was divided on whether to support the approval of Zynquista, primarily due to concerns about the higher risk of diabetic ketoacidosis in patients using the drug and the potential for unpredictable risks. However, Phase III trials in 2017 showed that treatment with Zynquista did not lead to severe hypoglycemia or episodes of diabetic ketoacidosis, and Zynquista also met the primary endpoints in the Tandem1 and Tandem2 Phase III studies.

Despite the FDA reiterating its prior stance and issuing a complete response letter to Lexicon, the company remained undeterred. In a statement released on Monday (December 3), Lexicon announced that it would file a second appeal with the FDA’s Center for Drug Evaluation and Research (CDER). Following this development, Lexicon’s shares dropped by as much as 30% in pre-market trading in the United States on Monday before recovering slightly.

Notably, Zynquista is not the only product in its class to have been rejected by the FDA for the treatment of type 1 diabetes. In 2014, the FDA approved AstraZeneca’s SGLT2 inhibitor Farxiga for the treatment of type 2 diabetes. Similar to Zynquista, Farxiga has been approved in Europe for the indication of type 1 diabetes but was denied approval by the FDA.

In November 2015, Sanofi and Lexicon Pharmaceuticals entered into an exclusive licensing agreement to co-develop Zynquista. In 2015, Sanofi made an upfront payment of $300 million and committed to paying $1.4 billion in milestones for the global license of Zynquista. Under the agreement, Lexicon was also eligible to receive a share of net sales and double-digit sales royalties. Lexicon was responsible for the clinical development of the drug for type 1 diabetes, while Sanofi oversaw its clinical development for type 2 diabetes.

However, due to the inconsistent performance of Zynquista in three Phase III clinical trials, Sanofi unilaterally notified Lexicon at the end of July this year, announcing the termination of their collaboration on the development, manufacturing, and commercialization of Zynquista in all ongoing global Type 1 and Type 2 diabetes projects.

In response to Sanofi’s unilateral withdrawal, Lexicon stated that the contract signed by both parties stipulates that, even upon effective termination of the alliance, Sanofi remains obligated to transfer the rights to Zynquista and continue funding ongoing clinical trials for a specified period post-termination as outlined in the agreement.

The collaboration dispute was settled in September, with both parties reaching an agreement to terminate the Zynquista partnership. However, the "breakup fee" was not cheap; Sanofi paid $260 million for this purpose.

Reference source: FDA nixes Lexicon’s diabetes hopeful Zynquista—again