Industry Observation I US High Court Rejects Patent Invalidation Appeal for the Circadian Rhythm Drug Tametinib

Click:16  Update time：2024-04-26  【Close】

Vanda Pharmaceuticals' circadian rhythm drug Hetlioz, which has been on the market for ten years, was ruled invalid by a court in 2023. Vanda actively responded by appealing to the US Supreme Court. But recently, the US Supreme Court rejected Vanda's lawsuit, making the company's prospects even more bleak.

For the entire year of 2023, Hetlioz's sales revenue was slightly above $100 million, a sharp decrease of 37% from $159.7 million in 2022.

Source: Getty Images

According to the SCOTUS ruling list released on Monday, the High Court rejected Vanda's request to object to the May 2023 ruling of the Federal Circuit Court of Appeals. About four months ago, the company appealed to the Supreme Court for a review of the ruling.
As early as 2018, Vanda first sued Israel's Teva Pharmaceuticals and Canada's Apotex Pharmaceuticals in Delaware, accusing generic drug manufacturers of infringing on certain patent rights of Hetlioz after applying for the production of a generic drug. The drug was first approved by the FDA in 2014 for the treatment of non 24-hour sleep wake disorders.

In December 2022, the Delaware Federal Court rejected Vanda's infringement claim and further ruled that Vanda's four related patents in Hetlioz were invalid. According to Reuters, the appellate court upheld this ruling in 2023, and Vanda had no choice but to seek assistance from the Supreme Court in January.

The failure of Vanda's patent battle may have a heavy impact on the company and Hetlioz's commercialization path. For the entire year of 2023, Hetlioz's sales revenue was slightly above $100 million, a sharp decrease of 37% from $159.7 million in 2022. In its latest financial report, Vanda attributed the decrease in sales to the launch of Hetlioz generic drugs in the United States. Vanda's total revenue in 2023 was $192.6 million, with Hetlioz's sales accounting for slightly over 50%. Due to the Supreme Court's rejection, Wanda's stock price fell by about 4.3% on Monday.

In early March, the FDA rejected Vanda's request for a hearing on regulatory agency Hetlioz due to time difference reaction disorder (JLD) in 2019. Additionally, Vanda revealed at around the same time that the FDA also declined Hetlioz's request for supplementary indications due to insomnia. The American Sleep Medicine Association lists sleep disorders and daytime drowsiness as the basic characteristics of JLD. For example, travelers experience time zone cognitive interference in their nighttime sleep and/or daytime drowsiness due to rapid and frequent time zone changes. Currently, there is a lack of effective methods for treating time difference, and travelers need to overcome it on their own. The duration and severity of discomfort vary greatly among individuals. The second rejection was after the FDA reminded Vanda in February to discover deficiencies in the use of the drug for insomnia, and Vanda stated in a press release at the time that "discussions regarding labeling and post market requirements/commitments were excluded.".

Source: Dan Reiss/Fotolia

Tametinib is a circadian rhythm regulator that specifically binds to two high affinity melatonin receptors, Mel1a (MT1R) and Mel1b (MT2R). These receptors exist at a high density in the suprachiasmatic nucleus (SCN) of the brain, which is responsible for synchronizing sleep/wake cycles. Tametinib has been shown in previous clinical studies to improve sleep parameters, simulating the de synchronization effect of circadian circadian biological clocks. Tametformin has been studied in hundreds of individuals to date and has shown good tolerance characteristics. Tametinib can be used to treat the circadian rhythm of free movement in patients (including those with photosensitive impairments, such as blindness).

Tametinib is a white to grayish white powder with a melting point (DSC) of approximately 78 ℃ and is highly soluble or arbitrarily soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycol (PEG-300 and PEG-400), and only slightly soluble in water. The natural pH of a saturated solution of tamethinib in water is 8.5, and its water solubility is basically not affected by pH. Compared to MT1R, tamethinib has an affinity for MT2R that is 2 to 4 times higher. Its affinity (Ki) for MT1R is 0.3 to 0.4, while its affinity for MT2R is 0.1 to 0.2.

Wanda Pharmaceutical has obtained relevant patent protection in China, with specific patent application number CN201380016945.6. The patent is currently valid and is expected to expire on January 25, 2033.

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