API and IP Newsletter
Contents
USFDA approval in September 2023-Gepirone
We follow FDA approvals. We generally would cover, chemistry, IP and regulatory aspects of FDA approved molecules.
In September FDA approved Gepirone. It is sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder.
Gepirone is an old molecule. It was synthesized by Bristol-Myers Squibb in 1986 and was developed and marketed by Fabre-Kramer Pharmaceuticals. The molecule changed hands also before final MA sought by Fabre-Kramer.
It is the first and only oral selective 5HT1a receptor agonist for the treatment of major depressive disorder in adults
The drug was rejected three times in last 20 years by FDA. The old estimates of peak sale was between USD 300-500 mio USD/a. New estimates are not available in public domain.
Exxua contains gepirone in the salt form as gepirone hydrochloride (HCl). The chemical name is 2,6- piperidinedione,4,4-dimethyl-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-, monohydrochloride
There’s already one active DMF
Gepirone HCl is a white to off-white crystalline powder, which is readily soluble in water. Exxua is supplied as extended-release tablets for oral administration. Each extended-release tablet contains 18.2 mg, 36.3 mg, 54.5 mg, or 72.6 mg, gepirone equivalent to 20 mg, 40 mg, 60 mg, or 80 mg of gepirone HCl respectively.
Since there are no compound patent protection, API is commercially available, one could expect many ANDA filers on NCE-1 date in September 2027.
General information
Dr. Reddy’s arm faces antitrust complaint in U.S. over cancer drug Revlimid
Besides Dr. Reddy’s and its wholly owned subsidiary Dr. Reddy’s Laboratories, Inc., Celgene, Bristol Myers Squibb and several generic pharmaceutical companies were named defendants in the complaint in the District of New Jersey, USA.
News here.
6 Drugs Approved Despite Failed Trials or Minimal Data
In recent years, the FDA has granted approval to some novel drugs despite failed clinical trials or minimal evidence. Guidance issued in rare or uniformly fatal diseases like amyotrophic lateral sclerosis and the approvals of Aduhelm in Alzheimer’s and Qalsody in ALS indicate a trend toward greater regulatory flexibility.
News here
Intellectual Property
Grünenthal Vs Teva
This is a litigation about Teva’s long-acting testosterone drug Nebido in Netherlands. In preliminary injunction proceedings, the District Court of The Hague has ruled in favour of Grünenthal.
Nebido (Bayer) is long-acting slow release testosterone preparations, containing testosterone undecanoate, that is used for therapeutic treatment of hypogonadism in males.
It is administered every ten to 14 weeks via intramuscular injection.
Though originally Bayer developed Nebido, Grünenthal GmbH acquired its production and sales in 2022.
Since February 2023, the Dutch Patent Office (OCNL) has registered the German company Grünenthal GmbH as the holder of EP1457208 and Grünenthal B.V. is holding the Dutch marketing authorisation for Nebido. The patent expires in March 2024.
The patent EP1457208 relates to Methods and pharmaceutical compositions for reliable achievement of acceptable serum testosterone levels.
In Netherlands, product must be listed in The G-Standaard. The G-Standaard is the Dutch drug database, which is used by all parties in healthcare, including physicians, pharmacists, wholesalers, manufacturers, health insurers and the government.
The G-Standaard contains all the products that are dispensed by or used in the pharmacy. It enables an efficient exchange of information between healthcare parties. In very broad sense it is an equivalent of Orange Book in US and Patent Registry of Health Canada.
As regards to the product, Nebido is presented in an ampoule or injection vial containing four ml of solution. This contains 250 ml dissolved in castor oil and co-solvent, benzyl benzoate. The medicine contains 2000 mg of benzyl benzoate.
Teva sought marketing authorisation from Dutch authority for marketing generic version of Nebido. Teva received MA. After receiving approval in December 2022, Teva’s testosterone was listed in G-Standaard.
After Teva’s product listed in G-Standaard, Grünenthal moved the court for preliminary injunction, as per Grünenthal, patent covering Nebido is valid till March 2024 in Netherlands and Teva’s product would infringe.
On 13 September, the interim relief judge had ordered Teva to remove its product from the October 2023 G-Standaard.
Further, in preliminary injunction proceedings, the District Court of The Hague has ruled in favour of Grünenthal found the patent preliminarily valid and infringed.
Interestingly, the equivalent of this patent was litigated in Germany and UK. The Federal Patent Court in Munich invalidated the German part of EP 208, as well as several requests for relief, due to lack of inventive step starting from the Von Eckardstein prior art.
Most of technical details are not available in public domain in English. Dutch versions are read with the help of Google translator for this write-up.
Mainly three documents, which are clinical study references, namely the Behre, Nieschlag and von Eckardstein, involving 1000 mg testosterone undecanoate injections in castor oil, were used to render the asserted patent claims obvious.
The formulation vehicle used in the studies was 40% castor oil and 60% benzyl benzoate.
None of the references disclosed the use of a co-solvent. Though the formulation vehicle used in the studies was 40% castor oil and 60% benzyl benzoate, but this was not known to the public until well after the priority date of the asserted patent.
Teva also argued that, since UK and German courts found the Grünenthal patent invalid, the Dutch court should throw out the case for infringement.
But the Dutch court countered that this argument was irrelevant and decided in favour of Grünenthal. The Court said that the Dutch patent claims are narrower than in the German and English Claims.
H.M. Behre et al., Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism : phase I studies , 140 Eur. J. Endocrinol. 414 (1999). Behre compared the half-life of a single dose of 1000 mg TU in castor oil with a single dose of 1000 mg TU in tea seed oil.
E. Nieschlag et al., Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men , 51 Clin. Endocrinol. 757 (1999). Nieschlag studied the suitability of using four intramuscular injections of 1000 mg TU in castor oil at six week intervals.
S. von Eckardstein & E. Nieschlag, Treatment of Male Hypogonadism with Testosterone Undecanoate Injected at Extended Intervals of 12 Weeks: A Phase II Study , 23(3) J. Androl. 419 (2002). von Eckardstein studied the efficacy and safety of prolonged TU treatment at extended injection intervals—starting at injections every six weeks followed by a gradual increase in the interval to every twelve weeks after the tenth injection—over a 3.2 year period.
