Pfizer's patent on blockbuster pregabalin is set to expire at the end of the year

Lyrica(pregabalin, Pregabalin) is the first drug to be jointly certified by the United States and Europe for the treatment of two kinds of neuralgia, and has been rated as one of the "top ten medical advances in 2007" by time magazine ". Since pregabalin was put on the market, it has been fully recognized by doctors and the market for its remarkable curative effect. With the continuous approval of indications, the drug has been listed in dozens of countries and regions and is the best-selling analgesic in the world. Its sales in 2017 were $5.1 billion, of which the sales in the United States were $3.46 billion.

Lyrica in the United StatesThe patent protection deadline is December 30, 2018, which means that its sales will start to decline from 2019.

 

Introduction to Pregabalin

Name: Pregabalin (pregabalin)

Trade name: Lyrica

Chemical name: S-3-Aminomethyl-5-methylhexanoic acid

Time to market: 2004.12 (FDA)

Original research company: Wamer-ambert (later sold by Pfizer)

Main indications: diabetic peripheral neuralgia, postherpetic neuralgia, fibromyalgia, spinal cord injury neuralgia.

Dosage form: Capsule, tablet

Chemical structure: (molecular weight 159)

Mechanism of pregabalin

Pregabalin is the neurotransmitter GABAAn analog of gabapentin. The mechanism of action of pregabalin is similar to that of gabapentin, showing anticonvulsant and analgesic effects in different animal models, but the detailed mechanism of action is not clear. Pregabalin is similar to the neurotransmitter GABA in structure, but does not directly act through the GABA mechanism. At the same time, this product is different from traditional antiepileptic drugs. Within the effective concentration range, it does not interact with GABAA or GABAB receptors, does not metabolize into GABA or GABA agonists, does not inhibit the uptake and degradation of GABA, does not act on sodium and calcium channels, and the release and uptake of glutamate. At the same time, pregabalin does not show affinity with active amino acid receptors such as glutamate and GABA, but pregabalin can replace the binding of labeled GABA to calcium channel α2 and δ subreceptors, inhibit a subunit α2-δ protein of voltage-dependent calcium channels in the central nervous system, reduce calcium ion influx, thereby reducing the release of excitatory neurotransmitters such as glutamate, norepinephrine and substance P, and affect GABA neurotransmission. In addition, pregabalin can significantly increase the level of GABA in the body, and increase the dose of pregabalin can significantly enhance the activity of glutamate decarboxylase

 

Patent battle over pregabalin

Pregabalin has 3Key patents, US6197819 protected compounds (expired December 30, 2018),US6001876/USRE41920 protected pain indications (expired December 30, 2018), and US5563175 protected epilepsy indications (expired October 08, 2013).

The multi-billion dollar market has become a coveted cake, ActavisNine manufacturers, including Alphapharm, Mylan, Cobalt, Lupin, Sandoz, Sun Pharma, Teva and Wockhardt, submitted generic drug applications to FDA to prepare for the listing of pregabalin generic drugs in 2013. Subsequently, Pfizer and other patentees filed infringement lawsuits.

Many imitation manufacturers first denied the creativity of pregabalin and pointed out that "certain homologous compounds were known to have anticonvulsant activity"According to the principle of "homologous series should have similar properties", pregabalin is obvious and the patent US6197819 is not inventive.

The generic manufacturer went on to deny the creativity of pregabalin in the treatment of pain, still using a similar strategy, pointing out that anticonvulsants are often used for analgesia, such as the analog gabapentin has long been found to be used to treat neuropathic pain, hence the patent US6001876/USRE41920Not creative.

In fact, small differences in structure can lead to significant clinical differences, and failure to grasp the molecule itself is a waste of time, otherwise me-too.Drugs are not patented. Several other defences were also largely unsubstantiated, and the charges against Pfizer were not enough of a threat. On February 7, 2014, the U.S. Court of Appeals for the Federal Circuit ruled that Pfizer's pregabalin patent was valid, thus preventing competition for generic drugs of the analgesic drug until 2018. In the ruling, the court found that generic drug manufacturers including Actavis, Lupin and Teva would infringe Pfizer's patent if their pregabalin generic drugs were listed.

In addition to the patent invalid, imitation manufacturers ActavisAnd Lupin's patent circumvention strategy is also very interesting, because the compound patent US6197819 has four claims, namely:(1)S-( )-4-amino-3-(2-methylpropyl) butanoic acid (single isomer);(2)4-amino-3-(2-methylpropyl) butanoic acid and pharmaceutically acceptable salts;(3) a pharmaceutically acceptable salt (single isomer) of S-( )-4-amino-3-(2-methylpropyl) butanoic acid;(4) a pharmaceutical preparation containing a compound as claimed in claim 1 or claim 3.

Pregabalin is chiral, SThe activity of the S type is higher than that of the R type, and the S type is clinically used, that is, the compound and its salt as claimed in claims 1 and 3. Because the patent is too simple to write, Actavis and Lupin's generic drug quality standard is R-type content of 0.01-0.2, that is to say, generic drugs are not pure S-type, naturally not within the scope of protection of claims 1, 3 and 4.

In desperation, Pfizer can only use claim 2Sue, Lupin argued that the 4-amino-3-(2-methylpropyl) butanoic acid represented a racemic mixture, while the generic drug was a non-racemic mixture. Pfizer, of course, is not convinced, saying that 4-amino-3-(2-methylpropyl) butanoic acid represents the name of the compound, and the absence of prefix is not automatically limited to racemate. In the end, Pfizer won the lawsuit. Americans will have to wait until 2018 to use pregabalin generic drugs. However, in this case, the wisdom shown by generic drug manufacturers is worth learning. If there is no restriction of claim 2, they have succeeded and entered the market 5 years earlier than their competitors.

Chinese Patent CN101330907B of PregabalinAuthorized on August 29, 2012, with an expected expiration date of October 23, 2026, the excipient in the patent contains a matrix forming agent and a swelling agent, the matrix forming agent contains polyvinyl acetate and polyvinyl pyrrolidone, the swelling agent contains crosslinked polyvinyl pyrrolidone, which is different from Pfizer's new long-acting sustained-release dosage form. The excipient in the sustained-release preparation mainly contains a swelling agent and a skeleton material, the swelling agent contains polyoxyethylene and crosslinked polyvinyl pyrrolidone, and sodium alginate.

 

Long-acting version of pregabalin received FDA approvalApproved

As cheap generics approach the market, in order to extend the exclusivity period, Pfizer asked the FDAA once-daily extended-release version of pregabalin was submitted for the treatment of pain caused by herpes zoster or diabetic peripheral neuropathy, but not for fibromyalgia like the original pregabalin preparation. Approval of this new preparation of pregabalin can help Pfizer win over patients with the original formula of pregabalin, which requires two to three times a day.

To keep blockbuster franchises alive in the face of generic competition, drugmakers often introduce new, more convenient versions of preparations to entice patients to continue using their drugs. In addition, Pfizer is also working on pediatric exclusive rights, which could extend its patent protection by 6Months.

2017 10In May, the long-acting version of the preparation received FDA approval, thus preparing for the upcoming fierce generic competition of the best-selling drug pregabalin to defend its sales.