API and IP Newsletter
Contents
Mankind Pharma sets a new benchmark launches 120 premium DMF quality drugs for Indian patients
Ten drugs targeted for Medicare price negotiations as Biden pitches cost reductions
FDA approval in August 2023: Zuranolone
We follow FDA approvals.
Zuranolone was approved by FDA for medical use in the treatment of postpartum depression in August 2023.
Zuranolone, sold under the brand name Zurzuvae. ZURZUVAE™ (zuranolone), the first and only oral treatment approved for women with postpartum depression.
We cover chemistry and brief IP/regulatory aspect in this write-up. We generally do not comment about clinical studies and mechanism of action of the drug. We analyse import-export database and post our educated guesses about generic product development.
WO 2014169833
Example 20 of WO 2014169833 teaches the synthesis of compound SA-4, i.e. Zuranolone.
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4- carbonitrile (100 mg, 0.97 mmol ) and SA (50 mg,0.12 mmol). The mixture was stirred at RT for 15h. The reaction mixture was poured in to 5 mL H20 and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (9mg, 17.4%).
WO2018039378A1
A crystalline compound of Zuranolone is covered in WO2018039378A1.
You would notice 1H-pyrazole-4- carbonitrile is key raw material. Aragen recently also imported API and there could be possibility that TCG and Aragen are working on development Zuranolone project.
General information
Mankind Pharma sets a new benchmark launches 120 premium DMF quality drugs for Indian patients
In its steadfast commitment towards enhancing quality healthcare access, Mankind Pharma, a leading pharmaceutical company is proud to unveil a significant stride with the introduction of 120 drug master file (DMF) quality medicines in the Indian market. Committed to delivering exceptional healthcare solutions at affordable rates, Mankind Pharma's initiative aims to ensure universal access to medicines of international calibre.
News here.
Ten drugs targeted for Medicare price negotiations as Biden pitches cost reductions
The drugs include the blood thinner Eliquis, diabetes treatment Jardiance and eight other medications. The negotiation process was authorized under the Inflation Reduction Act, which Biden signed last year, capping decades of debate over whether the federal government should be allowed to haggle with pharmaceutical companies.
News here
Intellectual Property
Delaware district court found Brivaracetam compound patent valid and infringed
Annora, Apotex and MSN (Defendants) filed ANDAs.
OB listed patents for Brivaracetam are as follows:
Defendants argued that the US 6911461 patent is invalid because it would have been obvious to a skilled artisan as of the priority date of the #461 patent to select levetiracetam as a lead compound from which to develop new anti-seizure drugs and to modify levetiracetam by increasing its lipophilicity with the addition of a propyl group to the 4-position of its pyrrolidine ring.
UCB, the inventor, argued at trial that an artisan of ordinary skill in the applicable field of medicinal chemistry would not have selected levetiracetam as a lead compound from which to develop new anti-seizure drugs and that, in any event, it would not have been obvious to a skilled artisan to increase levetiracetam's lipophilicity or to add to it a propyl group.
In view of these set of arguments, the sole issue for the Hon. Judge of Deleware Court was to decide is whether it would have been obvious to an artisan of ordinary skill as of the #461 patent's priority date to modify levetiracetam by increasing its lipophilicity with the addition of a propyl group to the 4-position of its pyrrolidine ring.
The Court decided in favour of USB, the reasoning was as follows:
A skilled artisan would have understood in February 2000 that levetiracetam had been approved by the FDA before the priority date of the #461 patent
A skilled artisan would have understood that levetiracetam was known only to bind to a receptor at a unique site known as the "levetiracetam binding site" or "LBS."
If a binding site is well-characterized, a skilled artisan can modify a lead compound in ways that attempt to make modified compounds that interact with the binding site more efficaciously.
A binding site is considered "poorly characterized" if its molecular structure and shape are not known. If a binding site is poorly characterized, a skilled artisan cannot definitively determine without testing how a compound will interact with the site.
LBS was poorly characterized as of the #461 patent's priority date. A skilled artisan would have understood that the LBS was in the brain but would not have known its structure.
The term "lipophilicity" for this judgement refers to the ability of a chemical compound to dissolve in fats or oils as opposed to water.
Lipophilicity is a necessary, but not sufficient, factor to achieve central nervous system activity.
Lipophilicity is measured by log P, (which is equivalent to log D for the relevant compounds), Log P is an inherent property of a compound.
A compound with a higher log P is more lipophilic, while a lower log P means that a compound is less lipophilic and thus is more water soluble.
A skilled artisan would not have pursued lipophilicity as an end goal in designing a new drug.
Lipophilicity is a key characteristic in a drug's ability to penetrate the blood-brain barrier.
A compound's log P alone will not tell a skilled artisan whether the compound will pass through the blood-brain barrier.
For example, it's possible for a more lipophilic compound to have increased permeability for other cells in the body; if the compound enters those cells, the compound is prevented from going into the brain and thus brain permeability is decreased.
One of the prior art document cited was Pardridge. It states that, for molecules in a certain molecular weight range, blood-brain barrier transport of the drug may be increased in direct proportion to lipid solubility, another term for lipophilicity.
But Pardridge acknowledges that it has not been demonstrated that increasing lipid solubility always translates into proportionate increase in blood brain barrier permeability. Pardridge also acknowledges that any benefits from lipidizing a drug and increasing blood-brain barrier permeability may be offset by the unfavourable effects of lipidization.
Levin was cited as another prior art document. Levin taught the relationship between permeability and log P and molecular weight was predictable for a certain class of compounds with molecular weights under 400.
The compounds of Levin are structurally different from the compounds at issue here. Levin does not correlate log P with central nervous system activity.
The conclusions by the Court
Defendants did not establish by clear and convincing evidence that a skilled artisan would have had a reasonable expectation of success that modifying any compound to Increase lipophilicity would result in a compound with increased antiepileptic activity.
Defendants did not establish a direct relationship between blood-brain barrier permeability and antiepileptic activity.
Defendants did not establish a direct relationship between lipophilicity and brain uptake.
Defendants did not establish a direct relationship between brain uptake and antiepileptic activity.
Defendants did not establish by clear and convincing evidence a motivation to increase levetiracetam 's lipophilicity.
Defendants did not establish a skilled artisan would have considered levetiracetam 's brain uptake deficient.
Hence, Delaware district court found Brivaracetam compound patent valid and infringed. Though it is certain that aggrieved parties will appeal, as per present decision brivaracetam generic launch looks challenging before 2026.
Decision here.
