Review of Polymorph Patent Application of 30 Small Molecule New Drugs Approved by the FDA in 2023

In 2023, the FDA's Center for Drug Evaluation and Research (CDER) approved a total of 55 new drugs, which included 38 new molecular entities, of which 30 were small molecule drugs. In terms of administration routes and dosage forms among these small molecule drugs, there were 5 liquid formulations (including 2 injections and 3 eye drops), 1 nasal spray, and 24 solid/semi-solid formulations (comprising 23 solid dosage forms and 1 gel), as illustrated in Table 1.

Table 1. Basic information of 38 new molecular entities approved by the FDA in 2023

The review of polymorph patent fillings for the 24 solid or semi-solid small molecule new drugs revealed that polymorph patents had been applied for in 20 cases, representing 83% of the total solid or semi-solid small molecule new drugs. Refer to Table 2 for detailed information.

Tablet 2. Basic information and polymorph patent information of 24 small molecule new drugs for solid/semi-solid preparations

Table 3 provides a detailed analysis of the expiration dates for both compound patents and polymorph patents for these 20 drugs, along with the time gaps between them. It was found that 15 of these drugs have polymorph patents expiring later than their compound patents, with a gap exceeding 1 year. Specifically, 11 drugs show a time difference of 3 or more years, 8 drugs have a gap of 5 or more years, and notably, three drugs (Orserdu, Agamree and Ogsiveo) exhibit a time difference of over 10 years.

Table 3. Analysis of Compound Patents and Polymorph Patents for 20 Small Molecule New Drugs

To provide a clearer insight into how innovator companies extend the lifecycles of their products using polymorph patent layouts, we will delve into three representative drugs: Skyclarys, Zurzuvae, Ogsiveo. The authorization of these drugs represents crucial breakthroughs in the treatment of their respective diseases. Additionally, their market share projections highlight their potential to become blockbuster drugs.  

Skyclarys

Skyclarys (Omaveloxolone) is a drug developed by Reata Pharmaceuticals, a medication approved for the treatment of Friedreich ataxia (FA), a progressive neurodegenerative disorder, in adults and adolescents aged 16 and older. It stands as the sole FDA-approved treatment for this specific condition. Omaveloxolone’s effectiveness is attributed to its dual action: activating the antioxidative transcription factor Nrf2 and inhibiting the pro-inflammatory transcription factor NF-κB. On February 28, 2023, Reata Pharmaceuticals announced the FDA’s approval for Skyclarys, presenting a new avenue for potentially alleviating disease progression in Friedreich ataxia patients. 

In the commercialized version of the drug, the active ingredient is the crystalline form of Omaveloxolone. The original compound patent (US8124799B2) for this is set to expire on December 3, 2029. Meanwhile, the polymorph patent (US8993640B2), which covers various amorphous and solvent form/hydrates of Omaveloxolone, will expire later on April 24, 2033. The application of the polymorph patent effectively extends the product’s protection by about 40 months.

Zurzuvae

Zurzuvae (Zuranolone), an oral medication developed by Biogen and Sage Therapeutics, is designed to treat postpartum depression (PPD), a prevalent complication affecting 15%-30% of women during and after pregnancy. Unlike existing antidepressants that often take time to show significant effects, Zurzuvae stands out with its rapid efficacy. It functions as a positive allosteric modulator of γ-aminobutyric acid A (GABAA) receptors and is noted for its high oral bioavailability and affordability. Biogen and Sage Therapeutics received FDA approval for Zurzuvae on August 4, 2023, offering a swift and effective treatment option for those suffering PPD symptoms.

The marketed form of Zurzuvae contains Zuranolone in its crystalline state. Its compound patent (US9512165B2) is set to expire on April 17, 2034. Additionally, the polymorph patent (US11236121B2), which details a range of Zuranolone polymorphs from type A to type P, including anhydrous forms, hydrates, and solvates, will expire on August 23, 2037. By applying the polymorph patent, the protection duration of the product has been effectively extended by around 40 months.

Ogsiveo

SpringWorks Therapeutics developed Ogsiveo (Nirogacestat Hydrobromide), the first oral tablet for treating desmoid tumors in adult patients. Nirogacestat is a selective inhibitor targeting the gamma secretase (GS) enzyme. It works by binding to GS, which prevents the proteolytic activation of Notch receptors. This inhibition of Notch signaling pathway may lead to apotosis in tumor cells that exhibit excessive Noth expression. On November 28, 2023, SpringWorks Therapeutics announced FDA approval for Ogsiveo, marking it as a treatment option for systemic management of progressive fibrous dysplasia in adults.

The active ingredient in the commercial version of Ogsiveo is the crystalline form of Nirogacestat Hydrobromide. The primary compound patent for Ogsiveo (US7342118B2) will expire on August 18, 2025. Meanwhile, the polymorph patent (US10941118B2), which discloses various forms of Nirogacestat Hydrobromide polymorphs ranging from type A to type N, is due to expire on August 9, 2039. Importantly, the implementation of the polymorph patent has resulted in extending the product’s protection by approximately 14 years.

Summary

An examination of data from the last six years (as detailed in Table 4) shows that aside from 2022, the FDA has consistently approved 40 to 60 new drugs annually, with 30 to 40 of these being small molecule new drugs, and 20 to 30 being small molecule oral solid formulations. Despite various challenges faced by the pharmaceutical industry these years, there was a significant increase in the number of approved new drugs last year, reaching levels comparable to the peak observed between 2018 and 2020. It is noteworthy that in the first five years, the rate of polymorph patent applications for small molecule drugs in solid or semi-solid formulations remained steady at 60% to 70%. However, this year saw a rise to 83%, indicating a growing focus on the research of drug solid-state and the application of polymorph patents.

Table 4. Summary of new drugs approved by FDA in the last 6 years

The focus on drug crystal forms and the application of polymorph patents has increasingly become a critical aspect for innovator companies in the development of new drugs. This heightened attention stems from two main factors. Firstly, the crystal forms of a drug plays a vital role in its stability, the feasibility of its process development, and its bioavailability. These aspects are crucial in the new drug development and are key considerations for regulatory authorities when approving small molecule drugs. Secondly, securing effective patent protection for drug crystal forms creates substantial technological barriers, allowing innovator companies to fend off competition from generic manufacturers. This strategy extends the market protection duration for new drugs and leads to greater economic benefits. Hence, research on drug crystal forms and strategic application of polymorph patents holds significant importance for innovator companies.

For many year, Crystal Pharmatech has been extensively engaged in the polymorphic research of small molecule drug. The company offers a range of services in drug solid-state research and development, including crystal screening and developability assessment. Additionally, Crystal Pharmatech specializes in providing various services related to the application and analysis of polymorph patents, which are customized to meet diverse drug research and development requirements, as detailed in Table 5.

Table 5. Services related to Polymorph patent.

Reference:

[1] https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023.

[2] https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm.

[3] For granted patents, the official expiration date as announced is considered authoritative.

[4] Expiration date of the polymorph patent minus the expiration date of the compound patent.