17 Aug 2013
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
No. | Brand name | Active Ingredient | Innovator | Indication | Target | Drug type | Dosage form |
1 | Brenzavvy | Bexagliflozin | TheracosBio | Type 2 diabetes mellitus | SGLT-2 | Small molecule | Oral solid |
2 | Jaypirca | Pirtobrutinib | Eli Lilly | Mantle Cell Lymphoma | BTK inhibitor | Small molecule | Oral solid |
3 | Orserdu | Elacestrant | Stemline Therapeutics | ER+、HER2-、ESR1 mutated advanced or metastatic breast cancer | SERD | Small molecule | Oral solid |
4 | Jesduvroq | Daprodustat | GSK | Anemia caused by chronic kidney disease for adults on dialysis for at least four months | HIF-PHI inhibitor | Small molecule | Oral solid |
5 | Filspari | Sparsentan | Travere Therapeutics | Adults with primary immunoglobulin A nephropathy | Endothelin and angiotensin II receptor antagonist | Small molecule | Oral solid |
6 | Skyclarys | Omaveloxolone | Reata Pharmaceuticals | Friedrich’s ataxia | NF E2 related factor 2 stimulants | Small molecule | Oral solid |
7 | Zavzpret | Zavegepant Hydrochloride | Pfizer | Migraine | CGRP receptor antagonists | Small molecule | Nasal spray |
8 | Daybue | Trofinetide | Acadia | Rett syndrome | Analogue of the neuropeptide (1-3) IGF-1 | Peptide | Oral solution |
9 | Rezzayo | Rezafungin Acetate | Cidara Therapeutics | Candidemia and invasive candidiasis | Glucan synthase inhibitors | Cyclic Peptide | Injection |
10 | Joenja | Leniolisib Phosphate | Pharming | Activated phosphoinositide 3-kinase delta syndrome | PI3Kδ inhibitor | Small molecule | Oral solid |
11 | Qalsody | Tofersen | Biogen | Amyotrophic lateral sclerosis in adults who have a SOD1 gene mutation | RNA interference | ASO | Injection |
12 | Veozah | Fezolinetant | Astellas | Moderate to severe hot flashes caused by menopause | Neurokinin 3 receptor antagonists | Small molecule | Oral solid |
13 | Miebo | Perfluorohexyloctane | Bausch+Lomb Corp. & Novaliq GmbH | Dry eye disease | Lipid modulators | Small molecule | Eye drops |
14 | Xacduro | Sulbactam,Durlobactam | Innoviva | Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia | β-lactamase inhibitor | Small molecule | Injection |
15 | Posluma | Flotufolastat F-18 Gallium | Blue Earth Diagnostics | Use with positron emission tomography imaging in certain patients with prostate cancer | Target PSMA | peptidomimetics | Injection |
16 | Paxlovid | Nirmatrelvir,Ritonavir | Pfizer | Mild-to-moderate COVID-19 in adults at high risk for progression to severe COVID-19 | 3C protease inhibitor,CYP3A4 protease inhibitor | Small molecule | Oral solid |
17 | Inpefa | Sotagliflozin | Lexicon | Heart failure | SGLT-1/2 inhibitor | Small molecule | Oral solid |
18 | Litfulo | Ritlecitinib Tosylate | Pfizer | Severely patchy hair loss | JAK3 inhibitor,TEC inhibitor | Small molecule | Oral solid |
19 | Vanflyta | Quizartinib Dihydrochloride | Daiichi Sankyo | As part of a treatment regimen for newly diagnosed acute myeloid leukemia that meets certain criteria | FLT3 inhibitor | Small molecule | Oral solid |
20 | Xdemvy | Lotilaner | Tarsus | Demodex blepharitis | GABA-A receptor antagonists | Small molecule | Eye drops |
21 | Izervay | Avacincaptad Pegol Sodium | Iveric Bio | Geographic atrophy secondary to age-related macular degeneration) | Complement C5 inhibitor | Small molecule | Eye drops |
22 | Zurzuvae | Zuranolone | Biogen&Sage Therapeutics | Postpartum depression | GABA A receptor positive allosteric modulator | Small molecule | Oral solid |
23 | Aphexda | Motixafortide Acetate | BioLineRx | Multiple myeloma | CXCR4 inhibitor | Cyclic peptide | Injection |
24 | Sohonos | Palovarotene | Ipsen | Reduce the volume of new heterotopic ossification in adults and pediatric patients with fibrodysplasia ossificans progressiva | Retinoic acid receptor gamma agonist | Small molecule | Oral solid |
25 | Ojjaara | Momelotinib Dihydrochloride | GSK | Intermediate or high-risk myelofibrosis in adults with anemia | JAK1/JAK2/ALK2 inhibitor | Small molecule | Oral solid |
26 | Exxua | Gepirone Hydrochloride | Fabre-Kramer Pharmaceuticals | Major depressive disorder | 5-HT1A serotonin receptor agonist | Small molecule | Oral solid |
27 | Rivfloza | Nedosiran Sodium | NovoNordisk | Patients 9 years and older with primary hyperoxaluria type 1 | ASGR1&L-lactate dehydrogenase inhibitor | siRNA | Injection |
28 | Velsipity | Etrasimod Arginine | Pfizer | Moderately to severely active ulcerative colitis in adults | Sphingosine 1 phosphate receptor modulator | Small molecule | Oral solid |
29 | Zilbrysq | Zilucoplan Sodium | UCB | Generalized myasthenia gravis in adults who are anti-acetylcholine receptor (AChR) antibody positive | Complement C5 inhibitor | Cyclic peptide | Injection |
30 | Agamree | Vamorolone | Santhera Pharmaceuticals& ReveraGen BioPharma | Duchenne muscular dystrophy | Glucocorticoid receptor agonist | Small molecule | Oral solid |
31 | Fruzaqla | Fruquintinib | Hutchmed&Takeda | Refractory, metastatic colorectal cancer | EGFR | Small molecule | Oral solid |
32 | Defencath | Heparin Sodium,Taurolidine | CorMedix | Reduce the incidence of catheter-related bloodstream infections in adults with kidney failure receiving chronic hemodialysis through a central venous catheter | AT III agonist, LPS inhibitor | Small molecule | Injection |
33 | Augtyro | Repotrectinib | BMS | ROS1-positive non-small cell lung cancer | ROS1/TRK/ALK protein inhibitor | Small molecule | Oral solid |
34 | Truqap | Capivasertib | AstraZeneca | HR+、HER2- breast cancer | AKT inhibitor | Small molecule | Oral solid |
35 | Ogsiveo | Nirogacestat Hydrobromide | SpringWorks Therapeutics | Adults with progressing desmoid tumors who require systemic treatment | A γ-secretase inhibitor | Small molecule | Oral solid |
36 | Fabhalta | Iptacopan Hydrochloride | Novartis | Paroxysmal nocturnal hemoglobinuria | Factor B inhibitor | Small molecule | Oral solid |
37 | Filsuvez | Birch Triterpenes | Amryt | Wounds associated with dystrophic and junctional epidermolysis bullosa | N/A | Small molecule | Gel |
38 | Wainua | Eplontersen | AstraZeneca & Ionis | Polyneuropathy of hereditary transthyretin-mediated amyloidosis | TTR inhibitor | ASO | Injection |
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
No. | Brand name | Active ingredient | Innovator | Polymorph Patent Status |
1 | Brenzavvy | Bexagliflozin | TheracosBio | Granted |
2 | Jaypirca | Pirtobrutinib | Eli Lilly | Partial granted |
3 | Orserdu | Elacestrant | Stemline Therapeutics | Granted |
4 | Jesduvroq | Daprodustat | GSK | Granted |
5 | Filspari | Sparsentan | Travere Therapeutics | Under examination |
6 | Skyclarys | Omaveloxolone | Reata Pharmaceuticals | Granted |
7 | Joenja | Leniolisib Phosphate | Pharming | Withdrawn (crystal forms disclosed in compound patent) |
8 | Veozah | Fezolinetant | Astellas | Withdrawn |
9 | Paxlovid | Nirmatrelvir,Ritonavir | Pfizer | Granted (crystal forms disclosed in compound patent) |
10 | Inpefa | Sotagliflozin | Lexicon | Granted |
11 | Litfulo | Ritlecitinib Tosylate | Pfizer | Partial granted |
12 | Vanflyta | Quizartinib Dihydrochloride | Daiichi Sankyo | Granted |
13 | Zurzuvae | Zuranolone | Biogen&Sage Therapeutics | Granted |
14 | Sohonos | Palovarotene | Ipsen | Not found |
15 | Ojjaara | Momelotinib Dihydrochloride | GSK | Granted |
16 | Exxua | Gepirone Hydrochloride | Fabre-Kramer Pharmaceuticals | Not found |
17 | Velsipity | Etrasimod Arginine | Pfizer | Granted |
18 | Agamree | Vamorolone | Santhera Pharmaceuticals & ReveraGen BioPharma | Granted |
19 | Fruzaqla | Fruquintinib | Hutchmed&Takeda | Granted |
20 | Augtyro | Repotrectinib | BMS | Granted |
21 | Truqap | Capivasertib | AstraZeneca | Granted |
22 | Ogsiveo | Nirogacestat Hydrobromide | SpringWorks Therapeutics | Granted |
23 | Fabhalta | Iptacopan Hydrochloride | Novartis | Granted |
24 | Filsuvez | Birch Triterpenes | Amryt | Not found |
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
No. | Brand name | Compound patent | Expiration date[2] | Polymorph patent | Expiration date[3] | Time gap[4](Month) |
1 | Brenzavvy | US7838499B2 | 2029/1/30 | US8987323B2 | 2032/5/14 | ~45 |
2 | Jaypirca | US10695323B2 | 2036/12/16 | US20210330643A1 | Filing date 2019/07/29 | N/A |
3 | Orserdu | US7612114B2 | 2026/08/18 | US11643385B2 | 2039/7/3 | ~155 |
4 | Jesduvroq | US8324208B2 | 2028/12/11 | US11117871B2 | 2038/3/13 | ~111 |
5 | Filspari | US6835741B2 | Expired | US20220048900A1 | Filing date 2019/12/20 | N/A |
6 | Skyclarys | US8124799B2 | 2029/12/3 | US8993640B2 | 2033/4/24 | ~40 |
7 | Joenja | US8653092B2 | 2032/2/19 | US20180265509A1 | Filing date 2011/7/1 | N/A |
8 | Paxlovid | US11351149B2 | 2041/8/5 | US11351149B2 | 2041/8/5 | N/A |
9 | Inpefa | US8476413B2 | 2028/5/29 | US8217156B2 | 2030/10/7 | ~28 |
10 | Litfulo | US9617258B2 | 2034/12/3 | US20210387989A1 | Filing date 2019/10/21 | N/A |
11 | Vanflyta | US7820657B2 | 2028/9/26 | US8883783B2 | 2031/7/12 | ~34 |
12 | Zurzuvae | US9512165B2 | 2034/4/17 | US11236121B2 | 2037/8/23 | ~40 |
13 | Ojjaara | US8486941B2 | 2030/1/3 | US9469613B2 | 2035/6/11 | ~65 |
14 | Velsipity | US8580841B2 | 2030/3/5 | US10301262B2 | 2036/6/21 | ~75 |
15 | Agamree | US3947409A | Expired | US11382922B2 | 2040/7/16 | >198 |
16 | Fruzaqla | US7829574B2 | 2028/5/9 | US10519142B2 | 2035/9/7 | ~88 |
17 | Augtyro | US9714258B2 | 2035/1/23 | US10294242B2 | 2036/7/5 | ~17 |
18 | Truqap | US8101623B2 | 2030/3/10 | US9487525B2 | 2033/4/16 | ~33 |
19 | Ogsiveo | US7342118B2 | 2025/8/18 | US10941118B2 | 2039/8/9 | ~168 |
20 | Fabhalta | US9682968B2 | 2034/7/14 | US11603363B2 | 2041/5/25 | ~82 |
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 (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 (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.
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.
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
Year | 2018 | 2019 | 2020 | 2021 | 2022 | 2023 |
New drugs approved by FDA | 59 | 48 | 53 | 50 | 37 | 55 |
Small molecule new drugs | 39 | 32 | 34 | 31 | 17 | 38 |
Solid/Semi-solid formulations drugs | 31 | 26 | 20 | 23 | 15 | 24 |
Drugs with polymorph patent application | 19 | 17 | 12 | 16 | 10 | 20 |
Proportion | 61% | 65% | 60% | 70% | 67% | 83% |
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.
Drug development stage | Polymorph patent strategy analysis | Patentability assessment | Polymorph patent application research scheme | Polymorph patent application | Patent reply support | Formulation of non-infringement strategy | Formulation of defense strategy |
Pre-Tox | √ | √ | √ | √ | |||
Pre-IND | √ | √ | √ | √ | |||
Phase I | √ | √ | √ | √ | |||
Phase II | √ | √ | √ | √ | √ | √ | √ |
Phase III | √ | √ | √ | √ | √ | √ | √ |
NDA | √ | √ | √ | √ | √ | √ | √ |
Post Marketing | √ | √ | √ | √ | √ | √ | √ |
Reference:
[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.