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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

 

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

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


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:

[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.


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