Mechanism of Action: Breast Cancer Resistance Protein Inhibitors

Drugs with Mechanism of Action: Breast Cancer Resistance Protein Inhibitors

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Exclusivity Expiration
Helsinn Hlthcare	AKYNZEO	netupitant; palonosetron hydrochloride	CAPSULE;ORAL	205718-001	Oct 10, 2014		RX	Yes	Yes			Y
Helsinn Hlthcare	AKYNZEO	netupitant; palonosetron hydrochloride	CAPSULE;ORAL	205718-001	Oct 10, 2014		RX	Yes	Yes			Y	Y
Helsinn Hlthcare	AKYNZEO	netupitant; palonosetron hydrochloride	CAPSULE;ORAL	205718-001	Oct 10, 2014		RX	Yes	Yes			Y
Helsinn Hlthcare	AKYNZEO	netupitant; palonosetron hydrochloride	CAPSULE;ORAL	205718-001	Oct 10, 2014		RX	Yes	Yes

Breast Cancer Resistance Protein Inhibitors Market Analysis and Financial Projection

The market dynamics and patent landscape for Breast Cancer Resistance Protein (BCRP/ABCG2) inhibitors reflect a rapidly evolving field driven by the urgent need to overcome multidrug resistance (MDR) in cancer treatment. Here’s an in-depth analysis:

---

Market Dynamics

1. Growing Demand for Overcoming Drug Resistance

   • BCRP overexpression is linked to resistance in cancers such as triple-negative breast cancer (TNBC), leukemia, and colorectal cancer[6][15]. This drives demand for inhibitors that restore chemotherapy efficacy.
   • The global cancer immunotherapy market, valued at $45.8 billion in 2016, is projected to reach $120 billion[2], with BCRP inhibitors playing a niche but critical role in combination therapies.

2. Repurposing Existing Drugs

   • Febuxostat, a xanthine oxidase inhibitor used for gout, unexpectedly emerged as a potent BCRP inhibitor with an IC₅₀ of 27 nM—lower than Ko143 and elacridar[1][4]. Its established safety profile accelerates clinical adoption.
   • Cisapride (IC₅₀ = 0.4 µM) and roflumilast (IC₅₀ = 0.9 µM), initially approved for gastrointestinal and pulmonary diseases, respectively, show promise as BCRP inhibitors[9][12].

3. Novel BCRP Inhibitors in Development

   • Ac15(Az8)₂, a triazole-bridged flavonoid dimer, demonstrates selective BCRP inhibition and enhances topotecan efficacy in xenograft models[13].
   • Vemurafenib (IC₅₀ = 1.1 µM) and dabigatran etexilate (IC₅₀ = 1.9 µM) are among 75 FDA-approved drugs identified as strong BCRP inhibitors, hinting at new therapeutic combinations[10].

4. Combination Therapies

   • Immunomedics’ patent (US 10,954,305) combines the BCRP inhibitor sacituzumab govitecan (an anti-Trop-2 ADC) with SN-38 to treat resistant cancers[14]. Such strategies aim to extend drug efficacy and market exclusivity.

---

Patent Landscape

1. Core Innovations

   • Structural and Method Patents:
     • Phigenix’s U.S. Patent 11,033,628 covers PAX2 inhibitors and companion diagnostics for resistant breast cancer[3], reflecting a trend toward precision medicine.
     • CA2707718A1 discloses acrylonitrile derivatives as BCRP inhibitors, though it was later abandoned[11].

2. Combination Therapy Patents

   • Immunomedics’ patent highlights ABCG2 inhibitors + antibody-drug conjugates (ADCs) to bypass resistance[14]. Similar strategies dominate recent filings.

3. Repurposing and New Uses

   • Patents for pivarubicin and benzarubicin (anthracycline derivatives) in TNBC treatment underscore efforts to reposition existing drugs[8].

4. Diagnostic Integration

   • Phigenix’s patent includes methods for PAX2/DEFB1 expression testing to guide inhibitor use[3], aligning with FDA/EMA guidelines requiring DDI risk assessment[10].

---

Competitive Landscape

Company/Institution	Key Contributions	Strategic Focus
Phigenix, Inc.	PAX2 inhibitor patents + companion diagnostics[3]	Precision oncology
Immunomedics (now Gilead)	Sacituzumab govitecan + ABCG2 inhibitor combinations[14]	ADC-based therapies
Academic/Research Collaborations	Febuxostat validation[1][4]; Ac15(Az8)₂ development[13]	Novel inhibitor discovery

---

Challenges and Opportunities

• Clinical Hurdles: Early-generation inhibitors (e.g., Ko143) failed due to toxicity[6]. Next-gen inhibitors like Ac15(Az8)₂ prioritize safety and selectivity[13].
• Regulatory Scrutiny: FDA/EMA require IC₅₀-based DDI assessments for BCRP inhibitors[10], complicating development but ensuring safer combinations.
• Market Opportunities: Companion diagnostics (e.g., DEFB1 testing[3]) and AI-driven drug discovery[9][12] reduce trial costs and accelerate approvals.

---

Key Takeaways

• The BCRP inhibitor market is fueled by repurposed drugs (febuxostat, cisapride) and novel agents (Ac15(Az8)₂).
• Patent activity focuses on combination therapies, diagnostics, and structural innovations.
• Strategic partnerships between biopharma and academia are critical to overcoming clinical and regulatory challenges.

---

"Febuxostat inhibits ABCG2 more strongly than Ko143 and elacridar, suggesting its potential as the first clinical ABCG2 inhibitor." — Miyata et al., Frontiers in Pharmacology[1]

References

1. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00208/full
2. https://ipwatchdog.com/2017/08/10/immunotherapy-patent-landscape-patent-claims-immunotherapeutic-inventions/id=86634/
3. https://www.globenewswire.com/news-release/2021/06/15/2247639/0/en/Phigenix-Inc-Announces-Issuance-of-U-S-Patent-Covering-Precision-Medicine-Diagnostic-and-Novel-Therapeutic-for-Treating-Drug-Resistant-Breast-Cancer.html
4. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00518/full
5. https://link.epo.org/web/publications/studies/en-patents-and-innovation-against-cancer-study.pdf
6. https://www.oaepublish.com/articles/cdr.2019.31
7. https://drughunter.com/articles/pan-kras-inhibitors-tumor-cell-activated-kars-not-kras-inhibitors-mk2-degraders-i
8. https://patents.justia.com/patent/20230255993
9. https://pmc.ncbi.nlm.nih.gov/articles/PMC5302078/
10. https://pubmed.ncbi.nlm.nih.gov/36529162/
11. https://patents.google.com/patent/CA2707718A1/en
12. https://journals.sagepub.com/doi/pdf/10.1177/1087057116657513
13. https://pmc.ncbi.nlm.nih.gov/articles/PMC9653733/
14. https://uspto.report/patent/grant/10,954,305
15. https://pmc.ncbi.nlm.nih.gov/articles/PMC9820944/