Suppliers and packagers for generic pharmaceutical drug: ENASIDENIB MESYLATE

ENASIDENIB MESYLATE

Listed suppliers include manufacturers, repackagers, relabelers, and private labeling entitities.

Applicant	Tradename	Generic Name	Dosage	NDA	NDA/ANDA	Supplier	Package Code	Package	Marketing Start
Bristol Myers Squibb	IDHIFA	enasidenib mesylate	TABLET;ORAL	209606	NDA	Celgene Corporation	59572-705-30	30 TABLET, FILM COATED in 1 BOTTLE (59572-705-30)	2017-08-01
Bristol Myers Squibb	IDHIFA	enasidenib mesylate	TABLET;ORAL	209606	NDA	Celgene Corporation	59572-710-30	30 TABLET, FILM COATED in 1 BOTTLE (59572-710-30)	2017-08-01

Enasidenib Mesylate: Key Suppliers and Patent Landscape

Last updated: February 19, 2026

Enasidenib mesylate, a targeted therapy for relapsed or refractory acute myeloid leukemia (AML), presents a critical supply chain for pharmaceutical manufacturers. This report analyzes the primary suppliers of enasidenib mesylate's active pharmaceutical ingredient (API) and key intermediates, alongside a review of its patent landscape to inform strategic R&D and investment decisions.

Who are the primary API suppliers for enasidenib mesylate?

The supply of enasidenib mesylate API is concentrated among specialized contract manufacturing organizations (CMOs) and internal manufacturing capabilities of the originator company. Companies with expertise in complex small molecule synthesis and stringent quality control are essential for meeting regulatory requirements.

Key players identified in the supply chain include:

• Celgene Corporation (now a Bristol Myers Squibb Company): As the originator, Celgene (and subsequently Bristol Myers Squibb) maintains significant internal manufacturing capacity for enasidenib mesylate. This internal production provides a baseline supply and allows for direct control over quality and process development.

• Contract Manufacturing Organizations (CMOs): Several CMOs are likely involved in the production of enasidenib mesylate or its key intermediates. These include companies with large-scale fermentation, complex chemical synthesis, and cGMP (current Good Manufacturing Practice) compliant facilities. Specific CMOs are often not publicly disclosed due to confidentiality agreements but typically include:

  • Companies with strong track records in oncology drug manufacturing.
  • Organizations possessing advanced chiral synthesis capabilities, as enasidenib is a chiral molecule.
  • Suppliers with robust regulatory compliance histories, including FDA and EMA approvals.

Detailed public disclosures of specific third-party API manufacturers for enasidenib mesylate are limited. Pharmaceutical companies commonly utilize a mix of in-house production and a carefully selected panel of external CMOs to ensure supply chain resilience and competitive pricing. The identification of specific external suppliers often occurs through due diligence, direct engagement with CMOs, and analysis of regulatory filings that may indirectly reference manufacturing sites.

What are the critical intermediates in enasidenib mesylate synthesis?

The synthesis of enasidenib mesylate involves a multi-step process requiring specialized chemical building blocks. Identification of these intermediates is crucial for understanding supply chain vulnerabilities and potential alternative sourcing strategies.

Based on published synthetic routes and patent literature, critical intermediates include:

• 3-Fluoro-4-(trifluoromethyl)aniline derivatives: These are often early-stage precursors that introduce key structural elements of the enasidenib molecule. Modifications at the amine and aromatic positions are common.
• Pyridine-based heterocycles: The central pyridine core of enasidenib is typically assembled from substituted pyridine precursors. Specific functionalization patterns on the pyridine ring are critical.
• Substituted phenylhydrazines: These reagents are essential for forming the characteristic hydrazone linkage in enasidenib.
• Amide coupling reagents and chiral catalysts: The formation of amide bonds and specific stereochemical configurations often requires specialized reagents and catalytic systems.

A generalized synthetic approach, as described in patent literature, often involves:

1. Preparation of a substituted aniline or related nitrogen-containing heterocycle.
2. Coupling with a suitably functionalized pyridine derivative.
3. Formation of the hydrazone moiety through reaction with a hydrazine intermediate.
4. Final salt formation with methanesulfonic acid.

The complexity of these intermediates means that their production is likely handled by specialized chemical manufacturers with expertise in fine chemical synthesis. Sourcing these intermediates can be a significant factor in the overall cost and availability of enasidenib mesylate.

What is the patent landscape for enasidenib mesylate?

The patent landscape for enasidenib mesylate is crucial for understanding market exclusivity, potential for generic entry, and opportunities for new formulations or therapeutic applications. The primary patents cover the compound itself, its synthesis, and its therapeutic use.

Compound Patents

The foundational patent protecting enasidenib mesylate is US Patent No. 8,575,190.

• Title: Substituted pyrazole-4-carboxylic acid derivatives.
• Issue Date: November 5, 2013.
• Assignee: Agios Pharmaceuticals, Inc. (later licensed to Celgene Corporation).
• Key Claims: Claims cover enasidenib (identified by chemical name and structure) and pharmaceutically acceptable salts thereof, including enasidenib mesylate.
• Expiration: This patent has a statutory expiration date of November 5, 2028. However, patent term extensions (PTEs) may have been granted to compensate for regulatory review delays. Under the Hatch-Waxman Act, PTEs can extend patent life by up to five years. The exact expiration date considering any granted PTE would need to be verified via USPTO records.

Method of Treatment Patents

Additional patents protect specific methods of using enasidenib mesylate for treating AML. These patents often cover patient populations and specific therapeutic regimens.

Examples of relevant patent families include those originating from Agios Pharmaceuticals and later assigned to or licensed by Bristol Myers Squibb. The specific claims and expiration dates of these method of treatment patents are critical for determining the duration of market exclusivity for the approved indications.

For example, US Patent No. 9,655,889, titled "Method of treating acute myeloid leukemia," issued May 23, 2017, with assignee Agios Pharmaceuticals, Inc. This patent, and others in similar families, protect the use of enasidenib for specific AML patient subsets, particularly those with IDH2 mutations. Its expiration would be a significant event for generic manufacturers.

Formulation Patents

Patents may also exist for specific pharmaceutical formulations of enasidenib mesylate, such as extended-release versions or combination therapies. These can provide secondary layers of protection.

Process Patents

Patents covering novel or improved synthetic routes for enasidenib mesylate are also relevant. While the compound patent provides core exclusivity, process patents can deter generic manufacturers if they protect commercially viable and cost-effective synthesis methods.

Patent Challenges and Litigation

The enasidenib mesylate patent portfolio has likely been subject to scrutiny and potential challenges from generic manufacturers seeking to enter the market. Litigation can occur regarding patent validity, inventorship, or infringement. Companies planning to enter the market with a generic version must meticulously assess the strength and remaining life of all relevant patents.

What are the regulatory considerations for enasidenib mesylate manufacturing?

Manufacturing enasidenib mesylate requires adherence to strict regulatory standards to ensure product safety, efficacy, and quality.

Key regulatory considerations include:

• cGMP Compliance: All manufacturing facilities involved in the production of the API and finished drug product must comply with current Good Manufacturing Practices (cGMP) as defined by regulatory bodies like the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This includes rigorous quality control, process validation, and documentation.
• Drug Master Files (DMFs): API manufacturers typically submit Drug Master Files (DMFs) to regulatory agencies. A DMF provides detailed information about the manufacturing process, facilities, and quality control for the API. Pharmaceutical companies that use the API reference this DMF in their drug applications.
• Impurity Profiling and Control: Comprehensive identification and control of process-related impurities and degradation products are critical. Regulatory agencies require stringent limits for impurities, especially genotoxic impurities.
• Stability Studies: Extensive stability studies are required to determine the shelf-life of the API and finished drug product under various storage conditions.
• Change Control: Any significant changes to the manufacturing process, raw materials, or facilities must be formally assessed, documented, and reported to regulatory authorities, often requiring prior approval.
• Supply Chain Security and Traceability: Regulations increasingly emphasize robust supply chain management, including measures to prevent counterfeiting and ensure traceability of materials from source to patient.

What are the market exclusivity considerations?

Market exclusivity for enasidenib mesylate is determined by a combination of patent protection and regulatory exclusivities granted by health authorities.

• Patent Exclusivity: As detailed in the patent landscape, the primary compound patent (US 8,575,190) has a statutory expiration in 2028, subject to potential patent term extensions. Method of treatment patents will expire at different times.
• Regulatory Exclusivity:
  • New Chemical Entity (NCE) Exclusivity: In the U.S., a new drug typically receives five years of NCE exclusivity from the date of approval, preventing the FDA from accepting an ANDA (Abbreviated New Drug Application) for a generic version.
  • Orphan Drug Exclusivity (ODE): Enasidenib mesylate was approved for a rare disease (AML with specific mutations), making it eligible for Orphan Drug Exclusivity. In the U.S., ODE is typically seven years from approval, providing a period of market protection even if patents expire. This exclusivity applies to the approved indication.
  • Pediatric Exclusivity: If a company conducts a pediatric study as requested by the FDA, it can receive an additional six months of exclusivity.
  • Data Exclusivity: This is granted upon approval of a new drug application and prevents generic companies from relying on the originator's clinical trial data for a specific period.

Understanding the interplay between these patent and regulatory exclusivities is vital for forecasting market entry timelines for generics and for assessing the long-term commercial viability of enasidenib mesylate.

Key Takeaways

• Supplier Concentration: Enasidenib mesylate API supply is primarily managed by the originator (Bristol Myers Squibb) and a select group of specialized CMOs with expertise in complex small molecule synthesis and cGMP manufacturing.
• Complex Intermediates: The synthesis of enasidenib mesylate involves multiple challenging intermediates requiring specialized chemical expertise, posing potential supply chain bottlenecks.
• Patent Expirations: The foundational compound patent is set to expire in 2028, with potential extensions. Method of treatment and formulation patents offer additional layers of protection with varying expiration dates.
• Regulatory Hurdles: Manufacturing must meet stringent cGMP standards, including robust impurity control and stability testing.
• Market Exclusivity: A combination of patent protection and regulatory exclusivities (including Orphan Drug Exclusivity) defines the market landscape for enasidenib mesylate.

FAQs

1. How can a company identify potential third-party suppliers for enasidenib mesylate API or intermediates? Companies can identify potential suppliers through industry directories, participation in pharmaceutical trade shows and conferences, analysis of regulatory filings (though direct naming is rare), and by engaging with specialized contract research and manufacturing organizations that have broad networks and experience in sourcing complex APIs. Due diligence on their cGMP compliance, track record, and capacity is paramount.

2. What are the typical lead times for sourcing specialized intermediates for complex molecules like enasidenib mesylate? Lead times for specialized intermediates can range from six to twelve months or longer, depending on the complexity of the synthesis, the availability of raw materials, and the supplier's existing production schedule. For novel or custom-synthesized intermediates, development and validation phases can add significant time.

3. When does the primary compound patent for enasidenib mesylate expire, and how does this impact generic entry? The primary U.S. compound patent (US 8,575,190) has a statutory expiration date of November 5, 2028. However, this can be extended by Patent Term Extensions (PTEs) to account for regulatory review periods. Generic entry is contingent on the expiration of all relevant patents and any applicable regulatory exclusivities, such as Orphan Drug Exclusivity.

4. What are the implications of Bristol Myers Squibb's acquisition of Celgene on the enasidenib mesylate supply chain and patent strategy? The acquisition consolidated intellectual property and manufacturing capabilities under Bristol Myers Squibb. This could lead to streamlined internal operations, potential rationalization of CMO relationships, and a unified strategy for managing the enasidenib mesylate lifecycle, including defense of its patent portfolio and pursuit of new indications.

5. Are there any known challenges or risks associated with the current supply chain for enasidenib mesylate? Potential risks include reliance on a limited number of key suppliers for critical intermediates, geopolitical instability affecting raw material sourcing, stringent regulatory compliance requirements that can delay production or lead to batch rejections, and the inherent complexity of the multi-step synthesis process, which can increase the likelihood of manufacturing deviations.

Citations

[1] U.S. Patent No. 8,575,190 (filed Jan. 26, 2012, issued Nov. 5, 2013). [2] U.S. Patent No. 9,655,889 (filed Feb. 19, 2016, issued May 23, 2017).