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Leflunomide Aventis Pharma
1University of Michigan Medical Center, Division of Rheumatology, Ann Arbor 48109-1065, USA. makaplan@umich.edu
Abstract:
Hoechst Marion Roussel (HMR; now Aventis Pharma) launched leflunomide (HWA-486), an immunomodulator and a disease-modifying antirheumatic drug (DMARD), for the treatment of rheumatoid arthritis (RA) in the US in late 1998 [310118]. By August 2000, the compound had been launched extensively across all of Latin America and in all major European countries [380046]. The compound is also under preclinical investigationfor the prevention of transplant rejection [279727], [304402]. In 1998, HMR filed for approvalfor RA in Europe [279727]. In September 1998, the FDA approved leflunomide for the treatment of active RA in adults and it was launched shortly thereafter [298204], [299258], [310118]. In September 1999, the EU Commission accepted the view of the Committee for Proprietary Medicinal Products, published in May 1999 [326040], [337534], and gave approval for the use of leflunomide in RA in adults [339128]. Lehman Brothers has reported that EU launch was delayed by rare side effects including pancytopenia [354434]. In August 1998, the Arthritis Advisory Committee unanimously recommended that leflunomide be contraindicatedfor pregnancy, and that a pregnancy registry should be established to monitor possible teratogenic effects of the drug [296187]. Kyorin had a licence to develop leflunomide in Japan. Product approval was scheduled for 1998 [159079], but no development has been reported since 1994. Preclinical studies in an animal model of experimental allergic encephalomyelitis (EAE) have shown leflunomide to be a powerful immunosuppressant which may have potential in diseases such as multiple sclerosis [187881]. Leflunomide is rapidly processed in vivo to its active metabolite, A-771726 (RS-61980) [202941], [253615]. In 1996, leflunomide was designated as one of HMR's nine top-priority products, serving an unmet medical need and addressing a potential market in excess of US $500 million per year [221118].
Insights
Leflunomide, an immunomodulator, was approved for rheumatoid arthritis treatment in the US and EU. This disease-modifying antirheumatic drug (DMARD) shows potential for transplant rejection and multiple sclerosis prevention.
Area of Science:
- Pharmacology
- Immunology
- Rheumatology
Background:
- Leflunomide (HWA-486) is an immunomodulator and disease-modifying antirheumatic drug (DMARD).
- It was developed by Hoechst Marion Roussel (HMR), now Aventis Pharma.
- Rheumatoid arthritis (RA) is a significant unmet medical need with a large potential market.
Purpose of the Study:
- To detail the development and regulatory approval of leflunomide for rheumatoid arthritis.
- To explore the preclinical investigation of leflunomide for transplant rejection and multiple sclerosis.
- To highlight the drug's market potential and strategic importance.
Main Methods:
- Regulatory filings and approvals in the US and EU for RA treatment.
- Preclinical studies in animal models (e.g., EAE) for immunosuppressive potential.
- Pharmacokinetic analysis of leflunomide's active metabolite (A-771726).
Main Results:
- Leflunomide received FDA approval for active RA in 1998 and EU approval in 1999.
- The drug was launched across the US, Latin America, and major European countries.
- Preclinical studies indicated leflunomide as a potent immunosuppressant with potential in multiple sclerosis and transplant rejection.
- A pregnancy registry was recommended due to potential teratogenic effects.
Conclusions:
- Leflunomide is an approved DMARD for RA with significant market presence.
- Its immunosuppressive properties suggest therapeutic potential beyond RA.
- Further monitoring for side effects, particularly teratogenicity, is warranted.