Box 34 Antibodies And Derivatives Used As Biotherapeutic Agents And Their Specific Targets

CD3 (muromonab-CD3), CD20 (Ritux-imab), CD25 (Basiliximab; Daclizumab), CD33- (Gemtuzumab-ozogamicin), CD52 (Alemtuzumab) Platelets-IIa/IIIb (Abciximab)

TNF-a (Etanercept; Infliximab) HER-2 proto-oncogene product (Trastuzumab), IL-2 (Ontak) Respiratory syncytial virus (Palivizumab), (hyperimmune globulin Respigam)

Interferon Beta Use in Multiple Sclerosis

The first interferon beta for treatment of multiple sclerosis (MS)—Betaseron (interferon beta-1b)—received FDA approval in July 1993, based on a placebo-controlled study evaluating the incidence of exacerbations. Subsequently, a second interferon beta, Avonex (an interferon beta-1a), was shown to be effective for reducing the incidence of exacerbations and reducing the accumulation of physical disability. Betaseron received orphan drug designation prior to approval, and was still within the seven-year period of marketing exclusivity at the time Avonex was under review. However, Biogen, the manufacturer of Avonex, provided evidence that Avonex was not the same drug as Betaseron within the meaning of the orphan drug regulations, by showing a significantly better safety profile with regard to skin necrosis at injection sites. Consequently, Avonex and Betaseron were deemed to be different drugs and Biogen received marketing approval for Avonex in May 1996. Biogen also held an orphan drug designation for Avonex and had a seven-year period of marketing exclusivity that expired in May 2003.

Serono, a third manufacturer of an interferon beta product, Rebif (another interferon beta-1a), also conducted clinical studies in MS patients. Serono completed their studies and submitted a Biologies License Application (BLA) for Rebif in February 1998. The major safety and efficacy data came from a controlled study of two different doses of Rebif vs. placebo. Based on the findings, the FDA concluded that Rebif was safe and effective for the treatment of MS. However, within the framework of the orphan drug regulations, Rebif was regarded as the "same drug" as both Betaseron and Avonex. Serono was not able to supply evidence to establish that Rebif was not the "same drug," and the product was denied marketing approval until the bar of marketing exclusivity was removed, either by expiration of the exclusivity period, or by Serono providing evidence that Rebif was not the "same drug." Serono recognized that the period of exclusivity for Betaseron would expire in July 2000, leaving only the marketing exclusivity for Avonex as an issue after that date. Thus, in late 1999, Serono initiated another clinical study with the intent to demonstrate superior clinical efficacy of Rebif compared with Avonex.

Orphan Drug Regulations

The orphan drug regulations allow a sponsor of an orphan-designated drug a period of marketing exclusivity, free from

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