Product case study Rebif

Rebif (tradename) is an rIFN-P-1a first approved for medical use in the EU in 1998 and subsequently in the USA in 2002. It is indicated for the treatment of patients with relapsing-remitting MS, to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability.

Rebif is produced via recombinant DNA technology in a CHO cell line. It displays an identical amino acid sequence to that of native human IFN-P-1a and, like the native product, is glycosylated. After cell culture the interferon is purified using a series of chromatographic steps (affinity, ion-exchange, gel-filtration and reverse-phase liquid chromatography). It is formulated as a sterile solution in pre-filled syringes and contains mannitol, HSA, sodium acetate, acetic acid and sodium hydroxide as excipients. It is administered subcutaneously three times weekly.

Product pharmacokinetics were evaluated in healthy volunteers and a single s.c. injection (60 ^g) resulted in a peak serum concentration Cmax = 5.1 IU ml-1, with a median time of peak serum concentration Tmax = 16 h. The serum elimination half-life t1/2 was of the order of 70 h.

The product was evaluated in two multicentre clinical studies that established safety and efficacy. The first (the 'PRISMS' study) was a randomized, double blind placebo-controlled study involving 187 patients. The primary efficacy end-point was the number of clinical relapses recorded. The mean number of relapses over 2 years for the placebo group patients was 2.56, whereas that of the Rebif-treated group was 1.73, a relative reduction of 32 per cent. Rebif treatment also provided positive relative outcomes for several secondary end-points, including the proportion of patients with sustained disability progression.

The most common side effects noted included injection site reactions and flu-like symptoms with serious potential side effects including depression, as well as liver and blood abnormalities. Rebif is manufactured and marketed by Serono Inc.

Figure 8.7 Overview of the manufacture of Betaferon, a recombinant human IFN-P produced in E. coii. The product differs from native human IFN-P in that it is unglycosylated and cysteine residue 17 had been replaced by a serine residue. E. coii fermentation is achieved using minimal salts/glucose media and product accumulates intracellularly in inclusion body (IB) form. During downstream processing, the Ibs are solubilized in butanol, with subsequent removal of this denaturant to facilitate product refolding. After two consecutive gel-filtration steps, excipients are added, the product is filled into glass vials and freeze-dried. It exhibits a shelf life of 18 months when stored at 2-8 °C

Figure 8.7 Overview of the manufacture of Betaferon, a recombinant human IFN-P produced in E. coii. The product differs from native human IFN-P in that it is unglycosylated and cysteine residue 17 had been replaced by a serine residue. E. coii fermentation is achieved using minimal salts/glucose media and product accumulates intracellularly in inclusion body (IB) form. During downstream processing, the Ibs are solubilized in butanol, with subsequent removal of this denaturant to facilitate product refolding. After two consecutive gel-filtration steps, excipients are added, the product is filled into glass vials and freeze-dried. It exhibits a shelf life of 18 months when stored at 2-8 °C

relapses by about 30 per cent in many patients. In some instances, a sustained reduction in the accumulation of MS brain lesions (as measured by magnetic resonance imaging) is also observed. However, there is little evidence that IFN-P significantly alters overall progression of the disease. A summary overview of the production of one such product (Betaferon) is presented in Figure 8.7.

The molecular mechanism by which IFN-P induces its therapeutic effect is complex and not fully understood. It is believed that the pathology of MS is linked to the activation and proliferation of T-lymphocytes specific for epitopes found on specific myelin antigens. Upon migration to the brain, these lymphocytes trigger an inflammatory response mediated by the production of proinflammatory cytokines, most notably IFN-y IL-1, IL-2 and TNF-a. The inflammatory response, in addition to other elements of immunity (e.g. antibodies and complement activation), results in the destruction of myelin surrounding neuronal axons. IFN-P likely counteracts these effects, in part at least, by inhibiting production of IFN-y and TNF-a and hence mediating down-regulation of the pro-inflammatory response.

Table 8.10 Some pathogens (bacterial, fungal and protozoal) whose phagocytic-mediated destruction is impaired in persons suffering from CGD. Administration of IFN-y, in most cases, enhances the phagocyte's ability to destroy these pathogens. These agents can cause hepatic and pulmonary infections, as well as genitourinary tract, joint and other infections

Staphylococcus aureus Plasmodium flaciparum

Listeria monocytogenes Leishmania donovani

Chlamydia psittaci Toxoplasma gondii Aspergillus fumigatus

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment