The challenges of rhGAA manufacture

In 1993, Synpac Pharmaceuticals became involved in developing an Enzyme ReplacementTherapy for Pompe´s disease when it began supporting the research of Y.T. Chen, M.D., Ph.D., Chief of Medical Genetics, Department of Pediatrics at Duke University Medical Centre. Dr. Chen’s work was successful and in 1996 Synpac (NC), Inc. was formed to acquire the technology developed by Dr. Chen and to initiate a program to manufacture the recombinant human acid alpha glucosidase for clinical trials and commercial use. Synpac (NC), Inc. is a subsidiary of Synpac Pharmaceuticals (UK), manufacturers of bulk penicillin. Synpac is owned by the Koos group, the fourth largest business conglomerate of Taiwan.

Synpac’s technology

Synpac’s technology is based on the expression of the human GAA gene introduced into Chinese hamster ovary (CHO) cells. Expressing human proteins in CHO cells is a well established system to produce biologically active recombinant proteins for human therapeutic use. A number of CHO cell products are approved and on the market. Rather than invest in the costly construction of manufacturing facilities and hiring of a large staff, Synpac has used experienced contractors to manufacture the enzyme. After the acquisition of the technology in 1996, the CHO cells were adapted to growth in suspension with serum free growth medium. A master cell bank of the CHO cells was generated and shown to be free of bacteria, fungus, mycoplasma and adventitious viruses. The growth of the CHO cells was adapted to large scale production. A procedure to purify the GAA enzyme, which removes CHO cell proteins and other molecules in the growth medium, was developed. Problems with aggregation and precipitation of the enzyme were resolved by developing a formulation buffer that provides long term stability of the enzyme in solution. Refinement of the CHO cells’ growth conditions and enzyme purification steps continues as the scale of the manufacturing increases to reach projected market levels.

Trials

After filing an Investigational New Drug (IND) application with the Food and Drug Administration in the United States in late April 1999, clinical trials to test the safety and efficacy of GAA started at Duke University Medical Centre under the direction of Dr. Chen in June 1999. This pilot study will include 3 infants who have Pompe’s disease and is expected to last approximately 6 months. Synpac plans to continue treating these patients with the enzyme if the treatment shows benefit and plans to expand the trials to include more infants in a Phase 3 study as soon as possible. Trials to include juveniles and adults are scheduled to commence in the year 2000.

Conclusion

Synpac is committed to bringing a recombinant enzyme therapy for Pompe´s disease to market and is pursuing an aggressive timeline and regulatory strategy to do so.