The clinical development of recombinant forms of HGF were directed by an extensive understanding of the biologic effects of these factors. The human gene encoding EPO was cloned in 1983 (22), and clinical development of epoetin alfa began soon after. Initial studies were focused on patients with an endogenous EPO deficiency, such as patients with severe chronic renal failure receiving dialysis. The effects of epoetin alfa were apparent in the first dose levels with an increase in hemoglobin concentration and hematocrit. A reduction in the requirement for red blood cell transfusions was ultimately proved in the pivotal phase 3 trial. Further studies focused on defining a safe rate of rise in hemoglobin and an appropriate target; however, a conservative target rather than normalization of hematocrit was initially approved in the dialysis setting. In patients with underlying heart disease, the safety and benefits of correction to a normal hematocrit are still under investigation almost 20 years after the initiation of clinical studies (32,33).
For the development of rHuEPO in the setting of cancer, a major challenge was to recognize the benefits of maintaining hematocrits at higher volumes than had been the previous practice when only blood transfusions were available. A second challenge was to obtain sufficient information on the reduction in the need for transfusions and improvement in quality of life to justify the cost of therapy with rHuEPO. Recent guidelines developed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) address the optimum use of rHuEPO. They do not yet evaluate the impact of darbepoetin alfa on this field.
Another set of blood factors studied were the factors stimulating the platelet lineage. The development of factors stimulating platelets was impaired by several observations. The first was that the factors available, rHuIL-11 and rHuTPO, act on increasing the number and ploidy of megakaryoctes but do not stimulate platelet shedding. Therefore, the increase in platelet counts is slow. Second, IL-11 was pleiotropic and was associated with significant adverse events. The recombinant thrombopoietins (rHuTPO, PEG-rHuMGDF) tested in the clinic induced antibodies that inhibited their own activity and the activity of TPO, leading to prolonged thrombocytopenia.
HGFs such as SCF and flt3 ligand were also tested for activity on multipotential stem cells. rHuSCF enhanced progenitor cell mobilization induced by rHuG-CSF. The problems of severe stem cell deficiency states such as aplastic anemia remain unsolved, and rHuSCF was associated with side effects related to mast cell activation. Nevertheless, rHuSCF received marketing approval in Australia, New Zealand, and Canada.
Was this article helpful?