Innovative drug development for infertility therapy

Abstract

Innovative drug development is essential to improve therapy over time by offering better efficacy, safety and/or treatment convenience. This thesis summarizes the sequential clinical development of three innovative fertility drugs namely follitropin-b (recombinant FSH), ganirelix (GnRH antagonist) and corifollitropin alfa (recombinant long-acting FSH agonist). Follitropin-b replaced urinary FSH, ganirelix introduced a new and short treatment protocol, and corifollitropin alfa replaced the first 7 daily (r)FSH injections during ovarian stimulation in a GnRH antagonist protocol. The development of these drugs has dramatically changed hormonal treatment of women participating in an ART program from being lengthy and complicated to short and simple.

Comparative preclinical pharmacology is essential to determine the mechanism of action, specificity, and bioactivity to predict the potency in humans. The first-in-human phase I studies of follitropin-b and corifollitropin alfa included subjects with hypogonadotropic hypogonadism (HH) as the immunogenicity is hard to predict in preclinical models. Apart from safety and pharmacokinetics, it was examined whether follitropin-b could stimulate multiple follicular growth in the complete absence of LH activity. The first-in-human study of the fusion molecule corifollitropin alfa in HH men was focusing on its potential immunogenicity. Only thereafter, a phase I study in pituitary-suppressed female volunteers was performed with increasing doses of corifollitropin alfa.

Phase II research of follitropin-b was limited to the question whether patients down-regulated with different GnRH agonist protocols could be treated with pure recombinant FSH lacking LH activity. In contrast, the GnRH antagonist ganirelix was tested in a double-blind, dose-finding study including 6 dose groups of which the lowest and highest dose group were discontinued and finally one dose was selected for further development. Corifollitropin alfa was initially tested in a feasibility study and thereafter in a phase II controlled dose-finding study that demonstrated that the optimal dose was between the lowest and highest test dose. Subsequent dose selection was based on modeling and simulation taking into account the inverse relationship between exposure to corifollitropin alfa and body weight and that FSH activity has to retain for 7 days above the threshold to support multiple follicular development.

In comparative phase III studies of follitropin-b, ganirelix and corifollitropin alfa, the number of oocytes or the pregnancy rate was the primary endpoint. In time, follitropin-b was compared to urinary FSH and developed in a long GnRH agonist protocol. Subsequently, the GnRH antagonist ganirelix was compared to a long GnRH agonist protocol and finally a single dose of corifollitropin alfa was compared to daily follitropin-b using a ganirelix protocol. Main safety endpoints during phase III trials focused on the incidence of adverse events including Ovarian Hyperstimulation Syndrome (OHSS), hypersensitivity, immunogenicity, and the health outcome of offspring. Registration of new drugs requires a positive benefit/risk ratio based on the evaluation of all efficacy and safety parameters. Following drug approval, retrospective analyses may support further development of treatment regimens or for specific subgroups of patients. Prospective Phase IV studies may obtain additional efficacy and/or safety data to extend labeling to the final drug posology and profile.