Orphan Drug Development: The Regulatory, Economic and Scientific Aspects of Intravenous Baclofen

Abstract

If baclofen, a medication commonly used for the treatment of spasticity, is abruptly discontinued a withdrawal syndrome can ensue. Although suspected to be rare, this syndrome can be severe and include increased muscle tone and spasms, status epilepticus, hallucination, and a neuromalignant syndrome with subsequent rhabdomyolysis and multisystem organ failure leading to death if not treated appropriately. The ideal treatment would be replacement of oral or intrathecal (IT) baclofen, however, there are cases when that is not feasible. In these circumstances, an intravenous (IV) formulation of baclofen would enable rapid reinstatement of baclofen therapy until the original route of administration can be resumed. The focus of this dissertation is the economic, regulatory, and scientific aspects of the development of intravenous (IV) baclofen for the prevention or treatment of baclofen withdrawal. As baclofen withdrawal is expected to be rare, IV baclofen is being developed as an orphan drug. Therefore, the development of IV baclofen included an estimation of the population at-risk for baclofen withdrawal, characterization of the significance, prevalence, and treatment of baclofen withdrawal, as well as preclinical and clinical trials in dogs and healthy volunteers. The first clinical study discussed in this dissertation was a dose escalation study to evaluate the safety, tolerability, and pharmacokinetics of IV baclofen at clinically relevant doses. This study was used to select the doses most likely to meet bioequivalence criteria when compared to oral administration for the comparative bioavailability study presented in Chapter 7. To gain additional toxicity information at high doses, data from literature and the dose escalation study was used to design a canine toxicity study. The research presented in this thesis will be used to support the FDA approval of IV baclofen and suggests that it will play a key role in the prevention or treatment of baclofen withdrawal. Subsequent repeated dose studies in patients taking oral or IT baclofen would further guide dosing and bridging strategies to improve the management of baclofen withdrawal.