Clinical trials for prion disease: difficult challenges, but hope for the future

Prion diseases are uniformly fatal, often rapidly progressive, neurodegenerative diseases resulting from the transformation and accumulation of a native protein, the prion protein, into an abnormally shaped protein, called the prion. Human prion diseases, such as CreutzfeldtJakob disease (CJD), come in three forms: sporadic, genetic, and acquired (such as variant CJD). 1 Many therapeutic strategies have been tested as potential treatments for prion diseases in cell cultures and in animals. 2 Unfortunately, drugs that work in cell culture have generally not worked as well in animals, and the few drugs reported to work in animal models were beneficial only in the early, preclinical phase of the disease. When assessed in human beings in case series or case reports, these drugs showed no clear long-term clinical efficacy. 3,4 So far, only one randomised controlled trial of human prion disease, with the opioid-like analgesic flupirtine, has been published. 5 However, no significant benefit was seen for either the primary outcome (cognitive function) or the secondary outcome (survival). 5 In 2001, a paper reported on the effectiveness of the antimalarial drug quinacrine (also known as mepacrine) in eliminatation of prions from a cell-culture model of prion disease. 4 Because quinacrine has been used for many decades and has a well described safety and tolerability profile, the UK Medical Research Council designed a trial of quinacrine for the treatment of prion disease, known as PRION-1. In this issue of The Lancet Neurology, Collinge and co-workers 6 present the results of this first UK trial to treat human prion diseases with quinacrine. PRION-1 was initially intended to be a partially randomised, patient-preference treatment trial, but ultimately this trial was only an observational study—albeit an important and well designed one. This trial offered patients with any form of prion disease the choice of entering one of three arms of an unblinded study: randomisation to receive quinacrine immediately or after 6 months; immediate quinacrine; or no quinacrine. Some patients chose to change group during the study. Primary endpoints were death and treatment response. Collinge and co-workers present data from 107 pa tients with prion disease in both the main PRION-1 study (84 patients) and an earlier pilot study (23 patients; six were offered open-label quinacrine and 17 were offered either quinacrine or no quinacrine). Because only one patient chose the randomisation arm at enrolment, the study is effectively an observational study that compared patients who chose quinacrine with those who did not. Patients who chose to receive quinacrine differed from those who chose to not receive the study treatment. More than twice as many patients chose not to receive quinacrine as chose to receive it, and patients with the least cognitive impairment (based on the mini-mental state examination) and best level of function (based on clinical dementia rating and Barthel index) tended to choose the quinacrine arm. Additionally, more patients with genetic forms of prion disease chose the quinacrine arm and more patients with the sporadic form of the disease chose no quinacrine compared with patients with other forms of the disease (although disease severity might have accounted for this; the more severe the disease, the less likely the patients were to choose quinacrine). These differences make a fair comparison of the two cohorts impractical.