Quinacrine Fails to Stop Prion Disease
Abstract & Commentary
By Norman R. Relkin, MD, PhD and Cary S. Gunther, MD, PhD. Dr. Relkin is Director, Memory Disorders Program, and Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Gunther is a Resident, Neurology and Psychiatry, Weill Cornell Medical College. Dr. Relkin reports that he receives grant/research support from Baxter Bioscience, and is a consultant to Eisai, Pfizer, Myriad, and Smart Genetics. Dr. Relkin also reports he is leading a Phase 3 clinical trial of Intravenous Immunoglobulin for treatment for Alzheimer's disease, funded by the National Institute on Aging and Baxter Healthcare. Dr. Gunther reports no financial relationships relative to this field of study.
Synopsis: In the first non-randomized trial of Quinacrine for the treatment of prion diseases, there was no benefit in terms of survival or neurological outcome.
Source: Collinge J, Gorham M, Hudson F, et al. Safety and efficacy of quinacrine in human prion disease (PRION-1 study): A patient-preference trial. Lancet Neurology 2009;8:334-344; Geschwind M. Clinical trials for prion disease: Difficult challenges, but hope for the future. Lancet Neurology 2009;8:304-306.
Quinacrine, a drug used to treat cerebral malaria and rheumatoid arthritis, does not significantly increase survival in patients with prion disease, according to a clinical trial recently completed in the United Kingdom. Quinacrine may provide transient neurologic benefits in some cases, however.
Quinacrine has been shown to prevent conversion of the normally occurring prion precursor protein (PrPC) to pathogenic forms (denoted PrPSC) in cell cultures. This observation, combined with the established ability of quinacrine to cross the blood-brain barrier, motivated the PRION-1 study of quinacrine in human prion disease.
The organizers of the PRION-1 trial recruited subjects through a national referral system in the U.K. In an initial pilot study of 23 persons with prion disease, patients were offered a choice of quinacrine, no quinacrine, or randomization to immediate vs deferred quinacrine at a total daily dose of 300 mg after loading. When only one patient agreed to randomization, the subsequent study was carried out in an open-label fashion, with patient choice as the sole determinant of treatment. The main study involved a total of 84 patients with sporadic (45), iatrogenic (2), variant (18), and inherited (42) forms of prion disease. The primary endpoints of the study were death and treatment response. Treatment response was defined as improvement on two or more neurologic rating scales without signs of deterioration.
Overall, twice as many patients chose to receive quinacrine as no treatment. Although the data suggested a possible mortality benefit in subjects receiving quinacrine, there was no significant reduction in mortality after taking into account possible confounders such as disease severity, inherited vs acquired disease and time since onset of symptoms. Four of 40 patients taking quinacrine demonstrated transient improvement on neurologic symptom rating scales. However, all four of the responders sustained quinacrine-related toxicities.
The primary safety endpoint was the occurrence of adverse events likely related to quinacrine. There were 17 significant adverse effects reported in 16 patients on quinacrine, and 11 events, such as liver function abnormalities and skin color changes, were thought to be related to the drug. Although the trial's primary outcome measures were negative, the investigators suggested that the positive effects observed in a small number of subjects may warrant further study of quinacrine in prion disease.
Commentary
Currently, a diagnosis of prion disease means rapid, irreversible cognitive and behavioral decline leading to premature death. To date, no agent that has been tested in randomized, controlled trials has been shown to prolong survival or improve cognition in affected patients. Although mortality was not decreased by quinacrine in the PRION-1 trial, transient neurologic benefits were seen in some patients. Arguably, any improvement in a patient with prion disease is a reason for encouragement. Unfortunately, the four quinacrine-treated patients in this study who improved on neurological rating scales, all suffered adverse events, which limits the conclusions that can be drawn. The authors are currently conducting further analyses to pinpoint the nature of benefits seen.
In considering reasons for the trial's failure, the authors note that the quinacrine levels they achieved in patients were probably lower than the concentrations required to stop prion propagation in cell cultures. In several cases, dosing of quinacrine was limited by its toxicity. A bright orange-yellow skin discoloration often accompanies quinacrine use and this prevented blinding of clinical raters to the treatment arm. The designers of this study took an innovative approach to this problem by videotaping exams with black and white media and having them reviewed by blinded raters.
The PRION-1 study adds to our knowledge of the neurological milestones in the course of prion disease and highlights some of the hurdles that can stand in the way of conducting clinical trials in patients with this devastating illness. It is notable that subjects or family members giving consent overwhelmingly preferred to decide their own treatment rather than undergo randomization. The authors felt that patients in the initial stages of disease, knowing its progressive and fatal nature, would not accept possible randomization to deferred treatment; caregivers for patients in later stages of disease did not want the risk of a treatment that might slightly extend life without significant reversal of disease effects.
Currently, a double-blind controlled trial of quinacrine in sporadic CreutzfeldtJakob disease is being completed in San Francisco. That trial should provide further information about survival time, neurologic signs, cognitive effects and functional capacity resulting from quinacrine administration in prion disease. Another agent that showed activity against prions in in vitro studies, doxycycline, is also under study in Europe. To be effective, potential prion disease therapies may need to target the conversion of normal cellular prion protein to PrPSC, and not just clearance of the pathogenic form of the protein after its generation. Other approaches to anti-prion therapy that in vitro evidence suggests may prove useful, include passive immunization, gene therapy, and cell therapy.
In the first non-randomized trial of Quinacrine for the treatment of prion diseases, there was no benefit in terms of survival or neurological outcome.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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