The drug quinacrine does not increase survival in patients with prion disease. The results of the first major prospective study of a treatment for human prion disease in the UK are published in an Article early Online and in the April edition of The Lancet Neurology.
Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), can arise spontaneously, be inherited through a genetic mutation, or develop through infectious transmission. The commonest form is sporadic CJD, which affects about 1 people per million annually worldwide. These neurodegenerative disorders are uniformly fatal and progress rapidly. Currently, there are no therapeutic interventions that prevent or reverse progression in human prion diseases.
However, quinacrine (mepacrine), a drug used to treat malaria and some arthritic illnesses has been shown to be effective in treating prion-infected mouse cells by blocking the conversion of normal prion proteins into the abnormal disease-causing form. Oral quinacrine is also known to be safe and well-tolerated in humans and can cross the 'difficult to penetrate' blood-brain barrier.
In this study, John Collinge from the MRC Prion Unit in London and colleagues, report the findings of a patient-preference trial (PRION-1)*, in which patients were offered the choice of quinacrine, no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine, to assess the efficacy and safety of oral quinacrine (300 mg a day) in all forms of prion disease in the UK.
They recruited 107 patients (23 in a pilot study and 84 in the main study) with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) from across the UK using a national referral system. Patients were eligible if they had any form of prion disease and were aged 12 years or older. Neurological assessments and clinical investigations were done at the start of the study, and after 1, 2, 4, and 6 months, and then at regular intervals of 3 months.
Only two of 84 patients or their carers agreed to randomisation, so PRION-1 was primarily an observational study of patients who chose quinacrine or not. The authors identified disease severity as a strong determinant of this choice, with those least and most severely affected least likely to choose the drug.
In total, 78 patients died—one randomly assigned to deferred treatment, 26 of 38 who took the drug immediately, and 51 of 69 who initially chose no quinacrine. Mortality was lower in patients who chose to take quinacrine than in those who did not, but after adjusting for confounding factors such as disease severity and type of disease there was no significant difference in survival.
Findings also showed that the only patients who had transient improvements (improvement on two or more neurological rating scales without deterioration in any other scales at the same time point) during the study had taken quinacrine.
The authors report that although quinacrine was associated with increased incidence of adverse events, most were mild and led only to dose reduction or discontinuation. Only two serious adverse events were considered as being connected with the drug.
Importantly, say the authors, although the study showed that national recruitment and retention is feasible and acceptable to patients and carers, it highlighted the difficulty of randomised controlled trials in human prion disease. Affected patients with a rapidly progressing fatal disease often want whatever treatment is available and are reluctant to be randomised to deferred treatment, and in the case of advanced disease, some families are not prepared to accept an intervention that at best is expected to just slow or halt the progression.
The authors conclude that earlier diagnosis must be: "a high priority if patients are to be included in treatment trials, as those with mild to moderate disease are probably most likely to accept randomisation."
In an accompanying Comment, Michael Geschwind from the University of California, USA, says: "Notably, the results of this study show that treatment trials for rare, rapidly progressive and fatal diseases are possible." However, he points out that it is unlikely that quinacrine will be the "penicillin" for CJD.
Professor John Collinge, MRC Prion Unit, UCL Institute of Neurology, London, UK. T) +44 (0)207 837 4888 E) j.collinge@prion.ucl.ac.uk
Hazel Lambert, Medical Research Council Press Office, London, UK. T) +44 (0)207 637 6011 E) Hazel.Lambert@headoffice.mrc.ac.uk
Professor Michael Geschwind, University of California, San Francisco, USA. T) +1 415 476 2901 E) mgeschwind@memory.ucsf.edu
For full Article and Comment see: http://press.thelancet.com/quinacrine.pdf
Notes to Editors:
*The Chief Medical Officer for the UK asked the Medical Research Council (MRC) to prepare a protocol for a clinical trial in human prion disease to investigate the therapeutic potential of quinacrine. A formal consultation process with patients, families, carers and representatives of patients was done in the UK to develop an acceptable study protocol.
Journal
The Lancet Neurology