The Generative Brain

Repurposed small molecules: quinacrine, doxycycline, flupirtine, pentosan polysulphate

Before any prion-specific drug existed, doctors tried existing medicines that blocked prion formation in cells or looked safe in the brain. Quinacrine (an old malaria drug), doxycycline (an antibiotic), flupirtine (a painkiller) and pentosan polysulphate (infused into the brain fluid spaces) were each tested in people with symptomatic prion disease, mostly sporadic CJD. None extended survival. Flupirtine slowed a thinking-test score in one small trial but never became standard care. These studies are why later trials insist on stronger animal evidence, earlier diagnosis and better outcome measures. No repurposed-drug trial is known to be running. Information only.

Key facts

  • Scope: between roughly 1997 and 2013 the completed human studies were flupirtine (Germany, 28 people, randomized), pentosan polysulphate (UK 7 and Japan 11, uncontrolled), quinacrine (France 32, UK 107, US 54) and doxycycline (France and Italy, 121, randomized); only symptomatic people took part, most with sporadic CJD.
  • Quinacrine UK: the PRION-1 study of 300 mg a day in 107 volunteers, reported in March 2009, found no evidence of longer survival once patients who chose the drug were compared fairly with those who did not.
  • Quinacrine US: the double-blind placebo-controlled trial of 300 mg a day in sporadic CJD, led at UCSF with 54 people, saw no benefit; its lead author called the 2-month randomized phase a design weakness.
  • Doxycycline: 121 people were randomized (62 to 100 mg a day) from 663 referred; the trial stopped at 4.5 years for futility with no survival benefit, good tolerability, and drug reaching the brain at autopsy in 11 patients.
  • Doxycycline background: the trial contradicted two earlier observational reports of benefit, and its commentator warned that observational or historical series should not be relied on and that nearly half of 663 screened patients may not have had CJD.
  • Flupirtine: a double-blind trial in 28 patients reported slower decline on the ADAS-Cog cognitive scale (p about 0.02) and no survival effect; it was never widely adopted and had no cell or mouse data behind it.
  • Pentosan polysulphate: seven UK and eleven Japanese patients had the drug infused into the brain ventricles; neither study was randomized, the Japanese study was clearly negative and the nominal positive in the UK study was attributed to a confounder.
  • Why they failed to translate: quinacrine did not prolong survival in a mouse model, pentosan worked in mice only early in disease, and flupirtine had no prion data, so the negative results could largely have been predicted.
  • Design lessons stated by the field: compounds that work in animals only before symptoms should be tested only in people without symptoms; strains differ in drug response; many enrolled patients were too advanced to respond; placebo-controlled multinational trials proved feasible in a fast, rare disease.
  • Who ran the work: the quinacrine and doxycycline trials were led by the groups of Michael Geschwind at UCSF, John Collinge at the MRC Prion Unit and Stephane Haik with Fabrizio Tagliavini in France and Italy.

Timeline

  1. 1997Flupirtine trial recruitment begins (to 2001).
  2. 2004Flupirtine trial published in Neurology.
  3. 2004French quinacrine compassionate use series published with no significant effect.
  4. 2005US quinacrine randomized trial recruitment begins (to 2009).
  5. 2008UK pentosan polysulphate observational study published.
  6. 2009PRION-1 quinacrine results published in Lancet Neurology.
  7. 2009Japanese pentosan polysulphate study published.
  8. 2013US quinacrine trial published in Neurology.
  9. 2014Doxycycline trial published online in Lancet Neurology.
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