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THE LANCET Neurology Vol 1 May 2002 http://neurology.thelancet.com 3

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A phase II trial of AN-1792 (Elan,Dublin, Ireland, and Wyeth, Madison,NJ, USA), an experimental vaccineagainst Alzheimer’s disease, wasstopped on January 11 this year whenit became clear that four patients in thetrial had developed signs andsymptoms consistent with asepticmeningoencephalitis.

Since then, 11 further patients havealso been affected. All 15 had receivedbetween one and three doses of AN-1792. “All are now stable,recovering, or recovered, but this isnaturally disappointing for allconcerned”, says Ivan Lieberburg,Chief Scientific and Medical Officer atElan. The coding on the other 360patients in the trial has not beenbroken, and Elan and Wyeth arehoping to monitor them for a furtheryear for safety issues, CNS changes (asmeasured by MRI), cognitive decline,and immune function.

Problems first occurred in onepatient from France in late November2001, who showed signs ofneurological deficit, low-grade fever,and headache. This was followed by asimilar case, at a different Frenchinvestigational site, in early December.No link could be found between thepatients and although a viral cause wasinvestigated, it was ultimately ruledout. At that point, there was nothing toconfirm that the vaccine was definitelyresponsible. “Nevertheless, we tookthe decision in early January that if any

further cases occurred, then dosingwould stop”, says Lieberburg. Twofurther cases were reported on January11, and dosing was immediatelysuspended.

“This comes as a big blow,”comments William Mobley (StanfordUniversity, CA, USA). “There was so

much hope amongst researchers,caregivers, and patients themselvesthat here, at long last, was somethingthat could slow or even stop theinexorable decline of Alzheimer’sdisease”, he says. But could the adversereactions have been foreseen; did thistrial go ahead prematurely to satisfythis hope? Lieberburg strongly refutesthis suggestion, pointing out that thedevelopment of any new drug orvaccine rarely runs smoothly. “Ourpreclinical work was thorough andextensive and this clinical trial was anatural progression from two earliertrials [see panel]. None of the animalsor the 80 Alzheimer’s patients

previously dosed with AN-1792developed any sign of braininflammation”, stresses Lieberburg.

Mobley agrees that the workcannot really be faulted, although hedoes have one caveat. “With hindsight,now that we know there are problemsin some human patients given human�-amyloid, it may have been prudentto dose transgenic mice with themouse form of �-amyloid, rather thanjust the human form. This may havehighlighted a potential autoimmuneresponse, but this is speculation untilthe experiment is done”, says Mobley.

The adverse reactions in somepatients are clearly linked to theimmunisation, but Lieberburg reportsthat, to date, nothing has been foundto explain them. “Affected patientshad received either one, two or threedoses; their antibody titres variedwidely, and the time from last dose toonset of symptoms was anythingbetween 5 days and 69 days”, he says.Current tests are now checking theHLA subtypes of patients and T-cellresponses are being measured. “Wewon’t have the results of these tests forsome time, but it is possible that asubgroup of patients may havemounted a cell-mediated immuneresponse to the vaccine”, addsLieberburg. Mobley considers this aninteresting hypothesis and points outthat the low frequency of the reactionmay explain why it only becameapparent during this larger trial. “Ifonly 15 out of 300 patients(approximately 5%) mount this typeof response, then the earlier trialswouldn’t have had enough power todetect it”, he says.

Lieberburg is keen to point outthat the efforts to develop safe andeffective immunotherapies willcontinue. The company has severalsecond-generation active vaccineproducts with very different propertiesfrom AN-1792 in preclinicaldevelopment, as well as a monoclonalantibody against �-amyloid, whichcould circumvent any problems withactive vaccination. “This is a set-back,but nothing more; we have nointention of giving up”, he says.Kathryn Senior

Dosing in phase II trial of Alzheimer’s vaccine suspended

Elan headquarters in Dublin, Ireland

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Stages in AN-1792 developmentl AN-1792 contains the synthesised 42-amino acid �-amyloid protein in

combination with the QS21 adjuvant (Antigenics, NY, USA).l 1997–2000: safety and toxicology tests done in five species—mice, rabbits,

monkeys, rats, and guinea pigs. None of the animals tested developedencephalitis. Experiments in a transgenic-mouse model for Alzheimer’s diseaseshowed that AN-1792 improved neuropathology and memory impairment.

l 1999–2000: 20 early–moderate stage Alzheimer’s patients received a single doseof AN-1792. They were followed-up for 1 year and showed no sign of encephalitis.

l 2000–2001: 64 early–moderate stage Alzheimer’s patients received increasingdoses of AN-1792. All patients were followed-up for 1 year; none developed signsof brain inflammation.

l June 2001 to January 2002: 300 early–moderate stage Alzheimer’s patientsreceived multiple doses of AN-1792 (the highest dose of AN-1792 and the lowestdose of adjuvant that were used in second phase I trial) while 75 patients receivedplacebo. The 15 patients who developed encephalitis were all in the group thatwas treated with AN-1792.