25 April 2008. A flurry of clinical trial news this past week brought mostly disappointment. Pharmaceutical partners Elan/Wyeth have temporarily suspended dosing in their Phase 2 trial for an active Aβ immunotherapy, while Pfizer announced that atorvastatin (Lipitor) has no effect on cognitive decline. The only good news—and it’s just a small morsel—comes from the Russian Phase 2 trial of Dimebon. The dual anticholinesterase/NMDA antagonist seems to have improved not only cognition but also behavior in a Phase 2 trial.
Elan and Wyeth have been hoping that their new active vaccine for AD, ACC-001, would avoid the inflammatory reactions sparked by their first Aβ vaccine, AN1792. But an adverse side effect has forced the temporary suspension of the trial. Andrew Lewis, director of corporate communications at Elan, wrote to ARF that “this action follows discussions with the U.S. Food and Drug Administration (FDA) regarding a serious adverse event reported to FDA through the standard reporting procedure.” That serious adverse event (SAE) was a case of vasculitis, or inflammation of the blood vessels, according to the study site principal investigator. However, a biopsy did not confirm that diagnosis, according to Lewis. The patient developed skin lesions, was treated and discharged from the hospital, and is recovering. “In order to better clarify the etiology of the lesions, further evaluations are ongoing,” wrote Lewis.
This marks the second setback for Elan/Wyeth in their effort to develop a vaccine for Alzheimer disease. Earlier trials of AN1792 faltered when patients developed meningoencephalitis (see ARF related news story). Follow-up investigations blamed the presence of polysorbate 80 in the formulation for the causative inflammatory T cell response (see Pride et al., 2008). ACC-001 was developed in part to circumvent that type of T cell activation. The antigen is a 7-amino acid fragment from the amino terminal of Aβ, conjugated to a mutated diphtheria toxin protein called CRM 197. The conjugate lacks the epitope at the Aβ C-terminal that may cause inflammatory T cell responses (see Agadjanyan et al., 2005).
The multicenter Phase 2 trial of ACC-001 began in the U.S. last November. A European arm of the trial began last May, and it was a German patient who developed the lesions. The companies have also voluntarily suspended dosing in the E.U. Phase 2 study. This problem does not affect Elan’s ongoing Phase 2 and 3 trials of AAB-001, a passive immunotherapy.
It is not yet clear if the skin lesions were related to the antigen, the alternative adjuvant QS-21, or to something else entirely. The CRM 197 carrier protein is used in other vaccines including Wyeth’s Prevnar, which is given to infants and toddlers to prevent pneumonia. Used in 87 countries, Prevnar is the world’s best-selling vaccine, which suggests that if the carrier precipitated the skin lesions, then it is most likely an unusual event or related to old age. Similarly, the adjuvant QS-21 has been used in many trials (clinicaltrials.gov lists 28 ongoing trials) including for prostate, breast, and lung cancers. Antigenics, maker of the adjuvant, note on their website that QS-21 has been used in more than 3,500 people. Cynthia Lemere, Brigham and Women’s Hospital, Boston, who studies immunotherapy for AD, told ARF that QS-21 is a strong adjuvant inducing a much more proinflammatory Th-1 response than some other adjuvants, and it is possible that it may be related to the adverse reaction. “It is hard to get an antibody response in the elderly, so you have to be pretty aggressive with the adjuvant,” she said. But she also added that if QS-21 caused the problem, then she would have expected it would have shown up in earlier trials. “Overall, I don’t think this is necessarily bad news. The important thing to keep in mind is that the trial is not over; it is just suspended while the companies try to figure out what is going on,” she said. Lemere is not involved in these trials but disclosed having received support from Elan and Wyeth for research in animal models of AD.
The patient was in the antigen-adjuvant group, not the placebo group, but Lewis was unable to say whether the patient received the low (3 μg), medium (10 μg), or high dose (30 μg). Interestingly, early work from Dennis Selkoe’s lab at Brigham and Women’s Hospital, Boston, showed that Aβ can form tiny deposits in the skin at the dermal/epidermal junction (see Joachim et al., 1989). In fact, Lemere told ARF that she studied those deposits as a potential diagnostic test for AD but found no difference between AD patients and normal elderly controls. She said it is not known how the Aβ gets there. “It is insoluble. It somehow comes out of solution and gets deposited as fibrils or prefibrillar Aβ, but I think it is unlikely that that is the cause of this person’s reaction,” she said. Lemere noted that because many people have Aβ in their skin but the lesions only developed in the person’s extremities, it is hard to see how this patient’s adverse reaction could be related to skin Aβ. Presumably, others in the trial also have Aβ deposits in their skin, yet so far, only one patient has developed lesions. “Time will tell. I think they should be commended for being careful and for suspending it for now and figuring out what is wrong,” she said. ARF will continue to cover this story as more information becomes available.
In other clinical trial news, Howard Feldman, University of British Columbia Hospital, Canada, revealed at the annual American Academy of Neurology meeting in Chicago last week that patients taking a combination of atorvastatin (Lipitor) and donepezil fared no better than those taking donepezil and a placebo. Feldman presented on behalf of the Steering Committee of the LEADe (Lipitor’s Effect on Alzheimer’s Dementia) trial sponsored by Pfizer. The results put yet another damper on the idea that statins help slow the progression of AD. Though a pilot study of atorvastatin alone suggested some benefit in AD patients (see ARF related news story), other data is equivocal. Epidemiological studies suggest either no protective effect of statins for cognitive decline (see ARF related news story) or an effect for just simvastatin (see ARF related news story), while several case-control studies also show no benefit (see ARF related news story).
Ben Wolozin of Boston University agreed that it can be difficult to reconcile the prospective and epidemiological data on statins. He offered one possible interpretation. “A pharmaco-epidemiological study looks at people with risk factors for the medicine that they are taking. Thus, if we look at statins by epidemiology, the patients all had high cholesterol (before taking the statin), which is a risk factor for AD. If you reduce that risk factor, you reduce AD. If you do the same study prospectively, as with the LEADe study, the patients do not have this cardiovascular risk factor. So perhaps in this case the statin has no benefit because there was no cholesterol-related risk factor to start with,” he wrote to ARF via e-mail (see also his comment below). In fact, Feldman told ARF via e-mail that people on statins or having high cardiac risk, which would be an indication for a statin, were precluded from participating, so that LEADe is a study of patients with lower cardiac risk and lower cholesterol levels. This leaves unaddressed the question of whether atorvastatin would have an effect in the large group of people with high LDL cholesterol and high cardiac risk.
LEADe, carried out over 18 months and studying 640 patients with mild to moderate AD, is the largest statin study on AD to date. Rates of decline in both cognition and global function (measured with ADAS-cog and ADCS-CGIC batteries, respectively) were the same for atorvastatin/donepezil and placebo/donepezil groups, though Feldman reported that there was a small but not statistically significant numerical advantage for atorvastatin at each time point in the trial. Interestingly, in 10 percent of patients who received MRI scans, those in the statin group had significantly less shrinkage in hippocampal volume. It’s unclear at present if this is a good thing, since reduced hippocampal volume appeared, paradoxically, to indicate improvement in one prior trial (see ARF related news story). But Feldman told ARF via e-mail that while there have been some uncertainties in the vaccine trials, which may have been anomalous due to the specifics of that therapy, there is good evidence for hippocampal volumetric loss in AD, and that one goal is to preserve hippocampal volume. “Every indication is that most effective treatments would aim to preserve volume, which is the effect seen in this substudy,” he wrote. Post-hoc subgroup analysis also suggested that men taking the statin did better than men taking placebo, but whether there is a true sex difference in response to the statin remains to be determined.
One nugget of good news came from an ongoing Russian study of 183 patients taking either Dimebon, a dual anticholinesterase/NMDA antagonist, or placebo. Six-month (see ARF related news story) and 12-month (see ARF related news story) data already showed that patients taking the drug had significantly better scores in global function and cognitive scales than those on placebo. Now, it appears some improvement in behavior can be chalked up to Dimebon as well. On March 15 at the annual meeting of the American Association for Geriatric Psychiatry, held in Orlando, Florida, Jeff Cummings, University of California, Los Angeles, presented data to suggest that behavioral symptoms, including depression, apathy, hallucinations, and irritability, stabilized in patients with mild to moderate AD who took the drug for one year. This had the added bonus of reducing caregiver stress, which is often a key factor in the decision to institutionalize the patient. Behavioral symptoms came up as an underused readout during a discussion about innovative trial design (see ARF related news story) Should these results hold up in larger U.S. trials that compare Dimebon to current AD treatments, the Russian drug might yet give current AD treatments a run for their dime.—Tom Fagan.