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.

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  1. The results of the LEADe study provide clear evidence that atorvastatin does not delay the progression of Alzheimer disease. This result contrasts with a previous, preliminary study on atorvastatin by Sparks and colleagues, and it is disappointing [1]. However, the negative result is consistent with our recent epidemiological study, in which we compared the incidence of AD among subjects taking simvastatin, atorvastatin, and Lipitor, and observed a reduction in the incidence of AD only among subjects taking simvastatin [2].

    Results are also expected imminently for the CLASP study, which investigated the effects of simvastatin on progression of AD using a prospective format similar to the LEADe study. The results of the CLASP study will be particularly informative. Simvastatin has shown the most consistent positive effect over a number of different study paradigms, but there could be a difference between results obtained when examining the effects of simvastatin in patients with cardiovascular risk factors (such as occurs in an epidemiological study) compared to results obtained when studying the effects of simvastatin in a patient population that exhibited normal cholesterol levels at the outset of the study. So, stay tuned.

    References:

    . Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005 May;62(5):753-7. PubMed.

    . Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 2007;5:20. PubMed.

  2. Aβ Immunotherapy Trial Interrupted by Suspected Vasculitis in the Skin
    Alzforum reported on 28 April 2008 that dosing in the Elan/Wyeth Phase 2 trial of active Aβ immunotherapy for Alzheimer disease was temporarily suspended following a suspected case of vasculitis in the skin. Dr Cynthia Lemere commented on the possible mechanism of the vasculitis and raised the problem of how Aβ is deposited in artery walls in the skin of elderly patients.

    The presence of Aβ in artery walls could reflect failure of perivascular transport of soluble proteins along the walls of cutaneous arteries. Experimental studies (1) have shown that soluble proteins drain from the extracellular spaces of the brain along the basement membranes of capillaries and arteries and that this effectively represents the lymphatic drainage pathway for the brain. Aβ is deposited in these pathways in cerebral amyloid angiopathy in humans (2) and in mice (3).

    Perivascular drainage of soluble Aβ from the brain is probably driven by the contrary waves that result from the pulse waves traveling along arteries (4). As arteries stiffen with age, the amplitude of the pulse wave is reduced and the consequent reduction in motive force for perivascular drainage may contribute to the development of cerebral amyloid angiopathy in the elderly (4).

    There is evidence that perivascular drainage of amyloidogenic peptides is not confined to the brain. Transthyretin amyloid is deposited in artery walls in peripheral nerves (5), and cystatin C amyloid angiopathy involves not only cerebral arteries but also arteries in other organs (6), reflecting a general phenomenon of “protein elimination failure arteriopathy (PEFA)” (2). The report nearly 20 years ago by Joachim, Mori, and Selkoe (7) of Aβ deposited in the walls of arteries in the skin and intestines supports the concept that Aβ drains along perivascular pathways in organs other than the brain.

    Deposition of Aβ in arteries in the skin may be analogous to the failure of elimination of granular osmiophilic material (GOM) from the walls of arteries in the skin in CADASIL, a condition in which the cerebral arteries are the most severely affected (8). In transgenic mice with CADASIL, arteries in the brain and other organs including the tail are severely affected (9). These observations lead to the conclusion that the highly developed perivascular drainage in the brain also occurs in other organs of the body, albeit to a lesser extent.

    Two possibilities emerge to account for vasculitis in the skin in the patient treated with Aβ immunotherapy: (a) drainage of Aβ from skin along perivascular pathways and its deposition as amyloid in artery walls followed by immune complex formation in the vessel walls themselves and inflammation, and (b) drainage of Aβ immune complexes from the skin interstitial fluid along perivascular drainage pathways and a vasculitic reaction in the artery walls.

    One major question that remains is whether Aβ or immune complexes will enter artery walls in a similar way in organs other than the skin and induce vasculitis.

    References:

    . Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008 Apr;34(2) Epub 2008 Jan 16 PubMed.

    . Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 2008 Apr;18(2):253-66. PubMed.

    . Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models. Brain Pathol. 2006 Jan;16(1):40-54. PubMed.

    . Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol. 2006 Feb 21;238(4):962-74. PubMed.

    . Peripheral nerve amyloidosis. Brain Pathol. 1996 Apr;6(2):163-77. PubMed.

    . Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects. Brain Pathol. 2006 Jan;16(1):55-9. PubMed.

    . Amyloid beta-protein deposition in tissues other than brain in Alzheimer's disease. Nature. 1989 Sep 21;341(6239):226-30. PubMed.

    . CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. 1997 Sep;56(9):947-64. PubMed.

    . Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Am J Pathol. 2003 Jan;162(1):329-42. PubMed.

References

News Citations

  1. Human Aβ Vaccine Snagged by CNS Inflammation
  2. Atorvastatin, Vaccine Trial Data Published
  3. Philadelphia: All Is Not Well with the Statin Story
  4. Statins—New Data Suggest Benefits for AD/PD
  5. Sorrento: Immunotherapy Update Hot Off Lectern of AD/PD Conference
  6. Boston: Clinical Trial Results for Dimebon Unveiled
  7. Washington: Alzhemed Non-story Yields Spotlight to Phase 2 Treatments
  8. Alzheimer Activism: How To Modernize Clinical Trials?

Paper Citations

  1. . Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis. Neurodegener Dis. 2008;5(3-4):194-6. PubMed.
  2. . Prototype Alzheimer's disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol. 2005 Feb 1;174(3):1580-6. PubMed.
  3. . Amyloid beta-protein deposition in tissues other than brain in Alzheimer's disease. Nature. 1989 Sep 21;341(6239):226-30. PubMed.

External Citations

  1. ACC-001
  2. clinicaltrials.gov

Further Reading

Papers

  1. . Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine - a novel immunotherapeutic strategy. PLoS One. 2008;3(5):e2124. PubMed.