A putative amyloid-lowering agent, the blood pressure drug nilvadipine has proven ineffective in people with mild to moderate Alzheimer’s disease in a Phase 3 trial. In the September 24 PLoS Medicine, researchers led by Brian Lawlor at St. James’ Hospital, Dublin, reported that 18 months of treatment did not slow cognitive decline on the primary endpoints, the ADAS-Cog12 and the CDR sum of boxes. Biomarker analyses have not yet been published, so it is unclear if the drug hit its biologic targets.
- Nilvadipine did not slow cognitive decline in mild to moderate AD.
- Researchers are still analyzing biomarkers of target engagement.
Although nilvadipine lowers blood pressure by blocking calcium channels, this is thought to be unrelated to amyloid plaque reduction. In cell and animal models, nilvadipine suppresses Aβ production and boosts clearance of the peptide across the blood-brain barrier (Jul 2011 news). Mouse studies also indicate that nilvadipine inhibits the spleen tyrosine kinase (SYK), which activates the tau kinase GSK-3β, hence the drug potentially reduces tau phosphorylation, as well. In that same study, researchers reported that a known SYK inhibitor mimicked the effects of nilvadipine on amyloid and tau (Paris et al., 2014). Whether the purported amyloid and tau effects are related is unknown.
In the Phase 3 trial, which began in 2013, researchers used a dose of nilvadipine, 8 mg once daily, that has minimal effects on blood pressure. Researchers recruited 511 participants from nine European countries, with 253 of them randomized to take nilvadipine, the rest placebo. Treatment and placebo groups were well-matched overall, although the treatment group had about twice as many diabetics. Participants had an average age of 73 and MMSE of 20 and met NINCDS-ADRDA criteria for Alzheimer’s, but the diagnosis was not confirmed with biomarkers.
No safety issues emerged. There were slightly more adverse events in the treatment group, but these were judged unrelated to the drug. About 10 percent of participants dropped out in both the treatment and placebo groups. The treatment only modestly lowered blood pressure, with median systolic pressure falling by five points.
The nilvadipine trial was powered to detect a 50 percent slowing of cognitive decline on the primary endpoints, but found no difference (see image). In addition, the researchers saw no change in the Disability Assessment for Dementia, which measures functional outcomes. In prespecified subgroup analyses, treated participants with an MMSE above 20 appeared to decline more slowly than the placebo group, but those with a lower MMSE declined faster on drug. Males and ApoE4 carriers also declined more slowly on drug than on placebo. However, the numbers in these subgroups were too small to be statistically meaningful. Biomarker analyses of Aβ levels in cerebrospinal fluid and blood, as well as MRI data on cerebral blood flow, are ongoing. The researchers did not measure effects on SYK, so it is unclear if 8 mg was enough to inhibit the kinase.
Lawlor suggested that because nilvadipine lowers amyloid, it might work better at preclinical disease stages, a point echoed by Costantino Iadecola at Weill Cornell Medical College in New York. “It is becoming eminently clear that in AD, as in other brain disease, acute or chronic, the earlier the intervention the better,” he wrote to Alzforum. He was not involved in the study. “I hope that funding can be obtained to repeat the study in presymptomatic biomarker-positive patients, an intervention that is likely to have a greater impact,” Iadecola added.
The nilvadipine formulation used contains two mirror-image enantiomers of the same drug. Both inhibit SYK, but only the plus enantiomer blocks calcium channels and lowers blood pressure. Lawlor is considering testing only the minus enantiomer in patients at an earlier disease stage. Because this form has no effect on blood pressure, researchers could use a higher dose.—Madolyn Bowman Rogers
- Paris D, Ait-Ghezala G, Bachmeier C, Laco G, Beaulieu-Abdelahad D, Lin Y, Jin C, Crawford F, Mullan M. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J Biol Chem. 2014 Dec 5;289(49):33927-44. Epub 2014 Oct 20 PubMed.
- Lawlor B, Segurado R, Kennelly S, Olde Rikkert MG, Howard R, Pasquier F, Börjesson-Hanson A, Tsolaki M, Lucca U, Molloy DW, Coen R, Riepe MW, Kálmán J, Kenny RA, Cregg F, O'Dwyer S, Walsh C, Adams J, Banzi R, Breuilh L, Daly L, Hendrix S, Aisen P, Gaynor S, Sheikhi A, Taekema DG, Verhey FR, Nemni R, Nobili F, Franceschi M, Frisoni G, Zanetti O, Konsta A, Anastasios O, Nenopoulou S, Tsolaki-Tagaraki F, Pakaski M, Dereeper O, de la Sayette V, Sénéchal O, Lavenu I, Devendeville A, Calais G, Crawford F, Mullan M, NILVAD Study Group. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med. 2018 Sep;15(9):e1002660. Epub 2018 Sep 24 PubMed.