Search for AD Drugs Turns to a Hypertension Medicine

A research consortium led by an Irish group is gearing up to conduct a multicenter Phase 3 clinical trial of the blood pressure medication nilvadipine in Alzheimer’s disease (AD) patients. The study’s go-ahead is subject to successful completion of ongoing negotiations with the granting body, the European Commission (EC) Seventh Framework Programme. But if all goes according to plan, the study is slated to start in January 2012 with funding to the tune of €6 million (US$8.4 million).

Preliminary clinical data have hinted that nilvadipine might be beneficial to patients with AD, but how the drug will fare in a large, randomized trial is hard to predict based on those earlier studies. “I think there is sufficient justification for moving forward with the trial, because until we have effective treatments, we need to explore all plausible strategies, and this is one of them,” said Paul Aisen, at University of California, San Diego School of Medicine, who is not involved in this work. “At this point, we really don’t have any evidence of clinical efficacy for nilvadipine in AD, so we need a substantially large, randomized trial to see if there is an effect.”

One factor that plays in nilvadipine’s favor is that the drug has been prescribed in parts of Europe and Japan (but not the U.S.) for more than a decade. “There is a wealth of experience with the drug to suggest that it is well tolerated and unlikely to raise safety concerns,” said John Breitner, at McGill University in Montreal, Canada, who is also independent of the nilvadipine trial. The approach of looking at existing medicines to see if they have an effect on Alzheimer’s is a valuable one for academic investigators to take, according to Brian Lawlor at Trinity College Dublin and St. James's Hospital, who will be heading the nilvadipine trial. For one thing, pharma tends to have limited interest in such drugs, and the time from clinical trials to market is likely to be shorter than for new drugs.

Although nilvadipine has never been sold in the U.S., it is manufactured by Astellas Pharma US, the U.S. affiliate of Astellas Pharma Inc., Japan’s second-largest pharmaceutical company. Astellas is not pursuing nilvadipine for AD treatment. The patent on the original composition of the drug expired a few years back, and Archer Pharmaceuticals, a commercial spinoff of the Roskamp Institute in Sarasota, Florida, now owns intellectual property rights to developing the drug as a treatment for AD.

There have been no new drug treatments approved for AD since 2003, and the field has been plagued by failed Phase 3 trials. “We have broken our teeth with vast and very expensive efforts for the treatment of Alzheimer’s for more than 20 years. There have been some successes, but they have been modest,” said Breitner. “Many people are fairly pessimistic about our ability to change the course of the disease once the symptoms are present.” But that is no reason not to persevere. “If you have an agent with some promise, as they do here, they should try to see if it will be effective,” he added.

Nilvadipine appears to work by a different mechanism than other drugs that have been tested for treating AD, which typically target the amyloid-β peptide, the main component of the plaques found in the brains of AD patients. “Nilvadipine has some effects on amyloid-β, but also other effects,” said Brian Lawlor. “Putting so much focus on one target has not proven to be effective.”

Some single-target drugs have failed in Phase 3 (e.g., Lilly’s semagacestat; see ARF related news story), as have so-called dirty drugs that hit several targets, some suspected of affecting amyloid pathways and some not (e.g., Medivation’s Dimebon; see ARF related news story).

The proposed trial will bring together academic institutions and not-for-profit organizations in countries across Europe, including Italy, Germany, Greece, The Netherlands, Sweden, the U.K., and Luxembourg, as well as the pharmaceutical companies Penn Pharmaceuticals (U.K.) and Archer Pharmaceuticals. It will enroll 500 patients and last about 18 months. “It is extremely positive that the EC is funding a clinical trial like this one because there isn’t a tradition for public money funding clinical trials in Europe,” said Cristina Sampaio of the Institute of Molecular Medicine at the Santa Maria Hospital in Lisbon, Portugal, and the European Medicines Agency. “We will gain a lot of valuable information from studying these patients.”

Nilvadipine belongs to a class of blood pressure-lowering medications that block calcium channels on cells (see ARF related news story). Researchers have long been studying the connection between blood pressure (and blood pressure medications) and AD (see ARF related news story), but that relationship remains “complex,” said Deborah Blacker at Harvard School of Public Health. Blacker headed a curation team for the AlzRisk database, where she compiled a synopsis of the hypertension literature (see ARF related news story).

“In general, the results of studies of anti-hypertensive medicines in people with AD have been mixed,” said Breitner. “We have snippets of evidence that suggest certain kinds of anti-hypertensive drugs, or specific drugs appear in some studies to be beneficial.” Nilvadipine appears to be one such drug. A small study had shown that nilvadipine in hypertensive patients with mild cognitive impairment prevented further cognitive decline for up to 20 months (Hanyu et al., 2007) and improved cerebral blood flow.

In 2010, a team from the Roskamp Institute, led by Michael Mullan, provided experimental results to explain the potential benefit of nilvadipine in AD (Paris et al., 2010). Those data suggest that any such benefit is not related to the drug’s blood pressure-lowering function.

The Roskamp group tested a battery of calcium channel blockers in cells overexpressing a version of the human amyloid precursor protein (APP), and they found that only two such agents, nilvadipine and amlodipine, decreased the production of amyloid-β from APP. The authors concluded the mechanism responsible for this reduction is unlikely to be related to the calcium channel blocking function, as none of the other drugs tested reduced amyloid-β. Using an in-vitro model of the blood-brain barrier, they also showed that nilvadipine increased the passage of amyloid-β through the barrier. “So this drug is interesting because it has a dual mechanism of action in that it stops amyloid-β production and also increases movement of the peptide across the blood-brain barrier,” said lead author Daniel Paris at the Roskamp. Paris and colleagues validated the in-vitro findings in two transgenic mouse models of AD to show that intraperitoneal injections of 2 mg/kg of nilvadipine reduced amyloid-β levels in the brain and increased levels in the blood.

One limitation of the in-vitro work is that, to see the effects on amyloid-β production and secretion, the researchers had to use drug amounts ranging from 1 to 10 micromolar concentrations—much higher than would be present in the body. When used at high concentration, many compounds affect APP processing. In addition, the study did not identify a specific molecular target for nilvadipine’s effects. “There are many studies that report an effect at high micromolar concentrations, but that can be misleading,” said Ilya Bezprozvanny at UT Southwestern Medical Center in Dallas. “First, you want to know what the target is, and then you need to be hitting the target at a concentration in the 100-nanomolar range or less, which is physiologically relevant.” Nilvadipine binds to L-type calcium channels with 1-nanomolar affinity (Cho et al., 1989).

Ongoing studies by Paris and colleagues are addressing these concerns, but those data are unpublished. “We are in the process of identifying the molecular targets of nilvadipine responsible for its amyloid-β-lowering properties and have several promising candidates,” said Paris. “By blocking those potential targets, we have already shown we can mimic the effects of nilvadipine.”

To move forward on the preclinical data, Mullan and colleagues at Roskamp approached researchers at Trinity College Dublin to conduct an open-label safety trial of nilvadipine in AD patients. The Phase 1 trial, funded by Archer Pharmaceuticals, involved giving a daily dose of 8 mg nilvadipine to 55 AD patients for six weeks. Usually, early-stage clinical AD trials test several doses to establish dose-response, and frequently longer than six weeks; however, in this case, the trial used an old drug for which a standard anti-hypertensive dose is established.

The drug was well tolerated by the patients and had no dangerous blood pressure-lowering effects (Kennelly et al., 2010). “In general, we found that, for AD patients with high blood pressure who took nilvadipine, their blood pressure was reduced as a result of taking the drug. On the other hand, patients with normal or low blood pressure had no change in blood pressure after taking the drug,” said Sean Kennelly at Trinity College, lead author of the safety trial.

The authors conducted some basic tests of cognitive function in the patients, which suggested that nilvadipine stabilized cognition and improved executive function in treated individuals (Kennelly et al., 2011). The trial used the MMSE and an executive function test called EXIT25. The latter is not a standard outcome measure used in AD trials designed to determine the efficacy of a drug, such as the ADAS-cog, CDR Sum of Boxes, or Activities of Daily Living scales. “It is open label, so the conclusions you can draw are limited,” Kennelly said. “But we were giving blood pressure medication to people who did not have high blood pressure, so we did not want to go straight to a large, randomized study.”

In addition, an increasing number of studies of AD, including Phase 1 and 2 trials, are moving toward using surrogate and diagnostic markers of AD in place of cognitive tests, said Barbara Tate at Satori Pharmaceuticals in Boston (see ARF related news story). “Those markers, developed thanks to the Alzheimer’s Disease Neuroimaging Initiative, give us tools to measure endpoints early on in a trial to tell us if we are going in the right direction,” she said. “Clinical batteries are so poor they end up with false positives, but biomarkers are hopefully pretty clean.”

Such biomarkers are expected to be part of the upcoming Phase 3 trial of nilvadipine. Although final details need to be ironed out, investigators plan to measure amyloid-β plasma levels in patients to see whether the drug has a similar effect as in the animal models. “We also plan to look at novel markers as part of a yet-to-be-agreed substudy,” said Lawlor.

“We will wait and see for the Phase 3 results. Even if it does not work as expected, it is a safe drug and I would not think something dangerous will occur, so that is a good reason to try,” said Sampaio. The trial consortium, she added, will also develop an infrastructure and establish processes that will enable many more trials of different drugs to be carried out.—Laura Bonetta.

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References

News Citations

  1. Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor
  2. Dimebon Disappoints in Phase 3 Trial
  3. No Pressure, But Could Hypertension Medication Prevent AD?
  4. AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension
  5. As ADNI Turns Four, $64 Million Data Start Rolling In

Paper Citations

  1. Hanyu H, Hirao K, Shimizu S, Sato T, Kiuchi A, Iwamoto T. Nilvadipine prevents cognitive decline of patients with mild cognitive impairment. Int J Geriatr Psychiatry. 2007 Dec;22(12):1264-6. PubMed.
  2. Paris D, Bachmeier C, Patel N, Quadros A, Volmar CH, Laporte V, Ganey J, Beaulieu-Abdelahad D, Ait-Ghezala G, Crawford F, Mullan MJ. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Mol Med. 2011 Mar-Apr;17(3-4):149-62. PubMed.
  3. Cho H, Ueda M, Shima K, Mizuno A, Hayashimatsu M, Ohnaka Y, Takeuchi Y, Hamaguchi M, Aisaka K, Hidaka T. Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity. J Med Chem. 1989 Oct;32(10):2399-406. PubMed.
  4. Kennelly SP, Abdullah L, Paris D, Parish J, Mathura V, Mullan M, Crawford F, Lawlor BA, Kenny RA. Demonstration of safety in Alzheimer's patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study. Int J Geriatr Psychiatry. 2010 Oct 29; PubMed.
  5. Kennelly S, Abdullah L, Kenny RA, Mathura V, Luis CA, Mouzon B, Crawford F, Mullan M, Lawlor B. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients-an open-label trial. Int J Geriatr Psychiatry. 2011 May 10; PubMed.

External Citations

  1. AlzRisk database

Further Reading

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