Mixed results for disease-modification strategies for Alzheimer’s disease
High-profile programmes aiming to develop the first disease-modifying drug for Alzheimer’s disease have suffered major setbacks recently, but there is still strong support for a range of efforts to transform disease treatment.
By Alisa Opar NATURE Rev | drug discovery | Sep 2008 | vol 7
Studies presented at this year’s International Conference on Alzheimer’s Disease (ICAD), Chicago, USA, 26–31 July 2008, highlighted several promising drugs with novel mechanisms of action that are being pursued with the aim of modifying the progression of the disease.
“The number of agents in the pipeline and the variety of approaches that are being taken is exciting,” says Norman Relkin, a neurologist and neuroscientist at Weill Cornell Medical College, New York, USA. “Past experience suggests that most of these will fail in development, but the chances are good that at least two to four will prove to be effective and safe for clinical use in the next 5–7 years. That will really dramatically change the way we treat the disease.”
Currently, five drugs are approved to treat memory problems and other symptoms of Alzheimer’s disease, although in March, a review concluded that these treatments offer only marginal benefits (Ann. Intern. Med. 148, 379–397; 2008). As yet, there are no drugs on the market that stop, slow or prevent the disease — an immense unmet need given that the disease affects ~37 million people worldwide.
Disappointingly, over the past year, two highly anticipated investigational drugs that might have begun to meet this need have failed. Both of these agents were based on the predominant anti-amyloid strategy — that targeting amyloid-beta (Ab) peptide, which aggregates in the plaques that are a hallmark of Alzheimer’s disease, would affect disease progression. In June this year, Myriad Genetics shelved tarenflurbil, which modulates gamma-secretase, a key protease involved in Ab production, after it showed no benefit for patients with Alzheimer’s disease in Phase III trials. And, in August 2007, Neurochem’s tramiprosate, which was designed to inhibit plaque formation by binding to Ab, failed late-stage US clinical trials.
These setbacks haven’t dissuaded others from continuing efforts with alternative agents that target Ab. “Although the trials completed to date have been negative, that doesn’t mean it’s the end of the amyloid story, because there are other strategies in clinical trials,” says Gordon Wilcock, University of oxford, UK.
One of these, bapineuzumab (elan/Wyeth), garnered a mixed response at ICAD. In a Phase II study of 229 patients, the humanized monoclonal antibody designed to clear Ab from the brain failed to show an overall benefit in cognitive function. However, post-study analysis revealed benefits in non-carriers of apolipoprotein e4 (APOE4) — a gene variant that increases the risk of developing Alzheimer’s disease.
Dennis Selkoe, a neurologist at Harvard Medical School, USA, and one of the founding scientists of Athena Neurosciences, which elan acquired in 1996, believes that the drug still has strong potential. “My opinion is that the Phase II data from the bapineuzumab trial strongly support the Phase III design, which is four large trials encompassing 4,100 patients with Alzheimer’s divided by APOE genotype,” says Selkoe. Results from the Phase III trials are anticipated in 2010.
In addition to questions about the efficacy of bapineuzumab, there are also some safety concerns; 12 patients taking the drug developed vasogenic oedema compared with zero patients in the placebo group. Selkoe feels that this does not represent a critical concern. “Safety was adequate because the vasogenic oedema was manageable and less frequent in APOE4-negative subjects. And there was no permanent untoward effect in the small number of patients (<10% of all treated subjects) who showed vasogenic oedema transiently on MRI.” Some analysts are more doubtful that the drug will overcome its efficacy and safety issues. “Bapineuzumab is unlikely to come to market,” says eric Snyder, Mehta Partners, New York.
Other novel anti-amyloids generating interest included the gamma-secretase inhibitor semagacestat (lY-450139; eli lilly). A Phase III trial due to finish in 2012 will determine whether the agent can slow the progression of Alzheimer’s disease. Given the failure of tarenflurbil, “this is the next major test,” says Snyder. “The safety seems in line, and they have a biomarker suggesting efficacy.”
PBT2 (Prana Biotechnology), which acts to prevent plaque build-up by interfering with the interaction of Ab with zinc and copper, also produced some noteworthy results. In a 12-week Phase II trial with 78 people, PBT2 reduced plaque in cerebrospinal fluid, and those receiving the higher dose also showed significant cognitive improvements compared with placebo. The drug’s predecessor, PBT1, was shelved after Phase II because of its toxicity.
The surprise newsmaker at ICAD wasn’t an anti-amyloid, but an agent targeted at another process thought to have a key role in the pathogenesis of Alzheimer’s disease— the formation of neurofibrillary tangles containing aggregates of an abnormal form of the protein tau. Phase II results of a trial evaluating methylthioninium chloride (TRx-0014; TauRX), which targets the tau aggregation pathway, in 321 patients showed an 81% reduction in mental decline after 50 weeks in patients who received 60 mg doses. “This is the first disease-modifying drug for Alzheimer’s disease to unequivocally meet its end point in Phase II. It’s clearly a jolt for the field, and deserves to be followed up in Phase III,” says Snyder. “The results were spectacular, but they need to be confirmed and extended to have confidence in the results,” says John Trojanowski, Director of the University of Pennsylvania Institute on Aging, USA. “All of these approaches need to be tried; we need as many drugs in the pipeline as possible. It may be necessary to have a tau therapy and an Ab therapy, or multiple tau- and Ab-focused interventions.”
Two other older drugs presented at ICAD affect Alzheimer’s symptoms. Patients who received dimebon (Medivation), an orally active inhibitor of cholinesterase and NMDA (N-methyl-d-aspartate) receptors, sold in Russia as an antihistamine, had significantly improved cognitive function, activities of daily living, behaviour and memory (Lancet 372, 207–215; 2008). Relkin presented interim results from a 9-month Phase II trial of the intravenous immunoglobulin Gammagard (Baxter International), currently approved to treat disorders of the immune system. Patients given Gammagard maintained — and in some cases improved cognitive function. Phase III trials for both of these drugs are gearing up.
Biomarkers were also a focus at the conference. These measures may be useful in detecting the disease before symptoms appear and in evaluating the effectiveness of experimental therapies (Nature Rev. Drug Discov. 6, 295–303; 2007). “We want to be able to show that we’re really having an effect on the disease process,” says Ronald Black, Assistant vice President of Neuroscience at Wyeth, which, like other companies, is incorporating biomarkers into its trials. “For biomarkers, there’s no real regulatory roadmap, and the science is very new. It’s a challenge.”
According to Trojanowski, the most effective are cerebrospinal-fluid biomarkers that measure tau and Ab, and Pittsburgh compound-B (PIB), a marker used with PeT scans to assess plaques in the brain. “We think that if we had a predictive biomarker that was as sensitive and specific as a pregnancy test, we would be in a position to identify people who we know absolutely will develop the disease and intervene therapeutically,” he says.
It’s still early days, but the field is making progress. one report at ICAD supported previous findings of an inverse relationship between the presence of amyloid in the brain and levels of the most amyloidogenic form of Ab — Ab42 — in cerebrospinal fluid, detected using PIB. “Ultimately, we’ll have a panel of biomarkers,” says Trojanowski. “Some will be diagnostic, some will change with disease progression, some will respond to therapeutics.”
Guidelines published in May by a european task force on disease-modifying trials in Alzheimer’s disease could also help foster drug development (Lancet Neurol. 7, 436–450; 2008). The consensus on suitable end points “formalized what a lot of us have been doing anyway, but will allow us to compare results of different trials,” says Wilcock, who co-authored the guidelines. “If we have consensus, it might mean that the licensing authorities have a similar consensus. And the closer we can get to agreement with licensing authorities and regulatory authorities, the better it will be for developing better treatments.” |
