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The hunt for drugs to modify Alzheimer's disease
In Context
The hunt for drugs to modify Alzheimer’s disease The US Food and Drug Administration last licensed a new drug to treat Alzheimer’s disease 4 years ago. In 2008, the first trial data of drugs designed to modify the underlying pathology of this disorder will be released. James Butcher investigates what the future might hold for these drugs.
Bsip Mendil/Science Photo Library
For the marketing departments of pharmaceutical companies, being the first to launch a drug that can be advertised as a disease-modifier of Alzheimer’s disease is nothing short of a Holy Grail, with blockbuster status sure to follow. But proving to the regulatory authorities that a compound arrests the underlying pathology of the disease is not easy, as those who run clinical trials are finding out the hard way. Short 6-month trials were used in the 1990s to prove the symptomatic efficacy of cholinesterase inhibitors. But to show disease modification, longer trials are needed, and these are likely to lose a large proportion of patients to follow-up. However, phase III trials of putative disease-modifying drugs are ongoing, with some interesting results expected in 2008. One of the most high-profile candidates is bapineuzumab, a humanised monoclonal antibody that targets amyloid-β peptide (Aβ). The previous vaccine candidate from Elan and Wyeth, AN-1792, used aggregated Aβ1–42 as an antigen, but development was stopped in phase II when 6% of the treated patients developed aseptic meningoencephalitis. To try to avoid
An elderly woman taking a test to assess the progress of her Alzheimer’s disease
1038
these side-effects, the companies are now testing passive Aβ immunotherapy with bapineuzumab. “The upside of making antibodies in the laboratory and giving them to patients is that you know what you’ve raised them against, and so they are more likely to be safe and the correct dosage can be calculated”, explains Gordon Wilcock, who works at the University of Oxford, UK. “The downside is that they are expensive to produce and they have to be topped-up fairly regularly. A question mark has also been raised over whether these antibodies increase the risk of microhaemorrhages in the brain”, he says. The results of the two phase II studies of bapineuzumab will be made public in mid-2008, say Elan and Wyeth. However, on the basis of a planned interim analysis of one of the phase II trials and an assessment of the latest data on AN-1792, the company decided to initiate a phase III study of bapineuzumab before the end of 2007. But, of course, success in phase III trials is not guaranteed. One drug that seems to be on shaky ground is tramiprosate (Alzhemed), a glycosaminoglycan mimetic that binds to Aβ peptides, preventing them from forming Aβ aggregates. On August 26, 2007, Neurochem, the Canadian firm that developed the drug, announced the results of a phase III trial that enrolled 1052 patients from Canada and the USA with mild to moderate Alzheimer’s disease. The patients, who had all been treated for at least 4 months with licensed therapies before enrolment, were randomly assigned placebo, 100 mg tramiprosate twice a day, or 150 mg tramiprosate twice a day. Another phase III trial, based in Europe, is ongoing.
“The North American phase III trial did not meet its target so the trial does not provide evidence in favour of Alzhemed, at least for regulatory purposes”, says the principal investigator of the trial, Paul Aisen, of Georgetown University Medical Center, Washington, DC, USA. “The analysis plan that had been selected was quite problematic in terms of a poor fit with the observed data; there was a large degree of variance amongst sites”, explains Aisen, who notes that further reanalysis of the data is ongoing. “The company has announced that a panel of experts has been convened to review, reanalyse, and probe deeper into the data from the trial, and the panel will recommend to the company what additional steps are appropriate for the development of Alzhemed.” These steps might include adjustments to the European phase III trial and recommendations about additional studies, says Aisen, who expects Neurochem to make a decision, based on advice from the panel, by the end of 2007. The other phase III trial of tramiprosate, in which 930 European patients have been enrolled, is ongoing. Bruno Vellas of the University of Toulouse, France, who is the principal investigator of the trial, emphasises the difficulties with trials that test putative disease-modifying agents. “My personal feeling is that if we have a drug that is very active then of course we will see an effect, but if we have a drug that is moderately active then I think that it could be very difficult to objectively assess the effectiveness of the drug”, he says. “To do this sort of trial we use 70–80 sites around the world and we have many site effects”, explains Vellas. “We do trials over an 18-month period
http://neurology.thelancet.com Vol 6 December 2007
and during that time the patients can have many life events—they can lose a caregiver, they can have some concomitant disease, and that can increase the difficulty to see some effect.” Vellas notes that the enrolled patients have the least progressive forms of the disease and are stable on cholinesterase inhibitors; this means that any effect from the drug is difficult to detect, because the patients’ decline is very slow. “Maybe the solution is to have fewer centres, but more patients per centre”, suggests Vellas. “One of the problems is that we have too few big centres that are able to include at least 10–20 patients each; we have too many centres that only include 2–5 patients each.” Vellas says that if the phase III European trial of tramiprosate is also negative, then investigators will have no option but to try to resolve these issues. Another compound that is in phase III trials is tarenflurbil (Flurizan), a stereo-isomer of a non-steroidal anti-inflammatory drug that does not have cyclo-oxygenase activity but does inhibit γ-secretase. Myriad, the company that is developing the compound, said on Nov 1, 2007, that the US phase III trial is proceeding on schedule and that the 18-month study will be completed at the end of March, 2008, as planned; the top-line results of the study will be made available by the end of June, 2008. The US trial will enrol around 1600 patients and the European trial around 800 patients, according to Wilcock, the principal investigator of the European trial. Wilcock was also the principal investigator of a phase II, 12-month trial of the drug in which 207 patients with mild to moderate Alzheimer’s disease were randomly assigned to placebo, 400 mg tarenflurbil twice a day, or 800 mg tarenflurbil twice a day. “At 12 months the trial was positive on two of the three outcome measures, so technically you could say it was a failed trial, but in fact the picture that emerged from the activities of daily
living and the CDR [clinical dementia rating] sum of boxes showed diverging slopes as you would predict for a disease-modifying, rather than a symptom-modifying, drug”, says Wilcock. The data have been presented at scientific conferences but have not been published in full yet. Another unpublished phase II trial tested dimebon in 183 patients with mild to moderate Alzheimer’s disease. “Dimebon’s mechanisms are just being elucidated now”, says the trial principal investigator Rachelle Smith Doody, of Baylor College of Medicine, Houston, USA. “It came to attention because its physical structure is predicted to be both a cholinesterase inhibitor and an NMDA receptor antagonist and it does have both of those actions but they’re weak”, she explains. “Most of the work on its mechanisms is proprietary and not even known to me but I know it’s underway”, she says. “Dimebon has gotten in my view undeserved hype”, says Lon Schneider, of the University of Southern California Keck School of Medicine, USA. “This [phase II trial] has been touted incorrectly as the largest effect ever seen and as nearly the second coming of Alzheimer’s disease”, he says. “The company suggests, based on scanty preclinical work, that it may have some metabolic effects directly on mitochondria. This claim is of course because it’s hard to sell just a symptomatic drug.” But Smith Doody counters this argument by saying that, although the mechanisms of dimebon’s action are unknown, “it has already shown a signal in phase II. And that’s an interesting position to be in. I think I’d rather be there than have a great mechanism and no clinical activity”, she says. But despite disagreements among experts over the most promising drug candidates, everyone agrees that investigators face major challenges when writing the protocols for diseasemodifying trials. “The current trend has been to simply take the standard 6-month placebo-controlled trials, and
http://neurology.thelancet.com Vol 6 December 2007
Cordelia Molloy/Science Photo Library
In Context
Drugs designed to modify Alzheimer’s disease are being tested in placebocontrolled trials
tweak them a bit by lengthening them to 18 months by allowing ongoing treatment with cholinesterase inhibitors, adding a biomarker as a secondary outcome to argue disease modification, but they basically use the standard outcomes to assess efficacy”, explains Schneider. However, longer trials are not necessarily better, he notes, because more drop-outs can be expected in longer studies than in shorter ones. Crucially, Steven DeKosky, of the University of Pittsburgh School of Medicine, USA, believes that the two major trial networks—the Alzheimer’s Disease Cooperative Study (ADCS) and the European Alzheimer’s Disease Consortium (EADC)—are underfunded. “We must be more efficient in how we do the trials, but we must have more resources to do them properly”, he says. “This is a place where public– private collaborations will be helpful, perhaps vital. As new techniques and breakthroughs lead to new medication possibilities from small pharma and biotechs, not all of which will be picked up by big pharma for testing, it will fall to the governments to support the ADCS and the EADC for such studies. But outside of the smaller proof-ofconcept studies, we are not resourced sufficiently to do definitive studies at present budget levels”, predicts DeKosky.
For the ADCS website see https://adcs.ucsd.edu/Home.htm For the EADC website see http:// eadc.alzheimer-europe.org/
James Butcher 1039
The hunt for drugs to modify Alzheimer’s disease The US Food and Drug Administration last licensed a new drug to treat Alzheimer’s disease 4 years ago. In 2008, the first trial data of drugs designed to modify the underlying pathology of this disorder will be released. James Butcher investigates what the future might hold for these drugs.
Bsip Mendil/Science Photo Library
For the marketing departments of pharmaceutical companies, being the first to launch a drug that can be advertised as a disease-modifier of Alzheimer’s disease is nothing short of a Holy Grail, with blockbuster status sure to follow. But proving to the regulatory authorities that a compound arrests the underlying pathology of the disease is not easy, as those who run clinical trials are finding out the hard way. Short 6-month trials were used in the 1990s to prove the symptomatic efficacy of cholinesterase inhibitors. But to show disease modification, longer trials are needed, and these are likely to lose a large proportion of patients to follow-up. However, phase III trials of putative disease-modifying drugs are ongoing, with some interesting results expected in 2008. One of the most high-profile candidates is bapineuzumab, a humanised monoclonal antibody that targets amyloid-β peptide (Aβ). The previous vaccine candidate from Elan and Wyeth, AN-1792, used aggregated Aβ1–42 as an antigen, but development was stopped in phase II when 6% of the treated patients developed aseptic meningoencephalitis. To try to avoid
An elderly woman taking a test to assess the progress of her Alzheimer’s disease
1038
these side-effects, the companies are now testing passive Aβ immunotherapy with bapineuzumab. “The upside of making antibodies in the laboratory and giving them to patients is that you know what you’ve raised them against, and so they are more likely to be safe and the correct dosage can be calculated”, explains Gordon Wilcock, who works at the University of Oxford, UK. “The downside is that they are expensive to produce and they have to be topped-up fairly regularly. A question mark has also been raised over whether these antibodies increase the risk of microhaemorrhages in the brain”, he says. The results of the two phase II studies of bapineuzumab will be made public in mid-2008, say Elan and Wyeth. However, on the basis of a planned interim analysis of one of the phase II trials and an assessment of the latest data on AN-1792, the company decided to initiate a phase III study of bapineuzumab before the end of 2007. But, of course, success in phase III trials is not guaranteed. One drug that seems to be on shaky ground is tramiprosate (Alzhemed), a glycosaminoglycan mimetic that binds to Aβ peptides, preventing them from forming Aβ aggregates. On August 26, 2007, Neurochem, the Canadian firm that developed the drug, announced the results of a phase III trial that enrolled 1052 patients from Canada and the USA with mild to moderate Alzheimer’s disease. The patients, who had all been treated for at least 4 months with licensed therapies before enrolment, were randomly assigned placebo, 100 mg tramiprosate twice a day, or 150 mg tramiprosate twice a day. Another phase III trial, based in Europe, is ongoing.
“The North American phase III trial did not meet its target so the trial does not provide evidence in favour of Alzhemed, at least for regulatory purposes”, says the principal investigator of the trial, Paul Aisen, of Georgetown University Medical Center, Washington, DC, USA. “The analysis plan that had been selected was quite problematic in terms of a poor fit with the observed data; there was a large degree of variance amongst sites”, explains Aisen, who notes that further reanalysis of the data is ongoing. “The company has announced that a panel of experts has been convened to review, reanalyse, and probe deeper into the data from the trial, and the panel will recommend to the company what additional steps are appropriate for the development of Alzhemed.” These steps might include adjustments to the European phase III trial and recommendations about additional studies, says Aisen, who expects Neurochem to make a decision, based on advice from the panel, by the end of 2007. The other phase III trial of tramiprosate, in which 930 European patients have been enrolled, is ongoing. Bruno Vellas of the University of Toulouse, France, who is the principal investigator of the trial, emphasises the difficulties with trials that test putative disease-modifying agents. “My personal feeling is that if we have a drug that is very active then of course we will see an effect, but if we have a drug that is moderately active then I think that it could be very difficult to objectively assess the effectiveness of the drug”, he says. “To do this sort of trial we use 70–80 sites around the world and we have many site effects”, explains Vellas. “We do trials over an 18-month period
http://neurology.thelancet.com Vol 6 December 2007
and during that time the patients can have many life events—they can lose a caregiver, they can have some concomitant disease, and that can increase the difficulty to see some effect.” Vellas notes that the enrolled patients have the least progressive forms of the disease and are stable on cholinesterase inhibitors; this means that any effect from the drug is difficult to detect, because the patients’ decline is very slow. “Maybe the solution is to have fewer centres, but more patients per centre”, suggests Vellas. “One of the problems is that we have too few big centres that are able to include at least 10–20 patients each; we have too many centres that only include 2–5 patients each.” Vellas says that if the phase III European trial of tramiprosate is also negative, then investigators will have no option but to try to resolve these issues. Another compound that is in phase III trials is tarenflurbil (Flurizan), a stereo-isomer of a non-steroidal anti-inflammatory drug that does not have cyclo-oxygenase activity but does inhibit γ-secretase. Myriad, the company that is developing the compound, said on Nov 1, 2007, that the US phase III trial is proceeding on schedule and that the 18-month study will be completed at the end of March, 2008, as planned; the top-line results of the study will be made available by the end of June, 2008. The US trial will enrol around 1600 patients and the European trial around 800 patients, according to Wilcock, the principal investigator of the European trial. Wilcock was also the principal investigator of a phase II, 12-month trial of the drug in which 207 patients with mild to moderate Alzheimer’s disease were randomly assigned to placebo, 400 mg tarenflurbil twice a day, or 800 mg tarenflurbil twice a day. “At 12 months the trial was positive on two of the three outcome measures, so technically you could say it was a failed trial, but in fact the picture that emerged from the activities of daily
living and the CDR [clinical dementia rating] sum of boxes showed diverging slopes as you would predict for a disease-modifying, rather than a symptom-modifying, drug”, says Wilcock. The data have been presented at scientific conferences but have not been published in full yet. Another unpublished phase II trial tested dimebon in 183 patients with mild to moderate Alzheimer’s disease. “Dimebon’s mechanisms are just being elucidated now”, says the trial principal investigator Rachelle Smith Doody, of Baylor College of Medicine, Houston, USA. “It came to attention because its physical structure is predicted to be both a cholinesterase inhibitor and an NMDA receptor antagonist and it does have both of those actions but they’re weak”, she explains. “Most of the work on its mechanisms is proprietary and not even known to me but I know it’s underway”, she says. “Dimebon has gotten in my view undeserved hype”, says Lon Schneider, of the University of Southern California Keck School of Medicine, USA. “This [phase II trial] has been touted incorrectly as the largest effect ever seen and as nearly the second coming of Alzheimer’s disease”, he says. “The company suggests, based on scanty preclinical work, that it may have some metabolic effects directly on mitochondria. This claim is of course because it’s hard to sell just a symptomatic drug.” But Smith Doody counters this argument by saying that, although the mechanisms of dimebon’s action are unknown, “it has already shown a signal in phase II. And that’s an interesting position to be in. I think I’d rather be there than have a great mechanism and no clinical activity”, she says. But despite disagreements among experts over the most promising drug candidates, everyone agrees that investigators face major challenges when writing the protocols for diseasemodifying trials. “The current trend has been to simply take the standard 6-month placebo-controlled trials, and
http://neurology.thelancet.com Vol 6 December 2007
Cordelia Molloy/Science Photo Library
In Context
Drugs designed to modify Alzheimer’s disease are being tested in placebocontrolled trials
tweak them a bit by lengthening them to 18 months by allowing ongoing treatment with cholinesterase inhibitors, adding a biomarker as a secondary outcome to argue disease modification, but they basically use the standard outcomes to assess efficacy”, explains Schneider. However, longer trials are not necessarily better, he notes, because more drop-outs can be expected in longer studies than in shorter ones. Crucially, Steven DeKosky, of the University of Pittsburgh School of Medicine, USA, believes that the two major trial networks—the Alzheimer’s Disease Cooperative Study (ADCS) and the European Alzheimer’s Disease Consortium (EADC)—are underfunded. “We must be more efficient in how we do the trials, but we must have more resources to do them properly”, he says. “This is a place where public– private collaborations will be helpful, perhaps vital. As new techniques and breakthroughs lead to new medication possibilities from small pharma and biotechs, not all of which will be picked up by big pharma for testing, it will fall to the governments to support the ADCS and the EADC for such studies. But outside of the smaller proof-ofconcept studies, we are not resourced sufficiently to do definitive studies at present budget levels”, predicts DeKosky.
For the ADCS website see https://adcs.ucsd.edu/Home.htm For the EADC website see http:// eadc.alzheimer-europe.org/
James Butcher 1039