這是今天蠻重要的新聞, AAIC上, 三大藥廠公佈近期的阿茲海默藥物試驗結果. 原則上來 說, 和之前學界理解差異不大, 但仍有一些新發現. 對於, 醫界或病人來說可能還要等大 規模臨床試驗後才比較好做判斷. 藥廠目前看起來比較想以目前結果吸引投資者的目光. Biogen的藥物aducanumab補充了一個受試者群, 但和之前預測有些差別. 原本預測這次的 給藥量可能會是一個很好的平衡但結果不然. 儘管如此, 此藥物還是被認為有希望可以繼 續研究. Eli Lilly的藥物solanezumab經過公司的堅持有了逆轉的跡象. 在先前的實驗, 以清除 beta-amyloid的藥物似乎都不能證明其療效. 但在經過一串的追蹤之下, 有使用該藥物 的族群顯示了比較少的惡化. 而且當使用安慰劑的病人開始使用該藥物後, 病情也可以開 始減少惡化. 但還有一些受試者還沒完全追蹤完畢. Roche的gantenerumab也取得了良好的量測數據.儘管不知道如何解讀這個數據, 也無法與 臨床相匹配. 這裡我不確定臨床匹配的意思為何. 總的來說, 這些藥物是否能成功研發也要等研究完成才會知道結果. 記者這裡舉了一個心 臟病藥的例子, 希望大家永遠不要過度期待研究中的結果. -- Promising Alzheimer's Drugs Disappoint With Incremental Data New data being presented this morning on experimental Alzheimer’s drugs from Biogen and Eli Lilly are likely to leave researchers and investors slightly disappointed, while not changing anyone’s mind about whether or not the medicines can eventually slow the progression of the disease, as many hope. The presentations being made here at the Alzheimer’s Association International Conference here in Washington, D.C., are scientifically important, but they are also, in a sense, afterthoughts. Both companies have committed to large trials to prove the drugs work in slowing the progression of Alzheimer’s in its early stages. They are trying to convince everybody else that they made the right decision. For doctors and patients, the best course is probably just to reserve judgement until larger studies are available. It’s only investors, who want to value these companies based on the odds of success of the drugs, and scientists and other drug companies, who are deciding how to develop other experimental medicines, who are really going to take any action based on these results. And for them, the new results probably change little. It’s an exciting time, because it really is possible that these medicines could slow a disease that could otherwise bankrupt our healthcare system and destroy tens of millions of lives. On the other hand, more than 99% of Alzheimer’s drugs tested in clinical trials have failed. With all that said, let’s take a look at today’s news. Biogen Data Disappoint In March, Biogen presented data from a 166 patient study of its drug aducanumab that impressed researchers and astounded Wall Street. In data at three doses (1 milligram per kilogram of body weight; 3 mg/kg; and 10 mg/kg) over 54 weeks, the drug seemed to prevent the buildup of plaque in the brain and also result in better scores on tests designed to measure patient’s ability to think (known as cognition) and get through daily life (called function). The brain changes seemed to get better the higher the dose used, a sign that the drug was working as expected. That has generated a huge amount of excitement. But 54-week data on one dose Biogen had used was missing: the 6 mg/kg dose. Aducanumab also caused brain swelling, which was also dose dependent. Would this be a Goldilocks dose that balanced the drug’s risks and benefits? The news is mixed. The dose-dependent relationship holds up for the 6 mg/kg dose. “The 6 mg per kg lines up perfectly where you would predict it to be,” says Jeff Sevigny, a senior medical director at Biogen. But at 10 mg/kg, the improvements on scales designed to measure mental function were statistically significant. Researchers had hoped the same would be true of the 6 mg/kg dose, but it is not. “That reduces my confidence in these results,” says P. Murali Doraiswamy of the Duke Institute for Brain Sciences. Ronald Petersen, who directs the Mayo Clinic’s Alzheimer’s Disease Research Center and consults for Biogen, says that the data are “partially supportive but not totally convincing.” Essentially, in his view, “the overall story does not change.” He says he wonders what other cognitive testing Biogen collected that has not been presented. Lon S. Schneider, director of the California Alzheimer’s Disease Center at the Keck School of Medicine of USC, worries that the fact that the 6 mg/kg data – and new placebo data that are also being added today – could create a false impression of efficacy. Sevigny says Biogen checked for such an effect but doesn’t see evidence. Schneider also points out that if the effect were as big as what is seen in the study, Biogen wouldn’t need two big trials of 1300 patients each to confirm it. But he’s optimistic that the aducanumab could help patients. More detail: Compared to placebo, the amount of amyloid plaque seen on PET scans decreased by 0.135 in the 3 mg/kg group, 0.210 in the 6mg/kg group, and 0.268 in the 10 mg/kg group. (That’s the exciting dose response!) A similar relationship was seen on two measures of cognitive function. On the Mini Mental State Examination, a 30-point scale based on a survey, patients in the placebo group worsened by an average of 2.81 points at 52 weeks. Clinical decline on the MMSE in the treatment arms was 2.18 points in the 1 mg/kg, 0.70 in the 3 mg/kg, 1.96 in the 6 mg/kg arm (that’s not in line with the other results) and 0.56 in the 10 mg/kg arm. That was statistically significant for the 3 mg/kg and 10 mg/kg doses, but not for the others. On the Clinical Dementia Rating-Sum of the Boxes, a 30-point scale, patients in the placebo group worsened by an average of 1.87 points at 54 weeks compared to 1.72 in the 1 mg/kg group, 1.37 in the 3 mg/kg group, 1.11 in the 6 mg/kg group and 0.63 in the 10 mg/kg treatment arm. It’s churlish to be too disappointed here. Biogen’s decision to move into a larger study based on these very consistent data still makes sense. But knowing about 6 mg dose doesn’t really add much to the results that were presented in March. Eli Lilly Data Slightly Bolster Confidence Like aducanumab, Eli Lilly’s solanezumab is designed to clear a substance called beta amyloid, thought to be a culprit in creating Alzheimer’s plaques, out of the brain. In 2012, it failed in two different studies to slow decline from the disease. But Lilly has stubbornly refused to give up, pointing to after-the-fact analyses that seemed to show the drug worked in milder patients and making a daring and very risky bet on doing new large trials. The data presented today are a follow-on analysis of one of the failed solanezumab studies. What Lilly did was clever: it figured out how to do a type of study that was proposed by a Food and Drug Administration researcher years ago, called a delayed start study. After the study finished, 1,322 patients, whether they were originally getting solanezumab or placebo, were allowed to enter an extension study in which they got the drug. They were followed for 3.5 years. Traditionally, these studies are mostly used to collect safety data. What’s innovative here is Lilly developed a statistical model to try and use the extension study to measure whether solanezumab is having an effect on the progression of the disease. The idea is this: existing Alzheimer’s drugs like Aricept help patients by treating their symptoms, helping them think, while the disease continues to progress. Give such a treatment to someone in the placebo group, and that person looks just like the people in the drug group. But if a drug is preventing a disease from progressing, the people who started on placebo should never catch up to those who got started on the medicine earlier. And that’s what is seen in this new analysis of solanezumab. Initially, the patients who got solanezumab saw their symptoms worsen less than those who received placebo. But when the placebo group started taking solanezumab, the two lines became parallel. Eric Siemers, a medical fellow at Lilly, argues that this pattern would be unlikely to happen by chance, and should give us some comfort that solanezumab is working. Mayo’s Petersen, who consults for Lilly, agrees: “It does lend some credence to the further work they’re doing with solanezumab.” The really exciting thing about this is that if solanezumab works, this could be a new way to study Alzheimer’s drugs after they are approved to get more data about them. That’s a hugely important contribution on Lilly’s part. But we’re still all left waiting for the data from the upcoming solanezumab studies. The last patient visit in the study should occur in October 2016. “This is not about stock prices and it’s not about people’s enthusiasm levels,” said Siemers when I accused the companies of trying to raise investor expectations. “It’s about getting medicines to patients. Roche is also presenting data on its anti-amyloid drug, gantenerumab, from a study that was stopped because it was thought to be statistically futile to continue. Data on tests of spinal fluid and PET scans of the brain look good. It’s hard to know how to interpret that, though. Should we be glad those measures look good, or disappointed that they don’t match up with the clinical results. After sorting through all these results and discussing them with half a dozen researchers, I don’t think they really change the overall picture here. These new Alzheimer’s drugs are promising and risky, and it makes sense to develop them because of the huge amount of medical and financial upside if one works. I would add a note of caution about putting too much stock in these analyses, though. A quick story: a decade ago, Pfizer was spending a huge amount of money on a new drug called torcetrapib to prevent heart attacks. When I first started writing about it, there were a lot of skeptics. But as time passed, the field got more excited about the drug and Pfizer funded scientific studies to explain why the medicine should work. It seemed there were fewer and fewer real skeptics. Until, that is, it turned out torcetrapib, instead of saving lives, upped the death rate. The problem with looking at lots of incremental data about an experimental medicine is that you can start to see things that are not there. If you’re an investor, deciding how likely it is that you think these medicines will work is a combination of guesswork and gut checks, not a science. Whatever you thought before these data is probably as likely to be right as what you think after absorbing them. The news today is that nothing has really changed. 網址: http://www.forbes.com/sites/matthewherper/2015/07/22/promising-alzheimers-drugs -disappoint-with-incremental-data/ ( http://tinyurl.com/nuczc7r ) --

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