NEWS OF THE WEEK
MURKY RESULTS FOR ALZHEIMER’S DRUGS PHARMACEUTICALS: Biogen and Eli Lilly
& Co. each offer lukewarm new data on key amyloid-busting antibodies
N
EW DATA on two highly anticipated Alzheim-
er’s disease treatments are not clear wins for either drug. Unveiled last week at the Alzheimer’s Association International Conference, the middling results are a reminder of the daunting task of slowing down the neurodegenerative disease. Biogen provided additional data from a Phase Ib study of aducanumab, an antibody that ties up amyloid-β, the protein responsible for the telltale plaque coating the brains of people with Alzheimer’s. In March, Biogen released interim data from the study showing that higher doses cleared more amyloid from patients’ brains and yielded better performance on cognition tests. But at the time, the company only presented data for 1-, 3-, and 10-mg doses of the antibody. The best results—at 10 mg—were accompanied by brain swelling, a common complication of antiamyloid therapy. The hope was that the
POSSIBLE PEPTIDE ORIGIN STORY CHEMICAL EVOLUTION:
Researchers make peptides under ancient Earth conditions An amino acid reacts with a lactic acid dimer through an esteramide exchange reaction. Oligomer elongation occurs by addition of lactic acid and subsequent esteramide exchange. OH
O O
OH +
O
OH
O
O
H N
OH + R
I
N THEIR QUEST to understand how life on Earth
formed, scientists long ago determined that amino acids—simple yet important building blocks within all organisms—can form under conditions mimicking those of ancient Earth. But the question remains: How might those amino acids combine to form more complex molecules such as peptides? A team of researchers associated with the NSF/NASA Center for Chemical Evolution proposes one possible pathway. The team, led by Nicholas V. Hud O and Facundo M. Fernandez of Georgia Tech H2N and Ramanarayanan Krishnamurthy of Scripps OH Research Institute, California, demonstrates R Amino acid that under plausible prebiotic conditions, α-hydroxy acids and OH O O α-amino acids H OH N HO react to form OH O depsipeptides: O O R Lactic acid oligomers conCEN.ACS.ORG
10
BIOGEN
X-ray crystal structure of the Fab region of Biogen’s aducanumab (blue) in complex with A-β1-11 peptide (yellow).
6-mg dose would strike a balance between efficacy and safety. Unfortunately, that didn’t happen. Although amyloid clearance with the 6-mg dose fell neatly between the levels seen with 3 and 10 mg, the dose didn’t significantly slow cognitive decline. Industry watchers warn against drawing broad conclusions, pointing out that just 30 people were in the 6-mg study group. Biogen has already begun two Phase III studies of the drug that each will include roughly 1,350 people with a mild form of the disease. Meanwhile, Eli Lilly & Co. offered data from an extension of two failed Phase III studies of its amyloidclearing antibody, solanezumab. The antibody was given to people with mild Alzheimer’s who earlier had taken either a placebo or the drug, allowing Lilly to track whether starting treatment earlier improved efficacy. The company found that the drug works best when given earlier in the disease. However, some experts worry that drugs that clear amyloid might never translate into better, more productive lives for people with Alzheimer’s disease. “For both antibodies, statistically significant may not mean clinically meaningful,” says Samuel E. Gandy, associate director of the Mount Sinai Alzheimer’s Disease Research Center. “That’s the distinction to be made. I think the approach would work if begun earlier, but ‘earlier enough’ may mean puberty.”—LISA JARVIS
taining a mix of ester and amide bonds (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201503792). Specifically, the team mixed lactic acid and the amino acid glycine in a 1:1 ratio and subjected the mixture to dry and wet cycles designed to simulate day and night on early Earth. During the dry phase, the mixture was heated to 85 °C for 18 hours. Then, the researchers rehydrated the concoction for 30 minutes and held it at 65 °C for 5.5 hours during the wet phase. Using mass spectrometry, the team revealed that after four dry/wet cycles, the product mixture included depsipeptides made of up to 10 units. The researchers propose that the reaction starts with the formation of lactic acid dimers and oligoesters. An amino acid then displaces a lactic acid unit through an ester-amide exchange reaction. The oligomer grows through repeated addition of lactic acid and subsequent ester-amide exchanges. Pointing out a common drawback of origin-of-life studies, Matthew Powner of University College London, says, “No one knows what exact conditions are prebiotic.” But Powner, who was not involved in the new study, looks forward to seeing whether longer peptides can be formed, chirality can be induced, and other amino acids can be incorporated. Hud and his collaborators plan to use the system to study whether they can form peptides of a single chirality starting from racemic mixtures, an important step toward understanding the origins of the chirality of life.—CELIA HENRY ARNAUD
JULY 27, 2015
