The treatment appeared safe, with no difference in the number of adverse events or serious adverse events between the placebo and treatment arms. However, tolerability was an issue. During the first eight weeks of the study, 27 people in the treatment arm either temporarily or prematurely stopped taking the medication due to side effects, compared with six people in the placebo group. The most common problem was skin rashes or itching, which resolved when the drug was stopped. In the final month of the study, participants reported no problems. This suggests people adapt to the dosage over time, Lues said. In future trials, the researchers are considering titrating the dose up to give the body more time to adapt, she added.
On the exploratory measures, the researchers saw a highly significant (p=0.002) effect on brainwave activity, as measured by EEG. In early AD, theta rhythms peak while alpha power wanes (see Moretti et al., 2009; Montez et al., 2009). In the PQ912 treatment arm, both measures became more normal, with theta power decreasing and alpha rising. The results fit with the hypothesis that pyroGlu Aß oligomers poison synapses, and that their absence allows brain function to normalize, Lues noted. The researchers are still analyzing fMRI data to find out if functional connectivity changed in the participants.
In keeping with the EEG results, people on PQ912 performed better on the One Card Back test, which measures working memory, compared to their baseline performance. The placebo group remained stable on this measure. The treatment group also had a trend toward improvement on a test of attention, but no difference from placebo on five other measures.
Finally, the researchers saw encouraging trends on several cerebrospinal fluid markers. The synaptic protein neurogranin rises in CSF during AD, apparently reflecting synaptic damage (see Sep 2015 news; Sep 2015 news). On drug, neurogranin edged down. The decline missed significance, but the researchers noted that if they excluded from analysis three patients who started taking donepezil during the trial, the results became significant.
Meanwhile, the inflammatory marker YKL40 fell in treated patients, also just shy of significance. Besides modifying Aß, the enzyme QC also activates chemokines and spurs an inflammatory response. Thus, QC inhibitors may have a second mechanism of action that quiets the immune response, noted Hans-Ulrich Demuth from the Fraunhofer Institute for Cell Therapy & Immunology, Leipzig, Germany. Demuth helped found Probiodrug and now advises the company. The researchers examined CSF Aß and tau as well, but saw no change in these AD biomarkers. Lues noted this was not expected in such a short study.
The CSF also provided signals that PQ912 was hitting its target. QC was inhibited by 92 percent in patients on drug, in agreement with Phase 1 data for this dose. Levels of pyroGlu Aß oligomers in CSF appeared to drop, but Lues noted that this data should be interpreted cautiously, since levels in the CSF are so low that they are at the limit of detection for the assay. Additional analysis from the SAPHIR trial will be presented at the 2017 Clinical Trials on Alzheimer’s Disease conference in Boston in November.
The researchers plan to test several doses in future trials, and for longer time periods, Lues said. Animal studies show that inhibiting QC by 60 percent is sufficient for cognitive benefits. This level of inhibition can be achieved with a dose of 150 or 200 mg twice daily in people, she noted. “That makes us confident we can lower the dose,” Lues told Alzforum. In future trials, participants will be allowed to take acetylcholinesterase inhibitors.
Probiodrug also develops an antibody against pyroGlu Aß that it plans to take to the clinic (see Nov 2015 conference news). Eli Lilly tested a similar antibody; it lowered brain amyloid load in Phase 1, but produced an adverse immune reaction (see Aug 2016 conference news).—Madolyn Bowman Rogers