Probiodrug‘s PQ912 decreased markers of inflammation and damage in the nerve cell connections of Alzheimer’s patients, according to a Phase 2a clinical trial.
The company will present the results of the SAPHIR trial, which covered the therapy’s safety and effectiveness, at the 10th Clinical Trials on Alzheimer’s Disease Conference in Boston, Nov. 1-4.
Dr. Philip Scheltens, director of the Alzheimer’s Center at VU University Medical Center in Amsterdam, will discuss the findings in a presentation titled “Phase 2a study results with the glutaminylcyclase inhibitor PQ912 in early Alzheimer’s Disease.” He was the principal investigator of the trial.
Researchers have found high levels of the glutaminylcyclase enzyme in the brains of Alzheimer’s patients. PQ912 inhibits the enzyme. Preclinical-trial studies that Probiodrug did in mouse models of the disease showed that PQ912 improved the animals’ cognition.
The SAPHIR trial (NCT02389413) was a 12-week, double-blind, randomized, placebo-controlled trial. It investigated PQ912’s ability to treat people with early Alzheimer’s disease who had never been treated before.
The trial’s primary objective was to determine if PQ912 was safe, and if patients could tolerate it well.
Secondary objectives included seeing it was effective against Alzheimer’s, including delaying the disease’s progression. One of the effectiveness yardsticks was whether PQ912 could inhibit glutaminylcyclase enzyme production. Researchers looked at cerebrospinal fluid biomarkers of the enzyme to determine that it could.
Other measures of effectiveness the team used included electroencephalogram, or EEG, scans of patients’ brain activity and their neuropsychological test battery, or NTB, scores. Those scores can detect cognitive changes in Alzheimer’s patients.
Researchers recruited 120 patients for the trial, which was conducted in seven European countries. Sixty patients were randomly assigned to the PQ912 arm and 60 to the placebo arm.
Probiodrug announced the initial trial results earlier this year.
A key safety finding was that about the same number of patients in the PQ912 and placebo arms experienced either adverse or serious adverse events. The adverse event figures were 49 in the PQ912 group and 45 in the placebo group. The serious adverse event figures were eight in the treated group and five in the control group.
More PQ912-treated than placebo patients dropped out of the trial because of adverse events, however. The treated group had more skin or gastrointestinal problems than the control group, particularly in the first six weeks of treatment.
In terms of effectiveness, the results showed that PQ912 significantly reduced glutaminylcyclase enzyme levels.
Another effectiveness finding was that it greatly reduced biomarkers of inflammation and damage in patients’ nerve cell connections. In contrast, these levels rose in the placebo group. The marker that researchers used for inflammation was the YKL40 protein and for damage the neurogranin protein.
In addition, EEG scans showed less of a type of brain wave activity that previous research has linked to the development and progression of Alzheimer’s.
Patients treated with PQ912 also had better scores than the control group on two of the neuropsychological test battery exams. One was the One Card Back Test, which assesses working memory. The other was the Detection Test, which measures attention.
The promising SAPHIR results prompted Probiodrug to develop plans for a tailored Phase2b clinical trial that will assess the safety and effectiveness of an optimal dose range of PQ912 in early Alzheimer’s patients. The program will have arms in Europe and the United States.
“The positive SAPHIR study results created an accelerating positive momentum toward starting a clinical Phase 2b program for PQ912,” Inge Lues, Probiodrug’s chief development officer, said in a press release. “The Phase 2a results are tremendously useful in enabling the design of a tailored program comprising two clinical studies, one planned in Europe and the second in the USA. We expect that this program will answer important questions enabling us to progress PQ912 into the confirmatory Phase 3 program.”
Konrad Glund, Probiodrug’s chief executive officer, said the company is also targeting other Alzheimer’s mechanisms. “The increasing evidence for targeting toxic Abeta oligomers [amyloid beta protein] as a key culprit of the AD [Alzheimer’s disease] pathology, in which pGlu-Abeta seems to play a significant role, is providing sound support for our efforts,” he said. “We are confident that this double-pronged strategy will efficiently expedite and safeguard the advanced development of PQ912.”
Scientists have long contended that clusters of harmful amyloid beta protein in Alzheimer’s patients’ brains are among the drivers of the disease.