DUBLIN – Shares in Probiodrug AG climbed by almost 19 percent during early trading Monday on topline data from an exploratory phase IIa trial of its first-in-class glutaminylcyclase (QC) inhibitor PQ912 in early stage Alzheimer's disease patients. The stock subsequently shed most of those gains, however, as investors opted to take some profit now instead of waiting for the early stage program to deliver more solid data further down the line.

It will be a long time yet before the Halle, Germany-based firm will be able to establish conclusively whether or not the drug has a future as an Alzheimer's therapy. For now, Halle, Germany-based Probiodrug has achieved what it set out to do: to establish that PQ912 looks to be safe enough and efficacious enough to warrant further study of a longer duration.

The placebo-controlled phase IIa trial recruited 120 patients across 21 clinical sites in seven European countries. Patients were treatment naïve and had a mean Mini-Mental State Examination (MMSE) score at baseline of 25.5 (range 21-30), where 30 indicates normal functioning.

The study by no means offered a completely clean bill of health for the drug, however. Although there were no statistically significant differences between the two study arms in terms of total number of adverse events (49/60 for the drug treatment arm vs. 45/60 for the control arm) or in the number of patients who experienced a serious adverse event (n=8 for the drug treatment arm vs. n=5 for the control arm), dropout rates were considerably higher in the drug treatment group than in the placebo group (n=6 and n=0, respectively, p=0.027). The number of patients straying from the trial protocol was also substantially higher in the drug treatment group than in the control group (n=16 vs. n=2, p<0.01)

Skin problems, including rash, erythema, urticaria and gastrointestinal problems were the main reasons, Probiodrug chief medical officer Frank Weber explained on a conference call. But the company is not locked into the dose (800 mg twice daily) it employed in the study. "We made a strategic decision to use the high dose," Weber said. "We did an accelerated stress test of the drug."

The dose used – 800 mg twice daily – was the highest administered during a phase I multiple-ascending dose trial. It was deployed in the present trial in order to assess the effects of high target occupancy, but in a longer study, Weber said, it would be possible either to use a lower dose or to titrate the dose more gradually than was the case here. "The vast majority of the discontinuations happened in the first six weeks of the study," he said. "After six weeks, there were no further treatment discontinuations."

The three-month study was not powered to demonstrate efficacy, but the investigators did see some pointers in that direction, notably a decrease in levels of pyroglutamyl-Abeta (pGlu-Abeta) in the cerebrospinal fluid (CSF) of those on PQ912 and a rise in the concentration of the same toxic oligomer in the CSF of those in the control group.

That finding represents direct evidence that the drug is behaving as intended – glutaminyl cyclase is the enzyme responsible for the N-terminal post-translational modification of the peptide. A preclinical study, due to appear in the July 2017 issue of the Journal of Pharmacology and Experimental Therapeutics, linked target occupancy with PQ912 to improved cognition in murine models of Alzheimer's. In that study, 60 percent target occupancy translated into the improvements seen, leading the study authors to conclude that upward of a 50 percent occupancy would lead to "robust treatment effects."

The phase IIa study also detected reductions in levels of two other important biomarkers, neurogranin, a post-synaptic, calmodulin-binding brain protein, whose accumulation is associated with synaptic loss in Alzheimer's, and YKL 40, a marker of inflammation. The study also found positive effects in favor of PQ912 on two cognitive tests, One Card Back Test, a measure of working memory, and the Detection Test, a measure of attention. There were no differences on five other cognitive tests, however. Electroencephalogram readings of brain signaling activity also favored PQ912, Probiodrug said.

The data are early stage, but they do provide tentative clinical proof of concept for a novel mechanism, which Probiodrug itself has pioneered.

The company will now gauge market interest – from prospective partners and investors. "We are interested in collaborating, and we will evaluate the interest of pharma," CEO Konrad Glund said on the call. "The data, in our estimation, will provide a basis for that." The company will, in parallel, also look at funding opportunities for pursuing the next steps on a solo basis. Probiodrug held €18.7 million (US$20.9 million) in cash and equivalents at the end of the first quarter.

In what was by far the stock's heaviest trading day of the past 12 months, shares in Probiodrug (Amsterdam:PBD) ended the day at €17, an eventual gain of just 5 percent on the previous close of €16.20.