HALLE (SAALE), Germany—Searching for the key to unlock the mystery of defeating Alzheimer’s disease (AD)—or at least slow its progression—Probiodrug AG has announced the results of its preclinical trial exploring the combination therapy of glutaminyl cyclase (QC) inhibitor PQ912 and pGlu-Abeta specific antibody PBD-C06, targeting pGlu-Abeta. This dual weapon has shown clear additive effects in reducing pGlu-Abeta as well as Abeta in an Alzheimer-mouse model, according to the company.
Probiodrug’s lead product candidate, PQ912, is a highly specific and potent inhibitor of QC, which has shown therapeutic effects in Alzheimer’s animal models. PQ912 is currently in a Phase 2a study, the SAPHIR trial. In a preceding Phase 1 study with healthy young and elderly volunteers, PQ912 has shown to be safe and well tolerated and also revealed high QC inhibition.
The success of the trial was based on finding an additive effect on lowering pGlu-Abeta (pyroglutamate-Abeta), as well as total Abeta, with a double-pronged approach of targeting toxic pGlu-Abeta by combining the QC inhibitor PQ912 to block pGlu-Abeta formation and the mouse version of the pGlu-Abeta specific antibody, PBD-C06, to increase clearance in an AD animal model.
“Considering the complex Alzheimer’s pathology, therapeutic progress will likely be very much facilitated by combination strategies, as in other indications,” Dr. Inge Lues, chief development officer at Probiodrug, stated in a news release.
“Our results are very exciting as they clearly indicate an attractive approach for combination by either increasing the effect size on lowering toxic pGlu-Abeta and total Abeta, or potentially by lowering a single agent’s dose when combined to avoid limiting safety issues. Other combinations of interfering with pGlu-Abeta and Abeta are currently running,” she adds.
Lues told DDNews, “According to combination theories, it is assumed that addressing different or the same pathways by two single agents should lead to either no additive effect or less than an additive effect, (same molecular pathway/target); an additive effect if complementary, two-pronged approaches to reduce the same toxic target molecules are combined, (as in the PQ912/PBD-C06 case), the two approaches not being completely independent; or a synergistic effect when different, independent pathways converging to the same readout are affected.”
On the role of pGlu-Abeta or Abeta, Lues says, “It has been convincingly shown in scientific literature that the state of pGlu-Abeta/Abeta aggregation is the critical toxic culprit in Alzheimer’s disease. While Abeta plaques are considered to be quite benign, soluble Abeta aggregates called oligomers are the key entities causing synaptic failure as the key starting point of the disease pathology.”
“Comparing oligomers made of pGlu-Abeta or a mixture of pGlu-Abeta with full-length Abeta 1-42 oligomers shows that those oligomers containing pGlu-Abeta are by far more toxic than the pure Abeta ones,” Lues explains, adding, “Although the Abeta plaques might come into play as a reservoir of oligomers.”
“One can imagine that the combination effect on disease progression could be more pronounced,” Lues adds. “Additionally lower doses of the single agents for the same effect could maximize tolerability of the therapy. It can also be hypothesized that the time window for an optimally effective therapy could be broadened, i.e. patients could be safely and effectively treated for longer.”
The total results of the preclinical trial “are not yet available to the public,” she says. “We are in the process of preparing a manuscript for publication, as the data became available only very recently.”
The combination study was performed in a well-characterized double transgenic Alzheimer animal model, APPswlhQC. In independent pre-studies, the single agents showed a dose-dependent effect on lowering pGlu-Abeta and total Abeta. While there was a modest reduction in pGlu-Abeta and total Abeta following low dose treatment with each single agent, there was a significant reduction in pGlu-Abeta and total Abeta in the combination-treated mice.
The combination was very well tolerated, with no signs of intolerability or toxicity observed. The pharmacodynamic effects on pGlu-Abeta and total Abeta were captured by ELISA and by IHC (immunohistochemistry).
According to the Bliss model, the combination results correspond to a strong additive effect. The combination prevented the 10-fold increase of pGlu-Abeta observed in control animals during the treatment period. Selected doses of the single agents led to about 35-percent reduction in hippocampal pGlu-Abeta plaque load, whereas the combination treatment significantly reduced plaque load by about 65 percent, the company reports. It is important to emphasize that specific targeting of pGlu-Abeta by combination treatment also reduced total Abeta.
The Bliss Independence model is based on the principle that drug effects are outcomes of probabilistic processes and assumes that drugs act independently in such a manner that neither of them interferes with the other (different sites of action), but each contributes to a common result.
Data were generated in collaboration with QPS of Graz, Austria, as well as Cynthia Lemere of Brigham and Women’s Hospital and Harvard Medical School, who said of the preclinical results in a news release, “These data are exciting because they indicate that although both approaches may work as monotherapies, they are likely to have even greater potential if these two complementary approaches are combined.”
