HALLE(SAALE), Germany, September 13, 2016 - Probiodrug AG (Euronext Amsterdam: PBD), a biopharmaceutical company developing novel therapeutic solutions to treat Alzheimer’s disease (AD), announced today first results of a preclinical combination trial targeting pGlu-Abeta.
An additive effect on lowering pGlu-Abeta (pyroglutamate-Abeta) as well as total Abeta was observed with a double-pronged approach of targeting toxic pGlu-Abeta by combining the Glutaminyl Cyclase-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.
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. In the combination study in parallel cohorts, efficacy was compared for low dose of each single agent and the same doses in combination. Therapeutic treatment started at eight months of age, after the onset of pathology, and continued for four months. The combination was very well tolerated. No signs of intolerability or toxicity were observed. Pharmacodynamic effects on pGlu-Abeta and total Abeta was captured by ELISA and by IHC (immunohistochemistry).
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. 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% reduction in hippocampal pGlu-Abeta plaque load whereas the combination treatment significantly reduced plaque load by about 65%. It is important to emphasize that specific targeting of pGlu-Abeta by combination treatment also reduced total Abeta.
Data were generated in collaboration with Cynthia Lemere of Brigham and Women’s Hospital, Harvard Medical School, and QPS, Graz, Austria.
Commenting on the announcement, Dr Inge Lues, CDO of Probiodrug, said: “Considering the complex Alzheimer’s pathology, therapeutic progress will likely be very much facilitated by combination strategies, as in other indications. 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 as shown here, 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.”
Cynthia Lemere, Scientist at Brigham and Women’s Hospital, added: “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.”
