Combination therapy with Glutaminyl Cyclase (QC) inhibitor PQ912 and pGlu-Abeta specific antibody PBD-C06 shows clear additive effects in reducing pGlu-Abeta as well as Abeta in Alzheimer-mouse model
HALLE (SAALE), Germany I September 13, 2016 I 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.”
About Probiodrug AG
Headquartered in Halle (Saale), Germany, Probiodrug AG (Euronext Amsterdam: PBD) is a biopharmaceutical company focused on the development of new therapeutic products for the treatment of Alzheimer’s disease.
Founded in 1997, the company successfully developed a novel therapeutic concept for diabetes – the DP4 inhibitors – which provided the basis for a novel class of antidiabetics – the gliptins. Its core capabilities are based on its long-standing expertise in the elucidation of the structure and function of enzymes involved in the modification of proteins and peptides, which play a central role in pathological conditions.
Today Probiodrug’s aim is to become a leading company in the development of Alzheimer’s disease treatments and to thereby provide a better life for Alzheimer’s disease patients. It has identified a new therapeutic concept linked to disease initiation and progression. The development approaches are targeting pyroglutamate-Abeta (pGlu-Abeta) as a therapeutic strategy to fight Alzheimer’s disease. The Company has medical use and composition of matter patents related to the inhibition of Glutaminyl Cyclase (QC) and anti-pGlu-Abeta- specific monoclonal antibodies, providing it, in the Company’s view, with a leading position in this field of research.
Probiodrug’s lead product candidate, PQ912, is a highly specific and potent inhibitor of Glutaminyl Cyclase (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.
About Alzheimer’s disease
Alzheimer’s disease is a neurological disorder, which is the most common form of dementia, and ultimately leads to death. Because Alzheimer’s disease cannot be cured and is degenerative, the affected patients must increasingly rely on others for assistance. Today, over 46 million people worldwide currently live with the condition and this number is expected to increase to 132 million by 2050. Alzheimer’s also has an estimated, global societal cost of US$ 818 billion (World Alzheimer Report 2015).