Clinical support for pGlu-Abeta targeting

Probiodrug to start Phase 2b clinical trial of PQ912 in Alzheimer’s

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HALLE, Germany—Aimed at ultimately finding a cure for Alzheimer’s disease (AD), biopharmaceutical company Probiodrug AG is preparing to start Phase 2b trials, a double-pronged parallel strategy of clinical studies with lead drug candidate PQ912, while reviewing potential pharma partners. The decision to go forward followed a successful Phase 2a clinical trial in June 2017, in which early-onset Alzheimer’s patients showed improvement in memory and cognition.
Konrad Glund, co-founder and CEO at Probiodrug, states that in the Phase 2a, SAPHIR program, PQ912 showed “a very strong target engagement of 92-percent QC inhibition, significant cognitive improvements in working memory in the ‘one card back’ test, a clear trend on psychomotor speed in the detection test at the functional level, a very significant positive effect on the EEG theta power and encouraging positive results on synaptic and inflammatory cerebrospinal markers.”
“Altogether, these results are very encouraging, as they provide evidence for pGlu-Abeta being synaptotoxic and strongly support the therapeutic strategy pursued by Probiodrug,” Glund says, who adds that the upcoming Phase 2b core program will consist of two clinical trials: one to be executed in the European Union (EU) and the other in the U.S.
“This program will build on the excellent and efficient infrastructure which was established for the Phase 2a SAPHIR study,” he says. “Moreover, it is based on the valuable results of the SAPHIR study, and has been designed with the guidance of international KOLs [key opinion leaders] in the Alzheimer’s field.”
The study “will include AD patients similar to those included in the SAPHIR Phase 2a trial, i.e. early-stage AD patients characterized by their cognitive status,” Glund adds. “We need the data from core Phase 2b to design any Phase 3 trial.”
The “increasing evidence for targeting toxic Abeta oligomers as a key culprit of the AD pathology, in which pGlu-Abeta seems to play a significant role, is providing sound support for our efforts,” Glund explains. “We are confident that this double-pronged strategy will efficiently expedite and safeguard the advanced development of PQ912.”
The Probiodrug design is revolutionary, he says. Probiodrug’s innovative approach involves the development of specific inhibitors for the enzyme glutaminyl cyclase, the enzyme which is inhibited by PQ912 and instrumental in the creation of pGlu-Abeta.
Contemporary approaches to treat Alzheimer’s are aiming for disease modification, Glund says. Probiodrug has identified a new concept based on the current understanding of early Alzheimer’s pathology.
This approach “is unprecedented,” he adds. “Prof. (Philip) Scheltens, a well-experienced and known neurologist who has been involved in many AD studies, was instrumental to set up the clinical development plan. We are following the path forward to translate the early findings into robust efficacy data. It is too early, however, to define the specific scope and characteristic effects.”
There “is a big medical need to find a cure for Alzheimer’s, and it is a big problem for society,” Glund says. “[David Cameron, former prime minister of the United Kindgom] made it a goal for 2025 of achieving a cure or an effective treatment for Alzheimer’s.”
Today, 47 million people live with dementia worldwide, and this number is projected to triple to more than 131 million by 2050, as the population ages, according to the World Alzheimer Report, 2016. Alzheimer’s has an estimated global societal cost of $818 billion, and will become a trillion-dollar disease by 2018.
Scheltens, director of the Alzheimer Center VU University Medical Center Amsterdam, presented a poster of the Phase 2a results at the 10th Clinical Trials on Alzheimer’s Disease Conference in Boston entitled “Phase 2a Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel-group Safety and Tolerability Study of PQ912 in Subjects with Early Alzheimer’s Disease (SAPHIR).”
Scheltens reported positive top-line pharmacodynamic and efficacy results in early-stage AD patients, showing significant improvements in a working memory test and a clear trend in a detection test.
Scheltens explained that pGlu-Abeta is crucial in the formation of synapto-/neurotoxic oligomers. These oligomers impair synaptic function and integrity. As pGlu-Abeta is formed by the enzyme Glutaminylcyclase and PQ912 is an inhibitor of the enzyme, treatment with PQ912 prevents pGlu-Abeta and oligomer formation, causing improved memory and cognition in early Alzheimer’s patients.
The primary endpoint was safety and tolerability, with no overall major safety concerns, he said. “Secondary endpoints: Very strong QC-inhibition in the brain, significant improvement in a cognitive test of the working memory domain and a shift towards normal in the theta wave of quantitative EEG, as well as encouraging results in the right direction on synaptic and inflammatory biomarkers determined in the spinal fluid.”
“The encouraging positive effects on secondary readouts are supporting the hypothesis of p-Glu-Abeta being a synaptotoxic Abeta variant and are making the program attractive to go forward,” he noted. “The study reveals a positive benefit-risk ratio and provides important guidance how to go forward.”
Scheltens said the Phase 2a study resulted in some anecdotal progress, as well. When the clinical trial concluded, some families of the patients/subjects remarked seeing improvement in their loved ones, who seemed more connected, less confused and to feel better. They wanted the trial to continue.

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