Vivoryon Therapeutics N.V. and Simcere Pharmaceutical Group Ltd. announced that China's Center for Drug Evaluation (CDE) of National Medical Products Administration (NMPA) has approved the Clinical Trial Application for varoglutamstat (SIM0408, PQ912), a medicine in development for the treatment of Alzheimer's disease (AD) developed in Greater China by Simcere. Varoglutamstat is a differentiated oral small-molecule inhibitor with a unique mode of action designed to address several key mechanisms underlying AD pathology, including Abeta pathology, tau pathology, neuroinflammation and synaptic impairment. Varoglutamstat is currently in Phase 2 clinical development in Europe (VIVIAD study) and the U.S. (VIVA-MIND study).

On June 29, 2021, Simcere and Vivoryon entered into a strategic regional licensing partnership to develop and commercialize medicines targeting the neurotoxic amyloid species N3pE (pGlu-Abeta) to treat AD in Greater China and comprises Vivoryon's clinical lead product candidate varoglutamstat (SIM0408, PQ912) as well as Vivoryon's preclinical monoclonal N3pE-antibody PBD-C06. Varoglutamstat, is a differentiated small-molecule inhibitor with a unique dual mechanism of action (MOA) designed to address all hallmarks of Alzheimer's disease (AD): Abeta pathology, tau pathology, neuroinflammation and synaptic impairment. Firstly, varoglutamstat blocks the enzyme glutaminyl cyclase (QPCT), which is found in the brains of AD patients in much higher quantities than in healthy individuals and which has been shown to be linked to AD pathology.

QPCT catalyzes the formation of N3pE amyloid a particularly neurotoxic variant of Abeta peptides, which is not present in the brains of healthy individuals and only found in AD patients. N3pE amyloid in the brain acts as a seeding element for Abeta aggregation, thus providing a starting point for plaque formation. It and has been described to correlate with the cognitive ability of AD patients.

Varoglutamstat acts further upstream of other therapeutics, aiming to prevent the toxic Abeta variant N3pE from forming and seeding plaques, rather than reducing them after they have formed. Secondly, varoglutamstat exploits the fact that the enzymatic activity of glutaminyl cyclases is also required for the stability and full potency of the proinflammatory protein CCL2, with QPCTL, an isoform of QPCT, upregulating CCL2 by converting it into pE-CCL2. Thus, blocking QPCTL holds the potential to reduce neuroinflammation.

Moreover, CCL2 is also a promoter of the tau pathology, which, in turn is linked to synaptic impairment, enabling simultaneous targeting of these pathologies. In contrast to many other drugs in development in AD which are antibodies that have to be injected or infused, varoglutamstat can be very conveniently administered as an oral pill. Varoglutamstat has not yet been approved by any regulatory authority and the safety and efficacy have not yet been established.

Vivoryon has received Fast Track designation for varoglutamstat in early AD by the U.S. Food and Drug Administration (FDA) in December 2021.