Setting the stage for development

Rounding up some recent news of preclinical studies and results around the world A quartet of brief stories to give you a quick peek across the globe (a few select portions, anyway) into what researchers have turned up in preclinical efforts in recent months.

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Zealand presents new data on ZP-I-98
COPENHAGEN, Denmark—Zealand Pharma A/S presented new preclinical data on its novel GIP receptor agonist, ZP-I-98, at the 51st European Association for the Study of Diabetes annual meeting that took place Sept. 14-18 in Stockholm, Sweden. One investigational approach to enhance the efficacy of GLP-1 receptor agonists, used for the management of type 2 diabetes, includes combination therapy with a glucose-dependent insulinotropic peptide (GIP) receptor agonist. Recent preclinical studies conducted in diet-induced obese mice by Zealand with its novel GIP receptor agonist, ZP-1-98, have shown that a GIP/GLP-1 combination therapy could enhance the treatment of type 2 diabetes by inducing both robust glycemic control as well as a greater loss of body weight than seen by a single treatment. ZP-1-98 has a long-acting profile, which indicates that it could be suitable for convenient once-weekly dosing.
Commenting ahead of the presentation, Keld Fosgerau, acting senior vice president and head of research at Zealand, said: “Our recent preclinical results support the attractive therapeutic          rationale of combining the incretin hormones GIP and GLP-1 for better management of type 2 diabetes. In addition to robust glycemic control, we believe that the strong weight loss effects of this dual strategy combined with an expected once-weekly treatment profile represent potentially significant benefits for patients.”
Single injection prevents meth relapse
JUPITER, Fla.—Recovering addicts often grapple with the ghosts of their addiction—memories that tempt them to relapse even after rehabilitation and months, or even years, of drug-free living. Now, scientists from the Florida campus of The Scripps Research Institute (TSRI) have made a discovery that brings them closer to a new therapy based on selectively erasing these dangerous and tenacious drug-associated memories.
“We now have a viable target and by blocking that target, we can disrupt, and potentially erase, drug memories, leaving other memories intact,” said Courtney Miller, a TSRI associate professor. “The hope is that, when combined with traditional rehabilitation and abstinence therapies, we can reduce or eliminate relapse for meth users after a single treatment by taking away the power of an individual’s triggers.”
The research builds on previous work in Miller’s lab. In 2013, the team made the surprising discovery that drug-associated memories could be selectively erased by targeting actin, the protein that provides the structural scaffold supporting memories in the brain. However, the therapeutic potential of the finding seemed limited by the problem that actin is critically important throughout the body—taking a pill that generally inhibits actin, even once, would likely be fatal.
In the new study, Miller and her colleagues report a major advance—the discovery of a safe route to selectively targeting brain actin through nonmuscle myosin II, a molecular motor that supports memory formation. To accomplish this, the researchers used a compound called blebbistatin that acts on this protein. The results showed that a single injection of blebbistatin successfully disrupted long-term storage of drug-related memories—and blocked relapse for at least a month in animal models of methamphetamine addiction.
“What makes myosin II such an exciting therapeutic target is that a single injection of blebbistatin makes methamphetamine-associated memories go away, along with dendritic spines, the structures in the brain that store memory,” said Research Associate Erica Young, a member of the Miller lab and a key author of the new study, along with Research Associates Ashley M. Blouin and Sherri B. Briggs.
Aerie and Ramot enter research collaboration
IRVINE, Calif. & TEL AVIV—In mid-September, Aerie Pharmaceuticals Inc., a clinical-stage pharmaceutical company focused on the discovery, development and commercialization of first-in-class therapies for the treatment of patients with glaucoma and other diseases of the eye, and Ramot at Tel Aviv University Ltd., Tel Aviv University's technology transfer company, announced a research collaboration and license agreement for a preclinical anti-beta amyloid small-molecule product candidate for neuroprotection and dry age-related macular degeneration (AMD).
The proprietary technology was originally developed by a team headed by Prof. Ehud Gazit of the George S. Wise Faculty of Life Sciences at Tel Aviv University. The technology is based on the combination of noncoded α-aminoisobutyric acid and aromatic recognition module to construct a novel chemical entity that is a safe and potent inhibitor of the formation of toxic amyloid assemblies. The collaboration will focus on evaluating Ramot’s preclinical anti-beta amyloid small molecule product candidate for neuroprotection in glaucoma and for reduction of geographic atrophy in advanced dry AMD. Beta amyloid is elevated in diseased tissues of patients with Alzheimer’s disease, glaucoma and dry AMD. Neurotoxic amyloid beta molecular complexes, or oligomers, are considered to be a common pathological agent leading to degeneration of neurons and neurosensory cells.
“We believe Aerie is the right partner to explore the full potential of this exciting molecule in ophthalmology,” Shlomo Nimrodi, Ramot's CEO, commented. “We have observed solid preclinical evidence that beta amyloid is a compelling target for both glaucoma and dry AMD, and we have great confidence that Aerie will pursue this opportunity with a high level of scientific acumen and diligence.”
TRV 101 significantly reduces both amyloid beta and tau toxic aggregates
PHILADELPHIA—Treventis Corp. announced this summer that its preclinical candidate TRV 101 had successfully demonstrated significant reduction in the toxic aggregates/oligomers of both amyloid beta and tau protein in multiple transgenic mouse models of Alzheimer's disease. Using industry-standard mouse models of amyloid beta (APP/PS1) and tau (rTg4510), a reduction of approximately 30 to 40 percent in both tau and amyloid beta oligomers was observed in the brain following oral administration of TRV 101 over a three- to seven-day period.
“Toxic oligomers or aggregates of beta-amyloid and tau protein are known to have synergistic and pathogenic roles in the progression of Alzheimer's disease. These data on TRV 101 show that it is possible to target and reduce both of these protein with a single small molecule, which is a significant advance for the company and the field of Alzheimer's disease research,” said Sean Cunliffe, CEO of Treventis.

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