IGFBP2

Sept. 29, 2022 12:00 UTC New publication highlights novel and differentiated NMDA receptor mechanism, and rapid and long-lasting antidepressant activity with lead clinical program, Zelquistinel Supports further development of Zelquistinel in a Phase 2 confirmatory study in Major Depressive Disorder, with expected initiation in early 2023 Company highlights business update, recent and upcoming clinical milestones, and additions to advisory network, after emerging from stealth last month INDIANAPOLIS--(BUSINESS WIRE)-- Gate Neurosciences, Inc. today announced the results of research, published in the International Journal of Neuropsychopharmacology, supporting the mechanism of action and clinical foundation of Zelquistinel – the company’s lead oral program in Phase 2 development – as a rapid-acting, long-lasting and safe antidepressant. Publication highlights robust preclinical pro novel mechanism for lead Phase 2 clinical program, Zelquistinel The peer-reviewed manuscript spotlights Zelquistinel’s novel mechanism and pharmacology by which it elicits rapid and long-lasting antidepressant effects. Zelquistinel was shown to positively modulate NMDA receptors (NMDARs) and enhance synaptic plasticity in the hippocampus and medial prefrontal cortex. A single dose of the molecule demonstrated a dose-dependent antidepressant-like response within one hour of administration that was sustained for more than 7 days. The studies highlighted in the publication build upon a robust underlying translational data package and predictive dose model that is consistent across Gate’s class of NMDAR modulators. Zelquistinel’s potential as an oral pill was confirmed by its high bioavailability and brain exposure, and also shows 1000-fold greater potency and a longer plasma half-life compared to its precursor molecule Rapastinel (GLYX-13). In terms of safety, Zelquistinel lacked the sedative, ataxic, and motor impairment effects that are typically observed with NMDAR antagonists and notably, it reversed NMDAR antagonist side effects upon co-administration. These data highlight Zelquistinel’s novel, potent, and highly differentiated mechanism of action with potential for a significantly improved safety pro to other NMDAR-targeted antidepressants in development for depressive disorders. “Zelquistinel’s mechanism of action represents a novel pharmacological approach which may help address patient needs in the treatment of depression,” said Maurizio Fava M.D., Psychiatrist-in-Chief at Massachusetts General Hospital, and a key advisor to Gate Neurosciences. “The upcoming Phase 2 study seeks to navigate the known challenges of conducting trials in psychiatry to confirm efficacy in Major Depressive Disorder.” Business Update Since its inception in 2019, Gate Neurosciences has assembled and advanced a clinical-stage pipeline of next-generation central nervous system therapies, as previously highlighted when the company emerged from stealth-mode in August 2022. Alongside the previously detailed Zelquistinel, Apimostinel and Rapastinel programs acquired from AbbVie, the company has also acquired exclusive rights to preclinical mGlu2/3 receptor antagonists from Eli Lilly which it is currently developing for sleep disorders, and is advancing a preclinical-stage Insulin Growth Factor 2 Receptor (IGF2R) program for cognitive disorders in collaboration with Northwestern University. Recent Milestones Completed financings totaling $25M from life science-focused investors, including Innoviva, Luson Bioventures, Biocrossroads, and ThornApple Capital, among others. Appointed new Board of Directors member Sarah Schlesinger M.D., a leading clinical investigator and chair of the Institutional Review Board at Rockefeller University, and member of the Board of Directors of Innoviva, Inc. Successfully advanced Investigational New Drug (IND) Applications for lead clinical programs. Initiated a Phase 1b clinical study exploring human target engagement biomarkers with 2nd generation injectable NMDAR program Apimostinel, in development for acute severe depression. Established extensive scientific and clinical advisor network, including leading psychiatrists across top institutions in the US. Hosted an R&D Day event at the 2022 ASCP Annual Meeting: “Update on NMDAR Modulators for Depressive Disorders.” Published in several peer-reviewed journals highlighting novel NMDAR mechanism and antidepressant activity of lead programs. The full list of publication can be found at gateneuro.com/publications. Upcoming Milestones First patient dosed in a single- and repeat-dose Phase 1b safety and EEG (electroencephalography) target engagement biomarker study of Apimostinel in 40 healthy volunteers in Q4 2022 with topline readouts expected in Q1 2023. Initiation of a confirmatory Phase 2 study of Zelquistinel in subjects with major depressive disorder (MDD) in early 2023, with topline readout expected mid-2024. Advancement of Rapastinel (GLYX-13) into investigator-led studies in collaboration with multiple leading research hospitals, under the FDA’s Expanded Access Program, beginning in 2023. Key Additions to Advisory Network Gate Neurosciences has continued expanding its network of 20+ scientific and clinical advisors from top psychiatry institutions across the US, who are providing encouraging perspectives on the company’s NMDA receptor modulator portfolio. Recent key additions include Maurizio Fava, M.D., Psychiatrist-in-Chief at Massachusetts General Hospital, and Thomas Laughren, M.D., Former Director for the Division of Psychiatry Products at the FDA. NMDAR Modulator Portfolio: Data Highlights & Mechanistic Understanding The core scientific focus of Gate’s pipeline is addressing synaptic dysfunction, the hallmark disease biology of many cognitive and psychiatric disorders, by enhancing synaptic plasticity and normalizing brain signaling. NMDARs play an essential role in synaptic plasticity and are the targets of an emerging class of rapid-acting antidepressants. Considerable recent progress has been made, along with a suite of publications, clarifying the underlying mechanisms various NMDAR-targeted molecules. Gate Neurosciences’ lead programs are highly differentiated from other NMDAR-targeted antidepressants by acting through positive modulation instead of antagonism. Gate’s molecules positively modulate NMDAR activity on glutamatergic neurons to enhance synaptic plasticity and elicit antidepressant activity. In contrast, antagonists act through NMDARs located on GABA interneurons, causing a profound ‘burst’ of neurotransmitters and accompanying dissociative side effects, before indirectly stimulating downstream effects on synaptic plasticity. Gate’s novel approach represents a more direct mechanism for enhancing natural neuronal plasticity processes, with the potential for a significantly improved safety profile. Recent literature highlighting Gate’s novel mechanism can be found on its website. Key data highlights from the company’s lead NMDAR programs include: Zelquistinel: 3rd generation oral NMDAR modulator Development as a rapid, durable, and well-tolerated chronic oral therapy to address more than 17 million Americans with MDD Supported by a robust, de-risking translational data package across ~350 patients, including consistent target engagement and EEG biomarkers, safety, and clinical antidepressant efficacy A Phase 2a exploratory dose-finding study in MDD (n=251) showed that Zelquistinel 10mg delivered once-weekly was generally safe and well-tolerated, and demonstrated statistically significant differences from placebo on MADRS change from baseline at multiple timepoints over the study Apimostinel: 2nd generation IV NMDAR modulator Development as an acute injectable procedure for the rapid reduction of depressive symptoms in millions of Americans with acute depressive episodes Molecule is 1000-fold more potent than precursor compound Rapastinel, and is the most potent compound in Gate’s class of NMDAR modulators A Phase 2a proof-of-concept study in MDD (n=151) showed that a single dose of Apimostinel 10mg was generally safe and well-tolerated with no ketamine-like side effects, and demonstrated a 5.4-point difference from placebo on HDRS-17 change from baseline at 24-hours (p=0.0034) and a 74% response rate (p=0.0067), among the largest seen to-date within the class of rapid antidepressants Early Stage Research and Development Highlights Company continues to advance preclinical programs towards IND milestones in 2023 GATE-102: oral mGlu2/3 receptor antagonist for hypersomnia GATE-301: IGFBP2 mimetic for neurodegenerative and neurodevelopmental disorders GATE-252: 4th generation oral NMDAR modulator for cognitive disorders Company established cutting-edge research operations at Northwestern University’s Falk Center for Molecular Therapeutics led by Dr. Joseph Moskal Ph.D., the original inventor of Gate’s NMDAR platform Collaborating with leading research institutions with access to world-class laboratory facilities, equipment, and capabilities Advancing development of objective biomarkers for mood disorders, including novel methods to identify and predict patient responder subsets Advancing early research into growth-factor signaling and other novel drug targets of interest that enhance neuronal function and synaptic plasticity “We are excited about the momentum Gate Neurosciences has gathered heading into the remainder of the year, along with our upcoming clinical milestones for our lead programs,” said Mike McCully, President & CEO of Gate Neurosciences. “I believe our next-generation portfolio has true transformative potential for patients suffering from neuropsychiatric and cognitive disorders.” About Gate Neurosciences Gate Neurosciences is a precision medicine biotechnology company focused on advancing next-generation CNS treatments that address growing needs in mental health. The company is developing a portfolio of novel mechanisms of action that enhance synaptic function to address neuropsychiatric and neurocognitive diseases, including major depressive disorder (MDD). Using learnings from extensive clinical, preclinical, and translational data and a better understanding of CNS development challenges, the company is advancing its clinical pipeline using evidence-driven, precision psychiatry approaches.

As the monkeypox outbreak continues in the United States and other parts of the world, researchers and public health officials scramble to test known drugs against the disease. For that and more research stories, continue reading. Tecovirimat Appears Safe and Effective Against Monkeypox A research study out of the University of California-Davis Health found tecovirimat (TPOXX) overall safe and effective to treat monkeypox symptoms and skin lesions, but researchers will still proceed with caution. The antiviral drug is approved to treat smallpox, which was eradicated globally in 1980. TPOXX inhibits the protein involved in the release of the enveloped virus. The CDC allowed doctors to prescribe TPOXX for compassionate use for adults and children with orthopoxvirus infections, including monkeypox. The new study evaluated 25 patients with monkeypox who received TPOXX. They published their research in the journal JAMA. “We have to be very careful in how we interpret the data,” George Thompson, M.D., co-author and professor at the UC Davis School of Medicine, Department of Internal Medicine, Division of Infectious Diseases, and the Department of Medical Microbiology and Immunology, said. “It is hard to differentiate the side effects due to therapy from those caused by the infection.” The recent monkeypox outbreak has led to more than 45,500 cases, as of Aug. 22. Typically, symptoms resolve on their own in two to four weeks, although up to 13% of patients require hospitalization. The patients in the study were referred to UC Davis Medical Center, primarily via the Sacramento County Department of Public Health. Patients were offered the drug if they had skin lesions on multiple body parts or sensitive areas such as the face or genital region. By Day 7, 40% of patients’ lesions had healed. By Day 21, 92% reported being healed and pain-free. On average, the patients had symptoms or lesions for 12 days before initiating antiviral therapy. “Polypill” Cuts Cardiovascular Death by 33% After a Heart Attack Investigators at The Mount Sinai Hospital and Mount Sinai School of Medicine found that a three-drug “polypill” prevented secondary adverse cardiovascular events in people who previously had a heart attack and cut CV deaths by 33%. The drug was developed by the Spanish National Center for Cardiovascular Research (CNIC) and Ferrer and was tested in the Phase III SECURE trial. The three drugs in the pill are aspirin, ramipril and atorvastatin. Standard therapy after a heart attack includes an antiplatelet drug such as aspirin, ramipril or another drug to control blood pressure and a lipid-reducing drug like a statin. However, patient compliance is around 50%. The study evaluated the polypill to determine if the improved adherence led to a decrease in CV events, which it did. The polypill is commercially sold under the name Trinomia. How Astrocytes Contribute to Brain Disorders Scientists at the Salk Institute have identified a molecule, insulin-like growth factor (IGF), that can reduce disease symptoms in mice with neurodevelopmental disorders such as Rett, Fragile X and Down syndromes. The molecule is produced by astrocytes, a special type of brain immune cells that interfere with normal brain cell development in several neurodevelopment disorders. Astrocytes are star-shaped glial cells that outnumber neurons by a factor of five and are responsible for holding nerve cells in place and helping them develop and function properly. The researchers isolated astrocytes and neurons from the developing brains of mice with genetic mutations that cause Rett, Fragile X and Down syndrome. They then evaluated the levels of 1,235 different proteins produced by each type of astrocyte. In each disease, they found hundreds of proteins at higher or lower levels, with 120 common to all three. Their studies found that all astrocytes impacted by the three syndromes had a high level of Igfbp2, a protein that blocks IGF. The neurons make enough IGF, but it can’t get where it needs to be because the molecules astrocytes produce interfere with it. Excess Igfbp2 produced by astrocytes slows the growth of neurons. By blocking Lgfbp2 in mice with Rett syndrome, symptoms of the disease decreased. The researchers note that they have a long way to go before turning this discovery into a therapeutic, but the finding may lead to several new approaches to neurological diseases. Blocking Key Enzymes Can Boost T-Cell Responses in Cancer Immunotherapy A team of researchers at Louisiana State University Health New Orleans identified a vital immunosuppressive pathway and a promising approach to protecting T-cells’ ability to attack cancer cells. Immune cells that attack and kill cancer cells are called CD8 T-cells. To be effective, CD8 T-cells need a protein called NOTCH1. NOTCH1 is weakened by a compound, adenosine, produced by cancer cells. The research team worked with a Massachusetts biotech company, Nimbus Therapeutics, to test a CBL-B inhibitor, which, when used with existing immunotherapeutics, significantly increased the potency of the immunotherapy. The CBL-B inhibitor prevented NOTCH1 degradation in response to adenosine, which improved CD8+ T-cell effector functions, anti-cancer response and immunosuppression resistance. Long Covid Rare in Kids, But More Common than Hospitalization Researchers from the National Institutes of Health found that the incidence of Long COVID was lower in kids than in adults, but that more kids had Long COVID than kids who were hospitalized with acute COVID-19. The researchers used RECOVER Pediatric Electronic Health Records Cohort, and the study was authored by Suchitra Rao, M.D. with Children’s Hospital Colorado. There was overlap with adults regarding Long COVID and hospitalization, but Long COVID included some unique features in children, such as the risk of the inflammatory syndrome PASC. The study examined electronic health record data from 659,286 children who were tested for SARS-CoV-2 and compared 59,893 children who tested positive with those who tested negative. “We concluded that many of the symptoms children experience post-COVID-19 are similar to what is seen in adults, but there are some features more unique to children, such as myocarditis, abnormal liver enzymes, hair loss, skin rashes and diarrhea,” Rao wrote.

Thierry Abribat, Founder and CEO of Amolyt On October 14th, Amolyt Pharma announced the first dosing in its Phase I trial of AZP-3601 in healthy subjects, a momentous occasion capping off years of hard work in pre-clinical development. The drug aims to walk the biological tightrope in the management of hypoparathyroidism, a rare disease causing muscular pain and cognitive challenges. Thierry Abribat, founder and CEO of Amolyt, pictured above. Photo courtesy of Amolyt. On October 14th, Amolyt Pharma announced the first dosing in its Phase I trial of AZP-3601 in healthy subjects, a momentous occasion capping off years of hard work in pre-clinical development. The drug aims to walk the biological tightrope in the management of hypoparathyroidism, a rare disease causing muscular pain and cognitive challenges. Based in France, with U.S. headquarters in Boston, Amolyt is advancing peptides derived from natural hormones for the treatment of rare endocrine and metabolic disorders. Amolyt is led by Thierry Abribat, a veteran biotech entrepreneur who began his career in big pharma at Sanofi , before moving into the academic space in Montreal. He went on to found three biotech companies including Alizé Pharma 2 which was acquired Jazz Pharmaceuticals in 2016. Abribat, who has spent his career focused on rare and orphan diseases in the endocrine and metabolic fields, was attracted to the biotech industry because of the opportunity to create something where once there was once nothing. “I love to form companies where you can really innovate,” Abribat said. “Really, my personal driver, my passion, is innovation – to do something that nobody else has done…when you realize that you’re doing that to help find solutions for patients who are suffering, it just feels really good.” Abribat’s current orphan of focus is hypoparathyroidism, a rare endocrine disease where the body does not produce enough of the parathyroid hormone (PTH) which regulates the amount of calcium in the bones. The disorder typically occurs after thyroid surgery, as the parathyroid glands are very close to the thyroid and are often removed in the process. It is most prevalent in middle-aged, peri-menopausal and post-menopausal women, but can also be caused by autoimmune disease or genetic factors with an early onset in childhood. The deficiency leads to low calcium levels in the blood and bones, as well as increase of phosphorus in the blood, causing a whole host of debilitating neuromuscular and cognitive symptoms. Patients will experience muscle cramps, muscle spasms and twitching, and the inability to concentrate. If left untreated, it can lead to potentially fatal complications. “If left untreated, you just die, because calcium is very important for all the cells and the organs of your body to survive, to function properly,” Abribat said. The current treatment regimen consists of significant calcium supplementation, along with vitamin D which helps to absorb calcium in the body. Abribat states that there is a significant unmet need in treatment options. “It helps the patients survive, of course. Twenty percent of the patients are quite well controlled with calcium, but the vast majority of the patients are not properly controlled because when you take calcium you have an increase of calcium in the blood and then it goes down, you take another one and it goes up, so those patients don’t have normal calcium levels over 24 hours,” Abribat said. There is one PTH hormone on the market, Takeda’s Natpara. “The problem, or limitation, of this drug is that it has a short half-life. It is not able to maintain calcium, not able to decrease enough the elimination of calcium in the urine. There is some improvement… [but] you need to have something that has a more stable effect, up to 24 hours,” Abribat said. Enter AZP-3601, a peptide analog of PTH targeting a specific configuration of the PTH1 receptor to safely produce sustained levels of calcium in the blood, thereby controlling the symptoms of hypoparathyroidism. It is also designed to prevent chronic kidney disease, one of the most dire consequences of the disorder. “The best approach is to make PTH replacement, you replace the hormone that’s missing,” said Abribat. “What you want to have as an analog of PTH for those patients, is [one] that is going to have a prolonged effect on serum calcium to reactivate what we call the kidney reabsorption of the calcium. So if you sustain calcium levels, you get rid of the symptoms, and if you suppress the calcium elimination by the kidney, you get rid of the kidney complications.” Amolyt collaborated with Massachusetts General Hospital in the development of the analog. Abribat went on to explain that the targeted treatment needs to be a very delicate line. “It’s a balance between the effect on the blood, the effect on the kidney, and the effect on the bone. So those are the three important compartments where you need to try to design the right product to be able to not do something on the one compartment, and impair the other compartments.” If the first indications obtained through animal models bear out, Abribat feels that Amolyt is on the right path to achieving this equilibrium. “It maintained calcium levels within normal range over 24 hours for the symptoms. It allows to decrease the elimination of the calcium by the urine so that it prevents kidney disease. And it preserves the bone integrity so there is no further risk of osteoporosis for the women,” Abribat said. He added that the phase I trial efficacy and safety endpoints will consist of achieving this intricate balance, first in healthy subjects, then in patients across the U.S. and Europe. “What will be needed as proof of efficacy will be that we maintain calcium at the normal levels over 24 hours, that we decrease the need for supplementation of calcium and vitamin D, so that we can decrease it significantly, and also that we can decrease the elimination of calcium,” said Abribat. “Those are the three really hard end points that we want to reach.” Abribat added that Amolyt is expecting to have some “very meaningful data” in healthy volunteers by mid-2021. From there, he hopes the path to commercialization will become clear. “From the phase one, the endpoints I just mentioned, we are going to have some data on these endpoints, and trust it’s going to give us good reasons to move into the last trial that’s going to be the basis for registration hopefully at some point,” said Abribat. “And by early 2022 we should also have some data in patients, looking at the safety and effectiveness of the product in patients. It will be a very important moment for us.” Next in line to enter the clinic is a first-in-class drug candidate called AZP-3404, a collaboration with the University of North Carolina at Chapel Hill and Maine Medical Center, which leverages the unique biology of IGFBP-2, a key regulator of glucose and fat metabolism. Resistance to degradation makes it suitable for once daily dosing and a valuable potential therapy for metabolic disorders. The team is collecting data to determine the most appropriate indication for AZP-3404, and hopes to begin a Phase I trial in early 2022.