ghrelin

BARCELONA — One of this weekend’s sleeper data presentations at Europe’s biggest oncology conference puts Pfizer in a leading position in a common cancer condition with no approved treatments in the US or Europe. The New York-based pharma giant’s GDF-15-directed monoclonal antibody helped cancer patients gain weight and, at the highest dose, experience improvements in appetite, physical activity and muscle mass in a Phase 2 trial, according to data presented at the European Society for Medical Oncology confab on Saturday. Analysts at Leerink Partners think the experimental medicine, code-named ponsegromab, has blockbuster potential. But the large pharma has many questions to work through before it can mount a registrational study next year for ponsegromab in cancer cachexia, a muscle-wasting condition that leads to severe weight loss and impacts a patient’s ability to tolerate cancer medications. Patients with cachexia also require more healthcare resources, leading to a “high clinical and economic burden,” according to another Pfizer-funded study presented at ESMO. Doctors have long sought a treatment for the metabolic condition, which some research suggests may be linked to up to 30% of cancer deaths. It’s also a strain on patients with chronic conditions like heart failure and chronic obstructive pulmonary disease, among others. The broad potential gives ponsegromab a shot at achieving sales of $1 billion or more, Leerink Partners analyst David Risinger wrote in a Sunday evening note. Despite its prevalence, though, the condition has not received “the attention it deserves,” Min Li, a professor and co-leader of the cancer biology program at the Stephenson Cancer Center in Oklahoma, said in an email. “We are now more confident in saying that we can see the light at the end of the tunnel,” Li said in the days after the ESMO presentation and simultaneous publication of the Phase 2 data in the New England Journal of Medicine . Having one of the world’s biggest pharma companies with ample R&D resources to approach late-stage testing could be a boon for the field. “Incredible progress is finally being made in this space, and we very much hope that Pfizer’s findings continue to be positive and pave the way for more successful trials to follow,” Andy Judge, a University of Florida professor and president of the Cancer Cachexia Society, told Endpoints in an email. Cachexia comes with a lot of complexities, likely leading to a challenging Phase 3 showdown for Pfizer. The company anticipates launching the trial next year and it still needs to hash out plans with regulators, according to a spokesperson, who said Pfizer will share more Phase 3 details at a later date. The condition is quite heterogeneous and impacts different cancers at varying rates, which could make it difficult to prove a treatment works in late-stage trials. Li noted that “there is no consensus on the optimal endpoint to evaluate cancer cachexia.” Another biotech, NGM Bio, warned in recent years of the lack of a clear regulatory path for cachexia. Another company received approval in Japan in 2020 for the medicine anamorelin, but the ghrelin receptor agonist was rejected in Europe a few years before. Also standing in the way is the number of organs and tissues involved in the systemic dysfunction. Going after a single pathway “has yielded limited efficacy,” Li said. Pfizer’s ponsegromab goes after growth differentiation factor 15, or GDF-15. The company’s researchers have said neutralizing GDF-15 could lead to improvements in caloric intake and boost physical activity. The candidate was discovered in-house and first entered the clinic in a 2018 healthy volunteer trial. Ponsegromab is also being tested in patients with heart failure . That study is enrolling patients with cardiac cachexia or fatigue in its main cohort and is expected to be completed next March, according to the federal trials database. Li noted other potential pathways in cancer cachexia could be targeted, such as “myostatin/activin signaling, IL-6, ghrelin, circular RNAs, metabolic enzymes, TNF and TGF.” Meanwhile, more studies are needed to “directly prove” that stabilizing muscle and fat reserves, “or even revers[ing] those losses,” has a direct impact on patient outcomes, Michael Rosenthal, assistant director of radiology at Dana-Farber/Brigham and Women’s Hospital, said in an email. Aside from the effects on weight, doctors will look for impacts on daily activities. “It would be impressive to see improvement in ECOG performance status and overall survival in a randomized trial of chemotherapy with or without ponsegromab,” Vincent Chung, a medical oncologist at City of Hope, said in an email. ECOG is a scale that assesses a patient’s ability to function, including walking and self-care activities. Pfizer is in the lead in cachexia drug development, and it’s no stranger to breaking open fields, having done so in areas like ATTR-CM, where it could soon face competition. Other drugmakers looking at cachexia include UK-based Actimed Therapeutics, Tokyo-based TMS and Vistagen, which says on its website that it is “evaluating the path forward” for its candidate for more Phase 2 development. Even if those medicines make it to market, it’s still important to think about treating cachexia in a “multi-dimensional way, rather than a single drug,” David Hui, director of supportive and palliative care research at the University of Texas MD Anderson Cancer Center, said in an interview on the sidelines of ESMO. Doctors currently work with a team of healthcare professionals to address cachexia with diet and exercise and medications to treat symptoms of pain, difficulty swallowing and other complications, he said. “Having the dietitian, physical therapy and supportive palliative care team working side by side together with the patient and family can, hopefully, lead to improved outcomes because everyone may have different concerns related to cachexia,” Hui said.

A team of scientists has made an important discovery that could lead to a novel treatment for obesity and obesity-associated diseases or conditions. Texas A&M AgriLife Research study may lead to novel obesity treatment New study provides insights on role of 'hunger hormone' receptor in obesity-realted chronic inflammation A team comprised primarily of Texas A&M AgriLife Research scientists has made an important discovery that could lead to a novel treatment for obesity and obesity-associated diseases or conditions. Details of the discovery can be found in the study "Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation," published in the January issue of Molecular Metabolism. Yuxiang Sun, Ph.D., is the lead investigator on a study that could lead to a novel treatment for obesity and obesity-associated diseases or conditions. (Texas A&M AgriLife photo by Michael Miller) "Chronic inflammation commonly associated with obesity is a key reason obese individuals often have many other chronic diseases," said Yuxiang Sun, Ph.D., professor and AgriLife Research Faculty Fellow in the Texas A&M College of Agriculture and Life Sciences Department of Nutrition and associate member of the Texas A&M Institute for Advancing Health Through Agriculture, IHA. Sun, who served as lead investigator for the study, was among several investigators from the Department of Nutrition. Study contributions were also made by other entities in The Texas A&M University System. Competitive funding for the study came from the National Institutes of Health. It was also supported by the IHA -- the world's first research institute to bring together precision nutrition, responsive agriculture and behavioral research to reduce diet-related chronic diseases. About the study The study focused on the role of one molecule involved in how our bodies deal with hunger: the growth hormone secretagogue receptor, GHSR, which mediates the effect of ghrelin, known as the "hunger hormone." Studies have shown that ghrelin promotes eating and increases fat. Ghrelin activates GHSR to increase appetite, fat accumulation and insulin resistance. Research has shown that under normal conditions, GHSR is highly active in the brain but much less active in other tissues such as liver and fat, also referred to as adipose tissue. For this reason, most ghrelin research has focused on the brain. "Intriguingly, in previous research, we found the complete removal of GHSR protects against diet-induced inflammation and insulin resistance in adipose tissue and the liver without affecting food intake," Sun said. "This was very puzzling because that GHSR has very low expression in fat and liver cells." A link between obesity and the immune system Sun and her team has made the novel observation that GHSR activity in macrophages -- a major immune cell type in tissues -- increases dramatically under the condition of obesity. In this study, Sun's team investigated whether ghrelin's effect in adipose tissues and the liver was due to the infiltration of GHSR-expressing macrophages into these tissues under the condition of obesity. "If that was the case, this infiltration by those particular GHSR-expressing macrophages would trigger chronic inflammation and insulin resistance," Sun said. Study results and implications To understand the role of GHSR in macrophages, the team developed a unique animal model to selectively shut down GHSR activity in macrophages. "Indeed, our study results showed that macrophage-specific GHSR deficiency reduces diet-induced systemic inflammation and insulin resistance," Sun said. "Remarkably, GHSR deficiency in macrophages reduced diet-induced macrophage infiltration, macrophage activation and fat deposition in adipose tissue and the liver." In addition to their effect on diet-induced chronic inflammation, the study also demonstrated that GHSR-deficient macrophages protect against acute inflammation induced by bacterial toxins. At a molecular level, they found GHSR programs macrophages through an insulin signaling pathway, Sun said. Basically, this study showed that macrophage GHSR controls chronic inflammation in obesity by regulating macrophage programming. She said the study's novel results demonstrate that macrophage GHSR plays a key role in meta-inflammation by promoting macrophage infiltration and inflammatory activation. "These exciting new findings helped to resolve a long-time mystery of GHSR in adipose tissue and the liver in obesity, by uncovering the novel immunoregulatory role of GHSR and revealing that GHSR signaling is a critical link between metabolism and immunity," Sun said. She said the study adds a new dimension to the biology of ghrelin, and underscores that ghrelin is not only a hunger hormone, but also an important nutrient-sensor and immune regulator. "This has profound implications for health and disease, as blocking GHSR in macrophages may serve as a promising immune therapy to prevent or treat obesity, diabetes and inflammation," Sun said.

Phase 2 trial to assess impact of peripherally-acting CB1 inhibitor on weight loss and metabolic biomarkers related to co-morbid obesity and chronic kidney disease San Francisco, California--(News - January 9, 2024) - Skye Bioscience, Inc. (OTCQB: SKYE) ("Skye" or the "Company"), a pharmaceutical company developing drugs targeting the endocannabinoid system, has received clearance of its Investigational New Drug ("IND") application with the U.S. Food and Drug Administration ("FDA") to initiate a Phase 2 clinical trial of nimacimab in patients with obesity and chronic kidney disease. Skye plans to initiate the Phase 2 trial in mid-2024. Nimacimab is a negative allosteric-modulating antibody targeting the cannabinoid 1 receptor ("CB1"), which has been implicated as an important target in cardiometabolic diseases including obesity and renal complications. The high correlation of these comorbid conditions, with 80% of patients with kidney disease being obese and 30% of obese patients having kidney disease, represents an opportunity for a mechanism that can affect their common underlying disease processes. Nimacimab was observed to have very limited accumulation in the CNS in pre-clinical studies, a safety issue in earlier generations of CB1 inhibitors. Safety and tolerability assessments from the completed Phase 1b study of nimacimab in non-alcoholic fatty liver disease ("NAFLD") patients with diabetes or prediabetes demonstrated no serious adverse events, no early terminations of treatment due to adverse events, and no adverse events of concern occurring in a dose-dependent manner. Encouraging trends were observed in exploratory biomarkers including cholesterol, liver enzymes and liver function in patients receiving nimacimab versus placebo after the four-week dosing period. Moreover, pharmacokinetic assessment of nimacimab highlighted a half-life of approximately three weeks, potentially allowing for monthly dosing, which would offer a competitive advantage over once-a-week subcutaneous dosing of current peptidic GLP-1 receptor agonists. Additionally, third-party research has strongly indicated the role of CB1 inhibition in modifying insulin and leptin sensitivity, preserving lean mass, and ultimately augmenting durability of weight loss. With nimacimab's differentiated characteristics, this novel molecule may provide an important alternative as a single or combination therapy targeting obesity and other metabolic, inflammatory and fibrotic conditions. "We believe that the encouraging safety pro nimacimab from preclinical and clinical studies exceeds that of small molecule CB1 inhibitors and that this class of drug offers the potential to treat a range of metabolic conditions," said Tu Diep, Chief Development Officer of Skye. "We look forward to evaluating multiple meaningful clinical endpoints in the Phase 2 trial, including weight loss, changes in albuminuria related to kidney function, and other biomarkers, in order to guide the future development of nimacimab." "With the growth of GLP-1 agonists we are also seeing large pharmaceutical companies acquiring drugs with complementary mechanisms of action to treat obesity," said Punit Dhillon, CEO and Chair of Skye. "We see peripheral CB1 inhibition playing a strong role in future combination therapies and are advancing nimacimab as a key possible component of such combinations." About the Endocannabinoid System and Peripheral CB1 Inhibition for Weight Loss The endocannabinoid system ("ECS") has emerged as one of the most relevant regulators of energy balance. The ECS acts through two cannabinoid receptors: types 1 and 2 (CB1 and CB2). CB1 is widely expressed in the CNS and brain but is also expressed in peripheral tissues such as adipose tissue, skeletal muscle, and in the liver, kidney, gut, and pancreas. In obese states, CB1 agonists such as anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), the body's naturally-produced endocannabinoids, are increased and may exert unfavorable effects on insulin-sensitive tissues. Peripheral inhibition of CB1 has been shown to cause a reduction in food intake and sustained weight loss through multiple mechanisms, including increasing incretin expression in the gut and reducing ghrelin expression. The ECS also contributes to the control of lipid and glucose metabolism, and it is well established that blockade of CB1 receptors enhances insulin sensitivity in both humans and rodents. Clinically, early development of small molecule drugs that blocked CB1 appeared encouraging with the approval of rimonabant (Sanofi) in Europe for weight loss and obesity. However, it was soon removed from the market because of side effects related to the high exposure of the drug to the CNS and brain, which resulted in safety issues such as depression, anxiety and suicidal ideation. A new class of drugs are now designed to only target CB1 in the periphery, while avoiding the CNS. About Nimacimab Nimacimab is a first-in-class humanized monoclonal antibody that acts as a negative allosteric modulator to inhibit CB1 signaling in the periphery. Inhibition of CB1 has shown anti-fibrotic, anti-inflammatory, and metabolic mechanisms of action with potential to address a broad range of diseases with notable unmet medical needs such as obesity, chronic kidney disease, and non-alcoholic steatohepatitis (NASH). Preclinical studies over 26 weeks showed that nimacimab has very limited accumulation in the brain. The safety and tolerability assessments from the completed Phase 1b study of nimacimab in non-alcoholic fatty liver disease ("NAFLD") patients with diabetes or prediabetes demonstrated no serious adverse events, no early terminations of treatment due to adverse events, and no adverse events of concern occurring in a dose-dependent manner. The most frequently reported treatment-emergent adverse events (>5% of subjects) in the pooled nimacimab and placebo groups were diarrhea, headache, dizziness (9.5 vs. 5.0%), upper respiratory tract infection, nausea and vomiting. Encouraging trends were observed in exploratory biomarkers of cholesterol, liver enzymes and liver function in patients receiving nimacimab versus placebo after the three-week dosing period. The promising PK data of approximately 21 days from the Phase 1 study suggests that nimacimab can be dosed once-a-month subcutaneously, which would potentially offer a competitive advantage over once-a-week subcutaneous dosing of current peptidic GLP-1 receptor agonists or even orally dosed GLP-1 receptor agonists due to their less desirable tolerability profile. About Skye Bioscience Skye is focused on unlocking the pharmaceutical potential of the endocannabinoid system to treat diseases with inflammatory, fibrotic, and metabolic processes. Backed by leading life science venture investors, Skye's strategy leverages biologic targets with substantial human proof of mechanism for the development of first-in-class therapeutics with significant clinical and commercial differentiation. Nimacimab, a negative allosteric modulating antibody that inhibits peripheral CB1, showed a favorable safety and tolerability pro a Phase 1 study. Skye plans to start a Phase 2 study in obesity and chronic kidney disease for nimacimab in mid-2024. SBI-100 Ophthalmic Emulsion, a CB1 agonist, is currently being studied in a Phase 2 study of patients with glaucoma and ocular hypertension. For more information, please visit: . CONTACT Investor Relations ir@skyebioscience.com (858) 410-0266 LifeSci Advisors, Mike Moyer mmoyer@lifesciadvisors.com 617-308-4306 FORWARD-LOOKING STATEMENTS This press release contains forward-looking statements, including statements regarding our product development, business strategy, timing of clinical trials and commercialization of cannabinoid-derived therapeutics. Such statements and other statements in this press release that are not descriptions of historical facts are forward-looking statements that are based on management's current expectations and assumptions and are subject to risks and uncertainties. If such risks or uncertainties materialize or such assumptions prove incorrect, our business, operating results, financial condition, and stock price could be materially negatively affected. In some cases, forward-looking statements can be identified by terminology including "anticipated," "plans," "goal," "focus," "aims," "intends," "believes," "can," "could," "challenge," "predictable," "will," "would," "may" or the negative of these terms or other comparable terminology. We operate in a rapidly changing environment and new risks emerge from time to time. As a result, it is not possible for our management to predict all risks, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements the Company may make. Risks and uncertainties that may cause actual results to differ materially include, among others, our capital resources, uncertainty regarding the results of future testing and development efforts and other risks that are described in the Risk Factors section of Skye's most recent annual or quarterly report filed with the Securities and Exchange Commission. Except as expressly required by law, Skye disclaims any intent or obligation to update these forward-looking statements. To view the source version of this press release, please visit