leptin

iStock/ synthetick After psychological side effects doomed the first generation of cannabinoid receptor 1–targeting drugs for weight loss, Novo Nordisk, Corbus Pharmaceuticals and Skye Bioscience are betting that a new mechanism of action will improve the safety profile. Nearly 20 years after the FDA’s rejection of what would have been the first approved drug in the class, a new generation of CB1 receptor inhibitors is undergoing early- and mid-stage clinical trials for the treatment of obesity. Novo Nordisk, Corbus Pharmaceuticals and Skye Bioscience are all hoping the improved safety profiles of their therapies will lead to a new method of treating the disease. “What’s interesting about this is it’s a comeback story for a class that was entirely abandoned,” said Corbus CEO Yuval Cohen. “In 2006, it was viewed as an exciting class of drugs—and then it had a catastrophic setback at FDA.” Rimonabant, the first-in-class cannabinoid receptor 1 (CB1) receptor antagonist from Sanofi, which was approved in Europe for weight loss, worked to suppress appetite by blocking endocannabinoid receptors in the brain. While rimonabant successfully helped patients lose weight, it greatly increased instances of depression, anxiety and suicidality in patients. In the CRESCENDO study , four rimonabant-treated patients committed suicide. The FDA deemed the drug unapprovable in 2006, and European regulators withdrew it from the market in 2008. “After the rejection, none of the other [pharma companies] tried to file [with the FDA],” Cohen told BioSpace . “There was such a stigma around it that it was considered an untouchable mechanism of action.” A New Approach Now, Novo, Corbus and Skye are hoping to bring a version to the market that is safer and just as effective as the early class by avoiding the CB1 receptors in the brain. Instead, these compounds will work on peripheral receptors throughout the body, which will also allow for higher dosing, Cohen said. “There’s a lot of evidence out there of this particular target being found in the peripheral tissues, especially in adipose tissues and important organs like the liver, muscles and even the GI tract,” said Skye CEO Punit Dhillon. Peripherally restricted CB1-targeting drugs, such as Skye’s nimacimab, Corbus’s CRB-913 and Novo’s monlunabant , do not cross the blood-brain barrier, therefore reducing the chance of neuropsychiatric effects such as depression. “The idea was to keep the bits that are working but avoid some of the risks involved with the first class, which was too much of it went into the brain,” Cohen said. In Phase Ib studies of nimacimab, patients reported no serious adverse events. “We’ve been really successful in terms of having zero incidents of any neuropsychiatric [effects] or depression or any concerns in our Phase I data,” Dhillon told BioSpace . However, last month, Phase IIa results from monlunabant revealed “mild to moderate neuropsychiatric side effects,” such as anxiety, irritability and sleep disturbances. No serious adverse events were reported in relation to the neuropsychiatric side effects, according to Novo. Patients treated with the drug saw an average of 15 lbs of weight loss after 16 weeks of treatment, compared to just 1.5 lbs for the placebo group. ‘Amazing Little Engines’ CB1 receptors are a type of G-protein coupled receptor—what Cohen describes as “amazing little engines” that activate appetite in all living things and push them to find food. Activation of the receptors promotes food intake, fat storage and energy storage in the body. One type of CB1-targeting drug is an inverse agonist, which “puts this process in reverse and hits the gas pedal,” Cohen explained. “So suddenly, rather than being obsessed with food-seeking, we are no longer hungry and obsessed with food.” With appetite suppressed, fat in the body is converted to energy and weight loss can occur. But instead of acting on CB1 receptors in the brain, the new class of inhibitors bind to peripheral receptors throughout the body thanks to a smaller molecule. This metabolic rewiring can reintroduce insulin sensitivity, glucose tolerance and other healthy lipid profiles that are compromised in patients with obesity, Dhillon said. Cannabinoid pathways are also integral to signaling the presence of a hormone called leptin, which tells the brain how much fat is stored in the body. “It is possible to get that response peripherally. If you can sensitize the body to the effects of leptin, it’s possible to be able to more easily release fat from fat cells,” Louis Aronne, Sanford I. Weill professor of metabolic research at Weill-Cornell Medical College and director of the Center for Weight Management and Metabolic Clinical Research, told BioSpace . One hypothesis is that fat gets locked in fat cells, and it is difficult in obesity to get it out, Aronne noted. “If you could take fat out of fat cells and have it floating around in the bloodstream instead of locked away in the fat cells, your brain would be able to sense the fatty acids as nutrition floating around and would use that as a trigger to suppress your appetite,” he explained. “That’s one way peripherally acting drugs could have central mechanisms.” CB1/GLP-1 Combinations Weight loss medications are one of biopharma’s hottest current trends. GLP-1 drugs, such as Novo’s Wegovy and Eli Lilly’s Zepbound, exploded onto the market to regulate blood sugar and restrict caloric intake by curbing appetite and making patients feel full longer. While CB1-targeting drugs can be used on their own, they also could be paired with GLP-1s. In fact, Skye is combining nimacimab and Wegovy in a Phase II study . Forty patients will be randomized to either a treatment group that will receive nimacimab injection or a placebo in conjunction with Wegovy. “We feel there is a strong argument that [CB1 inhibitors] can be combined with GLP-1s really well,” Dhillon said. “If GLP-1s are doing a good job [with caloric restriction], and CB1s are doing a good job in re-establishing metabolic pathways, then we’re getting it from both sides and hopefully achieving a better body composition over time.” Meanwhile, Corbus’ CRB-913 was used in conjunction with GLP-1 medications Wegovy, Zepbound and liraglutide in preclinical testing . Mice with diet-induced obesity showed decreased body weight when given CRB-913. These effects were enhanced when GLP-1 drugs were added, including statistically significant reductions in body fat, liver triglycerides, liver fat deposits, insulin resistance and leptinemia. “What we have shown preclinically is if you combine CB1-targeting drugs with incretin-targeting drugs, you can add on to the different effects and lead to more weight loss,” Cohen noted. “What this ends up being in clinical usage remains to be seen. But there are important populations where modifying with CB1 makes a lot of sense.” These populations include those who cannot or do not want to use GLP-1 drugs, those who need a higher degree of weight loss with combined mechanisms of action, and those who have reached their goal weight on GLP-1 drugs and want to switch to a drug to help maintain that weight loss, he said. Combining a CB1-targeting drug with a GLP-1 medicine could also mean the patient would take a smaller dose of the GLP-1—which could lead to fewer gastrointestinal side effects and a greater chance of adherence to the medication regimen, Aronne said. “One of the things that may happen with GLP-1s is we may use too much of it in an effort to get someone’s weight down,” he continued. “If you had a mechanism that gave additive weight loss, but it didn’t have nausea or vomiting or any of the GI side effects, that might be a brilliant way to help.” Time Will Tell Aronne sees the field of obesity treatment going in a similar direction to treatment for hypertension or other indications where medication is started early before the condition gets out of hand. “Eventually, instead of having to treat people with BMIs of 40 and above, we’re going treat people as soon as they get to obesity,” Aronne said. “[That way], you never get to a BMI of 30, 40 or 50, where the damage accrues.” Whether CB1 inhibitors are part of that treatment process remains to be seen. Early data are promising, but the answers will come from the trials of nimacimab, monlunabant and CRB-913. “I think the class is at a potentially important fork in the road,” Cohen said. “If the data are good, that could really just provide a complete change in the mindset around this mechanism.”

The news also resulted in a modest increase in Soleno’s stock price; it was up by 6.3% when markets closed on 27 August. Credit: eamesBot / Shutterstock. The US Food and Drug Administration (FDA) is set to decide on whether to approve Soleno Therapeutics ’ lead therapy, diazoxide choline (DCCR), for treating hyperphagia associated with Prader-Willi syndrome, a rare genetic disorder. The regulatory agency has accepted the new drug application (NDA) for DCCR and has granted it priority review status . The priority status allows for various privileges including a faster approval process of six months, compared to the usual ten months. The FDA has also set a Prescription Drug User Fee Act (PDUFA) target action date of 27 December 2024. The agency has also announced its intention to hold an advisory committee (AdComm) meeting to “discuss the application for DCCR”. An AdComm is convened upon request of the FDA to review and evaluate the safety and efficacy data of a therapy. While the AdComm recommendations can affect a therapy’s FDA approval,  its recommendations are non-binding, and the final decision is made by the FDA. The news also resulted in a modest increase in Soleno’s stock price; it was up by 6.3% when markets closed on 27 August after the news was released compared to the previous day. The company’s market cap currently stands at $1.9bn. See Also: Catalent gets grant for activated formylglycine-generating enzymes for protein production Novo Nordisk’s Wegovy sales weaken as Eli Lilly’s Zepbound exerts pressure DCCR is an extended-release tablet containing a crystalline salt formulation of diazoxide, an activator of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel. These channels are present in a variety of cells including pancreatic β cells, and adipocytes. The regulation of these cells can help manage hyperphagia, an excessive desire to eat, which is a hallmark of Prader-Willi syndrome. Soleno’s NDA is supported by data from five studies; a Phase I trial in healthy volunteers, three Phase II trials, and a Phase III trial. The placebo-controlled open-label Phase III DESTINY PWS study (NCT03440814) enrolled 125 participants with Prader-Willi syndrome aged four years or younger. After a year of follow-up, the trial met its primary endpoint by demonstrating significant improvements in the Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Greater improvements in HQ-CT scores were seen in patients with more severe baseline hyperphagia, with an HQ-CT score of over 22. Patients on DCCR also observed reductions in leptin, insulin, and insulin resistance, along with an increase in adiponectin. Soleno is also evaluating DCCR as a treatment for paediatric patients with genetic obesities, including SH2B1 deficiency obesity, obesity associated with PCSK1 mutation (rs6232 variant), and SIM1 deficiency obesity. The open-label Phase II trial (NCT05532020) is expected to enrol approximately 30 patients aged five years or younger suffering from either of the three genetic obesity disorders.

Marks Meaningful Progress Across Key Clinical Trials in Multiple Cancer Indications Completes Development of Oncology Molecular Biomarkers and Prepares for Preclinical Obesity Studies HOUSTON, July 08, 2024 (GLOBE NEWSWIRE) -- Bio-Path Holdings, Inc., (NASDAQ:BPTH), a biotechnology company leveraging its proprietary DNAbilize® liposomal delivery and antisense technology to develop a portfolio of targeted nucleic acid cancer drugs, today provides an update on the Company’s clinical progress and plans for expansion. “The Bio-Path team continues to work diligently toward advancing our important clinical work and have made meaningful progress in a number of areas critical to each program’s success,” said Peter H. Nielsen, President and Chief Executive Officer of Bio-Path. “With the increased clinical data that we have generated, we are now able to develop the biomarkers needed to incorporate into our oncology studies. In addition, we have completed preparations for preclinical work to support advancing prexigebersen as a potential treatment for obesity. In tandem, we are designing development plans for first-in-human clinical studies in this expansive global market for weight loss.” “The incremental advances that we are making across these programs collectively push our DNAbilize platform closer to delivering these medicines to patients. Moreover, we are continuing to see the broader potential of our platform beyond oncology and look forward to realizing its potential across multiple indications, starting with obesity,” continued Mr. Nielsen. Clinical Program Overview Bio-Path’s clinical development program consists of one Phase 2 clinical trial and three Phase 1 or 1/1b clinical trials. Bio-Path has developed a molecular biomarker package to accompany prexigebersen treatment and is currently expanding prexigebersen preclinical studies for the treatment of obesity. Development of Molecular Biomarkers – Bio-Path has developed a molecular biomarker package to accompany prexigebersen treatment, the goal of which is to identify patients with a genetic profile more likely to respond to treatment, thereby improving the probability of success for this program. The emerging role of biomarkers has enhanced cancer development over the past decade and has become a more common companion to many oncology programs. Prexigebersen Phase 2 Clinical Trial – Bio-Path’s Phase 2 clinical trial is treating Acute Myeloid Leukemia (AML) patients. This trial is comprised of three separate cohorts of patients and treatments, each separately approvable by the FDA as a new drug indication. The first two cohorts are treating patients with the triple combination of prexigebersen, decitabine and venetoclax. The first cohort includes untreated AML patients, and the second cohort includes relapsed/refractory AML patients. Finally, the third cohort is treating relapsed/refractory AML patients, who are venetoclax-resistant or intolerant, with the two-drug combination of prexigebersen and decitabine. Based on recent interim data for safety and efficacy, the Company plans to pursue next development steps by applying molecular biomarkers to future patient selection for enrollment into the Phase 2 clinical trial. Outcomes for these older patients who are unable to receive intensive chemotherapy due to the challenging side effect profile remain suboptimal with a median survival of only five to ten months. The study is currently paused for an interim analysis, amendment preparation and U.S. Food and Drug Administration (FDA) review. Bio-Path expects to complete enrollment in cohorts 1 and 2 of the study over the next eighteen months. Phase 1/1b Clinical Trial in BP1001-A in Advanced Solid Tumors – A Phase 1/1b clinical trial of BP1001-A in patients with advanced or recurrent solid tumors, including ovarian and uterine, pancreatic and breast cancer, is ongoing. BP1001-A is a modified product candidate that incorporates the same drug substance as prexigebersen but has a slightly modified formulation designed to enhance nanoparticle properties. The Phase 1 study has advanced to the second, higher dose level. The Phase 1b portion of the study is expected to commence after successful completion of the three BP1001-A monotherapy dose level cohorts and is intended to assess the safety and efficacy of BP1001-A in combination with paclitaxel in patients with recurrent ovarian or endometrial tumors. Phase 1b studies are also expected to be opened in combination with gemcitabine in late stage pancreatic cancer. In recent months, Bio-Path advanced to dose level 2 and expects to complete enrollment in order to advance to dose level 3 by year-end. Phase 1/1b Clinical Trial in BP1002 in Relapsed/Refractory AML – A Phase 1/1b clinical trial for BP1002 to treat relapsed/refractory AML patients, including venetoclax-resistant patients, is ongoing. BP1002 targets the protein Bcl-2, which is responsible for driving cell survival in up to 60% of all cancers. The drug venetoclax treats AML patients by blocking the activity of the Bcl-2 protein in AML patients. However, patients become resistant to venetoclax. BP1002 treats the Bcl-2 target by blocking the cell’s ability to produce Bcl-2, and could have the potential to eliminate the need for venetoclax. AML patients that fail frontline venetoclax-based therapy have very poor prognosis with median overall survival of less than three months. The first dose cohort consisted of a starting dose of 20 mg/m2, and there were no dose limiting toxicities. Bio-Path recently completed the second dose cohort of 40 mg/m2 and is completing an analysis of PK/PD data to be submitted to the FDA in order to advance to the next dose level. Upon submission of data and approval from FDA, Bio-Path expects to advance to dose level 3 in the fourth quarter of 2024. Phase 1 Clinical Trial in BP1002 in Refractory/Relapsed Lymphoma and Chronic Lymphocytic Leukemia (CLL) – A Phase 1 clinical trial to evaluate the ability of BP1002 to treat refractory/relapsed lymphoma and refractory/relapsed chronic lymphocytic leukemia (CLL) patients is currently ongoing. The Phase 1 clinical trial is being conducted at the Georgia Cancer Center, The University of Texas Southwestern and New York Medical College. In January 2024, Bio-Path announced successful completion of the first dose cohort in the Phase 1 clinical trial. A total of six evaluable patients are scheduled to be treated over two dose levels with BP1002 monotherapy in a standard 3+3 design, unless there is a dose limiting toxicity which would require an additional three patients to be tested. There were no dose limiting toxicities in the first dose cohort (20 mg/m2). Enrollment has continued for patients in the second BP1002 dose cohort of 40 mg/m2 and the Company expects to complete enrollment and to review these data by year-end. Preclinical Work for BP1003 – The Company continues to advance its drug candidate, BP1003, for the treatment of advanced solid tumors, including pancreatic cancer. BP1003 is an antisense RNAi nanoparticle targeting the STAT3 protein. Plans are to conduct a Phase 1 study of BP1003 in patients with refractory, metastatic solid tumors (pancreatic, non-small cell lung cancer). Prexigebersen as Potential Treatment for Obesity and Obesity-related Cancers – The RNAi target of prexigebersen is the Grb2 protein, which is involved in activating the RAS/ERK pathway for cell growth. By blocking the cell’s ability to produce Grb2, prexigebersen treatment may limit cell growth. In obesity, two such pathways are related to leptin and insulin. Activation of leptin or insulin receptors can stimulate the RAS/ERK pathway via Grb2i. Bio-Path believes development of prexigebersen for the treatment for obesity and obesity-related cancers could be accelerated given the large amount of safety data from prexigebersen treatment of leukemia patients and the continued unmet medical need. The Company is preparing for preclinical development evaluating prexigebersen for the treatment of obesity and will continue thereafter to conduct additional Investigational New Drug (IND)-enabling studies with an aim to advance prexigebersen into first-in-human studies in this indication. About Bio-Path Holdings, Inc. Bio-Path is a biotechnology company developing DNAbilize®, a novel technology that has yielded a pipeline of RNAi nanoparticle drugs that can be administered with a simple intravenous transfusion. Bio-Path’s lead product candidate, prexigebersen (BP1001, targeting the Grb2 protein), is in a Phase 2 study for blood cancers, and BP1001-A, a drug product modification of prexigebersen, is in a Phase 1/1b study for solid tumors. The Company’s second product, BP1002, which targets the Bcl-2 protein, is being evaluated for the treatment of blood cancers and solid tumors, including lymphoma and acute myeloid leukemia. In addition, an IND application is expected to be filed for BP1003, a novel liposome-incorporated STAT3 antisense oligodeoxynucleotide developed by Bio-Path as a specific inhibitor of STAT3. For more information, please visit the Company's website at http://www.biopathholdings.com. Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws. These statements are based on management's current expectations and accordingly are subject to uncertainty and changes in circumstances. Any express or implied statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Any statements that are not historical facts contained in this release are forward-looking statements that involve risks and uncertainties, including Bio-Path’s ability to raise needed additional capital on a timely basis in order for it to continue its operations, have success in the clinical development of its technologies, the timing of enrollment and release of data in such clinical studies, the accuracy of such data, limited patient populations of early stage clinical studies and the possibility that results from later stage clinical trials with much larger patient populations may not be consistent with earlier stage clinical trials, the maintenance of intellectual property rights, that patents relating to existing or future patent applications will be issued or that any issued patents will provide meaningful protection of our drug candidates, the impact, risks and uncertainties related to global pandemics, including the COVID-19 pandemic, and actions taken by governmental authorities or others in connection therewith, and such other risks which are identified in Bio-Path's most recent Annual Report on Form 10-K, in any subsequent quarterly reports on Form 10-Q and in other reports that Bio-Path files with the Securities and Exchange Commission from time to time. These documents are available on request from Bio-Path Holdings or atwww.sec.gov. Bio-Path disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. Contact Information: Investors Will O’Connor Stern Investor Relations, Inc.212-362-1200will@sternir.com Doug Morris Investor Relations Bio-Path Holdings, Inc. 832-742-1369 i Casado ME et al. (2023) Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies. Int J Mol Sci 24(2): 1422. Published online 2023 Jan 11. doi: 10.3390/ijms24021422)