Skye Bioscience, a pharmaceutical company developing drugs targeting the endocannabinoid system (ECS), has announced that it plans to develop nimacimab, the Company’s monoclonal antibody recently acquired from Bird Rock Bio, for weight loss and the treatment of obesity. The company has filed an Investigational New Drug (IND) application with the FDA for the initiation of a Phase 2 clinical study of nimacimab in patients with obesity and chronic kidney disease.
“GLP-1 and GIP receptor agonists have demonstrated that obesity can be treated therapeutically with safe and effective drugs, and have exposed a market opportunity that is just the tip of the iceberg. Despite the excitement and success around these drugs, a significant portion of the patient population cannot tolerate them and there is recognition of a need for differentiated therapeutic mechanisms,” said Punit Dhillon, CEO and Chair of Skye. “This need is underscored by recent activity of large pharmaceutical companies to acquire drugs with complementary mechanisms of action to treat obesity and highlights a trend toward combinations targeting two or even three mechanisms. As we look to a likely future where most major pharmas will have their own GLP-1 agonist, we see nimacimab as a key potential component of future combination therapies.”
Nimacimab is a first-in-class humanised monoclonal antibody that acts as a negative allosteric modulator to inhibit CB1 signalling in the periphery. Inhibition of CB1 has shown anti-fibrotic, anti-inflammatory and metabolic mechanisms of action with significant potential to address a broad range of diseases with notable unmet medical needs such as chronic kidney disease, obesity and non-alcoholic steatohepatitis (NASH).
Non-clinical studies over 26 weeks showed that nimacimab does not accumulate in the brain. A Phase 1 study showed PK of approximately 21 days with no safety concerns after four weeks of dosing, suggesting a favourable potential dosing regimen. Collectively, this data highlights nimacimab's potential as a new class of CB1 inhibitor.
The 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 central nervous system (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 unfavourable effects on insulin-sensitive tissues.
However, peripheral inhibition of CB1 has been shown to cause a reduction in food intake and a 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 the 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 ideations. A new class of drugs are now designed to only target the CB1 in the periphery, while avoiding the CNS.
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 (SAEs), 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 of cholesterol, liver enzymes and liver function in patients receiving nimacimab versus placebo after the three-week dosing period. Moreover, pharmacokinetic assessment of nimacimab highlighted a half-life of approximately three weeks, potentially allowing for monthly dosing. The drug is formulated in pre-filled syringes enabling convenient patient self-administration.
“The safety profile of nimacimab from preclinical and clinical studies is encouraging, and we believe it exceeds what others have demonstrated with small molecule drugs that also act to block the CB1 receptor. Because of the potential of this class of drug to treat a range of metabolic conditions, we believe a Phase 2 study to treat patients with obesity and comorbid chronic kidney disease offers the potential to evaluate multiple meaningful clinical endpoints beyond weight loss, such as changes in albuminuria to evaluate kidney function, that will guide the future development of nimacimab,” said Tu Diep, Chief Development Officer of Skye. “The promising PK data from the Phase 1 study suggests that nimacimab can be dosed once-a-month subcutaneously, which we believe would be a significant competitive advantage over once-a-week subcutaneous dosing of the current peptidic GLP-1 receptor agonists or even orally dosed GLP-1 receptor agonists due to their less desirable tolerability profile.”