−Removed: We are a clinical stage biopharmaceutical company with a mission to pioneer the development of new medicines that unlock the pharmaceutical potential of the endocannabinoid system ("ECS").
−Removed: Our clinical assets focus on the modulation of cannabinoid receptor 1 ("CB1") to provide novel treatments and alternatives for diseases caused by metabolic disorders, inflammation, fibrosis and neurodegeneration, such as obesity and glaucoma.
−Removed: Our Phase 2 clinical candidates include nimacimab, a negative allosteric modulating antibody that inhibits peripheral CB1 receptors, currently being developed for the treatment of obesity and SBI-100 Ophthalmic Emulsion ("SBI-100 OE"), a CB1 agonist (activator), currently being developed for the treatment of glaucoma and ocular hypertension.
−Removed: Both of these differentiated drug candidates are focused on distinct opportunities with large unmet needs:
−Removed: 1) Obesity - where a patients now need additional treatments that have the ability to preserve muscle tissue and improve metabolic dysfunction either as new monotherapies or in combination which existing treatments, and 2) Glaucoma - where novel drugs with distinct mechanisms are needed, especially those that are safe, well-tolerated and have neuroprotective potential.
−Removed: We have filed and successfully opened an Investigational New Drug ("IND") application with the U.S.
−Removed: Food and Drug Administration ("FDA") for nimacimab in obesity, and we plan to launch a Phase 2 clinical trial to evaluate nimacimab for the treatment of obesity as monotherapy compared against placebo, as well as evaluate the combination of nimacimab and a GLP-1 agonist in Q3 2024, with final data in late 2025.
−Removed: We are also continuing clinical development of SBI-100 OE for glaucoma and ocular hypertension, with the first data read out from our recently completed Phase 2a trial anticipated in Q2 2024.
−Removed: The Endocannabinoid System
−Removed: Peripheral CB1 Inhibitor
−Removed: The exploration of the CB1 pathway as a therapeutic target has seen a resurgence of scientific interest, particularly for its role in modulating key physiological functions such as appetite regulation, weight loss and related metabolic processes.
−Removed: Interest in CB1 inhibition has grown in part due to the unprecedented efficacy and commercial success but also the limitations of glucagon-like peptide-1 receptor (GLP-1) agonists for the treatment of obesity due to its distinct mechanisms and poor tolerability.
−Removed: While Novo Nordisk's Wegovy ® (semaglutide) once-weekly GLP-1 agonist injection for obesity had sales grow 442% to $4.7 billion in 2023, at the same time Novo Nordisk purchased Inversago, a clinical-stage company developing a peripherally-restricted CB1 inverse agonist therapy for weight loss.
−Removed: We believe this is in part because CB1 inhibition holds significant potential in obesity, and other metabolic diseases, as either a stand-alone drug or in combination with Novo Nordisk's GLP-1 agonist therapy, Wegovy ® .
−Removed: The history of CB1 inhibition for the treatment of weight loss in obesity is long and well documented.
−Removed: It started with the clinical validation of an approved drug, Accomplia ® , along with it's ultimate demise due to serious side effects.
−Removed: This was followed by a period of deep research into better understanding the mechanisms of weight loss, as well as, the corresponding side effects from CB1 inhibition - ultimately leading to a new class of "peripherally restricted" CB1 inhibitors.
−Removed: As a result, we now understand that inhibiting the CB1 receptor in peripheral tissues has the potential to not only cause weight loss, but may also, provide additional benefits such as improving insulin and leptin sensitivity, while specifically targeting fat loss and preserving lean muscle.
−Removed: In 2006, Accomplia ® (rimonabant) was approved for the treatment of obesity by the European Medicines Agency.
−Removed: Rimonabant was a CB1 inverse agonist that inhibited signaling both in the central nervous system and peripherally.
−Removed: Rimonabant consistently induced weight loss of 4-6 kg over 6-12 months vs.
−Removed: placebo, with accompanying improvements in metabolic control and hyperlipidemia (Van Gaal et al.
−Removed: Lancet, 2016, Astrup et al., Lancet, 2007).
−Removed: Subsequent meta-analyses showed that rimonabant increased risk of serious psychiatric adverse events such as anxiety, depression and suicidal ideation.
−Removed: It is believed that rimonabant's accumulation in the brain is the primary reason for the increased risk of serious psychiatric events.
−Removed: However, an increasing body of research suggests that the weight loss benefits of rimonabant may be achieved by targeting CB1 inhibition solely in the periphery and not in the brain, thereby avoiding risk of psychiatric adverse events.
−Removed: Although nimacimab is not in direct competition with GLP-1 agonists, a comparative analysis of rimonabant and semaglutide highlights significant differences in their gastrointestinal (GI) adverse event (AE) profiles.
−Removed: By evaluating rimonabant's GI tolerability and addressing the potential reduced risk of neuropsychiatric AEs with nimacimab—a peripherally acting antibody—nimacimab may emerge as an important next generation mechanisms beyond GLP-1 agonists for healthier, more sustainable weight loss and precision obesity including preserving muscle mass.
−Removed: (Van Gaal et al., Diabetes Care 2008 and Wilding et al., New England J Medicine 2021).
−Removed: Several mouse model studies support the hypothesis that selectively targeting CB1 inhibition exclusively in the periphery results in weight loss as well as other potential benefits.
−Removed: For example, Jenrin Discovery developed JD5037 a CB1 antagonist from ibipinabant with limited brain penetrance.
−Removed: Preclinical studies in the diet-induced obese mouse demonstrated that treatment with 3mg/kg daily of JD5037 over a 28-day period reduced body weight to normal levels.
−Removed: (Tam et al., Cell Metabolism 2012) Mice treated with JD5037 reduced body fat without loss of lean muscle mass.
−Removed: Treated mice experienced restoration of leptin sensitivity by decreasing leptin excretion by fat tissue, which resulted in increased fat loss.
−Removed: When these data are taken together with data from rimonabant, we can conclude that peripheral inhibition of CB1 is sufficient to induce weight loss, while preserving lean muscle mass and avoiding risks associated with inhibiting CB1 in the brain and central nervous system.
−Removed: Additional preclinical evidence also suggests that targeting both GLP-1 and inhibiting CB1 in the periphery with JD-5037 results in restoration of insulin sensitivity that is not seen with GLP-1 agonist therapy alone.
−Removed: (Liu et al., ACS Pharmacol.
−Removed: 2021 and Tam et al., Molecular Metabolism 2017)
−Removed: We are currently developing nimacimab, a patented peripherally-acting negative allosteric modulating CB1 inhibitor, initially for treatment of obesity.
−Removed: As a monoclonal antibody, nimacimab may offer a wider therapeutic window compared to competitive small-molecule peripheral CB1 inhibitors.
−Removed: Animal data generated positive safety data over 26 weeks and showed that, following dosing, nimacimab primarily remained in peripheral tissue outside the brain/central nervous system ("CNS") and the product candidate had a positive PK/PD supportive of once-monthly dosing.
−Removed: SBI-100 Ophthalmic Emulsion:
−Removed: CB1 Agonist (Activator)
−Removed: We are also developing a CB1 agonist for treatment of glaucoma and ocular hypertension.
−Removed: Approximately 7 million people in the United States and 60 million people worldwide suffer from glaucoma and ocular hypertension ("OH"), which is caused by slow drainage of the eye and leads to increases in intraocular pressure ("IOP").
−Removed: Ultimately, increased IOP is believed to be a main cause of optic nerve damage in glaucoma.
−Removed: Currently, only IOP lowering has been proven to be a modifiable risk factor for glaucoma onset and progression, and thus is the only acceptable endpoint for marketing approval by the FDA (De Moraes et al., Sci.
−Removed: 2023 and Leske et al., Arch Ophthalmol 2003).
−Removed: We believe that the unmet need for treatments in glaucoma is high.
−Removed: Approximately 40% of patients fail first line therapy and approximately 50% of patients require more than one therapy.
−Removed: SBI-100 OE is a CB1 agonist (activator) and is a patented prodrug of tetrahydrocannabinol ("THC") focused on lowering IOP related to glaucoma and ocular hypertension.
−Removed: Ophthalmology opinion leaders have described the unmet need for a new alternate class of medicine to lower intraocular pressure and ideally provide protection against detrimental neurodegenerative effects on the optic nerve.
−Removed: Third party research has demonstrated the utility of THC to lower intraocular pressure and also indicated its neuroprotective capabilities.
−Removed: In October 2023, Skye announced Phase 1 data indicating this differentiated eyedrop was safe and well tolerated, with a low rate of hyperaemia (red eyes) and no signs of intoxication from exposure to THC.
−Removed: Encouraging signs of reduction in IOP were also observed in the subset of healthy volunteers who had an elevated baseline IOP, indicating the potential utility of SBI-100 OE in reducing IOP in patients with glaucoma or ocular hypertension.
−Removed: We launched a Phase 2a clinical trial of SBI-100 OE in Q4 2023.
−Removed: Enrollment was completed in Q1 2024, with data expected in Q2 2024.
−Removed: Our aim is to be a leader in research and product development focused on the EC system.
−Removed: Our goal is to develop first-in-class products to treat significant unmet medical need in global markets.
−Removed: Our operating strategy emphasizes:
−Removed: Advancing Our Differentiated CB1 Inhibitor, Nimacimab, with a Focus on Obesity as a Stand Alone and Adjunct Therapy to GLP-1 by:
−Removed: • Continuing to build on Phase 1 clinical data supporting evidence demonstrating safety and evidence of weight loss through restoring leptin sensitivity and enhancing fat metabolism
−Removed: • Developing clinical data in Phase 2 supporting our hypothesis that nimacimab may cause weight loss while preserving muscle mass, which is not possible with current GLP-1 and GIP (glucose-dependent insulinotropic peptide) agonist therapies where reduction of muscle mass is a known side effect.
−Removed: • Showing through clinical data the potential for nimacimab to preserve muscle mass, and induce further reduction in weight loss when used in conjunction with GLP-1 and GIP agonist therapies
−Removed: • Exploring strategic collaborations for further development and deployment of nimacimab by expanding the clinical trial pipeline
−Removed: Advance Our First of Kind Eye Drop Formulation of CB1 Agonist SBI-100 OE as a New Treatment for Ocular Hypertension and Glaucoma by:
−Removed: • Continuing our Phase 2a proof-of-concept study to develop evidence supporting our hypothesis that SBI-100 OE will lower IOP in patients with ocular hypertension and glaucoma as it did in healthy patients during our Phase 1 clinical trial
−Removed: • Initiating a Phase 2b study evaluating SBI-100 OE against a current standard of care
−Removed: By adhering to this strategy, Skye aims to create medicines that significantly improve the lives of patients around the world.
−Removed: Our focus on the ECS and CB1 modulation reflects our commitment to developing innovative treatments for chronic diseases with large unmet needs characterized by neuropathic, inflammatory, and metabolic processes.
−Removed: Our Product Candidates
−Removed: Peripheral CB1 Inhibitor
−Removed: Unmet Need & Market Opportunity
+Added: Skye Bioscience, Inc.
+Added: is a clinical stage biotechnology company pioneering next-generation molecules that modulate G-protein-coupled receptors ("GPCRs") to treat obesity, overweight, and related conditions.
+Added: Our lead candidate, nimacimab, is a peripherally restricted negative allosteric modulating antibody targeting cannabinoid receptor 1 ("CB1")—a key GPCR involved in metabolic regulation.
+Added: We are conducting CBeyond TM , a Phase 2a proof-of-concept trial of nimacimab administered as a subcutaneous injectable for the treatment of obesity and overweight in the United States.
+Added: The CBeyond TM study is also assessing the combination of nimacimab and a GLP-1 receptor agonist.
+Added: We anticipate providing a top-line readout from the CBeyond™ study late in the third quarter or early in the fourth quarter of 2025, enabling a comprehensive view of nimacimab’s safety and efficacy profile.
+Added: Except where the context indicates otherwise, references to "we," "us," "our," "Skye" or the" Company" refer to the company and its subsidiaries.
+Added: Beyond nimacimab, our strategy is to develop and implement proprietary methods and platform technologies aimed at advancing a broad, scalable, and combinable portfolio of GPCR-based therapeutics to treat obesity, overweight and related conditions.
+Added: Our goal is to address not only the limitations of approved therapies, but also many of the anticipated challenges posed by next-generation treatments.
+Added: Through this anticipated future pipeline, we will remain committed to transforming metabolic health and delivering breakthrough treatments for high-burden, life-threatening conditions.
+Added: We believe there is a growing demand for therapies that offer improved safety, efficacy, tolerability, quality of life and long-term health outcomes while addressing the limitations of currently approved treatments.
+Added: Our objective is to drive innovation in the treatment landscape for obesity, overweight and metabolic disorders by developing first-in-class therapies that meet significant unmet medical needs globally.
+Added: Key elements of our strategy include:
+Added: • Advancing nimacimab through clinical development with an initial focus on completing the CBeyond Phase 2a study for the treatment of patients with obesity and overweight and evaluating its potential as a standalone, second-line or combination therapy.
+Added: • Expanding the clinical utility of nimacimab by exploring additional metabolic indications where inflammation and fibrosis c ontribute to disease progression, utilizing translational models to identify new therapeutic applications .
+Added: • Evaluating combination approaches by assessing nimacimab in combination with incretin-based therapies to enhance efficacy and patient outcomes in obesity and metabolic health management.
+Added: • Pursuing value add strategic partnerships and business development opportunities, including collaborations, licensing agreements, and other transactions to accelerate the clinical and commercial development of nimacimab.
+Added: • Developing next generation GPCR-targeting molecules designed to address metabolic disorders.
+Added: • Expanding our pipeline through in-licensing or acquisitions of complementary metabolic health technologies and product candidates that target GPCRs and align with our strategic vision.
+Added: The status of our development pipeline is as follows:
+Added: Our Product Candidate
+Added: We completed the acquisition of Bird Rock Bio, Inc.
+Added: (“Bird Rock”), a privately held, clinical-stage biotechnology company, in August 2023.
+Added: Through this transaction, we acquired nimacimab, a humanized IgG4 negative allosteric modulating ("NAM") antibody that specifically binds to the CB1 receptor with no cross-reactivity to other GPCRs, including cannabinoid receptor 2 ("CB2") .
+Added: Nimacimab was originally evaluated in a Phase 1 clinical study for nonalcoholic fatty liver disease related to a different development strategy.
+Added: We are now conducting a Phase 2a proof-of-concept trial of nimacimab in people with overweight and obesity and expect to report a top-line readout late in the third quarter or early in the fourth quarter of 2025.
+Added: To obtain 52 weeks of treatment data, the CBeyond trial will be extended to provide a longer-term assessment of safety, tolerability and efficacy.
+Added: The protocol extension will provide for continued assessment of both the nimacimab monotherapy (primary endpoint) and the nimacimab/GLP-1 combination cohort (exploratory endpoint).These results will represent the first in-human clinical data for nimacimab in the treatment of obesity.
+Added: Unmet Need and Market Opportunity
Global obesity rates have been rising dramatically, affecting more than one billion people worldwide (approximately 650 million adults).
−Removed: For example, approximately 42.4% of adults living in the United States are obese.
−Removed: This translates to more than 112.5 million American adults with a BMI of >30kg/m 2 , although it is likely that current rates and patient numbers are higher given obesity prevalence has increased 30.5% since 2000.
−Removed: Obesity is a complex disease characterized by excess and chronic inflammation of adipose tissues, and it results from a chronic energy surplus in which the body’s energy intake exceeds its energy expenditure.
+Added: Obesity and overweight are complex diseases characterized by excess and chronic inflammation of adipose tissues, and it results from a chronic energy surplus in which the body’s energy intake exceeds its energy expenditure.
Other stressors and environmental factors contribute to this chronic imbalance.
Today, obesity is the fifth-leading risk factor cited by the World Health Organization ("WHO") for contributing as a primary cause of death globally.
−Removed: Current estimates by the World Obesity Atlas suggest that over half the global population will be overweight or obese by 2035, compared to 38% in 2020.
−Removed: Early-generation therapies for obesity offered only modest help in weight reduction, with some drugs being removed from the market due to safety concerns.
−Removed: More recently, a new class of drugs have proven very effective at achieving weight loss.
−Removed: These incretin mimetics, including GLP-1 agonists such as semaglutide and GLP-1/GIP combinations such as tirzepatide, have changed the paradigm for anti-obesity treatments.
−Removed: Products derived from these compounds suppress appetite and induce satiety, reduce gastric emptying, and thus reduce calorie intake, achieving weight-loss of up to 20% within one year.
−Removed: However, these drugs come with some potentially significant gastrointestinal side effects that may arise, including diarrhea, nausea, abdominal pain and bloating, and in some cases patients may suffer from a condition known as gastroparesis, or paralyzed stomach.
−Removed: Additional side effects, although infrequent, include instances of acute pancreatitis, gallbladder disease, hypoglycemia, acute kidney injury and diabetic retinopathy (in diabetics).
−Removed: Beyond these potential side effects, it has been observed that muscle mass loss accounts for up to 40% of the weight lost in patients using these drugs, which is higher than the typical loss of approximately 25% muscle mass loss in normal weight loss settings.
−Removed: As a result of these side effects many patients are intolerant to these incretin-mimetic drugs.
−Removed: In most cases, even when therapy is tolerated, patients are unable to get to a healthy weight.
−Removed: When taken off therapy, patients can gain a majority of their weight back within the first year.
−Removed: Nevertheless, the market for this class of drugs is projected to grow to $20 billion in sales by 2030.
−Removed: Despite this unprecedented efficacy and commercial success, we believe there remains room for improvement over these new therapies.
−Removed: Potential of the Body's Endocannabinoid System for Pharmaceutical Drug Development in the Treatment of Obesity
−Removed: The cloning of CB1, along with the discovery of its endogenous ligands, the endocannabinoids ("ECs"), anandamide ("AEA") and arachidonoylglycerol ("2- AG"), has illuminated some of the biological intricacies and mechanisms involved in fat storage and development of obesity.
−Removed: ECs, CB1, and closely related cannabinoid type-2 receptors constitute the endocannabinoid system ("ECS").
−Removed: The ECS primarily functions to regulate energy storage and balance within the body, facilitated by CB1's activity in the brain and peripheral tissues.
−Removed: The ECS helps maintain many physiological processes by enabling different cellular functions , all with a role in achieving a global homeostasis despite fluctuations in the external environment.
−Removed: ECs are produced in the body, where their synthesis and degradation is regulated by different enzymes.
−Removed: These endocannabinoids act as agonists that can bind to and signal via specific endocannabinoid receptors expressed on various cell types and tissues.
−Removed: The CB1 receptor is one of the most abundant ECS receptors in the body.
−Removed: It is predominantly found in the CNS, where its role is associated with motor control, cognition, and emotional processing, and including modulation of processes of the eye.
−Removed: CB1 receptors are also found in peripheral tissues, or outside of the CNS, such as the liver, kidney, adipose tissue (fat cells), pancreas, and the gastrointestinal tract.
−Removed: One notable role of CB1 receptors in peripheral tissues is their involvement in metabolic regulation.
−Removed: In adipose tissue, activation of CB1 receptors has been linked to the promotion of fat storage, suggesting their role in the balance of energy storage and utilization.
−Removed: In the kidney, CB1 signaling helps modulate blood flow vital for the filtration of waste products and excess fluids, a process essential for maintaining proper electrolyte balance and blood pressure.
−Removed: CB1 in the liver is involved in the regulation of lipid metabolism and glucose homeostasis.
−Removed: Activation of CB1 receptors in the gastrointestinal tract can modulate the release of neurotransmitters and hormones that influence appetite, gastric motility, and nutrient absorption.
+Added: Current estimates by the World Obesity Atlas suggest that 54% of the global population will be overweight or obese by 2035, compared to 46% in 2025.
+Added: In addition, it is estimated that 39% of, or 770 million, children between the ages of five and nineteen years of age will be overweight or obese by 2035 compared to 28% of, or 550 million, such children in 2025.
+Added: Previous treatments for obesity have been limited by safety concerns and insufficient efficacy, which we believe hindered their success.
+Added: However, incretin-based therapeutics has shown significant weight loss and positive cardiovascular effects in clinical studies.
+Added: GLP-1 receptor agonists ("GLP-1") have been effective in reducing overall body weight, but this weight loss also includes, on average, an estimated 25-40% loss of lean muscle mass.
+Added: Patients using GLP-1 therapies also face tolerability issues, particularly gastrointestinal discomfort, which can affect the duration of treatment and lead to high rates of discontinuation.
+Added: Moreover, even for those patients who can tolerate therapy there are still up to 15% of these patients that lose less than 5% of weight at three months of treatment and are considered non-responders.
+Added: Despite the remarkable efficacy and commercial success of GLP-1 therapies, we believe there is still potential to improve the quality and sustainability of weight loss regimens, as well as, help patients who can not tolerate or do not respond to GLP-1 therapies.
+Added: We believe the combination of non-incretin mechanisms with incretin therapies like GLP-1s could improve outcomes compared to solely using GLP-1 therapies.
+Added: Alternatively, we believe a non-incretin mechanism could be used as a follow-up to standard GLP-1 treatments or as an alternative for specific patient groups with obesity and overweight.
+Added: Role of CB1 in the Treatment of Obesity and Other Metabolic Conditions
+Added: The CB1 receptor is one of the most abundant receptors in the endocannabinoid system ("ECS"), playing a significant role both in the central nervous system ("CNS") and peripheral tissues.
+Added: In the CNS, the CB1 receptors are involved in motor control, cognition, emotional regulation, and hunger cues.
+Added: However, CB1 receptors are also highly prevalent in peripheral tissues, including the liver, kidney, adipose tissue (fat cells), pancreas, and gastrointestinal tract.
+Added: Notably, the role of CB1 in peripheral tissues is crucial for metabolic regulation.
+Added: In adipose tissue, for example, activation of CB1 receptors is closely linked to the promotion of fat storage, making it a key target for obesity-related therapies.
+Added: In the kidney, CB1 signaling helps regulate blood flow, which is essential for waste filtration and maintaining electrolyte balance and blood pressure.
+Added: In the liver, CB1 plays a critical role in regulating lipid metabolism and glucose homeostasis.
+Added: Additionally, activation of CB1 receptors in the gastrointestinal tract influences the release of neurotransmitters and hormones that regulate appetite, gastric motility, and nutrient absorption.
+Added: Given its widespread influence on metabolic processes in peripheral tissues, targeting CB1 outside the CNS represents a promising therapeutic strategy for improving metabolic health and addressing obesity.
+Added: Building on the diverse roles of CB1 receptors in peripheral tissues, the "CB1 axis" emerges as a critical pathway for metabolic regulation, linking the activation of CB1 receptors across various organs to the broader control of energy balance and metabolic function.
The distribution and function of the CB1 axis provides a strong rationale to target this critical physiological system as a therapeutic to treat different pathological states.
Moreover, dysregulation of the CB1 axis in peripheral tissues has been associated with metabolic disorders such as obesity and kidney disease.
−Removed: Operating as a G-protein coupled receptor, CB1 typically associates with inhibitory Gi/o proteins to reduce cellular activity by inhibiting adenylyl cyclase and cAMP activity.
−Removed: Additionally, CB1 interaction with ß-arrestin can initiate a distinct signaling cascade, the full implications of which are not yet completely understood.
−Removed: This ß-arrestin pathway is known to affect receptor sensitivity and expression levels.
Recent research highlights that inhibiting CB1 outside the brain can influence leptin sensitivity and adipocyte signaling, directly impacting fat cell physiology.
Activation of CB1 promotes fat accumulation and disrupts mitochondrial function in obesity models, whereas inhibiting CB1 enhances mitochondrial biogenesis.
−Removed: This metabolic adjustment results in weight loss primarily through heightened energy expenditure, increased lipolysis, and fatty acid oxidation processes, particularly in brown adipose tissue, which serves as an energy source, contrasting white adipose tissue's role in long-term fat storage.
−Removed: It has been previously demonstrated that inhibiting the CB1 receptor can significantly reduce weight in obese patients.
−Removed: In 2006, Sanofi developed a CB1 inverse agonist called rimonabant, which demonstrated 8-10% weight loss after one year.
−Removed: Despite being approved by the European Medicines Agency, the drug was soon taken off the market because it was shown to result in a higher risk of adverse psychiatric side effects.
−Removed: As a result, rimonabant was taken off the market in Europe and Sanofi, along with other large pharmaceutical companies like Merck and Pfizer, stopped all development of CB1 inhibitors.
−Removed: Since the demise of rimonabant, a significant amount of research was conducted to better understand the CB1 blockade and why drugs like rimonabant failed.
−Removed: Ultimately it was determined that rimonabant readily entered the brain, resulting in significant psychiatric side effects.
−Removed: However, it was also discovered that blockade of CB1 receptors outside of the brain (i.e.
−Removed: peripheral CB1 receptors), could also result in meaningful weight loss and also improvement in other metabolic parameters.
−Removed: These studies have led to the development of "peripherally restricted" CB1 inhibitors that have significantly less penetration into the brain, resulting in a potentially safer drug while maintaining potentially similar weight loss characteristics.
−Removed: Moreover, researchers have shown that peripheral blockade of the CB1 receptors can also result in weight loss with less muscle mass loss (i.e.
−Removed: muscle wasting), while also improving metabolic parameters important in changing the course of the disease in obesity, such as improving insulin sensitivity.
−Removed: We believe incretin mimetics, like GLP-1 agonists, have established themselves as a potential foundation for the therapeutic treatment of weight loss.
−Removed: However, with their potentially challenging safety profile and marked incidence of muscle wasting associated with weight loss, we believe it is imperative to develop new drugs that can be complimentary to GLP-1 agonists, such as in combination with, as a follow-on to standard-of-care GLP-1 therapies, or even as an alternative therapy for obese patients who can not tolerate the side effects of GLP-1 agonists.
−Removed: Peripheral CB1 inhibition represents an important new mechanism with potential to help reduce these challenges and create improved therapeutic outcomes.
−Removed: In 2023, Skye acquired BRB along with its lead asset, nimacimab, a humanized IgG4 negative allosteric modulating (NAM) antibody that specifically binds to CB1 receptor and does not cross-react with other GPCRs including CB2.
−Removed: CB1 binding characteristics including specificity and affinity have been confirmed with both ELISA and flow cytometry-based assays.
−Removed: Assessing functional inhibition including demonstration of noncompetitive binding CB1 has been confirmed with both b-arrestin-based and GPCR-based endpoints.
−Removed: This functional and specific CB1 inhibiting antibody has also been characterized in multiple biodistribution assays, which collectively demonstrated a high degree of peripheral restriction with minimal detection in the CNS and brain in early time points as well as no accumulation in the brain over 28 days, despite nimacimab's 18-20 day half-life.
−Removed: This lack of blood-brain barrier (BBB) penetration, while not uncommon for a larger biologic such as an antibody therapeutic, is an important feature that helps underpin nimacimab's excellent safety profile.
−Removed: While different strategies have been developed to limit CB1 signaling, nimacimab's negative allosteric approach is differentiated relative to an inverse agonist inhibitor in a few notable ways.
−Removed: A fundamental functional difference relates to the ability of nimacimab to inhibit in a non-competitive fashion.
−Removed: Since nimacimab limits the receptor activity by binding away (allosterically) from the agonist (endocannabinoid) receptor binding pocket, it is able to inhibit the CB1 signal independently of receptor engagement.
−Removed: In contrast, an inverse agonist competes with the endocannabinoid for receptor binding and thus inhibition of CB1 signaling.
−Removed: While this distinction may not be as impactful in healthier patients with minimal pathology, this mechanistic distinction becomes more relevant in patients with notable disease progression where the CB1 axis (both receptor but importantly endocannabinoid density) can be significantly overactive in local tissues, enabling competition with an inverse agonist for receptor occupancy.
−Removed: This difference can be exaggerated when the bioavailability of an inverse agonist is limited, which highlights a second key distinction between nimacimab, an antibody therapeutic, and inverse agonists, which are currently all small molecule therapeutics.
+Added: This metabolic adjustment results in weight loss primarily through heightened energy expenditure, increased lipolysis, and fatty acid oxidation processes, particularly in brown adipose tissue.
+Added: CB1 Inhibition:
+Added: Small Molecule Clinical Experience and New Approaches
+Added: It has been previously demonstrated that inhibiting the CB1 receptor can significantly reduce weight in patients with obesity.
+Added: In 2006, Sanofi developed a small molecule CB1 inverse agonist called rimonabant, which demonstrated 10% weight loss after one year.
+Added: Despite being approved by the European Medicines Agency, the drug was soon taken off the market due to severe adverse neuropsychiatric side effects, including suicidal ideation.
+Added: Since rimonabant was taken off the market, a significant amount of research was conducted to better understand why rimonabant failed.
+Added: Ultimately it was determined that rimonabant, a small molecule, readily entered the brain, resulting in severe adverse neuropsychiatric side effects.
+Added: A new generation of small molecule CB1 inhibitors are being developed with the aim of achieving further peripheral restriction.
Small molecule-based CB1 inverse agonists have been modified to discourage distribution in the CNS and brain by increasing the polarity of surface residues, which also impacts membranous trafficking and bioavailability.
−Removed: While this altered small molecule yields a notable improvement in CNS distribution relative to non-biased small molecules such as rimonabant, its presence and significant CB1 occupancy in the brain has still been noted in a chronic preclinical setting.
−Removed: Coupled with an impact on bioavailability, this may limit the therapeutic index and thus its relative density in local tissues.
−Removed: In contrast, nimacimab has an excellent clinical safety profile with a large NOAEL (no observed adverse effect level) and an 18-20 day half-life which collectively supports a favorable pharmacologic profile capable of safely inhibiting CB1 signaling in relevant disease settings.
+Added: While these altered small molecules yield notable reductions in CNS distribution relative to non-biased small molecules such as rimonabant, its presence and significant CB1 occupancy in the brain has still been noted in chronic preclinical and clinical settings.
+Added: Phase 2 data related to this new generation of small molecules resulted in dose-dependent mild to moderate adverse neuropsychiatric side effects, such as irritability, anxiety and sleep disturbances, confirming that these molecules continue to cross the blood-brain barrier when dosed at levels required to achieve desired levels of weight loss.
+Added: We believe that the safest and most effective way to inhibit CB1 is with a large-molecule approach to potentially eliminate safety concerns from the molecule penetrating the blood-brain barrier.
+Added: We believe nimacimab, as a large molecule, has the potential to mitigate safety concerns associated with the CB1 class and may achieve similar or more favorable efficacy than other therapies in the CB1 class due to our ability to administer higher doses of nimacimab, without significant concentrations of nimacimab penetrating the blood-brain barrier.
+Added: Nimacimab Product Differentiation
+Added: Weight loss continues to be the primary endpoint to evaluate efficacy in patients with obesity and overweight.
+Added: However, we recognize, through our engagement with key advisors and healthcare providers, that the obesity and overweight market is heterogeneous and that different patients may need different therapies to manage their condition(s).
+Added: As these markets grow, we believe there is an increasing demand from healthcare providers for alternative therapies to treat obesity and other metabolic conditions, along with their associated comorbidities.
+Added: While the current GLP-1 drugs are efficacious, we believe there is room to optimize dosing regimens, develop drugs with more favorable side effect profiles, and build upon the current mechanisms to re-establish healthy metabolic pathways.
+Added: The current incretin mimetic drugs approved for weight loss act primarily through caloric restriction by increasing GLP-1 in the gut and signaling to the CNS feelings of satiety or fullness.
+Added: While caloric restriction is an effective way to manage weight loss, it has been shown that caloric restriction alone, without appropriate lifestyle intervention, will lead to loss of lean mass.
+Added: For example, based on clinical trial data for semaglutide, a GLP-1 agonist, on average 25-40% of the weight loss results from the loss of lean mass (which can include both muscle and bone).
+Added: In addition, up to 70% of patients experience gastrointestinal ("GI") side effects with semaglutide including nausea, vomiting and diarrhea, which can lead to discontinuation of treatment in some cases.
+Added: We believe nimacimab stands apart from GLP-1's and other incretin-based weight loss therapies because its primary mechanism goes beyond suppression of food intake.
+Added: While peripheral CB1 inhibition can reduce elevated leptin levels as well as modulate appetite-regulating hormones to broadly blunt appetite, key additional drivers of weight loss include increased energy expenditure, fat metabolism, and insulin sensitivity as well as reduced inflammation.
+Added: As a result, clinical data from this class of drugs have demonstrated not only weight loss but also lean mass preservation, improved insulin sensitivity, and reductions in cholesterol.
+Added: Additionally, preclinical obesity models using CB1 inhibitors have shown improvements in hyperleptinemia, leptin sensitivity, and increased energy expenditure.
+Added: This unique mechanism offers a potential alternative, and even complementary, approach to chronic weight management, broadening therapeutic options for patients with obesity and overweight.
+Added: Nimacimab’s Differentiation Within the CB1 Class
+Added: Within the CB1 inhibitor class, we believe nimacimab is distinct from competing drug candidates primarily because it is a large-molecule antibody, and has a distinct mechanism of noncompetitive inhibition that collectively confers several advantages over the small molecules in development.
+Added: Enhanced Selectivity and Safety - As an antibody, nimacimab exhibits high specificity for CB1, reducing the risk of off-target toxicity—a critical factor given the historical safety concerns with CB1 inhibition.
+Added: Our Phase 1 study established the potential for nimacimab’s favorable safety profile, with no observed neuropsychiatric adverse effects and excellent GI tolerability, a key differentiation from previous CB1-targeting drugs.
+Added: Negative Allosteric Modulation - Nimacimab functions as a negative allosteric modulator of CB1, which means it binds to a distinct area of CB1 'away' from the receptor’s primary active site (the orthosteric site) and thus inhibits CB1 activity without any competition from the endogenous ligands (endocannabinoids).
+Added: This noncompetitive mode of action is distinct from small-molecule inhibitors, which target CB1 receptor’s orthosteric site and require successful competition with endocannabinoids for receptor occupancy to inhibit CB1 signaling.
+Added: This can become critical as CB1 signaling is often overactive in metabolic diseases, and direct competition with an inverse agonist may be insufficient in tissues with excessive CB1 activity.
+Added: In such disease states, where both CB1 receptor density and endocannabinoid levels are elevated, orthosteric small molecules must outcompete high concentrations of endocannabinoids, which can negatively impact their Pharmacokinetic ("PK") profile and ultimately limit their efficacy.
+Added: Inverse Agonism - As described above, nimacimab is a noncompetitive inhibitor which we believe confers specific advantages.
+Added: Additionally, nimacimab can inhibit CB1 without an agonist present in which case it can drive the opposite signaling of CB1 agonists such as promoting increased cAMP and reduced b-arrestin recruitment.
+Added: Thus, nimacimab inhibits CB1 as both a noncompetitive antagonist and an inverse agonist.
+Added: Superior Dosing and PK Profile - Small-molecule CB1 inhibitors require daily oral dosing, which increases systemic exposure and potential toxicity risks.
+Added: Nimacimab, with its 18-22 day half-life, supports once-monthly subcutaneous dosing, enhancing patient compliance while maintaining consistent receptor inhibition.
+Added: Potential for Combination Therapies - The antibody format opens opportunities for combinations with therapeutics targeting orthogonal and/or distinct mechanistic pathways using bi- or tri-specific bioconjugation approaches.
+Added: Combining a more tolerable dose of a GLP-1 agonist (to drive caloric restriction) with a safe CB1 inhibition mechanism (to drive fat metabolism) could yield additive or even synergistic weight loss effects.
+Added: Our Phase 2a study includes an exploratory arm evaluating the combination of Wegovy (semaglutide) with Nimacimab to assess this potential.
+Added: Preclinical Data
+Added: The CB1 pathway is clinically validated and has many supporting studies that highlight peripheral mechanisms to promote productive metabolic changes, including weight loss.
+Added: However, sufficiency of nimacimab-driven weight loss and related metabolic gains remained a critical hurdle to be addressed.
+Added: Outside of clinical studies, we endeavored to understand if nimacimab could drive weight loss using a diet-induced obesity ("DIO") mouse model.
+Added: Since nimacimab does not cross-react with mouse CB1, a transgenic mouse was generated which targeted the murine CB1 ("mCB1") loci for insertion of human CB1 ("hCB1").
+Added: This targeted disruption of mCB1 for hCB1 knockin mice was confirmed genetically as well as functionally, as measured by productive CB1 signaling in a THC-induced hyperthermia model as well as the ability to generate obese mice with a high fat diet ("HFD").
+Added: We found that the use of nimacimab in this mouse DIO model demonstrated the following:
+Added: • significant dose-dependent weight loss compared to vehicle;
+Added: • significant fat mass loss with lean mass preservation;
+Added: • dose-dependent improvement in glucose tolerance.
+Added: The above figure highlights body weight and composition analyses performed with two-way analysis of variance ("ANOVA") repeated measurements.
+Added: A Tukey multiple comparison test was then performed for all pairwise comparisons.
+Added: Body weight reporting occurred at day 35 of treatment and body composition was measured with an echoMRI on day 33.
+Added: Beyond weight loss and productive body composition, the above data demonstrates positive changes in glycemic control with a dose-dependent improvement in glucose tolerance in obese mice.
+Added: Day 27 mice fasted for four hours before receiving an intraperitoneal injection of 10 grams of glucose with measurement of blood glucose over 120 minutes as part of the glucose tolerance test ("GTT").
+Added: GTT analyses included (1) a two-way ANOVA repeated measurements (a Tukey multiple comparison test) and (2) a baseline subtracted area under the curve ("AUC") analysis performed with a one-way ANOVA with a Tukey multiple comparison test.
+Added: In addition to clinical data sets from monlunabant and rimonabant, this DIO data supports the hypothesis that peripheral CB1 inhibition is sufficient for weight loss while central CB1 inhibition is not required for metabolic improvements such as weight loss.
+Added: Instead, this data suggest that central CB1 inhibition may only minimally contribute to efficacy, yet is likely to be a driver of neuropsychiatric adverse events.
Nonclinical Data
−Removed: Nonclinical studies were designed to characterize various pharmacodynamic aspects of nimacimab, including specificity and in vitro affinity binding, functional cell-based inhibition, as well as other mechanistic details.
−Removed: Key findings from these studies demonstrated that nimacimab is selective and does not bind to other GPCR targets while binding with low nM affinity to human CB1.
−Removed: The antibody was able to block CB1 activation by the natural endocannabinoid ligands AEA and 2-AG and demonstrated dose-dependent antagonist activity measured by both cAMP and b-arrestin signaling pathways.
−Removed: Pre-treatment with nimacimab blocked CB1 agonist-induced CB1 internalization and nimacimab did not induce internalization in the absence of agonist.
−Removed: Additionally, nimacimab had no effect on antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC), suggesting that nimacimab's mechanism of action is focused on blocking CB1 signaling and not any direct immune-mediated effects.
−Removed: Lastly, antibody blockade of CB1 on matured adipocytes from obese subjects significantly increased adiponectin production compared to vehicle control.
−Removed: These findings are of importance as adiponectin, an adipokine secreted by adipocytes, play a critical role in regulating glucose levels, lipid metabolism, and insulin sensitivity, which collectively support positive metabolomic regulation.
+Added: Two Investigational New Drug Applications ("IND")-enabling nonclinical studies with nimacimab were completed in non-human primates, which demonstrated a strong safety profile with a no adverse effect level ("NOAEL") of 75 mg/kg.
+Added: In addition, nimacimab was shown in two independent non-human primate biodistribution studies to have almost no exposure in the brain (~0.02%), with multi-dose studies demonstrating no accumulation.
+Added: A 3-week subcutaneous injection toxicity study in cynomolgus monkeys was completed to determine the toxicity and toxicokinetic ("TK") profile of two dose levels of 25 mg/kg and 75 mg/kg of nimacimab versus a matching placebo, following two subcutaneous ("SC") injections two weeks apart.
+Added: In this study, no mortality occurred and there were no effects noted on clinical signs, ophthalmology, electrocardiography, hematology, clinical chemistry, coagulation and urinalysis during the course of the study.
+Added: There were no nimacimab effects noted on organ weights, and no nimacimab-related macroscopic or microscopic observations.
+Added: Subsequently, a repeat-dose toxicity study was conducted in cynomolgus monkeys at two dose levels of 40 mg/kg and 75 mg/kg nimacimab versus matching placebo to determine the toxicity and TK profile of nimacimab administered every two weeks over 26 weeks (13 total doses), and to assess the reversibility of any changes following an eight week recovery period.
+Added: In this study, nimacimab was well-tolerated with results similar to the three week study with the only nimacimab-related macroscopic or microscopic observations consisting of reversible minimal to moderate inflammation at the injection site.
+Added: In general, the TK of nimacimab indicates slow absorption from subcutaneous injection sites, low systemic clearance, a limited volume of distribution and a long terminal half-life.
+Added: Based on the results of these studies, the NOAEL was considered to be the high dose of 75 mg/kg/dose.
+Added: Two non-human primate studies were conducted to further elucidate the CNS exposure of nimacimab.
+Added: The first study dosed cynomolgus monkeys with nimacimab at 3mg/kg and 40 mg/kg and collected cerebral spinal fluid ("CSF") at multiple timepoints as a surrogate measure for CNS exposure.
+Added: This data demonstrated that nimacimab has almost no exposure with little to no accumulation in the brain.
+Added: A second study evaluated direct CNS exposure by performing a biodistribution study with radiolabeled nimacimab.
+Added: Nimacimab was radiolabeled with 124-Iodine, and after confirmation of expected in vitro potency, administered intravenously ("IV") to 2 rhesus monkeys with positron emission tomography ("PET") scans were acquired for 30 minutes at 6 and 24 hours post-injection.
+Added: Overall, animals showed lower signals in the heart, lung, liver, spleen and kidney at 24 hours compared to 6 hours.
+Added: No significant uptake of nimacimab was observed in the brain at the time points studied.
+Added: Taken together, we believe these nonclinical studies demonstrate that nimacimab is safe, with an NOAEL of 75 mg/kg, and that very little, if any, nimacimab enters the CNS.
Clinical Data
−Removed: In a Phase 1b entitled "Safety, Tolerability and Pharmacokinetics of Nimacimab after Repeat Dosing in Subjects with Non-Alcoholic Fatty Liver Disease (NAFLD)," the purpose was to evaluate the safety and tolerabilty of multiple doses of nimacimab after four weeks of dosing in subjects with NAFLD.
+Added: In June 2017, Bird Rock initiated a Phase 1b study.
+Added: The purpose of the study was to evaluate the safety and tolerability of multiple doses of nimacimab after four weeks of dosing in subjects with non-alcoholic fatty liver disease ("NAFLD"), now known as metabolic-associated fatty liver disease ("MAFLD").
Secondary objectives included determination of pharmacokinetics of nimacimab for multiple doses and to determine levels of anti-drug antibodies ("ADA") after dosing with nimacimab.
+Added: The study was carried out in subjects who had baseline NAFLD.
+Added: This was done to enable the preliminary assessment of biomarkers of liver disease with short term therapy.
+Added: We believe the short duration of treatment, small number of patients in each cohort and lack of any dietary restrictions should be taken into account when considering the results.
In Part A of this study, 24 healthy volunteers were randomized to receive a single dose of either placebo or single ascending doses of nimacimab (0.6, 1.2 or 2.5 mg/kg).
−Removed: In Part B, 82 patients with pre-diabetes or diabetes and NAFLD were randomized to receive either placebo or multiple escalating doses of nimacimab (0.6, 1.2 or 2.5 mg/kg) once a week for four weeks.
+Added: In Part B of this study , 82 pat ients with pre-diabetes or diabetes and NAFLD were randomized to receive either placebo or multiple escalating doses of nimacimab (0.6, 1.2 or 2.5 mg/kg) once a week for four weeks.
There were no deaths, serious adverse events ("SAEs") or treatment-emergent adverse events ("TEAEs") that lead to discontinuation.
−Removed: All TEAEs were graded as mild to moderate in intensity except for 1 severe TEAE (dizziness) in the nimacimab 0.6 mg/kg dose group determined to have not been related to study drug.
+Added: All TEAEs were graded as mild to moderate in intensity except for one severe TEAE (dizziness) in the nimacimab 0.6 mg/kg dose group determined to have not been related to study drug.
The majority of TEAEs were not related to study drug and there was no apparent relationship between the dose level and the type, severity, or incidence of the TEAEs.
4 unchanged sentences
Only two subjects had consistently elevated titers over multiple time points of ADA.
−Removed: These data suggest that nimacimab has overall low immunogenicity.
+Added: This data suggest that nimacimab has overall low immunogenicity.
+Added: The placebo group in the Phase 1 study had an increase in weight while the treatment groups showed stable weight resulting in a numerical difference that represents an early trend for potential efficacy.
Decreases in mean alanine transaminase ("ALT") and aspartate aminotransferase ("AST") were observed during the study in the active treatment groups, but not in the placebo group.
3 unchanged sentences
No effect was observed in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and triglycerides.
−Removed: No significant treatment effect was observed on liver fat percentage, DNL, inflammatory biomarkers and OGTT test.
−Removed: Development Plan
−Removed: IND-enabling studies of nimacimab in non-human primates demonstrated a strong safety profile with a NOAEL of 75 mg/kg.
−Removed: Our Phase 2 study in obesity is designed to evaluate nimacimab's weight loss potential either as a single agent or in combination with a GLP-1 agonist like semaglutide.
−Removed: We believe the complementary mechanism of action of CB1 inhibition with nimacimab in combination with a GLP-1 agonist has the potential to provide more meaningful weight loss, and potentially more durable weight loss, than a GLP-1 agonist alone.
−Removed: Our Phase 2 clinical trial design will treat non-diabetic individuals with obesity (BMI≥30) or those overweight (BMI≥27) with at least one weight-related health issue.
−Removed: Participants will be treated with either nimacaimb, a GLP-1 agonist such as semaglutide, a combination of nimacimab plus a GLP-1 agonist, or placebo.
−Removed: This 26-week study will be followed by a 12-week observation period.
−Removed: The main goal is to measure the percentage of weight loss by week 26, with secondary goals assessing changes in waist size, body composition, fasting triglyceride levels, cholesterol, and A1c.
−Removed: The study will help us evaluate the effectiveness of nimacimab alone versus placebo, as well as compare the difference between nimcacimab and semaglutide and the potential enhanced effects of their combination.
−Removed: A key focus is the impact on body composition across different groups, especially since nimacimab is expected to better preserve muscle mass by promoting fat browning, a benefit observed in preclinical studies where CB1 inhibition led to significant weight reduction without muscle loss over 28 days.
−Removed: We plan to finalize the trial design and start the Phase 2 study in approximately mid-2024.
−Removed: SBI-100 Ophthalmic Emulsion:
−Removed: CB1 Agonist (Activator)
−Removed: Unmet Need & Market Opportunity
−Removed: Glaucoma is characterized by progressive ocular neuropathy associated with the initiation of apoptosis of retinal ganglion cells ("RGCs") in the optic nerve, which can progress and cause irreversible loss of vision.
−Removed: While the pathology of glaucoma is in the back of the eye, a key driver of this disease is often found in the front of the eye.
−Removed: Specifically, elevated intraocular pressure ("IOP") resulting from dysregulated outflow, and to a lesser extent production of aqueous humor ("AH") in the anterior/posterior chambers in the front of the eye, readily promotes damage to RGC axons through vascular ischemia and physical crush injury as the elevated ocular pressure compresses these critical cells.
−Removed: IOP is currently the only modifiable risk factor and lowering IOP results in reduced risk of progression of damage to the optic nerve.
−Removed: Moreover, IOP has been identified as an important risk factor in the pathogenesis of this disease.
−Removed: To reduce IOP, the current classes of glaucoma therapeutics target pathways that shift the balance of production or outflow of AH.
−Removed: This therapeutic landscape is made up of five drug classes focused on lowering IOP toward a target level whereby the rate of disease progression will be slowed sufficiently to avoid functional impairment from the disease.
−Removed: Prostaglandin analogues and β-blockers are the first-line therapies and the most commonly used medications for the management of glaucoma.
−Removed: There are other therapeutic agents less commonly used to reduce IOP, like cholinergic agonists, alpha agonists and ROCK inhibitors.
−Removed: While these treatments can be effective in some patients, side effects and lack of durable responses often lead to many patients progressing through multiple therapies in an effort to control IOP.
−Removed: Current treatments are legacy classes of drugs thus there is an unmet need for combinations and innovation in this therapeutic landscape.
−Removed: This unmet need is a potential opportunity for Skye's SBI-100 OE to have a positive impact in patients with glaucoma.
−Removed: Cannabinoid receptors are highly concentrated in the eye, especially in the anterior compartment that helps regulate IOP, and in the posterior compartment in the area of the retina and optic nerve.
−Removed: Activation of CB1 has previously been shown to lower IOP in both animal and human studies.
−Removed: SBI-100 OE represents a novel treatment option for glaucoma.
−Removed: The active pharmaceutical ingredient ("API"), SBI-100, is synthetically created using rational drug design and biochemical engineering to increase the hydrophilic properties of Δ9-tetrahydrocannabinol.
−Removed: This increased solubility coupled with a proprietary formulation to increase stability and residency time on the ocular surface allows for increased ocular tissue penetration.
−Removed: Once inside the eye, abundant esterases release the prodrug moiety, allowing for an active THC molecule to bind to abundant CB1 receptors throughout key ocular tissues such as the trabecular meshwork and ciliary body.
−Removed: Engagement of these receptors has been demonstrated to promote AH outflow via the trabecular meshwork as well as limit production via the ciliary body.
−Removed: Importantly, the active component of SBI-100 OE has been shown to have neuroprotective effects in both in vitro and in vivo studies.
−Removed: Since SBI-100 OE has been detected in retinal tissues in biodistribution studies, we are investigating if SBI-100 OE may additionally demonstrate a neuroprotective aspect in its treatment of glaucoma, providing further differentiation from the current therapies on the market.
−Removed: We licensed SBI-100, the active pharmaceutical ingredient in SBI-100 OE, from the University of Mississippi ("UM").
−Removed: SBI-100 OE is initially being developed to treat glaucoma and ocular hypertension.
−Removed: SBI-100 is Δ9-tetrahydrocannabinol-valine-hemisuccinate (Δ9-THCVHS), a synthetically manufactured amide ester prodrug of Δ9-tetrahydrocannabinol molecule formulated in a proprietary nanoemulsion formulation.
−Removed: In contrast to the parental Δ9-tetrahydrocannabinol molecule, which has very poor bioavailability, this novel synthetic molecule has been shown to penetrate into ocular tissue, where the prodrug moiety is quickly removed, allowing for the delivery of measurable amounts of active drug (Δ9-tetrahydrocannabinol) to the cornea, AH, iris-ciliary body, and retina choroid (RC), permitting interaction with cannabinoid receptors involved in regulating IOP.
−Removed: Preclinical Data
−Removed: In 2019, UM completed experiments showing that SBI-100 was statistically superior in lowering IOP compared to the prostaglandin-based therapy latanoprost, the current standard-of-care for treating glaucoma.
−Removed: Statistical significance was reached across multiple time points during a seven-day course of dosing using a validated rabbit normotensive ocular model and SBI-100 exerted pharmacologic activity consistent with once-daily to twice-daily dosing.
−Removed: Skye subsequently developed a proprietary nanoemulsion formulation to optimize the amount of SBI-100 that can be delivered to the eye in a single drop while also improving the duration of activity.
−Removed: Importantly, this formulation can be sterilized by filtration without impacting the attributes of SBI-100.
−Removed: This final formulation of the API, known as SBI-100 Ophthalmic Emulsion, significantly reduced IOP compared to other commercially available ophthalmic solutions and is now being evaluated in clinical trials.
−Removed: We evaluated the mechanism of action and IOP-lowering ability of the active moiety of SBI-100 when administered into an ex vivo model of a 3D-human trabecular meshwork using both healthy and glaucomatous-induced tissues.
−Removed: The trabecular meshwork plays a key role in removing a vital functional liquid in the eye, called aqueous humor, in order to maintain a healthy balance of pressure in the eye (an imbalance can lead to a detrimental increase in IOP).
−Removed: This study validated the mechanism of action of SBI-100 in lowering IOP, a defining disease process of hypertensive glaucoma.
−Removed: Moreover, biomarkers associated with inflammation and fibrosis in both normal tissue and tissues affected by glaucoma were significantly decreased, pointing to anti-inflammatory and anti-fibrotic activities often associated with cannabinoids in other disease states.
−Removed: Data also revealed that biomarkers associated with neovascularization, a disease process of new blood vessel formation that can damage the retina in a variety of ocular diseases, was also inhibited by the active moiety, prompting further study for the utility of this drug in diseases of the retina.
−Removed: Clinical Data
−Removed: We commenced dosing of the Phase 1 clinical study in December 2022 and in November 2023 we reported that our Phase 1 data demonstrated that SBI-100 OE was safe and well-tolerated.
−Removed: Importantly, we determined that there was minimal systemic exposure of the active metabolite of SBI-100 OE, THC, thus resulting in little to no side effects related to THC intoxication.
−Removed: Moreover, it was determined that after multiple days of dosing we saw minimal hyperaemia (i.e.
−Removed: redness of the eyes) following administration of SBI-100 OE.
−Removed: In December 2022, w e obtained FDA clearance of our Investigational New Drug application to conduct clinical studies in the US and in January 2023, our Phase 2 clinical trial protocol received study level approval from a central institutional review board (“IRB”).
−Removed: In February 2024, we announced that we completed enrollment of our Phase 2a clinical study for glaucoma and ocular hypertension.
−Removed: Due to the early completion of enrollment of our Phase 2a study, topline data will be available in Q2 2024.
−Removed: Development Plan
−Removed: As a novel agent for the potential treatment of glaucoma and ocular hypertension, SBI-100 OE may represent a new treatment opportunity for physicians and patients and we are leading the field in this area of research.
−Removed: We are currently advancing a Phase 2a trial of SBI-100 targeting primary open-angle glaucoma (POAG) and OH.
−Removed: This study enrolled 56 patients with POAG and OH, presenting intraocular pressures (IOP) between 21-34mmHg, and with no history of surgical interventions.
−Removed: Participants were randomized to receive either 0.5% SBI-100, 1% SBI-100, or a placebo, administered twice daily over a 14-day period.
−Removed: The study's main goal is to assess changes in diurnal IOP compared to placebo.
−Removed: Secondary objectives are to evaluate safety, tolerability, any psychotropic effects, changes in diurnal IOP from the study's start, and to explore potential biomarkers.
−Removed: Following the data release of our proof-of-concept Phase 2a study, we expect to initiate a Phase 2b study evaluating SBI-100 OE against a current standard of care such as timolol.
−Removed: Successful completion of this Phase 2b study by the end of 2025 may present an opportunity to hold an end-of-Phase 2 meeting with the US FDA to discuss our plan for Phase 3 studies for marketing authorization in glaucoma.
−Removed: Our industry is characterized by rapidly advancing technologies, intense competition, rapid pace of new innovation, and a strong emphasis on proprietary products and defense of intellectual property.
−Removed: We face competition from pharmaceutical companies, including generic drug companies, biotechnology companies, drug delivery companies, and academic and research institutions, among others.
−Removed: Competitors to nimacimab that are targeting peripheral inhibition of CB1 for the treatment of obesity and metabolic conditions include Inversago (acquired by Novo Nordisk in 2023) and Corbus Pharmaceuticals.
−Removed: We are not aware of any competitor attempting to inhibit CB1 in the periphery via a monoclonal antibody.
−Removed: There is also significant interest in and competitive activity targeting obesity and metabolic disorders from companies including Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Zealand Pharma, Pfizer, AstraZeneca, Regeneron, Carmot Therapeutics (acquired by Roche), Amgen, Viking Therapeutics, Structure Therapeutics, Versanis (acquired by Eli Lilly), Biohaven, Keros Therapeutics, Scholar Rock, Terns Pharmaceuticals, Altimmune, Omega Therapeutics, Kallyope, Rivus and others including several privately financed companies whose information is not regularly disclosed to the public.
−Removed: We are not currently aware of any competitors to SBI-100 Ophthalmic Emulsion that are developing a CB1 agonist for the treatment of glaucoma and OH.
−Removed: Merck, Novartis, Abbvie, Bausch + Lomb, and Alcon are generally known competitors currently offering treatments for glaucoma and ocular hypertension.
+Added: No significant treatment effect was observed on liver fat percentag e, de-novo lipogenesis, i nflammatory biomarkers and OGTT test.
+Added: We believe the preliminary trends seen in the Phase 1 study, over a short duration of treatment, demonstrated the potential for nimacimab to have similar or greater effects on modulation of weight and treating conditions known to be associated with obesity.
+Added: Clinical Development Plan
+Added: In August 2024, we initiated a 26 week Phase 2a proof-of-concept trial with a 13 week follow up, CBeyond TM for nimacimab in obesity.
+Added: The CBeyond TM clinical trial recruited approximately 136 evaluable patients in 16 clinical trial sites to assess differences in weight loss, body composition, and other attributes.
+Added: This CBeyond TM clinical trial's primary endpoint is to evaluate weight loss using nimacimab compared to placebo.
+Added: Secondary endpoints include evaluations of safety and tolerability, neuropsychiatric and cognitive evaluation, change in body composition by Dual-Energy X-ray Absorptiometry ("DEXA"), and changes in key metabolic biomarkers such as triglycerides, and insulin and leptin sensitivity.
+Added: Patients will also be recruited to an exploratory combination arm with a GLP-1 agonist.
+Added: To obtain 52 weeks of treatment data, the Company is planning a trial extension that increases the originally planned 26 weeks of treatment to provide a longer-term assessment of safety, tolerability and efficacy.
+Added: The protocol extension will provide for continued assessment for all four treatment arms including both the nimacimab monotherapy (primary endpoint) and the nimacimab/GLP-1 combination cohort (exploratory endpoint).
+Added: The biopharmaceutical industry is intensely competitive and is characterized by rapid technological progress.
+Added: In general, competition among pharmaceutical products is based in part on product efficacy, safety, reliability, availability, price and patent position.
+Added: An important factor is the relative timing of the market introduction of our products and our competitors’ products.
+Added: Accordingly, the speed with which we can develop products, complete clinical trials and approval processes and supply commercial quantities of the products to the market impacts our competitiveness.
+Added: Our competitive position also depends upon our ability to show differentiation with a product that is either more efficacious, particularly in the relevant target populations, offers a better safety or tolerability profile, is less expensive or quicker to manufacture, or represents a combination of these advantages.
+Added: We also depend upon our ability to attract and retain qualified personnel, obtain patent protection or otherwise develop proprietary products or processes and secure sufficient capital resources for the often substantial period between technological conception and commercial sale.
+Added: Large and established pharmaceutical companies are developing GLP-1 agonists or combinations with other incretin-mimetics, which compete in the same market as our product candidates.
+Added: These companies generally have greater experience and resources to support their research and development efforts, conduct testing and clinical trials, obtain regulatory approvals to market products, manufacture such products on a broad scale and market approved products.
+Added: These companies also have significantly greater research and marketing capabilities than we do and may also have products that have been approved or are in late stages of development and have collaborative arrangements in our target markets with leading companies and research institutions.
+Added: Established pharmaceutical companies may also invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that could make the products that we develop obsolete.
+Added: We also face competition from smaller companies who, like us, rely on investors to fund research and development and compete for co-development and licensing opportunities from large and established pharmaceutical companies.
+Added: Regarding the use of nimacimab to target peripheral inhibition of CB1 for the treatment of obesity and metabolic conditions, our direct competition includes monlunabant, a small molecule CB1 receptor inverse agonist.
+Added: Other companies are targeting proteins associated muscle preservation and growth with the aim of complementing the GLP-1 agonists by improving lean mass preservation.
+Added: While many of these drugs are in the same stage of development, they have a different and potentially more difficult regulatory path than nimacimab.
+Added: Based on the recent FDA guidance, companies who wish to receive marketing approval for lean mass preservation must obtain acceptance from the FDA as to the appropriate primary endpoints, while the FDA guidance for drugs approved for weight loss in the overweight and obese population remains unchanged and clearly defined.
Manufacturing
−Removed: We do not own or operate manufacturing facilities and we rely on third-party contract manufacturing organizations to supply Skye with drugs for pre-clinical and clinical studies.
−Removed: Nimacimab is a monoclonal antibody and we have developed a manufacturing process under current good manufacturing practice ("cGMP") to produce batches of drug substance and drug product for pre-clinical and clinical studies.
−Removed: Drug substance for nimacimab will be produced by a contract manufacturer through recombinant DNA technology utilizing genetically engineered host cells, upstream cell culture processes and downstream purification methods as required to manufacture the drug substance.
−Removed: Drug product will be produced by a contract manufacturer whereby nimacimab drug substance will be formulated and filled in to pre-filled syringes.
−Removed: SBI-100 Ophthalmic Emulsion
−Removed: Manufacturing of SBI-100 OE's active pharmaceutical ingredient, SBI-100, has been conducted in the United States by contract manufacturers under cGMP.
−Removed: Formulation and packaging of SBI-100 OE for nonclinical and clinical use is manufactured by contract manufacturers with necessary controlled substance licenses with appropriate local, state and federal government agencies to conduct research, manufacture and distribute controlled substances like THC.
+Added: We do not own or operate manufacturing facilities and we rely on third-party contract manufacturing organizations (“CMOs”) to supply nimacimab for our pre-clinical and clinical studies.
+Added: Nimacimab, a monoclonal antibody, is produced under current good manufacturing practices (“cGMP”) through recombinant DNA technology, leveraging established upstream cell culture processes and downstream purification methods.
+Added: The resulting drug substance is formulated and filled into pre-filled syringes by our third-party partners.
+Added: To meet anticipated clinical and commercial needs, we are making a substantial investment in our manufacturing infrastructure through these CMOs.
+Added: Key activities include:
+Added: • Formulation Optimization:
+Added: We are evaluating multiple formulations aimed at improving patient convenience.
+Added: • Process Optimization:
+Added: We continue to optimize our manufacturing to evaluate modifications to both our upstream and downstream processes to improve product yield.
+Added: The activities are aligned with our goals to establish a commercial manufacturing process that is reliable and repeatable at large commercial scales.
+Added: • Device Strategy:
+Added: We are exploring new delivery platforms for nimacimab, with a view towards improving patient experience and adherence in later-stage clinical studies and eventual commercial distribution.
+Added: We believe that our collaborative approach with leading CMOs and other partners involved in our chemistry, manufacturing and controls ("CMC") operations, positions us to reliably meet future clinical and commercial demand for nimacimab and further optimize its potential for the treatment of obesity, overweight, and related metabolic disorders.
Intellectual Property
−Removed: The success of most of our product candidates will depend in large part on our ability to:
−Removed: • Obtain and maintain patent and other legal protection for the proprietary technology, inventions and improvements we consider important to our business
−Removed: • Prosecute our patent applications and defend any issued patents we obtain
−Removed: • Preserve the confidentiality of our trade secrets
−Removed: • Operate without infringing the patents and proprietary rights of third parties.
−Removed: We intend to continue to seek patent protection for certain of our product candidates, drug delivery systems, molecular modifications, as well as other proprietary technologies and their uses by filing patent applications in the United States and other selected global territories.
−Removed: We intend for these patent applications to cover, where possible, claims for composition of matter, medical uses, processes for isolation and preparation, processes for delivery and formulations.
+Added: The success of most of our product candidates will depend in large part on our ability to, obtain and maintain patent and other legal protection for the proprietary technology, inventions and improvements we consider important to our business, prosecute our patent applications and defend any issued patents we obtain, preserve the confidentiality of our trade secrets, and operate without infringing the patents and proprietary rights of third parties.We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection intended to cover the compositions of matter of our product candidates, their methods of use, related technologies, and other inventions that are important to our business.
+Added: We employ a comprehensive approach to intellectual property protection and obtaining patent protection is not the only method that we utilize to protect our proprietary rights and technologies.
We also rely upon trade secrets and know-how and continuing technological innovation to develop and maintain our proprietary and intellectual property position.
1 unchanged sentence
The confidentiality agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through a relationship with a third party.
−Removed: The Company owns three granted U.S.
−Removed: patents, 32 granted foreign patents, and 25 pending US and foreign patent applications directed to the compositions of matter for the nimacimab antibody and molecular variants, and to methods of treatment and uses of nimacimab and its variants for treating a number of diseases responsive to the modulation of the CB1.
−Removed: The patents and applications, once granted, will expire between 2035 and 2036 and may be eligible for up to five years of extension (Hatch-Waxman).
−Removed: SBI-100 and SBI-100 OE
−Removed: As of the date of this Annual Report, we have licensed an invention from UM which include U.S.
−Removed: patents as well as a number of foreign counterparts, including the European Union, Japan, Canada and Australia.
−Removed: The patents that we license cover composition of matter and preparation of SBI-100, and their methods of use.
−Removed: The US patent for SBI-100 is expected to expire in 2029.
−Removed: Under our license agreement, UM retains ownership over the licensed patents and control over the maintenance and prosecution of the licensed patents and patent applications.
−Removed: Licensing and Other Agreements
−Removed: Skye wholly owns nimacimab.
−Removed: There are no in- or out-licensing arrangements, no contingent value rights and no royalties payable or due to Skye relating to this molecule.
−Removed: Under the terms of the securities purchase agreement (the "January PIPE SPA") entered into in connection with the January PIPE Financing, so long as the investors in the January PIPE Financing continue to beneficially own in the aggregate at least 40% of the securities issued in the January PIPE Financing (such securities, the "Closing Securities"), the Company may not transfer, license (other than in the ordinary course of business), encumber, or sell a royalty interest in any intellectual property relating to nimacimab unless Skye obtains the written consent of Qualified Investors that, together with their respective affiliates, beneficially own at least a majority of the then outstanding Closing Securities owned by the Qualified Investors and their respective affiliates.
−Removed: The term "Qualified Investors" means any investor that, together with its affiliates, continues to own at least 80% of the securities originally purchased by it under the January PIPE SPA.
−Removed: University of Mississippi granted Skye an exclusive license for all fields of use related to UM 5050 (referred to by Skye as SBI-100) and including, with the prior written consent of UM, the right to sublicense the intellectual property for UM 5050.
−Removed: All fields of use means no restrictions on use of the underlying inventions, including developing UM 5050 to treat any disease through any form of delivery under the license agreement.
−Removed: The license for SBI-100, a CB1 agonist, is expected to allow us to explore related uses for the active moiety of SBI-100.
−Removed: In 2022, after notifying the Australian Therapeutics Goods Administration through the Clinical Trial Notification scheme of our intent to initiate our Phase 1 clinical trial for SBI-100 OE, we triggered and paid the first milestone payment under our License Agreement for UM 5050 with UM.
−Removed: In 2023, we granted to Tautomer Bioscience an exclusive license to develop and commercialize SBI-100 as a novel suppository formulation for chronic intractable pain and other indications in South Africa and the rest of Africa.
−Removed: We have retained certain rights and options to obtain rights to the future use of new jointly developed intellectual property and other intellectual property owned or controlled by Tautomer Bioscience related to SBI-100.
+Added: As of March 19, 2025, we owned three granted U.S.
+Added: patents, 38 granted foreign patents, including granted patents in Europe, Japan, Korea and China, as well as other commercially relevant jurisdictions, and 16 pending U.S.
+Added: and foreign patent applications directed to the compositions of matter for the nimacimab antibody and molecular variants, and to methods of treatment and uses of nimacimab and its variants for treating a number of diseases responsive to the modulation of the CB1 receptor, including obesity and related metabolic conditions.
+Added: The patents, and, if issued, the patent(s) resulting from the pending patent applications will expire between 2035 and 2036, excluding any potential available patent term adjustment or patent term extension.
+Added: The use of nimacimab in therapeutic doses and methods for treating obesity and weight related comorbidities is further covered in an international (PCT) patent application owned by us and from which we expect to file U.S.
+Added: and other national-phase patent applications in commercially relevant jurisdictions.
+Added: If issued, the patent(s) resulting from the pending application have an expiration date of no earlier than 2045, excluding any potential patent term adjustment or patent term extension.
+Added: The use of nimacimab in a method of predicting whether a patient is at risk for developing Fast Progressing Renal Disease ("FPRD") and treating patients to avoid such risks is further covered in pending applications in the United States, Europe, Japan and Korea, as well as other commercially relevant jurisdictions.
+Added: These claims are directed towards methods of diagnosing FPRD and towards treatment of patients suffering from FPRD with nimacimab.
+Added: If issued, the patent(s) resulting from the pending application have an expiration date of no earlier than 2043, excluding any potential patent term adjustment or patent term extension.
Government Regulation
2 unchanged sentences
A failure to comply with such laws and regulations or prevail in any enforcement action or litigation related to noncompliance could have a material adverse impact on our business, financial condition and results of operations and could cause the market value of our common stock to decline.
−Removed: Food and Drug Administration (FDA)
−Removed: In the United States, pharmaceutical products are subject to extensive regulation by the FDA.
−Removed: The FDA regulates drugs under the Federal Food, Drug and Cosmetic Act ("FDCA") and its implementing regulations.
−Removed: The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.
−Removed: Failure to comply with the applicable U.S.
−Removed: requirements at any time during the product development process, approval process or after approval, may subject us to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.
−Removed: The process required by the FDA before a drug may be legally marketed in the United States, generally involves the following:
−Removed: • conduct of laboratory tests, animal studies and formulation studies in compliance with GLP regulations;
−Removed: • submission of an Investigational New Drug application ("IND") to the FDA , which must be found acceptable to proceed before clinical trials may begin;
−Removed: • approval and oversight of each study by an IRB before each clinical site may initiate the trial(s);
−Removed: • conduct of adequate and well-controlled clinical trials in accordance with good clinical practice ("GCP") requirements to establish the safety and efficacy of the proposed drug for each indication;
−Removed: • submission of an NDA to the FDA;
−Removed: • satisfactory development and completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMP requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;
−Removed: • satisfactory development and completion of an FDA BioResearch Monitoring (BIMO) inspection of the clinical study sites which participated in the studies supporting the NDA application;
−Removed: • FDA review and approval of marketing authorization application (NDA, BLA, etc).
−Removed: Nonclinical Studies
−Removed: Nonclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy.
−Removed: An IND sponsor must submit the results of the nonclinical tests, together with manufacturing information, analytical data and any available clinical data or literature, among other things, to the FDA as part of an IND.
−Removed: Some nonclinical testing may continue even after the IND is submitted.
−Removed: An IND generally becomes effective 30 days after receipt by the FDA unless, before that time, the FDA raises concerns or questions related to nonclinical or manufacturing documentation or one or more proposed clinical trials and places the IND on clinical hold.
−Removed: In such a case, the IND sponsor and the FDA work to resolve any outstanding concerns before the hold can be lifted and the clinical trial(s) can begin.
−Removed: As a result, submission of an IND does not always result in the FDA allowing clinical trials to commence.
−Removed: Clinical Trials
−Removed: Clinical trials involve the administration of the investigational new drug candidate to humans under the supervision of qualified investigators in accordance with GCP requirements.
+Added: Review and approval of drugs and biologics in the United States
+Added: In the United States, the Food and Drug Administration ("FDA") regulates drugs under the Federal Food, Drug and Cosmetic Act (the "FDCA"), and its implementing regulations, and regulates biologics under the FDCA, the Public Health Service Act (the "PHSA"), and their implementing regulations.
+Added: The process required by the FDA before new drug and biologic product candidates may be marketed in the United States generally involves the following:
+Added: • completion of nonclinical or preclinical laboratory tests and formulation studies conducted in accordance with Good Laboratory Practice regulations ("GLPs"), and other applicable regulations, which studies can include animal studies;
+Added: • submission to the FDA of an IND, which must become effective before human clinical trials may begin;
+Added: • approval by an independent institutional review board ("IRB"), or ethics committee at each clinical site before each trial may be initiated;
+Added: • performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice regulations ("GCPs") to evaluate the safety and effectiveness of a proposed drug candidate, and the safety, purity and potency of a proposed biological product candidate, for its intended use;
+Added: • preparation and submission to the FDA of a New Drug Application ("NDA"), for a drug or a Biologics License Application ("BLA") for a biologic, after completion of all pivotal trials;
+Added: • a determination by the FDA within 60 days of its receipt of an NDA or BLA to file the application for review;
+Added: • satisfactory completion of an FDA advisory committee review, if applicable;
+Added: • satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug or biologic is produced to assess compliance with current Good Manufacturing Practice requirements ("cGMPs"), to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
+Added: • satisfactory completion of potential inspection of selected clinical investigation sites to assess compliance with GCPs;
+Added: • FDA review and approval of the NDA or BLA to permit commercial marketing of the product for particular indications for use in the United States.
+Added: Once a product candidate is identified for development, it enters the preclinical testing stage.
+Added: Preclinical tests, which can include animal studies, include laboratory evaluations of product chemistry, toxicity and formulation.
+Added: An IND sponsor must submit, among other things, the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of an IND.
+Added: An IND is a request for authorization from the FDA to administer an investigational product to humans.
+Added: An IND will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the trial includes an efficacy evaluation.
+Added: Some preclinical testing may continue even after the IND is submitted.
+Added: The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, places the IND on a clinical hold.
+Added: In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.
+Added: Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance with FDA requirements, in which case clinical trials may not begin or continue until the FDA notifies the sponsor that the hold has been lifted.
+Added: The FDA may also place a trial on a partial clinical hold.
+Added: A partial clinical hold is a delay or suspension of only part of the clinical work requested or ongoing under the IND.
+Added: No more than 30 days after imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold.
+Added: Following issuance of a clinical hold or partial clinical hold, an investigation (or full investigation in the case of a partial clinical hold) may only begin or resume after the FDA has notified the sponsor that the investigation may proceed.
+Added: Clinical trials involve the administration of the investigational product to humans under the supervision of qualified investigators in accordance with GCP requirements.
This includes the requirement that all research subjects/patients provide their informed consent in writing for their participation in any clinical trial.
−Removed: Clinical trials are conducted under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated.
−Removed: A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.
−Removed: In addition, an IRB, either central or at each institution participating in the clinical trial must review and approve the plan for any clinical trial before the study commences at a site.
−Removed: Information about certain clinical trials must be submitted within specific timeframes to the NIH for public dissemination on the www.clinicaltrials.gov website.
−Removed: Before marketing authorization, human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:
−Removed: The drug is initially introduced into a small number of healthy human subjects or patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness.
−Removed: The drug is administered to a specific patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy and safety of the product for specific diseases and to determine dosage tolerance and optimal dosage.
−Removed: The drug is administered to the established patient population expected to benefit based upon the risk/benefit profile.
+Added: Clinical trials must be conducted under protocols detailing, among other things, the objectives of the trial, dosing procedures, subject selection and exclusion criteria and the safety and effectiveness criteria to be evaluated.
+Added: Each protocol for each clinical trial must be submitted to the FDA as part of the IND, and a separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.
+Added: While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs or biologics, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.
+Added: The sponsor also must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information.
+Added: Furthermore, an independent IRB or ethics committee at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations.
+Added: The FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.
+Added: Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the investigational product has been associated with unexpected serious harm to patients.
+Added: In addition, some clinical trials are overseen by an independent group of qualified experts organized by the sponsor, known as a data safety monitoring board or committee.
+Added: Depending on its charter, this group may determine whether a trial may move forward at designated check points based on access to certain data from the trial.
+Added: There are also requirements governing the registration of certain clinical trials and reporting of clinical trial results to public registries, including clinicaltrials.gov.
+Added: Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:
+Added: The product candidate is initially introduced into healthy human subjects or, in certain indications, patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine maximal dosage.
+Added: The product candidate is administered to a limited patient population with a specified disease or condition to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy and safety of the product candidate for specific targeted diseases, and to determine dosage tolerance and optimal dosage.
+Added: The product candidate is administered to the established patient population expected to benefit based upon the risk/benefit profile.
Generally, this phase of studies are conducted at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.
−Removed: Reports detailing the results of the clinical trials must be submitted at least annually to the FDA and IND safety reports are submitted more frequently if serious adverse events possibly related to the investigational product occur.
−Removed: Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all.
−Removed: Furthermore, the FDA or the Sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk or due to a business decision.
−Removed: Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.
−Removed: Marketing Approval
−Removed: Assuming successful completion of the required clinical testing, the results of the nonclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an marketing authorization application requesting approval to market the product for one or more indications.
−Removed: For drug products, or biologic products under the review of Center for Drug Evaluation and Research (CDER), the marketing authorization application is an NDA or a BLA, and submission is subject to a substantial application user fee.
−Removed: Under the Prescription Drug User Fee Act ("PDUFA") commitments that are currently in effect, the FDA has a goal of reviewing and responding to a submission within ten months from the date of “filing” of a standard NDA for a new molecular entity.
−Removed: This review typically takes at least twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision.
−Removed: However, if issues arise during the review, the FDA may request additional information and the review period may be extended to permit the applicant to provide and the FDA to review that information, which may significantly extend this time period.
−Removed: The process for review and issuance of a license for a BLA is similar to the NDA review path..
−Removed: In addition, under the Pediatric Research Equity Act of 2003 ("PREA"), as amended and reauthorized, certain marketing authorizations or supplements to marketing authorizations must contain data that is adequate to assess the safety and effectiveness of the approved product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
−Removed: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
−Removed: The FDA also may require submission of a Risk Evaluation and Mitigation Strategy (REMS) plan to ensure that the benefits of the drug outweigh its risks.
−Removed: The REMS plan could include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.
−Removed: The FDA conducts a preliminary review of all pending marketing authorizations within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review.
−Removed: The FDA may refuse to file the application and request additional information rather than accept marketing authorization application for filing.
−Removed: In this event, the application must be resubmitted with the additional information requested.
−Removed: The resubmitted application is also subject to review before the FDA accepts it for filing.
−Removed: Once the submission is accepted for filing, the FDA begins an in-depth substantive review.
−Removed: The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.
−Removed: The FDA may refer an application for a novel product and/or first-in-class product to an advisory committee.
+Added: Post-approval trials, sometimes referred to as Phase 4 studies, may be conducted after initial regulatory approval.
+Added: These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
+Added: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA or BLA.
+Added: Concurrent with clinical trials, companies often complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate and finalize a process for manufacturing the product in commercial quantities in accordance with cGMPs.
+Added: The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final product.
+Added: In addition, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.
+Added: NDA and BLA review and approval process
+Added: Assuming successful completion of all required testing in accordance with applicable regulatory requirements, the results of the product development, including among other things, results from nonclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA or BLA requesting approval to market the product for one or more indications.
+Added: The NDA or BLA must include all relevant data available from preclinical and clinical studies, including negative or ambiguous results as well as positive findings, among other things.
+Added: The submission of an NDA or BLA requires payment of a substantial user fee to the FDA, and the sponsor of an approved NDA or BLA is also subject to an annual program fee.
+Added: A waiver of certain user fees may be obtained under certain limited circumstances.
+Added: The FDA conducts a preliminary review of all NDAs and BLAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review.
+Added: The FDA may refuse to file any NDA or BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information.
+Added: In this event, the NDA or BLA must be resubmitted with the additional information requested before FDA will review the application.
+Added: Once filed, the FDA reviews a BLA to determine, among other things, whether the product is safe, pure and potent for its intended use, and an NDA to determine, among other things, whether the drug is safe and effective for its intended use.
+Added: As part of the NDA and BLA review, the FDA also evaluates whether the manufacturing of the products is cGMP-compliant to assure and preserve the product's identity, strength, quality and purity.
+Added: Under the Prescription Drug User Fee Act ("PDUFA"), guidelines that are currently in effect, the FDA has a goal of reviewing and responding to a standard submission within ten months from the date of the“filing” of an original NDA or BLA to review and act on the submission.
+Added: This review typically takes twelve months from the date the NDA or BLA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision.
+Added: The FDA does not always meet its PDUFA goal dates, however, and the review process can be significantly extended by the FDA requests for additional information or clarification, the applicant's submission of additional information, or other reasons.
+Added: The FDA may refer an application for a novel biologic or drug to an advisory committee.
The FDA may also refer to the advisory committee certain scientific questions raised by an application.
−Removed: An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions.
+Added: An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and may provide a recommendation as to whether the application should be approved and under what conditions.
The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
−Removed: Before approving a marketing authorization application, the FDA typically will inspect the facility or facilities where the product is manufactured.
−Removed: The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
−Removed: Additionally, within the review period and before approving a marketing authorization application, the FDA will likely inspect one or more clinical trial sites to assure compliance with GCP requirements.
−Removed: The testing and approval process for an NDA/BLA requires substantial time, effort and financial resources, and each may take several years to complete.
−Removed: Data obtained from nonclinical and clinical testing are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval.
−Removed: The FDA may not grant approval on a timely basis, or at all.
−Removed: After evaluating the NDA/BLA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a complete response letter.
−Removed: A complete response letter generally contains a statement of specific conditions that must be met to secure final approval of the NDA/BLA and may require additional clinical or nonclinical testing in order for the FDA to reconsider the application.
+Added: During its review of an NDA or BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.
+Added: Additionally, within the review period and before approving a BLA or NDA, the FDA will likely inspect one or more clinical trial sites to assure compliance with GCPs and the integrity of the clinical data submitted.
+Added: After evaluating the NDA or BLA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a complete response letter ("CRL").
+Added: A CRL generally contains a statement of specific conditions that must be met to secure final approval of the NDA or BLA and may require additional clinical or nonclinical testing in order for the FDA to reconsider the application.
Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
−Removed: If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter for the NDA/BLA.
+Added: If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter for the NDA or BLA.
An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
−Removed: For some products, such as our product candidates where abuse potential is a possibility, an additional step of Drug Enforcement Administration (DEA) review and scheduling is required.
+Added: If the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product's labeling;
+Added: require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the product's safety or effectiveness or safety, purity, and potency after approval;
+Added: require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including a risk evaluation and mitigation strategy ("REMS"), which can materially affect the potential market and profitability of the product.
+Added: If the FDA concludes a REMS is needed, the sponsor of the NDA or BLA must submit a proposed REMS in connection with the application.
+Added: The FDA will not approve the application without an approved REMS, if one is required.
+Added: The REMS could include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.
+Added: Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of commercial products.
+Added: In addition, the Pediatric Research Equity Act ("PREA"), requires a sponsor to conduct pediatric clinical trials for most biologics and drugs.
+Added: Under PREA, original NDAs and BLAs (and certain supplements) for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration must contain a pediatric assessment or reports on the molecularly targeted pediatric cancer investigation, unless the sponsor has received a deferral or waiver or an exception applies.
+Added: The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and support dosing and administration for each pediatric subpopulation for which the product is deemed safe and effective.
+Added: The sponsor may request, or the FDA may grant, a deferral of pediatric clinical trials for some or all of the pediatric subpopulations.
+Added: A deferral may be granted for several reasons, including a finding that the drug or biologic is ready for approval for use in adults before pediatric clinical trials are complete or that additional data needs to be collected before the pediatric clinical trial begins.
+Added: Expedited development and review programs
+Added: The FDA has a number of programs intended to expedite the development or review of a marketing application for an investigational product.
+Added: For example, the fast track designation program is intended to expedite or facilitate the process for developing and reviewing product candidates that meet certain criteria.
+Added: Specifically, investigational drugs and biologics are eligible for fast track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.
+Added: The sponsor of a fast track product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once a marketing application is submitted, the application may be eligible for priority review.
+Added: With regard to a fast track product candidate, the FDA may consider for review sections of the application on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the applications and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA or BLA.
+Added: A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.
+Added: A product candidate can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
+Added: The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.
+Added: Any product candidate submitted to the FDA for approval, including a product candidate with a fast track designation or breakthrough designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.
+Added: An NDA or BLA is eligible for priority review if the product candidate is designed to treat a serious condition, and if approved, would provide a significant improvement in safety or efficacy compared to available therapies.
+Added: The FDA will attempt to direct additional resources to the evaluation of an NDA or BLA designated for priority review in an effort to facilitate the review.
+Added: The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of original NDAs or BLAs under its current PDUFA review goals.
+Added: In addition, a product candidate may be eligible for accelerated approval.
+Added: A product candidate intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
+Added: As a condition of approval, the FDA generally requires that a sponsor of a biologic receiving accelerated approval perform adequate and well-controlled confirmatory clinical trials, and may require that such confirmatory trials be underway prior to granting accelerated approval.
+Added: Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required confirmatory trials in a timely manner or if such trials fail to verify the predicted clinical benefit.
+Added: In addition, the FDA currently requires as a condition of accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.
+Added: Fast track designation, breakthrough therapy designation, priority review, and accelerated approval do not change the standards for approval, but may expedite the development or approval process.
+Added: Even if a product candidate qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.
Post-Approval Requirements
−Removed: Products manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion, and reporting of adverse experiences with the product.
+Added: Drugs and biologics manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion, and reporting of adverse experiences with the product.
After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to FDA review and approval prior to implementation.
−Removed: There also are continuing annual product fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
−Removed: The FDA may impose a number of post-approval requirements as a condition of approval of an NDA/BLA.
−Removed: For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.
+Added: There also are continuing annual program fees for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.
9 unchanged sentences
• fines, warning letters or holds on post-approval clinical trials;
−Removed: • refusal of the FDA to approve pending NDAs/BLAs or supplements to approved NDAs/BLAs, or suspension or revocation of product licenses or approvals;
−Removed: • product seizure or detention, or refusal to permit the import or export of products; or
+Added: • refusal of the FDA to approve pending NDAs, BLAs or supplements to approved NDAs or BLAs, or suspension or revocation of product licenses or approvals;
+Added: • product seizure or detention, or refusal to permit the import or export of products;
+Added: • consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;
+Added: • mandated modification of promotional materials and labeling and the issuance of corrective information;
+Added: • issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product;
• injunctions or the imposition of civil or criminal penalties.
−Removed: The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.
−Removed: Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label.
+Added: In addition, the FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.
+Added: Drugs and biologics may be promoted only for the approved indications and in accordance with the provisions of the approved label.
The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.
+Added: Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties.
+Added: Physicians may legally prescribe commercially-available products for uses that are not described in the product's labeling and that differ from those tested by use and approved by the FDA.
+Added: Such off-label uses are common across medical specialties.
+Added: Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.
+Added: The FDA does not regulate the behavior of such physicians in their choice of treatments.
+Added: The FDA does, however, restrict manufacturers' communications on the subject of off-label use of their products.
In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act ("PDMA"), which regulates the distribution of drugs and drug samples at the federal level and sets minimum standards for the registration and regulation of drug distributors by the states.
Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.
−Removed: Exclusivity and Approval of Competing Products
−Removed: Hatch Waxman Act
−Removed: Section 505 of the FDCA describes three types of marketing applications that may be submitted to the FDA to request marketing authorization for a new drug.
−Removed: A Section 505(b)(1) NDA is an application that contains full reports of investigations of safety and efficacy.
−Removed: A 505(b)(2) NDA is an application that contains full reports of investigations of safety and efficacy but where at least some of the information required for approval comes from investigations that were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.
−Removed: This regulatory pathway enables the applicant to rely, in part, on the FDA’s prior findings of safety and efficacy for an existing product, or published literature, in support of its application.
−Removed: Section 505(j) establishes an abbreviated approval process for a generic version of approved drug products through the submission of an Abbreviated New Drug Application ("ANDA").
−Removed: An ANDA provides for marketing of a generic drug product that has the same active ingredients, dosage form, strength, route of administration, labeling, performance characteristics and intended use, among other things, to a previously approved product.
−Removed: ANDAs are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and efficacy.
−Removed: Instead, generic applicants must scientifically demonstrate that their product is bioequivalent to, or performs in the same manner as, the innovator drug through in vitro, in vivo, or other testing.
−Removed: The generic version must deliver the same amount of active ingredients into a subject’s bloodstream in the same amount of time as the innovator drug and can often be substituted by pharmacists under prescriptions written for the reference listed drug.
−Removed: Hatch Waxman Patent Exclusivity
−Removed: In seeking approval for a drug through a NDA, applicants are required to list with the FDA each patent with claims that cover the applicant’s product or a method of using the product.
−Removed: Upon approval of a drug, each of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book.
−Removed: Drugs listed in the Orange Book can, in turn, be cited by potential competitors in support of approval of an ANDA or 505(b)(2) NDA.
−Removed: The ANDA or 505(b)(2) NDA applicant is required to certify to the FDA concerning any patents listed for the approved product in the FDA’s Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval.
−Removed: Specifically, the applicant must certify with respect to each patent that:
−Removed: • the required patent information has not been filed;
−Removed: • the listed patent has expired;
−Removed: • the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or
−Removed: • the listed patent is invalid, unenforceable or will not be infringed by the new product.
−Removed: Generally, the ANDA or 505(b)(2) NDA cannot be approved until all listed patents have expired, except when the ANDA or 505(b)(2) NDA applicant challenges a listed drug.
−Removed: A certification that the proposed product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification.
−Removed: If the applicant does not challenge the listed patents or indicate that it is not seeking approval of a patented method of use, the ANDA or 505(b)(2) NDA application will not be approved until all the listed patents claiming the referenced product have expired.
−Removed: If the ANDA or 505(b)(2) NDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders once the application has been accepted for filing by the FDA.
−Removed: The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification.
−Removed: The filing of a patent infringement lawsuit within 45 days after the receipt of notice of the Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) NDA until the earlier of 30 months, expiration of the patent, settlement of the lawsuit or a decision in the infringement case that is favorable to the ANDA applicant.
−Removed: Hatch Waxman Non-Patent Exclusivity
−Removed: In addition to patent issues, market and data exclusivity provisions under the FDCA can delay the submission or the approval of certain applications for competing products.
−Removed: The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to gain approval of a NDA for a new chemical entity.
−Removed: A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the activity of the drug substance.
−Removed: During the exclusivity period, the FDA may not accept for review an ANDA or a 505(b)(2) NDA submitted by another company that references the previously approved drug.
−Removed: However, an ANDA or 505(b)(2) NDA may be submitted after four years if it contains a Paragraph IV certification of patent invalidity or non-infringement.
−Removed: The FDCA also provides three years of marketing exclusivity for a NDA, 505(b)(2) NDA, or supplement to an existing NDA or 505(b)(2) NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant, are deemed by the FDA to be essential to the approval of the application or supplement.
−Removed: Three-year exclusivity may be awarded for changes to a previously approved drug product, such as new indications, dosages, strengths or dosage forms of an existing drug.
−Removed: This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and, as a general matter, does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for other versions of a drug.
−Removed: Five-year and three-year exclusivity will not delay the submission or approval of a full NDA;
−Removed: however, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.
−Removed: Orphan Drug Designation and Exclusivity
−Removed: Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug intended to treat a disease or condition that affects populations of fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product.
−Removed: Orphan designation must be requested before submitting a NDA.
−Removed: Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.
−Removed: If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan drug exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities.
−Removed: The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding towards clinical trial costs, tax advantages and user-fee waivers.
−Removed: Competitors, however, may receive approval of different products for the same indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication than that for which the orphan product has exclusivity.
−Removed: Regulation of Controlled Substances:
−Removed: Drug Enforcement Administration (DEA) Regulation
−Removed: Certain cannabinoids are regulated as “controlled substances” as defined in the Controlled Substances Act (the “CSA”), which establishes registration, security, recordkeeping, reporting, storage, distribution and other requirements administered by the DEA.
−Removed: The DEA is concerned with the control of handlers of controlled substances (and with the equipment and raw materials used in their manufacture and packaging) of controlled substances in order to prevent loss and diversion into illicit channels of commerce.
−Removed: The DEA regulates controlled substances as Schedule I, II, III, IV or V substances.
−Removed: Schedule I substances by definition have no established medicinal use and may not be marketed or sold in the United States.
−Removed: A pharmaceutical product may be listed as Schedule II, III, IV or V, with Schedule II substances considered to present the highest risk of abuse and Schedule V substances the lowest relative risk of abuse among such substances.
−Removed: Certain cannabinoids are listed by the DEA as Schedule I controlled substances under the CSA.
−Removed: Consequently, their manufacture, shipment, storage, sale and use are subject to a high degree of regulation.
−Removed: Annual registration is required for any facility that manufactures, distributes, dispenses, imports or exports any controlled substance.
−Removed: The registration is specific to the particular location, activity and controlled substance schedule.
−Removed: For example, separate registrations are needed for import and manufacturing, and each registration will specify which schedules of controlled substances are authorized.
−Removed: The DEA typically inspects a facility to review its security measures prior to issuing a registration.
−Removed: Security requirements vary by controlled substance schedule, with the most stringent requirements applying to Schedule I and Schedule II substances.
−Removed: Required security measures include background checks on employees and physical control of inventory through measures such as cages, surveillance cameras and inventory reconciliations.
−Removed: The registered entity must maintain records for the handling of all controlled substances and must make periodic reports to the DEA.
−Removed: These include, for example, distribution reports for Schedule I and II controlled substances, Schedule III substances that are narcotics, and other designated substances.
−Removed: The registered entity must also report thefts or losses of any controlled substance and obtain authorization to destroy any controlled substance.
−Removed: In addition, special authorization and notification requirements apply to imports and exports.
−Removed: In addition, a DEA quota system controls and limits the availability and production of controlled substances in Schedule I or II.
−Removed: Distributions of any Schedule I or II controlled substance must also be accompanied by special order forms, with copies provided to the DEA.
−Removed: The DEA may adjust aggregate production quotas and individual production and procurement quotas from time to time during the year, although the DEA has substantial discretion in whether or not to make such adjustments.
−Removed: To meet its responsibilities, the DEA conducts periodic inspections of registered establishments that handle controlled substances.
−Removed: In the event of non-compliance, the DEA may seek civil penalties, refuse to renew necessary registrations, or initiate proceedings to revoke those registrations.
−Removed: In certain circumstances, violations could lead to criminal prosecution.
−Removed: SBI-100 remains a Schedule I controlled substance, pending a request to re-schedule SBI-100 after marketing authorization by the FDA or execution of the August 23, 2023 request by the Assistant HHS secretary to DEA reschedule cannabis to Schedule 3.
+Added: Combination products
+Added: Certain of our product candidates, may be comprised of components, such as drug components and biologic components, that would normally be regulated under different regulatory pathways, regulatory authorities, and frequently by different centers at the FDA.
+Added: In addition, our injectable product candidates are being developed together with an injector device, which will render them combination products with a device component.
+Added: Specifically, under regulations issued by the FDA, a combination product may include:
+Added: • a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
+Added: • two or more separate products packaged together in a single package or as a unit and composed of drug and device products, device and biological products, biological and drug products or biological products, drug products and device products;
+Added: • a drug, or device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an individually specified drug, or device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product, the labeling of the other product would need to be updated (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose);
+Added: • an investigational drug, or device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
+Added: Under the FDCA and its implementing regulations, the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product.
+Added: The designation of a lead center generally eliminates the need to receive approvals from more than one FDA center for combination products, although it does not preclude consultations by the lead center with another FDA center.
+Added: The determination of which center will be the lead center is based on the “primary mode of action” of the combination product.
+Added: The FDA has established an Office of Combination Products to address issues regarding combination products and provide more certainty to the regulatory review process.
+Added: This office is responsible for developing guidance and regulations to clarify the regulation of combination products, and for assigning the FDA center that will have primary jurisdiction for review of a combination product where the jurisdiction is unclear or in dispute.
+Added: Following approval of a combination product, each component of a combination product retains its regulatory status (as a biologic, drug or device, for example) and is subject to the requirements established by the FDA for that type of component.
+Added: A combination product candidate with a biologic primary mode of action, as we expect our combination products to be regulated, generally would be reviewed and approved pursuant to a BLA.
+Added: In reviewing the BLA for such a product, however, FDA reviewers in the biologic center could consult with their counterparts in the drug or device centers to ensure that the drug and device component of the combination product candidate, as applicable, met all requirements applicable to its category.
+Added: In addition, under FDA regulations, combination products are subject to the cGMP requirements applicable to each component within the combination.
+Added: We believe our combination product candidates are likely to be reviewed by the FDA under a BLA.
+Added: Patent Term Restoration and Marketing Exclusivity
+Added: Depending upon the timing, duration and specifics of FDA approval of our current product candidates and any future product candidates, some of our U.S.
+Added: patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984 (commonly referred to as the "Hatch Waxman Amendments").
+Added: The Hatch Waxman Amendments permit restoration of the patent term of up to five years as compensation for patent term lost during product development and FDA regulatory review process.
+Added: Patent term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.
+Added: The patent term restoration period is generally one half the time between the effective date of an IND and the submission date of a BLA plus the time between the submission date of a BLA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence.
+Added: Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.
+Added: Patent and Trademark Office ("PTO"), in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.
+Added: In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA.
+Added: An abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA licensed reference biological product was created by the Biologics Price Competition and Innovation Act of 2009.
+Added: This amendment to the PHSA, in part, attempts to minimize duplicative testing.
+Added: Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the product and the reference product in terms of safety, purity and potency, can be shown through analytical studies, animal studies and a clinical trial or trials.
+Added: Interchangeability requires that a biological product be biosimilar to the reference product and that the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times to an individual, that the product and the reference product may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological product without such alternation or switch.
+Added: A reference biological product is granted 12 years of data exclusivity from the time of first licensure of the product, and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product.
+Added: “First licensure” typically means the initial date the particular product at issue was licensed in the U.S.
+Added: Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the structure of the biological product that does not result in a change in safety, purity, or potency.
+Added: Pediatric exclusivity is another type of regulatory market exclusivity in the U.S.
+Added: Pediatric exclusivity, if granted, adds six months to existing regulatory exclusivity periods for all formulations, dosage forms, and indications of the biologic.
+Added: This six-month exclusivity may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA issued “Written Request” for such a trial.
Federal and State Fraud and Abuse, Data Privacy and Security Laws and Regulations
10 unchanged sentences
A claim includes “any request or demand” for money or property presented to the U.S.
−Removed: A violation of the federal Anti-Kickback Statute also constitutes a false or fraudulent claim for purposes of the civil False Claims Act.
+Added: A violation of the federal Anti-Kickback Statute may also constitute a false or fraudulent claim for purposes of the civil False Claims Act.
Several pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.
17 unchanged sentences
Coverage and reimbursement
−Removed: Significant uncertainty exists as to the coverage and reimbursement status of any drug products for which we obtain regulatory approval.
−Removed: In the United States and markets in other countries, sales of any products for which we receive regulatory approval for commercial sale will depend, in part, on the availability of coverage and reimbursement from third party payors.
−Removed: Third party payors include government authorities, managed care providers, private health insurers and other organizations.
−Removed: The process for determining whether a payor will provide coverage for a drug product may be separate from the process for setting the reimbursement rate that the payor will pay for the drug product.
−Removed: Third party payors may limit coverage to specific drug products on an approved list, or formulary, which might not include all of the FDA-approved drugs for a particular indication.
−Removed: A decision by a third party payor not to cover our products, if approved, could reduce physician utilization of our products once approved and have a material adverse effect on our sales, results of operations and financial condition.
−Removed: Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.
−Removed: Adequate third party reimbursement may not be available to enable us to maintain price levels sufficient to realize an appropriate return on our investment in product development.
−Removed: In addition, the U.S.
−Removed: government, state legislatures and foreign governments have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products.
−Removed: By way of example, in the United States, the ACA contains provisions that may reduce the profitability of drug products, including, for example, increased rebates for drugs sold to Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries, and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.
−Removed: In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed bills designed to, among other things, reform government program reimbursement methodologies.
−Removed: For example, on August 16, 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law.
+Added: Successful sales of our product candidates in the U.S.
+Added: market, if approved, will depend, in part, on the extent to which our drugs will be eligible for adequate reimbursement by third-party payors, such as government health programs, such as Medicare and Medicaid, and private health insurance (including managed care plans).
+Added: Patients generally rely on such third-party payors to reimburse all or part of the costs associated with their prescriptions and therefore adequate coverage and reimbursement from such third-party payors are critical to new and ongoing product acceptance.
+Added: Coverage and reimbursement policies for drug products can differ significantly from payor to payor as there is no uniform policy of coverage and reimbursement for drug products among third-party payors in the United States.
+Added: Even if coverage is provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient to realize a return on our investment.
+Added: There may be significant delays in obtaining coverage and reimbursement as the process of determining coverage and reimbursement is often time consuming and costly.
+Added: Further, third-party payors are increasingly reducing reimbursements for medical drugs and services and implementing measures to control utilization of drugs such as requiring prior authorization or step therapy for coverage, among other things.
+Added: For products administered under the supervision of a physician or other healthcare professional, obtaining coverage and adequate reimbursement may be particularly difficult because of the higher prices often associated with such drugs.
+Added: Additionally, separate reimbursement for the product itself or the treatment or procedure in which the product is used or delivered may not be available, which may impact physician utilization.
+Added: Additionally, the containment of healthcare costs has become a priority of federal and state governments, and the prices of drugs have been a focus in this effort.
+Added: government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic drugs.
+Added: Adoption or expansion of price controls and cost-containment measures could further limit our net revenue and results.
+Added: Decreases in third-party payor reimbursement for our product candidates, if approved, or a decision by a third-party payor to not cover our product candidates could have a material adverse effect on our sales, results of operations and financial condition.
+Added: General regulatory cost control measures may also affect reimbursement for our products.
+Added: If we obtain approval to market a product candidate in the United States, we may be subject to spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs and/or any significant taxes or fees.
+Added: There is also significant uncertainty related to the insurance coverage and reimbursement of newly approved products and coverage may be more limited than the purposes for which the medicine is approved by the FDA or comparable foreign regulatory authorities.
+Added: In the United States, CMS, an agency within the DHHS, determines whether and to what extent a new medicine will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.
+Added: Factors payors consider in determining reimbursement are based on whether the product is:
+Added: • a covered benefit under its health plan;
+Added: • safe, effective and medically necessary;
+Added: • appropriate for the specific patient;
+Added: • cost-effective;
+Added: • neither experimental nor investigational.
+Added: Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.
+Added: Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products.
+Added: We cannot be sure that reimbursement will be available for any product candidate that we commercialize and, if reimbursement is available, the level of reimbursement.
+Added: In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price and best price.
+Added: Penalties may apply in some cases when such metrics are not submitted accurately and timely.
+Added: Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs.
+Added: Healthcare reform
+Added: government, state legislatures, and foreign governments have shown significant interest in implementing cost containment programs to limit the growth healthcare costs, including price-controls, restrictions on reimbursement, and requirements for substitution of generic products for branded prescription drugs.
+Added: For example, in March 2010, the Affordable Care Act, or ACA, was enacted in the United States and substantially changed the way healthcare is financed by both the government and private insurers.
+Added: The ACA contains provisions that may reduce the profitability of drug products.
+Added: Among other things, the ACA established an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;
+Added: extended manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations;
+Added: expanded eligibility criteria for Medicaid programs;
+Added: expanded the entities eligible for discounts under the 340B drug pricing program;
+Added: and increased the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program.
+Added: Since its enactment, there have been executive, judicial and Congressional challenges to certain aspects of the ACA.
+Added: On June 17, 2021, the U.S.
+Added: Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.
+Added: Thus, the ACA will remain in effect in its current form.
+Added: In addition, other legislative changes have been proposed and adopted since the ACA was enacted.
+Added: On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminated the statutory Medicaid drug rebate cap, for single source and innovator multiple source drugs, beginning January 1, 2024.
+Added: The rebate was previously capped at 100% of a drug’s average manufacturer price.
+Added: Additionally, there has been heightened governmental scrutiny in the United States of pharmaceutical pricing practices in light of the rising cost of prescription drugs and biologics.
+Added: Such scrutiny has resulted in several recent Congressional inquiries, presidential executive orders and proposed and enacted federal and state legislation and regulations designed to, among other things, reduce the cost of prescription drugs under Medicare, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.
+Added: Most recently, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022, or IRA, into law.
Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), with prices that can be negotiated subject to a cap;
imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023);
−Removed: and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025).
−Removed: The IRA permits the Secretary of the Department of Health and Human Services (HHS) to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
−Removed: For that and other reasons, it is currently unclear how the IRA will be effectuated.
−Removed: Additional state and federal healthcare reform measures may be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our products once approved or additional pricing pressures.
+Added: and replaces the Part D coverage gap discount program with a new discounting program (effective January 1, 2025).
+Added: The IRA permits the Secretary of the Department of Health and Human Services, or HHS, to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
+Added: At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.
+Added: In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.
+Added: Existing healthcare reform measures, as well as the implementation of additional cost containment measures or other reforms may prevent us from being able to generate revenue, attain profitability or commercialize our product candidates, if approved.
Foreign Regulation
In order to market any product outside of the United States, we must comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials and commercial sales and distribution of our products.
−Removed: While our management and many of our consultants are familiar with and have been responsible for gaining marketing approval in many countries, we have not reviewed the specific regulations in countries outside of the United States, as it pertains to cannabinoids.
−Removed: Additional Regulation
−Removed: We are a reporting company with the Securities and Exchange Commission (the "SEC"), and, therefore, subject to the information and reporting requirements of the Exchange Act of 1934, as amended (the "Exchange Act") and other federal securities laws, and the compliance obligations of the Sarbanes-Oxley Act of 2002 ("Sarbanes-Oxley Act").
−Removed: In addition, our financial reporting is subject to United States Generally Accepted Accounting Principles ("GAAP"), and GAAP is subject to change over time.
−Removed: We are also subject to federal, state and local laws and regulations applied to businesses generally.
−Removed: We believe that we are in conformity with all applicable laws in all relevant jurisdictions.
+Added: While our management and many of our consultants are familiar with and have been responsible for gaining marketing approval in many countries, we have not reviewed the specific regulations in countries outside of the United States.
Employees & Human Capital Resources
−Removed: As of the date of this Annual Report, we have a total of eleven full-time employees.
+Added: As of March 19, 2025, we have a total of 16 full-time employees, four of whom hold a Ph.D or MD degree.
None of our employees are represented by a labor union or covered by a collective bargaining agreement.
−Removed: The majority of our employees work remotely, which we believe has provided us with greater access to qualified personnel around the United States.
−Removed: At the Company, we strive to foster collaborative, communicative and flexible environment so that our employees feel supported in the workplace.
+Added: We consider our relationships with our employees to be good.
+Added: In addition, we rely on a number of consultants to assist us.
+Added: We strive to foster collaborative, communicative and flexible environment so that our employees feel supported in the workplace.
+Added: Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and new employees.
+Added: The principal purposes of our benefits and incentive plans are to attract, retain and motivate our employees, consultants and directors through the granting of stock-based compensation awards, providing competitive benefits packages and providing cash-based performance bonuses, in order to increase stockholder value and the success of our company by motivating such individuals to perform to the best of their abilities and achieve our objectives.
We anticipate that we will need to hire additional employees or independent contractors for our continued development efforts.
4 unchanged sentences
Our telephone number is (858) 410-0266.
−Removed: Our Internet website, which is located at http://www.skyebioscience.com, describes our company and our management and provides information about our technology and products.
+Added: Our website, which is located at http://www.skyebioscience.com, describes our company and our management and provides information about our technology and product candidates.
Information contained on our website is not incorporated by reference into, and should not be considered a part of this Annual Report.
Available Information
−Removed: Our filings, including Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments submitted under Sections 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are accessible at no cost on our company website promptly after submission to the Securities and Exchange Commission ("SEC").
+Added: Our filings, including Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and amendments submitted under Sections 13(a) or 15(d) of the Exchange Act are accessible at no cost on our company website at www.skyebioscience.com as soon as reasonably practicable after we electronically file such material with or furnish it to the Securities and Exchange Commission ("SEC").
Additionally, these documents are retrievable from the SEC's website ( www.sec.gov ).
−Removed: Corporate governance materials, such as our guidelines and committee charters, are also accessible on our investor relations webpage under "Corporate Governance." It's important to note that the content of our websites is not intended for inclusion by reference in our filings with the SEC, and any website references serve as inactive textual mentions only.
+Added: We use our investor relations website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD.
+Added: Investors should monitor such website, in addition to our press releases, SEC filings and public conference calls and webcasts.
+Added: Information relating to our corporate governance materials, such as our corporate governance guidelines and committee charters, are also accessible on our investor relations webpage under "Corporate Governance." It's important to note that the content of our websites is not intended for inclusion by reference in our filings with the SEC, and any website references serve as inactive textual mentions only.
Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.