Pramlintide Research & Studies

Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.

Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycemia, glycemic hypervariability, and an increased risk of microvascular complications. However, pramlintide as an adjunct to insulin therapy enhances glucagon suppression and thereby offers improved glycemic control. Clinical studies have shown that pramlintide improves glycemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of pramlintide are well reported, there still exists a high patient resistance for the therapy, as separate injections for pramlintide and insulin must be administered. Although marketed insulin formulations generally demonstrate a peak action in 60-90 minutes, pramlintide elicits its peak concentration at around 20-30 minutes after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone, and lipids have been employed. Also, approaches like noncovalent conjugation, polyelectrolyte complexation, and use of amphiphilic excipients for codelivery of insulin and pramlintide have been explored to address the issues with pramlintide delivery and improve patient adherence to the therapy. This approach may usher in a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. SIGNIFICANCE STATEMENT: To our knowledge, this is the first report that summarizes various challenges in insulin and pramlintide codelivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for pramlintide that could further broaden the reader's understanding of peptide codelivery.

Despite aggressive combination chemotherapy and surgery, outcomes for patients with osteosarcoma have remained stagnant for more than 25 years, and numerous clinical trials have identified no new therapies. p53 deletion or mutation is found in more than 80% of osteosarcoma tumors. In p53-deficient cancers with structurally altered p63 and p73, interfering with tumor cell metabolism using Pramlintide (an FDA-approved drug for type 2 diabetes) results in tumor regression. Pramlintide response is mediated through upregulation of islet amyloid polypeptide (IAPP). Here, we showed that osteosarcoma cells have altered p63, p73, and p53, and decreased IAPP expression but have the two main IAPP receptors, CalcR and RAMP3, which inhibit glycolysis and induce apoptosis. We showed that in osteosarcoma cells with high- or mid-range glycolytic activity, Pramlintide decreased cell glycolysis, resulting in decreased proliferation and increased apoptosis in vitro. In contrast, Pramlintide had no effect in osteosarcoma cells with low glycolytic activity. Using a subcutaneous osteosarcoma mouse model, we showed that intratumoral injection of Pramlintide-induced tumor regression. Tumor sections showed increased apoptosis and a decrease in Ki-67 and HIF-1α. These data suggest that in osteosarcoma cells with altered p53, p63, and p73 and a high glycolytic function, Pramlintide therapy can modulate metabolic programming and inhibit tumor growth.

The aim of this study was to examine the hypothesis that pramlintide would reduce hypoglycaemia by slowing gastric emptying and reducing postprandial glucagon secretion, thus limiting postprandial glycaemic excursions and insulin secretion, and thus to determine the efficacy of pramlintide on frequency and severity of hypoglycaemia in post-bariatric hypoglycaemia (PBH).

Findings of the current investigation displayed that pramlintide may act as a protective against oxidative conditions in endothelial cells through modulation of oxidative markers and transcription factor NF-κB.

Amylin is a pancreatic peptide hormone co-secreted along with insulin by the β-cells. It is found in amyloid deposits in both type 2 diabetic individuals and elder non-diabetic. The triple proline amylinomimetic compound (25,28,29-Pro-human amylin) named pramlintide was designed aiming to solve the solubility and amyloid characteristics of human amylin. We have found by using ion mobility spectrometry-based mass spectrometry that pramlintide is able to assembly into multimers. Pramlintide formed amyloid fibrils in vitro in a pH-dependent kinetic process within a few hours, as followed by thioflavin T, quantification of soluble peptide and further characterized by transmission electron microscopy, atomic force microscopy and X-ray diffraction. These data indicate that pramlintide can form amyloid fibers.

Postprandial glucose excursions negatively affect glycemic control and markers of cardiovascular health. Pramlintide, an amylinomimetic, is approved for treatment of elevated postprandial glucose levels in type 1 and type 2 diabetes mellitus.

To evaluate the weight-loss effects of pramlintide.

Pramlintide is a synthetic version of the naturally occurring pancreatic peptide called amylin. Amylin and pramlintide have similar effects on lowering postprandial glucose, lowering postprandial glucagon and delaying gastric emptying. Pramlintide use in type 1 and insulin requiring type 2 diabetes mellitus (DM) is associated with modest reductions in HbAlc often accompanied by weight loss. Limited data show a neutral effect on blood pressure. Small studies suggest small reductions in LDL-cholesterol in type 2 DM and modest reductions in triglycerides in type 1 DM. Markers of oxidation are also reduced in conjunction with reductions in postprandial glucose. Nausea is the most common side effect. These data indicate that pramlintide has a role in glycemic control of both type 1 and type 2 DM. Pramlintide use is associated with favorable effects on weight, lipids and other biomarkers for atherosclerotic disease.

Pramlintide, the first member of a new class of drugs for the treatment of insulin-using patients with type 2 or type 1 diabetes mellitus, is an analog of the peptide hormone amylin. Amylin is co-secreted with insulin from pancreatic beta cells and acts centrally to slow gastric emptying, suppress postprandial glucagon secretion, and decrease food intake. These actions complement those of insulin to regulate blood glucose concentrations. Amylin is relatively deficient in patients with type 2 diabetes, depending on the severity of beta-cell secretory failure, and is essentially absent in patients with type 1 diabetes. Through mechanisms similar to those of amylin, pramlintide improves overall glycemic control, reduces postprandial glucose levels, and reduces bodyweight in patients with diabetes using mealtime insulin. Reductions in postprandial glucose and bodyweight are important, since postprandial hyperglycemia is associated with an increased risk of microvascular and macrovascular complications, and increased weight is an independent risk factor for cardiovascular disease. Pramlintide is generally well tolerated, with the most frequent treatment-emergent adverse event being mild to moderate nausea, which decreases over time. Pramlintide treatment is also associated with improvements in markers of oxidative stress and cardiovascular risk and improved patient-reported treatment satisfaction. These factors make pramlintide an attractive option for the treatment of postprandial hyperglycemia in patients with diabetes using mealtime insulin.

Amylin is a hormone cosecreted with insulin by the beta cells of the pancreas. It suppresses postprandial glucagon secretion and slows gastric emptying. Pramlintide acetate is an amylin analogue that was approved by the US Food and Drug Administration in March 2005.

In patients with diabetes, dysregulation of multiple glucoregulatory hormones results in chronic hyperglycemia and an array of associated microvascular and macrovascular complications. Optimization of glycemic control, both overall (glycosylated hemoglobin [A1C]) and in the postprandial period, may reduce the risk of long-term vascular complications. However, despite significant recent therapeutic advances, most patients with diabetes are unable to attain and/or maintain normal or near-normal glycemia with insulin therapy alone. Pramlintide, an analog of amylin, is the first in a new class of pharmaceutical agents and is indicated as an adjunct to mealtime insulin for the treatment of patients with type 1 and type 2 diabetes. By mimicking the actions of the naturally occurring hormone amylin, pramlintide complements insulin by regulating the appearance of glucose into the circulation after meals via three primary mechanisms of action: slowing gastric emptying, suppressing inappropriate post-meal glucagon secretion, and increasing satiety. In long-term clinical trials, adjunctive pramlintide treatment resulted in improved postprandial glucose control and significantly reduced A1C and body weight compared with insulin alone. The combination of insulin and pramlintide may provide a more physiologically balanced approach to managing diabetes.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of pramlintide are reviewed.

Amylin is a 37-amino acid peptide neurohormone that is cosecreted with insulin from the pancreatic beta cells in response to meals. It lowers serum glucose by decreasing glucagon release, slowing gastric emptying, and decreasing food intake. Pramlintide, a synthetic amylin analogue, is approved by the US Food and Drug Administration for use with mealtime insulin in patients with type 1 diabetes and patients with type 2 diabetes who are using mealtime insulin only or the combination of insulin and metformin and/or a sulfonylurea.

Despite a number of incremental, beneficial improvements in diabetes mellitus therapy over the past few decades, the fundamental challenge of replicating the physiological entry into, and uptake of glucose from, the circulation remains unresolved. Pramlintide is an analogue of the beta-cell hormone amylin that simulates its important glucoregulatory actions. In humans, pramlintide slows gastric emptying and suppresses glucagon secretion during the prandial/postprandial period to slow and reduce the entry of glucose into the circulation. These actions, in conjunction with the glucose cellular uptake function of insulin, help normalise fluctuations in circulating glucose levels to a greater degree than is possible with insulin treatment alone. In clinical studies, pramlintide treatment as an adjunct to insulin decreased glycosylated haemoglobin levels (0.39-0.62%) with a concomitant weight loss (0.5-1.4kg) and no significant increase in severe hypoglycaemia. Pramlintide treatment as a potential adjunct to insulin therapy is in late-stage development for patients with type 1 diabetes and insulin-using patients with type 2 diabetes.

Adis CommentsPramlintide [AC 0137, AC 137, tripro-amylin, Symlin] is a synthetic human amylin analogue with proline substitutions at positions 25, 28 and 29, which limits the self-aggregation seen with native amylin. Pramlintide improves glycaemic control, and appears to reduce postprandial blood glucose peaks and flatten the glucose peaks and troughs observed in diabetic patients. The reduction of hypoglycaemia would be an immediate advantage, and the reduction of hyperglycaemia could potentially prevent diabetic complications. Development - US: Amylin has submitted an NDA in the US for pramlintide acetate (Symlin trade mark ) as an adjunctive therapy for the treatment of type 1 and type 2 diabetes mellitus. However, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee at their meeting on 26 July 2001, voted not to recommend approval of pramlintide for type 1 and type 2 diabetes. Although eight out of nine Committee members were convinced of the potential of pramlintide therapy, the Committee expressed concerns regarding safety issues and requested additional data addressing these concerns. Finally, on 12 October 2001, Amylin received an 'approvable letter' for Symlin- for the treatment of diabetes. In April 2002, Amylin commenced a trial in 250 patients with type 1 diabetes to evaluate the safety issues regarding cases of severe hypoglycaemia with pramlintide in combination with insulin reported in this group of patients. The trial will investigate dose titration in the initial first month of the treatment period combined with insulin adjustment for the optimisation of glucose control. Patients are then treated for 6 months at a steady-state dose of pramlintide or placebo, accompanied by the additional insulin adjustments. Amylin has completed patient enrolment in September 2002. Final approval is subject to satisfactory results from this safety and dose titration study and the four small pharmacology studies already completed or underway. Amylin plans to file an amendment to the pramlintide's NDA in the Q1 of 2003. Development - non-USA: A wholly owned subsidiary of Amylin Pharmaceuticals, Amylin Europe, filed a regulatory submission with the European Agency for Evaluation of Medicinal Products (EMEA) and Switzerland for pramlintide for the treatment of both type 1 and type 2 diabetes under the centralised procedure. Amylin completed pivotal phase III clinical trials with pramlintide acetate (Symlin trade mark ) for the treatment of type 1 and type 2 diabetes mellitus in North America and Europe. However, in October 2002, Amylin announced that following consultation with the Committee for Proprietary Medicinal Products (CPMP) of the EMEA, it has found that additional information is necessary to proceed with review of the MAA for pramlintide for diabetes. Since, the centralised procedure does not allow the adding of new information to the application that is already under review, Amylin has decided to withdraw the MAA for pramlintide. The company will continue discussions with the EMEA to clarify the information required for a resubmission of the application. The submission for pramlintide in Switzerland is currently under review. In a separate phase II programme, Amylin is investigating the use of pramlintide in type 2 diabetes mellitus patients who are not achieving satisfactory results with oral hypoglycaemic agents but who have not progressed to using insulin. Collaborations: Pramlintide was under joint development with Amylin Pharmaceuticals and Johnson and Johnson, as an injectable partner hormone for insulin for the treatment of both type 1 and type 2 diabetes mellitus. The terms of the agreement between Amylin and Johnson and Johnson were that Amylin had primary responsibility for development and regulatory submissions, while Johnson and Johnson had primary responsibility for marketing; development costs and eventual profits were to be shared equally. Later, Johnson and Johnson decided to terminate the collaboration to commercialise pramlintide. An earlier development collaboration betweion between Amylin and Glaxo Wellcome was also discontinued. However, Amylin is in new ongoing discussions with collaborative partners for pramlintide in Europe and Japan. Amylin has signed an agreement with CP Pharmaceuticals in the UK to manufacture pramlintide.

To provide an overview of the role of amylin, as well as that of pramlintide, a synthetic analog of amylin, in maintaining glucose homeostasis; and discuss the pharmacology, pharmacokinetics, efficacy, adverse effects, and role of pramlintide in the control of postprandial hyperglycemia.

Pramlintide is a human amylin analog, under development by Amylin (originally in collaboration with Johnson & Johnson), as an adjunct with insulin for the potential prevention of complications of type I diabetes, and as a single agent for type II diabetes [279804], [295121], [305454]. In December 2000, Amylin submitted a US NDA seeking approval to market pramlintide as an adjunctive therapy for type 1 and 2 diabetics using insulin [392527]; the application was accepted for review by the FDA in January 2001 [396938], and was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee on July 26 2001 [408924]. In May 2001, Amylin submitted an MAA for pramlintide to the EMEA [411323] and in October 2001, Amylin received an approvable letter from the FDA for both Type I and insulin-using Type II diabetes; however, at this time, discussions with the FDA were ongoing regarding additional clinical work that was required before the NDA would be approved [425570].