Results Confirm Proof of Concept for Amylin Replacement Therapy
SAN DIEGO, Aug. 15 /PRNewswire/ -- Amylin Pharmaceuticals, Inc. (Nasdaq: AMLN) today announced that in an initial Phase III study its diabetes drug candidate, pramlintide, improved metabolic control in people with type 1 diabetes. Metabolic benefits included improved glucose control without increased risk of hypoglycemia and improved weight control and cholesterol profiles. Pramlintide is a synthetic analog of the human hormone amylin which is deficient in patients with diabetes who use insulin. In the type 1 diabetes study, pramlintide's 12-month, intent-to-treat effects on lowering glucose and improving weight and cholesterol profiles were statistically significant and clinically meaningful.
In a parallel type 2 diabetes study, the lowering of glucose on an intent-to-treat basis in two of the three pramlintide dose groups achieved statistical significance after six months, but not after 12 months. These results may not have achieved statistical significance due to relatively large changes in insulin dosing by about 70% of patients and the smaller number of patients completing 12-months of treatment per group in this study compared to the type 1 study. Since insulin alone lowers glucose concentrations, this variability in insulin dosing obfuscated the pramlintide drug effect. There was no increase in the frequency or severity of hypoglycemia in the pramlintide treatment groups compared to placebo. Pramlintide produced statistically significant weight loss in all drug groups compared to placebo.
The two studies reported today are part of the PARADIGM Phase III trials being jointly sponsored by Amylin Pharmaceuticals and Johnson & Johnson, which have the goal of demonstrating that amylin replacement therapy can help many insulin-using patients with diabetes improve their metabolic control without increasing hypoglycemia and weight gain. Four other, more recently designed studies are ongoing. These initial Phase III results confirm that the protocol modifications previously adopted for the four ongoing trials to better isolate the pramlintide drug effect are well founded. Based upon observations during the conduct of these two initial studies, the improved study designs incorporated at the initiation of the other four ongoing Phase III trials, which will be the core of the planned regulatory filings, were improved to reduce the variability in insulin dosing and to focus on patients with poor glucose control.
"These data confirm the `proof of therapeutic concept' evidence observed in Phase II studies, that hormone replacement therapy employing a synthetic analog of human amylin conveys significant clinical benefit for those patients who are deficient in both amylin and insulin," said Orville G. Kolterman, M.D., Amylin Pharmaceuticals' Senior Vice President, Medical Affairs. "To my knowledge, this is the first time in 75 years that a non-insulin drug candidate has demonstrated statistically significant and clinically relevant results in Phase III for the treatment of type 1 diabetes. Furthermore, pramlintide improved not only glucose control but also positively affected body weight and cholesterol profiles, without increasing the risk of hypoglycemia. These product attributes contrast with the demonstrated tendency of intensive insulin therapy to increase hypoglycemia and cause weight gain, and thus may provide unique positioning for pramlintide among diabetes therapies."
"On the basis of these results, we and our partner, Johnson & Johnson, are committed to working towards completion of the pramlintide development program for type 1 and type 2 diabetes," noted Richard M. Haugen, Amylin Pharmaceuticals' President and Chief Executive Officer. Johnson & Johnson is Amylin Pharmaceuticals' collaboration partner in the development and commercialization of pramlintide.
Results in Type 1 Diabetes
The double-blind, placebo-controlled study in type 1 diabetes involved 477 patients for a 12-month treatment period. The pramlintide dosing regimen was 30 micrograms four-times daily, with certain patients escalating to 60 micrograms at 20 weeks.
Data from the intent-to-treat analysis of all type 1 patients (221 patients in the pramlintide treatment group) showed that the reduction in glycated hemoglobin (HbA1c) at 12 months compared to placebo was 0.30% (p = 0.0005). Variability in insulin dosing for many patients led to a diminished glucose lowering effect in the intent-to-treat results. Despite the variability in insulin dosing, 46% of patients evaluable at 52 weeks had a statistically significant, 12-month reduction in HbA1c > 0.5% (p =0.0060) compared to 29% of placebo patients. The average daily dose of regular insulin increased for patients on placebo and decreased for patients on pramlintide, each of which offset measurable reductions in HbA1c levels attributable to pramlintide. To better isolate the effect of pramlintide on an overall intent-to-treat basis, the Company has designed the two, ongoing studies in type 1 diabetes to maximize the number of patients maintaining stable insulin dosing over the study period.
In the intent-to-treat analysis for type 1 patients who entered the study with poor glucose control, the reduction in HbA1c at 12 months for patients treated with pramlintide compared to placebo was 0.40% (p = 0.0003, n = 144). Poor glucose control is defined by the American Diabetes Association and recent FDA draft guidelines as HbA1c > 8.0%. This result was statistically significant and this entry criteria corresponds to that which is being used in the ongoing Phase III studies.
Within the pramlintide treatment group, the 40 type 1 patients who entered the study with poor glucose control and who maintained stable insulin dosing for 12 months achieved an average HbA1c reduction of 0.66% compared to placebo (p = 0.0504); moreover, these effects were durable over the 12-month dosing period. Stable insulin is defined as the total daily insulin dose remaining within 10% of baseline levels throughout the study.
These improvements in glucose control were achieved without an increase in the frequency or severity of hypoglycemia (dangerously low blood glucose concentrations). These combined attributes are an important advantage for a blood-glucose-lowering agent. Of specific note, the incidence of severe hypoglycemia, as defined in the Diabetes Control and Complications Trial (i.e., requiring the assistance of another individual for treatment), was not different between the placebo and pramlintide treated patients.
Importantly, patients receiving pramlintide for 12 months also benefited from better weight control and cholesterol profiles. They achieved an average reduction in body weight of 2.9 pounds compared to placebo (p = 0.0111). Also, patients receiving pramlintide showed improvements in their cholesterol profiles, with an average increase in serum HDL/LDL cholesterol ratio of 8.4% (p = 0.0009).
The study confirmed pramlintide's excellent safety and tolerability profile during chronic dosing. The most common drug-related side effect in the study was initial transient nausea, which in most patients was relatively mild and generally dissipated during the initial 14 days of treatment. Approximately 45% of patients in the pramlintide group reported this event, versus 17% in the placebo group. Only 13% of patients receiving pramlintide dropped out of the study for adverse events, compared to 9% on placebo. At the end of the 12-month study period about 75% of the participants who completed the study elected to continue open-label dosing with pramlintide.
Results in Type 2 Diabetes
The double-blind, placebo-controlled study in type 2 diabetes involved 539 patients for a 12-month treatment period. The pramlintide dosing regimens were 30 micrograms, 75 micrograms, and 150 micrograms three-times-daily. The 30-microgram dose was a minimally effective dose.
On an overall intent-to-treat basis, at six months there was a statistically significant reduction in HbA1c of 0.38% (p = 0.0070, n = 133) and 0.39% (p = 0.0049, n = 126) in the 75-microgram and 150-microgram pramlintide groups, respectively, compared to placebo. At 12 months, while the reduction in HbA1c in each drug arm compared to placebo was comparable to the amount of reduction at six months, the 12-month values were not statistically significant. The results may not have achieved statistical significance due to relatively large changes in insulin dosing by about 70% of patients and the smaller number of patients treated per group in this study compared to the type 1 study. For example, compared to the 75 microgram dose arm, patients on placebo increased their average daily dose of regular insulin by 12% (p = 0.0010). The improved design of the two, ongoing Phase III studies in type 2 diabetes should better isolate pramlintide's effect and provide a basis for more robust intent-to-treat results.
In the intent-to-treat analysis for type 2 patients who entered the study with poor glucose control (entry HbA1c > 8.0%), the reductions in HbA1c at 12 months for patients treated with pramlintide compared to placebo were 0.35% (p = 0.0418, n = 115) in the 75-microgram dose group, and 0.42% (p = 0.0048, n = 105) in the 150-microgram dose group. The result from the 150-microgram dose group was statistically significant, and this entry criteria corresponds to that which is being used for the ongoing Phase III studies.
Within the pramlintide treatment groups, the type 2 patients who entered the study with poor glucose control and who maintained stable insulin dosing (+/- 10% baseline) for 12 months achieved an average HbA1c reduction compared to placebo of 0.85% (p = 0.1390, n = 23) in the 75-microgram dose group, and 0.70% (p = 0.3941, n = 20) in the 150-microgram dose group. The glucose lowering effect was achieved with no increase in the frequency or severity of hypoglycemia.
Importantly, patients receiving pramlintide for 12 months showed a statistically significant reduction in body weight ranging from 3.7 pounds (p =0.0023) to 7.0 pounds (p=0.0001), depending on dose and compared to placebo. Due to the limited amount of fasting cholesterol data available at baseline, conclusions regarding cholesterol profiles could not be drawn.
As in the case of type 1 patients, the study extended pramlintide's excellent safety and tolerability profile to chronic dosing. The most common drug-related side effect in the study was initial transient nausea, which in most patients was relatively mild and generally dissipated during the initial 14 days of treatment. Approximately 21% of patients in the pramlintide groups reported this event, versus 15% in the placebo group. Only 11% of patients receiving pramlintide dropped out of the study for adverse events, compared to 9% on placebo. At the end of the 12-month study period about 75% of the participants who completed the study elected to continue open-label dosing with pramlintide. This excellent safety and tolerability profile in the type 2 study was achieved in a group of patients with the co-morbidities which commonly accompany diabetes in an elderly population.
"The results in type 2 diabetes point to a role for amylin replacement among insulin-using patients," said Dr. Kolterman. "We believe the statistically significant glucose-lowering effect seen in the intent-to-treat analysis of patients who had poor glucose control combined with the magnitude of effect seen in those same patients who also maintained stable insulin bodes well in terms of the likelihood of achieving improved intent-to-treat results in the other two ongoing studies. Furthermore, the secondary benefit of improved weight control is a very important additional attribute of pramlintide therapy."
Ongoing Phase III Studies
"To measure more clearly the effect of pramlintide without undue influence of insulin on metabolic control in the ongoing four PARADIGM trials, we introduced new protocol designs which should result in stable insulin dosing in a higher percentage of enrolled patients," Dr. Kolterman continued. "In addition, we raised the entry HbA1c threshold for patients in the ongoing four studies to 8.0% to correspond with American Diabetes Association and recent FDA draft guidelines. With these Phase III protocol refinements, we believe that the data from subsets of patients who entered the initial Phase III studies with poor glucose control and maintained stable insulin regimens in those studies should more closely correspond to the overall intent-to-treat data in the ongoing four studies."
Data from the initial Phase III studies and previous studies suggest that different pramlintide dosing regimens may further enhance patient convenience. Therefore, two- and three-times-per-day dosing regimens are being studied in the ongoing four PARADIGM studies.
Amylin Pharmaceuticals currently is aiming to complete the ongoing four pivotal studies and submit regulatory applications for marketing in North America and Europe by the end of next year.
"In our view, the results of these initial Phase III studies are consistent with the growing body of preclinical and clinical data on the potential for amylin replacement therapy," said Maurizio Denaro, M.D., Amylin Pharmaceuticals' Executive Vice President and Chief Technical Officer. "We believe that when used in conjunction with insulin, pramlintide will help many patients with diabetes to achieve better control of metabolic functions, including lower blood glucose concentrations (without increased hypoglycemia) and improved weight control and cholesterol profiles. Pramlintide's excellent safety and tolerability profile appears to be consistent with the concept of replacing the actions of a naturally occurring human hormone with an analog to achieve highly selective efficacy for metabolic control."
Amylin Pharmaceuticals, Inc. is focused on developing novel medicines for treating metabolic disorders. The Company has pioneered research of the hormone amylin, which is believed to play an important role in glucose control and is missing or deficient in millions of people with diabetes. The Company is collaborating with Johnson & Johnson to develop pramlintide, a synthetic analog of human amylin, with the aim of improving metabolic control for people with diabetes. Pramlintide administration has resulted in clinically relevant improvement in glucose control and other indicators of metabolic control, such as body weight and cholesterol profiles, during Phase II and initial Phase III clinical testing when used as an adjunct to insulin therapy in people with diabetes. Four Phase III PARADIGM clinical studies are underway and are aimed at further demonstrating pramlintide's ability to improve metabolic control, thereby lowering the risk of degenerative complications. Regulatory submissions for pramlintide are planned for late 1998 in North America and Europe. The Company has expanded its research and development pipeline within the field of metabolic disorders by starting several new preclinical programs, including validation of exendin and GLP-1 for diabetes and obesity, the mono-di-tert-butylphenols for dyslipidemia, and several new drug targets for obesity. Amylin Pharmaceuticals is headquartered in San Diego, California.
This press release contains forward-looking statements that involve risks and uncertainties. Actual results may differ materially from those discussed herein, due to, among other things, the research, development, and market risks which could adversely affect the Company's timeline for clinical trials, regulatory approval, and if such approval is received, time to market thereafter. Additional risks and uncertainties are described in the Company's most recently filed SEC documents, such as its Form 10-K for the fiscal year ended December 31, 1996 and its most recent Form 10-Q.
Posted 16 Aug 97
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