The 75% continuing therapy was in the original press release:
AMYLIN PHARMACEUTICALS ANNOUNCES INITIAL PHASE III
RESULTS ARE POSITIVE IN TYPE 1 DIABETES AND ENCOURAGING
IN TYPE 2 DIABETES
Results Confirm Proof of Concept for Amylin Replacement Therapy
San Diego, CA - August 15, 1997 - 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.
Summary
"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. |
