LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company,
will present updated interim results from a Phase II clinical trial of
Puma’s drug neratinib at the 2017 San Antonio Breast Cancer Symposium
(SABCS) that is currently taking place in San Antonio, Texas. The
presentation entitled, “Effects of adding budesonide or colestipol to
loperamide prophylaxis on neratinib-associated diarrhea in patients with
HER2-positive early stage breast cancer: the CONTROL trial,” will be
presented at a poster session on December 7 at 5:00 p.m. CST. A full
copy of the poster is available on the Puma Biotechnology website.
Neratinib was approved by the U.S. Food and Drug Administration (FDA) in
July 2017 for the extended adjuvant treatment of adult patients with
early stage HER2-positive breast cancer following adjuvant
trastuzumab-based therapy, and is marketed in the United States as
NERLYNX® (neratinib) tablets.
The main adverse event seen to date in clinical trials of neratinib is
diarrhea and, more specifically, grade 3 diarrhea. In the Phase III
ExteNET trial of neratinib as extended adjuvant treatment of
HER2-positive early stage breast cancer that has previously been treated
with adjuvant Herceptin, 95.4% of the patients experienced all grade
diarrhea and 39.8% of the patients experienced grade 3 or higher
diarrhea (there was one event of grade 4 diarrhea). The CONTROL trial is
an international, open-label, Phase II study investigating the use of
loperamide prophylaxis with or without other agents in the reduction of
neratinib-associated diarrhea that has a primary endpoint of the
incidence of grade 3 diarrhea.
In the CONTROL trial, patients with HER2-positive early stage breast
cancer who had completed trastuzumab-based adjuvant therapy received
neratinib daily for a period of one year. The trial initially tested
high dose loperamide prophylaxis given for the first 2 cycles (56 days)
of treatment (12 mg on days 1-14, 8 mg on days 15-56 and as needed
thereafter). The CONTROL trial was then expanded to include two
additional cohorts. One cohort received the combination of loperamide
and budesonide and the other cohort received the combination of
loperamide plus colestipol. Budesonide is a locally acting
corticosteroid that the Company believes targets the inflammation
identified in a preclinical model of neratinib-induced diarrhea and
colestipol is a bile acid sequestrant that the Company believes targets
potential bile acid malabsorption that could result from such
inflammation.
The interim analysis of the trial presented in the poster included a
total of 137 patients who received neratinib plus loperamide
prophylaxis, 64 patients who received neratinib plus loperamide
prophylaxis for 2 cycles and budesonide for 1 cycle, and 120 patients
who received neratinib plus loperamide prophylaxis for 1 cycle and
colestipol for 1 cycle.
The results of the trial showed that the incidence of grade 3 diarrhea
for the 137 patients who received the loperamide prophylaxis was 30.7%.
For the 137 patients who received the loperamide prophylaxis, the median
number of grade 3 diarrhea episodes per patient was 1 and the median
cumulative duration of grade 3 diarrhea was 3 days. For the 137 patients
who received loperamide prophylaxis, 20.4% discontinued neratinib due to
diarrhea.
For the 64 patients who received the combination of loperamide plus
budesonide, the results of the trial showed that the incidence of grade
3 diarrhea was 26.6%. The median number of grade 3 diarrhea episodes per
patient was 1 and the median cumulative duration of grade 3 diarrhea was
2 days. For the 64 patients who received loperamide plus budesonide
prophylaxis, 10.9% discontinued neratinib due to diarrhea.
For the 120 patients who received the combination of loperamide plus
colestipol, the results of the trial showed that the incidence of grade
3 diarrhea was 10.8%. The median number of grade 3 diarrhea episodes per
patient was 1 and the median cumulative duration of grade 3 diarrhea was
3 days. For the 120 patients who received loperamide plus colestipol
prophylaxis, 1.7% discontinued neratinib due to diarrhea. Further
information is provided in Table 1 below:
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Table 1: Characteristics of Treatment-Emergent Diarrhea
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Study
|
|
|
CONTROL
|
|
|
ExteNET
|
|
|
|
|
|
|
|
|
Loperamide +
|
|
|
Loperamide +
|
|
|
Loperamide
|
|
|
|
|
|
Loperamide
|
|
|
budesonide
|
|
|
colestipol
|
|
|
prn
|
|
|
|
|
|
(n=137)
|
|
|
(n=64)
|
|
|
(n=120)
|
|
|
(n=1408)
|
|
|
Diarrhea, %
|
|
|
Any grade
|
|
|
79.6
|
|
|
86.0
|
|
|
66.7
|
|
|
95.4
|
|
|
Grade 1
|
|
|
24.8
|
|
|
25.0
|
|
|
30.0
|
|
|
22.9
|
|
|
Grade 2
|
|
|
24.1
|
|
|
34.4
|
|
|
25.8
|
|
|
32.5
|
|
|
Grade 3a
|
|
|
30.7
|
|
|
26.6
|
|
|
10.8
|
|
|
39.8
|
|
|
Grade 4
|
|
|
0
|
|
|
0
|
|
|
0
|
|
|
0.1
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Median cumulative duration, days
|
|
|
Any grade
|
|
|
14.0
|
|
|
24.0
|
|
|
16.0
|
|
|
59.0
|
|
|
Grade ≥2
|
|
|
5.0
|
|
|
6.0
|
|
|
3.5
|
|
|
10.0
|
|
|
Grade ≥3a
|
|
|
3.0
|
|
|
2.0
|
|
|
3.0
|
|
|
5.0
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Median diarrhea episodes/patient
|
|
|
Any grade
|
|
|
2.0
|
|
|
9.0
|
|
|
2.5
|
|
|
8.0
|
|
|
Grade ≥2
|
|
|
2.0
|
|
|
3.0
|
|
|
1.0
|
|
|
3.0
|
|
|
Grade ≥3a
|
|
|
1.0
|
|
|
1.0
|
|
|
1.0
|
|
|
2.0
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Action taken, %
|
|
|
Dose hold
|
|
|
15.3
|
|
|
18.8
|
|
|
9.2
|
|
|
33.9
|
|
|
Dose reduction
|
|
|
7.3
|
|
|
3.1
|
|
|
4.2
|
|
|
26.4
|
|
|
Discontinuation
|
|
|
20.4
|
|
|
10.9
|
|
|
1.7
|
|
|
16.8
|
|
|
Hospitalization
|
|
|
1.5
|
|
|
0
|
|
|
0
|
|
|
1.4
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Duration of neratinib treatment, months
|
|
|
Median
|
|
|
11.5
|
|
|
11.9
|
|
|
3.7
|
|
|
11.6
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
a No grade 4 events in the CONTROL study; one grade 4
event in the ExteNET study.
|
|
|
|
Hope S. Rugo, MD, USCF Helen Diller Family Comprehensive Cancer Center,
San Francisco, California, said, “We are pleased to see the maturation
of the data supporting observations of a reduction in incidence,
severity and duration of neratinib-associated diarrhea with loperamide
prophylaxis, loperamide plus budesonide prophylaxis or the loperamide
plus colestipol prophylaxis. Along with the continued reduction in the
incidence and severity of grade 3 diarrhea with neratinib, diarrhea
appears to be acute, self-limiting and manageable. The addition of
budesonide or colestipol to loperamide prophylaxis appears to greatly
improve the tolerability of neratinib and we look forward to the
completion of the colestipol cohort.”
Alan H. Auerbach, Chief Executive Officer and President of Puma
Biotechnology, said, “We are pleased to see the reductions in the
incidence of severe neratinib-related diarrhea in the CONTROL trial when
using the loperamide, loperamide plus budesonide or loperamide plus
colestipol regimens. The severe diarrhea appears to become more acute,
whereby it does not typically recur after the first month. We are also
very encouraged by the improvements in tolerability that have been seen
to date in the budesonide and the colestipol cohorts. This is a marked
improvement in tolerability over what was seen in the ExteNET trial and
we look forward to continuing to monitor this in the loperamide plus
colestipol cohort.”
About HER2-Positive Breast Cancer
Approximately 20% to 25% of breast cancer tumors over-express the HER2
protein. HER2-positive breast cancer is often more aggressive than other
types of breast cancer, increasing the risk of disease progression and
death. Although research has shown that trastuzumab can reduce the risk
of early stage HER2-positive breast cancer returning after surgery, up
to 25% of patients treated with trastuzumab experience recurrence.
IMPORTANT SAFETY INFORMATION
NERLYNX® (neratinib) tablets, for oral use
INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated
for the extended adjuvant treatment of adult patients with early-stage
HER2 overexpressed/amplified breast cancer, to follow adjuvant
trastuzumab-based therapy.
CONTRAINDICATIONS: None
WARNINGS AND PRECAUTIONS:
-
Diarrhea: Aggressively manage diarrhea occurring despite
recommended prophylaxis with additional antidiarrheals, fluids, and
electrolytes as clinically indicated. Withhold NERLYNX in patients
experiencing severe and/or persistent diarrhea. Permanently
discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade
≥ 2 diarrhea that occurs after maximal dose reduction.
-
Hepatotoxicity: Monitor liver function tests monthly for the
first 3 months of treatment, then every 3 months while on treatment
and as clinically indicated. Withhold NERLYNX in patients experiencing
Grade 3 liver abnormalities and permanently discontinue NERLYNX in
patients experiencing Grade 4 liver abnormalities.
-
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise
patients of potential risk to a fetus and to use effective
contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were
diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis,
decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail
disorder, dry skin, abdominal distention, epistaxis, weight decreased
and urinary tract infection.
To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology,
Inc. at 1-844-NERLYNX (1-844-637-5969) and
www.NERLYNX.com
or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch
.
DRUG INTERACTIONS:
-
Gastric acid reducing agents: Avoid concomitant use with proton pump
inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3
hours after antacid dosing.
-
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
-
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
-
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of
narrow therapeutic agents that are P-gp substrates when used
concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:
-
Lactation: Advise women not to breastfeed.
Please see
Full
Prescribing Information
for additional safety information.
The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given
orally once daily with food, continuously for one year. Antidiarrheal
prophylaxis should be initiated with the first dose of NERLYNX and
continued during the first 2 months (56 days) of treatment and as needed
thereafter.
To help ensure patients have access to NERLYNX, Puma has implemented the
Puma Patient Lynx support program to assist patients and healthcare
providers with reimbursement support and referrals to resources that can
help with financial assistance. More information on the Puma Patient
Lynx program can be found at www.NERLYNX.com
or 1-855-816-5421.
About Puma Biotechnology
Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on
the development and commercialization of innovative products to enhance
cancer care. The Company in-licenses the global development and
commercialization rights to three drug candidates—PB272 (neratinib,
oral), PB272 (neratinib, intravenous) and PB357. NERLYNX® (neratinib) is
approved for commercial use by prescription in the United States as
extended adjuvant therapy for early stage HER2-positive breast cancer
following adjuvant trastuzumab-based therapy and is marketed as NERLYNX.
Neratinib is a potent irreversible tyrosine kinase inhibitor that blocks
signal transduction through the epidermal growth factor receptors, HER1,
HER2 and HER4. Currently, the Company is primarily focused on the
commercialization of NERLYNX and the continued development of its other
advanced drug candidates are directed at the treatment of HER2-positive
breast cancer. The Company believes that NERLYNX has clinical
application in the potential treatment of several other cancers that
over-express or have a mutation in HER2.
Further information about Puma Biotechnology can be found at www.pumabiotechnology.com.
Forward-Looking Statements:
This press release contains forward-looking statements, including
statements regarding the benefits of NERLYNX® and neratinib, the
Company’s clinical trials and the announcement of data relative to those
trials. All forward-looking statements included in this press release
involve risks and uncertainties that could cause the Company’s actual
results to differ materially from the anticipated results and
expectations expressed in these forward-looking statements. These
statements are based on current expectations, forecasts and assumptions,
and actual outcomes and results could differ materially from these
statements due to a number of factors, which include, but are not
limited to, the fact that the Company has only recently commenced
commercialization and shipment of its only FDA approved product; the
Company’s dependence upon the commercial success of NERLYNX (neratinib);
the Company’s history of operating losses and its expectation that it
will continue to incur losses for the foreseeable future; risks and
uncertainties related to the Company’s ability to achieve or sustain
profitability; the Company’s ability to predict its future prospects and
forecast its financial performance and growth; failure to obtain
sufficient capital to fund the Company’s operations; the effectiveness
of sales and marketing efforts; the Company’s ability to obtain FDA
approval or other regulatory approvals in the United States or elsewhere
for other indications for neratinib or other product candidates; the
challenges associated with conducting and enrolling clinical trials; the
risk that the results of clinical trials may not support the Company’s
drug candidate claims; even if approved, the risk that physicians and
patients may not accept or use the Company’s products; the Company’s
reliance on third parties to conduct its clinical trials and to
formulate and manufacture its drug candidates; risks pertaining to
securities class action, derivative and defamation lawsuits; the
Company’s dependence on licensed intellectual property; and the other
risk factors disclosed in the periodic and current reports filed by the
Company with the Securities and Exchange Commission from time to time,
including the Company’s Quarterly Report on Form 10-Q for the quarter
ended September 30, 2017. Readers are cautioned not to place undue
reliance on these forward-looking statements, which speak only as of the
date hereof. The Company assumes no obligation to update these
forward-looking statements, except as required by law.
Contact: