On April4, 2017,
the Company announced that interim results from a Phase II
clinical trial of neratinib were presented at the 2017 AACR
Annual Meeting. 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, was presented as a
poster presentation.

The main adverse
event that has been 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. High dose loperamide
prophylaxis was given for the first 2 cycles (56 days) of
treatment. Initially, the loperamide dosing used was 16 mg on day
1, then 12 mg on days 2 and 3 and then 6-8 mg on days 4-56
(original dosing). The protocol was later amended to simplify the
regimen such that patients took 12 mg on days 1-14 and 8 mg on
days 15-56 (modified dosing). The CONTROL trial was also 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 the bile acid
malabsorption also seen in preclinical models of
neratinib-induced diarrhea.

The interim
analysis of the trial presented in the poster included a total of
137 patients who received neratinib plus loperamide prophylaxis
(28 patients taking the original dosing and 109 patients taking
the modified dosing), 64 patients who received neratinib plus
loperamide prophylaxis for 2 cycles and budesonide for 1 cycle,
and 26 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 23.4%. 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, 9.4% discontinued
neratinib due to diarrhea.

For the 26
patients who received the combination of loperamide plus
colestipol, the results of the trial showed that the incidence of
grade 3 diarrhea was 11.5%. The median number of grade 3 diarrhea
episodes per patient was 2 and the median cumulative duration of
grade 3 diarrhea was 2 days. For the 26 patients who received
loperamide plus colestipol prophylaxis, no patient (0%)
discontinued neratinib due to diarrhea. Further information is
provided in Table 1 below:

Table 1:
Characteristics of Treatment-Emergent Diarrhea

In the ExteNET
trial, higher grade (grade 2 and grade 3) diarrhea occurred early
and persisted throughout the duration of the 12-month treatment
period. In the CONTROL trial, in the loperamide prophylaxis,
loperamide plus budesonide prophylaxis and loperamide plus
colestipol prophylaxis arms, the results showed that higher grade
diarrhea (grades 2 and 3) occurred early but did not typically
recur. This is shown in more detail in Figure 1: Treatment
Emergent Diarrhea below:

During the course
of the CONTROL trial there has been an increase in the proportion
of patients previously treated with pertuzumab (mainly in the
neoadjuvant setting). For the 55 patients in the loperamide
prophylaxis cohort who received prior pertuzumab, the grade 3
diarrhea rate was 38.2% (Table 2). For the 82 patients who did
not receive prior pertuzumab, the grade 3 diarrhea rate was
25.6%. For the 39 patients in the budesonide cohort who received
prior pertuzumab, the grade 3 diarrhea rate was 10.3%. For the 25
patients in the budesonide cohort who did not receive prior
pertuzumab, the grade 3 diarrhea rate was 36.0%. This analysis
suggests that prior pertuzumab exposure may have led to a higher
rate of grade 3 diarrhea in the CONTROL trial that was not
effectively managed by loperamide prophylaxis alone but was more
effectively managed by loperamide plus budesonide.

Table 2:
Incidence ofGrade 3 Diarrhea in CONTROL by Prior
Pertuzumab Treatment

Forward-Looking
Statements