-
Afferent Pharmaceuticals Presents Updated
Positive Results with AF-219 from Phase 2B Chronic
Cough Study at the 2016 American
Thoracic Society (ATS) International Conference
Afferent
制药公司在
2016
年胸科协会国际会议上展示
AF-219
治
疗慢性咳嗽的
Ph2b
期积极
临床数据
SAN
FRANCISCO--(
BUSINESS
WIRE
)--Afferent Pharmaceuticals, a
leader in the development
of small
molecule compounds targeting the P2X3
receptor for the treatment of poorly
managed
and
common
neurogenic
conditions,
today
announced
that
AF-219
significantly
reduced
cough
frequency
in
the
first
cohort
of
a
two
cohort-
Phase
2b
study
dose-escalation
clinical
trial
in
chronic
cough patients. Results demonstrated that all
AF-219 doses, including the lowest dose of
50
mg
twice
daily,
demonstrated
a
statistically
significant
reduction
in
awake
cough
frequency
compared
to
placebo
(p≤0.002).
AF
-219
is
a
selective,
non-centrally-acting
and
orally
administered P2X3
antagonist that targets the mechanism by which
certain nerve fibers become
hyper-
sensitized
and
can
lead
to
chronic
and
debilitating
symptoms,
such
as
chronic
cough.
Chronic cough is defined as a cough
lasting more than eight weeks. Data were presented
at the
American
Thoracic
Society
(ATS)
International
Conference,
held
May
13-18,
2016
in
San
Francisco.
【
Afferent
制药公司今天宣布
AF-219
在一个两队
列的
Ph2
期剂量递增临床试验研
究中
，能显著降低第一队列慢性咳嗽患者的咳嗽频率。结果表明
AF-219
的所有剂量，包括
每日低剂量的
50mg
，相比对照均能显著降低夜间咳醒的频率。
AF-219
是选择性、非中枢作
用、口服
P2X3
受体拮抗剂，开发用于治疗以某种神经变得超敏从而导致慢性和衰弱的症状
包括咳嗽
。慢性咳嗽被定义为咳嗽持续八周以上。数据在
2016
年
5
月
13-18
日
的美国胸科
学会（
A
TS
）国际会议上提出。
】
Data from the second cohort of the
Phase 2b study, which evaluates lower doses of
AF-219 (as
low as 7.5 mg BID), are
expected to be presented at a medical/scientific
conference in the second
half of 2016.<
/p>
【
Ph2b
期第二队列是评估低剂量
AF-219
（低至
7.5 mg BID
）的疗效情况，将在
2016
年后半年
的医疗
/
科学会议上展出。
】
These
data
support
continued
clinical
development
of
AF-219
and
complement
the
initial
proof-of-concept
study
showing
similar
efficacy
results
in
this
unmet
condition.
The
company
anticipates beginning a Phase 3
registration program in early 2017.
【这些数
据将为
AF-219
的进
一步临床开发
提供支持，
并且在仍有临床需求的情况下补充概念证明试验。
公
司预计在
2017
年开始
Ph3
期注册项目。
】
Study Design and Results
The
29-patient
randomized,
double-blind,
placebo-controlled,
Phase
2b
crossover
study
was
conducted at 10 clinical sites in the
U.S. Patients, with a mean awake cough average of
almost 60
times per hour and a mean
duration of cough of 15 years, were randomized to
either AF-219 or
placebo arms. Those in
the treatment group received AF-219 50 mg,
followed by dose escalation
up to 100
mg, 150 mg and 200 mg, with each dose given twice
daily for four days sequentially.
Treatment period one was followed by a
three-to-seven day
washout
period. Patients were then
crossed over
to the alternate arm of the study and treated with
either AF-219 or placebo for 16
more
days.
Cough
frequency
was
measured
objectively
utilizing
a
cough
recording
device,
following each AF-219 treatment and
compared to a baseline recording. Nearly 300,
24-hr cough
recordings were collected
from this study.
【随机、双盲、安慰剂对照、
2b
期交叉研究在
29
例
患者中进行，
平均的清醒时咳嗽次数为每小时
60
次，
平均咳嗽持续
15
年，
患者随机分配到
AF-219
治疗组和安慰剂组。
AF-219
治疗组患者起初接受
50 mg
剂量，逐渐增加到
100
mg
、
150
mg
和
200 mg
，每个剂量每日两
次给药持续四天。随后患者进行交叉研究，随机继续给
药
AF-
219
治疗
16
天或者给予安慰剂。用
咳嗽记录装置测量咳嗽频率。最后收集到近
300
个
24-hr
咳嗽记录。】
All doses demonstrated significant
reduction in cough frequency, including at the
lowest dose of
50
mg
twice
daily.
The
lowest
dose
of
50
mg
BID
was
shown
to
have
similar
efficacy
as
the
previously evaluated dose of 600 mg BID
(published in
The
Lancet,
March 2015; online November
2014). An analysis of responders on the
50 mg dose showed nearly half of patients had at
least a
50%
reduction
in
cough
frequency,
and
35%
of
patients
had
at
least
a
70%
reduction
in
cough
frequenc
y.
【
所有的剂量均显示出能降少咳嗽频率，
< br>包括最低的
50
mg
剂量。
最低剂量
50 mg
BID
的疗效与之前发表在柳叶刀杂志的
6
00
mg
剂量相似。对数据分析后发现，
50
mg
剂量
时，
有一半的患者能减少至少
50%
的咳嗽次数，
有
35%
的患者能减少至少
< br>70%
的咳嗽次数。
】
AF-219 was generally well tolerated.
The incidence of dysgeusia (altered taste
perception), was
much lower at the 50
mg twice daily dose compared to higher doses, as
well as compared to the
first study at
600 mg twice daily, and a clear dose-dependent
effect was demonstrated. Specifically,
at the 50 mg dose, 57% of patients
noted the taste effect, even if only transiently,
at any point in
time
during
the
four
days
of
treatment.
Only
one
patient
discontinued
treatment
in
the
current
study
due
to
the
taste
effect.
In
the
previous
high-dose
study,
100%
of
patients
noted
the
taste
acuity
and
25%
discontinued
due
to
taste
effect.
There
was
one
serious
adverse
event
due
to
a
urinary tract infection.
【
AF-219
耐受性良好。
50 mg BID
发生味觉障碍（改变味觉）的概率
大大低于其他高剂量，观察到明显的剂量依赖效应。具体而言，
50 mg
剂量时，
57%
的患者
出
现味觉改变，
4
天治疗时间的某一个瞬间有味觉改变也囊括在该
数据中。仅有一名患者由
于味觉方面副作用停止治疗。在之前的研究中，
100%
的患者出现味觉效应，有
25%
的患者
因此停止治疗。出现了一例由于尿路感染引起的严重副反应。】
A
number
of
patient-reported
outcomes
(PROs)
were
also
collected,
including
a cough
severity
visual
analog
scale
(VAS),
in
which
patients
indicate
severity
of
cough,
the
Leicester
cough
questionnaire
(a
quality-of-life
measure),
and
a
cough
severity
diary.
PRO
findings
were
consistent
with
the
objective
measure
of
cough
frequency,
though
patient
perception
lagged
behind
the
objective
measurement.
The
study
data
show
that
the
effect
of
AF-219,
in
terms
of
patient-reported outcomes, is both dose
and time dependent.
【患者的自我报告（
PROs
）中，包
括咳嗽严重程度的视觉模拟评分
（
VAS
）
、
Leicester
咳嗽问卷
（生活质量指标）
、
咳嗽日记。
PRO
结果与实际测量的咳嗽频率一致，不过患者的认知要落后于客观测量的时间。研究数
据
表明，
AF-219
的疗效就患者自述的结果来说，是剂量和时
间依赖性的。】
―We are extremely
pleased that this study validates the efficacy we
had seen in our previous cough
study,
and
provides
critical
guidance
for
Phase
3
dose
selection.
In
addition
to
presenting
the
second cohort lower-dose results, we
look forward to results from our ongoing 12-week
chronic
cough
study
with
AF-219
later
this
year,
”
said
Kathleen
Sereda
Glaub,
CEO
of
Afferent
Pharmaceuticals.
―As
we
advance
development
of
AF
-219,
we
also
plan
to
evaluate
non-respiratory
indications in which P2X3 has been implicated,
with our next candidate,
AF-
130.‖
【公司
CEO
Kathleen Sereda Glaub
说：
―
这次临床试验验证了在先前的研究中看到的疗效，
为
Ph3
期剂量选择提供了关键的指导。除了还要展示第二队列的数据外，在慢性咳嗽
患者