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

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（ATS）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.【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 frequency.【所有的剂量均显示出能降少咳嗽频率，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600 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，在慢性咳嗽患者中持续12周的研究也很让人期待。除了现在有的AF-219项目，我们还计划开发AF-130在非呼吸疾病领域的临床研究。”】

Jacky Smith, MB, ChB, MRCP, PhD, professor and honorary consultant in Respiratory Medicine, University of Manchester and University Hospital Manchester NHS Foundation Trust, and a leading investigator in the field of chronic cough who presented the study results, said, “With millions of adults suffering from poorly controlled or treatment-resistant chronic cough, it is imperative that we find new options for this significant unmet medical need. AF-219 has clear promise as an efficacious, safe and well-tolerated treatment that could significantly improve the quality of life of these patients, who may also experience chest pain, vomiting, incontinence, sleep disturbances, work disruption and social isolation due to their cough.”【 公司顾问Jacky Smith博士说：“数百万成年人遭受着咳嗽这一难以控制还耐药的慢性疾病，因此该临床需求巨大的领域里找到新疗法是非常振奋人心的。AF-219有比较明确的前景作为有效、安全和耐受良好的药物来大大改善这些患者的生活质量，这些患者因为咳嗽还可能遭受着胸痛、呕吐、大小便失禁、睡眠紊乱、工作中断和社会隔离这些问题。”】

Mandel Sher, MD, clinical professor of medicine and pediatrics, Morsani College of Medicine, University of South Florida, as well as an allergist and head of

Center for Cough in Tampa Bay, said, “No new treatment for cough has been approved by the FDA in 50 years. The efficacy, safety and tolerability of AF-219 demonstrated in clinical studies to date are impressive, and potentially offer new hope for chronic cough patients who frequently suffer in isolation without adequate treatment—sometimes for many years.”【 公司负责人Mandel Sher说：“50年中FDA还未批准咳嗽方面的新药物。AF-219的临床研究结果是让人振奋的，为那些长期咳嗽而遭到隔离的患者带去新的选择。”】

Twelve-week and Idiopathic Pulmonary Fibrosis (IPF) Phase 2b Studies Ongoing

In December 2015, Afferent initiated a 12-week, Phase 2b study of AF-219 in chronic cough patients, which is expected to be complete by the end of 2016. This is a randomized, double-blind, placebo-controlled, parallel group study in which 200 chronic cough patients are treated for 12 weeks with 7.5, 20 or 50 mg, or matching placebo, twice daily. In addition, the company is evaluating AF-219 in an ongoing Phase 2b study in idiopathic pulmonary fibrosis patients (IPF) with bothersome cough and breathlessness.【为期12周的研究以及在特发性肺纤维化（IPF）中的Ph2b期研究正在进行：2015年11月，Afferent启动了为期12周的AF-219在慢性咳嗽患者中的Ph2b期研究。该研究是一项随机、双盲、安慰剂对照、平行组研究，在200名慢性咳嗽患者中进行为期12周的治疗，剂量为7.5、20或50 mg BID。此外，AF-219在IPF伴有咳嗽和呼吸困难的患者中进行了Ph2b期研究。】

About the AF-219 Proof-of-Concept Chronic Cough Study

Afferent’s initial high-dose proof-of-concept trial demonstrated a 75% reduction in cough frequency (Intent-to-treat population) in 24 refractory chronic cough patients with AF-219 treatment 600 mg twice daily for two weeks. In this first study, all 24 patients noted the change in taste acuity and 25% of these patients discontinued treatment as a result【关于AF-219在慢性咳嗽中的概念证明研究：Afferent启动了概念证明研究结果表明，在24名难治性慢性咳嗽患者中，AF-219 600 mg BID剂量治疗两周能减少75%的咳嗽次数。在这个研究中，所有的24名患者均出现味觉改变，其中25%的患者因此停止治疗。】

Chronic Cough – Debilitating Neurogenic Condition Affects Millions

Cough is the symptom for which patients most often seek medical attention. Cough can occur following an upper respiratory infection. In most patients, this cough manifests itself as an acute cough lasting a few days to weeks. However, in some patients, sensitized nerve fibers fail to return to a normal quiescent state, resulting in sub-acute or chronic cough lasting months to years. The prevalence of chronic cough is estimated to be over 10% of adults in the U.S. While an underlying etiology may contribute to cough in some of these patients (such as gasto-intestinal reflux disease or GERD, asthma, or chronic obstructive pulmonary disease), many patients are not well-controlled for their cough even with treatment for such underlying etiology, or with the addition of currently available cough medications.【慢性咳嗽——让上百万人神经衰弱：咳嗽是患者最常就医的症状之一。咳嗽可以产生于上呼吸道感染。在大多数患者中是持续几天到数周的急性咳嗽。然而，有些患者，由于致敏神经纤维不能恢复到正常的静态状态，从而形成持续数月乃至数年的亚急性或慢性咳嗽。慢性咳嗽的患病率在美国成年人中估计为10%。一些病因情况

会导致这些咳嗽症状（如气肠反流病或胃食管反流病、哮喘或慢性阻塞性肺疾病），在治疗这些病因时，即使增加了控制咳嗽的处方，很多患者还是不能很好的控制咳嗽症状。】

About P2X3 Receptor-Mediated Sensitization

Afferent’s clinical candidates – AF-219 and AF-130 – are orally available, first-in-class compounds that selectively block P2X3 receptors. P2X3 receptors play a key role in the sensitization of certain sensory nerves, notably C-fiber afferents. These nerves become activated and sensitized under pathological conditions mediated by a common cellular signal, ATP, when it is released in high concentrations due to cellular distress following injury or infection. Afferent’s compounds selectively block ATP activation of P2X3 channels, reducing a range of sensory signs and symptoms.

P2X3 receptor-mediated sensitization has also been implicated in inflammatory, visceral and neuropathic pain states, as well as airways

hyperreactivity, treatment-resistant hypertension, heart failure, migraine, itch and cancer pain.【关于P2X3受体介导的致敏作用：Afferent的临床候选药物，AF-219和AF-130，是口服首创的P2X3受体拮抗剂。P2X3受体在某些感官神经敏化中起着关键的作用，尤其是C纤维的传入过程。这些神经在病理条件下被一个共同的细胞信号ATP激活和致敏。当损伤或感染后，细胞应激产生高浓度ATP。Afferent的先导物能选择性阻断P2X3信号通路中的ATP活化，减少感觉信号和相应的症状。P2X3受体介导的致敏作用也涉及到炎症、内脏和神经性疼痛、气道高反应性、难治性高血压、心力衰竭、偏头痛、瘙痒和疼痛中。】