臨床研究報(bào)告

一期置媳、隨機(jī)惜傲、雙盲屡贺、安慰劑對(duì)照多劑量治療評(píng)估***在健康受試者中安全性妥凳、耐受性竟贯、藥代動(dòng)力學(xué)的研究

DCR學(xué)習(xí)代碼：13172

贊助商研究代碼：***-1H-01（SNO-2）

IND號(hào)：119145

***：臨床1期研究

研究適應(yīng)癥：安全性，耐受性逝钥，藥代動(dòng)力學(xué)

研究期間：2014年2月16日（篩選出第一個(gè)主題）– 2014年11月11日（最新隨訪）

贊助商N(yùn)ivalis Therapeutics屑那，Inc.（以前為N30 Pharmaceuticals）

3122 Sterling Circle，Suite 200

美國(guó)科羅拉多州博爾德市80301

贊助商聯(lián)系人Robert Hopkins艘款，DVM持际，MS

電話：+1（720）945-7716

傳真：+1（303）440-8399

研究者DaVita臨床研究

11750 W. 2nd Place，Suite 300哗咆，Lakewood蜘欲，CO 80228美國(guó)

研究人員克里斯·加洛韋（醫(yī)學(xué)博士）

電話：+1（303）566-3100

傳真：+1（303）542-7300

RN BSN的項(xiàng)目經(jīng)理Marla Elhard

電話：+1（303）566-3005

傳真：+1（855）544-8170

作者Christopher A. Graybill博士，醫(yī)學(xué)作家（達(dá)維塔）

斯科特·布蘭特利（Scott Brantley）博士岳枷，藥代動(dòng)力學(xué)科學(xué)家（Nuventra）

Eugene R. Heyman博士芒填，高級(jí)生物統(tǒng)計(jì)學(xué)家（Cardiocore）

醫(yī)學(xué)博士Daniel B. Goodman，副總裁兼醫(yī)療總監(jiān)

（心臟）

格雷格·吉恩（Greg Ginn）空繁，碩士殿衰，生物統(tǒng)計(jì)學(xué)家（DaVita）

這份報(bào)告的日期：2015年9月18日

這項(xiàng)研究是遵循良好臨床規(guī)范（GCP）的原則進(jìn)行的，包括基本文件的存檔盛泡。 本報(bào)告是按照國(guó)際協(xié)調(diào)會(huì)議（ICH）指南編寫(xiě)的闷祥。

概要

研究主題：一項(xiàng)1期，隨機(jī)，雙盲凯砍，安慰劑對(duì)照箱硕，多劑量評(píng)估***在健康受試者中的安全性，耐受性和藥代動(dòng)力學(xué)的劑量研究悟衩。

研究代碼

DCR學(xué)習(xí)代碼：13172

贊助商研究代碼：***-1H-01（SNO-2）

IND號(hào)：119145

贊助商：Nivalis Therapeutics剧罩，Inc.（以前稱為N30 Pharmaceuticals，Inc.）

3122 Sterling Circle座泳，Suite 200惠昔，Boulder，CO 80301美國(guó)

贊助者聯(lián)系人：Robert Hopkins挑势，DVM镇防，MS

研究中心：DaVita臨床研究

11750 W. 2nd Place，Suite 300潮饱，Lakewood来氧，CO 80228美國(guó)

項(xiàng)目經(jīng)理：RN BSN的Marla Elhard

研究者：醫(yī)學(xué)博士克里斯托弗·加洛韋（Christopher Galloway）

出版：撰寫(xiě)本報(bào)告時(shí)無(wú)

研究時(shí)間：初篩日期至最后隨訪時(shí)間：2014年2月16日– 2014年11月11日

臨床階段：I期

目標(biāo)

主要目標(biāo)：

?為了評(píng)估***在健康受試者劑量遞增中的安全性和耐受性。

次要目標(biāo)：

?多次服用后評(píng)估***及其主要代謝產(chǎn)物N91288的藥代動(dòng)力學(xué)（PK）香拉。

方法

設(shè)計(jì)：

這計(jì)劃作為一項(xiàng)雙盲啦扬、隨機(jī)、安慰劑對(duì)照缕溉、多劑量組研究考传，然而，后續(xù)增加了兩個(gè)單劑量組证鸥，在這個(gè)研究的多劑量組中，至少計(jì)劃4個(gè)遞增組每組8個(gè)受試者（6個(gè)試驗(yàn)藥勤晚，2個(gè)安慰劑）枉层，每一個(gè)受試者接受篩選（給藥前28天到給藥前3天），如果符合條件赐写，在給藥前一天返回醫(yī)院并進(jìn)行再次確認(rèn)資格鸟蜡，合格受試者會(huì)收到***或安慰劑研究藥物的口服劑量，在研究的第1天到第14天觀察安全性問(wèn)題挺邀，在臨床研究單位的基地直到在第15天沒(méi)有變化揉忘；藥代動(dòng)力學(xué)來(lái)自于研究第1天到第16天的早上。個(gè)別特殊的受試者可能持續(xù)49天從篩選期到研究結(jié)束端铛，一個(gè)安全委員會(huì)收到每組完成后的安全性數(shù)據(jù)泣矛，來(lái)決定是否進(jìn)入下一個(gè)增加劑量組的計(jì)劃。改變計(jì)劃劑量組禾蚕，重復(fù)劑量組您朽，或者根據(jù)協(xié)議中概述停止研究。

單劑量組每組也納入8個(gè)受試者（6個(gè)試驗(yàn)藥换淆，2個(gè)安慰劑）哗总，分別評(píng)估單劑量組的PK和食物攝入的影響几颜。

治療方法：

?***（10、50讯屈、250和500 mg）膠囊蛋哭，每天口服一次，連續(xù)14天（多次劑量組）或一次（單劑量組）

?匹配的安慰劑膠囊涮母，每天口服一次

程序和評(píng)估：

資格篩選包括病史谆趾，人口統(tǒng)計(jì)學(xué)信息，既往和伴隨用藥哈蝇，體格檢查棺妓，體格測(cè)量（身高，體重炮赦，體重指數(shù)[BMI]）怜跑，12導(dǎo)聯(lián)心電圖（ECG）評(píng)估，48小時(shí)動(dòng)態(tài)ECG心律失常（Holter）監(jiān)測(cè)）評(píng)估吠勘，生命體征測(cè)量性芬，臨床實(shí)驗(yàn)室檢查（血清學(xué)，血液學(xué)剧防，血液化學(xué)植锉，尿液分析，婦女妊娠試驗(yàn)）以及藥物和酒精檢查

PK評(píng)估：***和N1979的血液和尿液PK評(píng)估

安全性：12導(dǎo)聯(lián)心電圖記錄峭拘，不良事件（AE）監(jiān)測(cè)俊庇，動(dòng)態(tài)心電圖（Holter），臨床安全實(shí)驗(yàn)室測(cè)試鸡挠，伴隨用藥辉饱，身體檢查，脈搏血氧飽和度測(cè)定血紅蛋白氧飽和度拣展，妊娠試驗(yàn)彭沼，肺活量測(cè)定，遙測(cè)备埃，生命體征姓惑，體重；

納入的主要標(biāo)準(zhǔn)

年齡：18-55歲（含）

體重指數(shù)：≥19.5 kg / m2和≤32.0 kg / m2

對(duì)象：健康的白人男性和女性對(duì)象按脚，無(wú)臨床上重要的心臟發(fā)現(xiàn)史

研究藥物

活性物質(zhì)：***

劑型：膠囊

強(qiáng)度/批號(hào)：5 mg / N454451

強(qiáng)度/批號(hào)：25毫克/ N454891

強(qiáng)度/批號(hào)：50毫克/ N456044

制造商：Norwich Pharmaceuticals (Norwich, NY)

名稱：安慰劑

劑型：膠囊

批號(hào)：N454450

制造商：Norwich Pharmaceuticals (Norwich, NY)

評(píng)估標(biāo)準(zhǔn)/主要結(jié)局

藥效學(xué)：不適用

藥動(dòng)學(xué)：這是一項(xiàng)雙盲于毙、隨機(jī)、安慰劑對(duì)照乘寒、多劑量組研究望众。4個(gè)遞增劑量10, 50, 250 和500 mg，研究的每個(gè)組有8個(gè)受試者（6個(gè)試驗(yàn)藥，2個(gè)安慰劑）烂翰，在研究第1天到第14天夯缺，每個(gè)受試者收到研究藥物的口服劑量，***或者安慰劑甘耿，然后追蹤安全性和藥動(dòng)學(xué)評(píng)估踊兜；

血漿PK：第一天的PK參數(shù)取決于第一劑量組***的濃度-時(shí)間數(shù)據(jù)，包括最大濃度值（Cmax）佳恬，最大濃度值的時(shí)間（Tmax）捏境，在濃度-時(shí)間曲線下計(jì)算從0時(shí)刻到最后可測(cè)量和無(wú)窮大下的面積（AUC0-t，AUCinf）毁葱；和最終消除半衰期(T?).垫言，另外估計(jì)口服清除率(CL/F)和最大表觀分布容積(Vz/F)，包含14天濃度-時(shí)間數(shù)據(jù)中***的穩(wěn)態(tài)PK參數(shù)倾剿，Cmax, Tmax, t?, AUC0-12, AUC0-τ, CLss/F筷频，以及累計(jì)比率(Racc)。

***主要經(jīng)歷了葡萄糖醛酸化前痘，直至N1979凛捏，O-葡萄糖醛酸含量占所測(cè)葡萄糖醛酸代謝物總量的> 95％。N91288芹缔，跖餮ⅲ基-葡糖醛酸苷是次要成分，占總含量的<3％.這代謝物的藥動(dòng)學(xué)參數(shù)由N1979和N91288離子體的總血漿濃度決定的最欠，并被稱為N1979,在PK報(bào)告和整個(gè)文章中的主要代謝物示罗。N1979的在第一劑量組第一天濃度-時(shí)間數(shù)據(jù)包括：Cmax, Tmax, t?, AUC0-24,

AUCinf，原型代謝物與原型的比值（M/P）芝硬，來(lái)自***的14天穩(wěn)態(tài)PK參數(shù)濃度-時(shí)間數(shù)據(jù)包括：Cmax, Tmax, t?, AUCtau, Racc, and M/P 比值鹉勒，通過(guò)至少使用3個(gè)時(shí)間點(diǎn)的對(duì)數(shù)值（終末期的）血漿濃度對(duì)數(shù)線性回歸來(lái)估計(jì)最終消除半衰期

尿PK：隊(duì)列2在D1計(jì)算***和代謝物N1979PK參數(shù)即腎臟清除率（Clt）和累積回收量（Ae0-t）原型

安全性：安全性評(píng)估是基于AE報(bào)告醫(yī)學(xué)審查和12導(dǎo)聯(lián)ECG測(cè)量，動(dòng)態(tài)ECG（Holter）吵取，臨床安全性實(shí)驗(yàn)室檢測(cè)（包括血液學(xué)，CRP臨床化學(xué),尿液分析）锯厢，伴隨用藥皮官，體格檢查，通過(guò)脈搏血氧儀測(cè)定的血紅蛋白血樣飽和度实辑，孕檢炊甲，肺活量啰挪，遙測(cè)，生命體征測(cè)量，和體重哀托；

統(tǒng)計(jì)學(xué)方法

樣本量大小測(cè)定铺然，這是一個(gè)暴露動(dòng)力學(xué)研究，因此對(duì)于統(tǒng)計(jì)學(xué)分析推斷沒(méi)有把握度，沒(méi)有正式進(jìn)行樣本量測(cè)算斋否；受試者數(shù)量的選擇是基于可行性，被認(rèn)為足以滿足研究主題拭荤。

藥動(dòng)學(xué)參數(shù)：***和 N1979的PK參數(shù)被推導(dǎo)運(yùn)用WinNonlin軟件6.3版本茵臭，估計(jì)PK參數(shù)來(lái)自于使用非房室分析標(biāo)準(zhǔn)方法計(jì)算的血漿濃度，使用實(shí)際收集時(shí)間計(jì)算舅世，使用方差分析比較PK參數(shù)旦委；

安全性參數(shù)：將不良事件列表化；臨床實(shí)驗(yàn)室檢測(cè)雏亚，12導(dǎo)聯(lián)ECG數(shù)據(jù)缨硝、生命體征數(shù)據(jù)被匯總描述，并描述了與基線相比的變化罢低，ECG的分析數(shù)據(jù)（在第1-2天和第14-15天的3個(gè)時(shí)間點(diǎn)進(jìn)行三次重復(fù)測(cè)量查辩，以及在其他時(shí)間點(diǎn)進(jìn)行單次測(cè)量），包括心率奕短，QRS軸宜肉，PR間隔，QRS持續(xù)時(shí)間翎碑，RR間隔和 QT間隔谬返；QTcF被計(jì)算。所有的ECG要通過(guò)合格的日杈，能集中心臟安全性的心臟病專家進(jìn)行遣铝。

結(jié)果

受試者分布

總共有49例受試者被隨機(jī)安排進(jìn)入試驗(yàn)，47例受試者（96%）完成了試驗(yàn)莉擒，2例受試者由于個(gè)人原因（與實(shí)驗(yàn)無(wú)關(guān)）提前終止試驗(yàn)酿炸；總共49例受試者，其中37例男性12例女性涨冀，所有受試者均為白種人填硕，受試者平均年齡（±標(biāo)準(zhǔn)差）是39.1 (11.4)歲。

***的暴露

參與試驗(yàn)受試者的分組與劑量安排如下：

多劑量組（劑量14天）鹿鳖，每組6例受試者服用試驗(yàn)藥扁眯，2例受試者服用安慰劑，總共有24例受試者服用N9115,9例服用安慰劑（包括一例替代受試者）翅帜。

?第1組: 10 mg

?第 2組: 50 mg

?第3組: 250 mg

?第4組: 500 mg

單劑量組姻檀，每組6例受試者服用***，2例受試者服用安慰劑涝滴；

?第2a組：50 mg

?第5組：250 mg（高脂餐）

藥代動(dòng)力學(xué)：藥代動(dòng)力學(xué)概述每天口服*** 10至500 mg绣版，共14天胶台，所有劑量組在給藥后2小時(shí)內(nèi)達(dá)到峰值濃度，從而迅速吸收杂抽。Cmax幾何均值與劑量遞增成比例增加诈唬。、AUC0-tau的增加略大于劑量增加比例默怨。高脂餐組250 mg劑量的***Tmax為4小時(shí)讯榕，而在禁食狀態(tài)下為1.5小時(shí)，但*** Cmax和AUC0-t相對(duì)于禁食狀態(tài)的在90％以內(nèi)匙睹，表明食物對(duì)*** PK的影響最小愚屁。低劑量下末期半衰期（t?）的幾何平均估計(jì)值更長(zhǎng)，低劑量下為10.5至14.9小時(shí)劑量痕檬，高劑量組約5個(gè)小時(shí)霎槐，分別為250和500 mg劑量。對(duì)于所有劑量組梦谜，穩(wěn)態(tài)下的幾何平均清除率范圍在13.9至23.6 L / h之間丘跌，線性分析中注意到清除率的劑量依賴性降低。對(duì)于所有劑量組唁桩，暴露累積率Racc（AUC）和Racc（Cmax）的幾何平均值最小闭树，分別在> 1.2至> 1.33的范圍內(nèi)。這表明在低劑量每天重復(fù)一次后荒澡，***表現(xiàn)出最小的積累报辱，而在測(cè)試的最高劑量下則沒(méi)有積累。

每天口服10至500毫克后单山，***會(huì)通過(guò)葡萄糖醛酸化作用快速而廣泛地代謝為兩種非活性代謝物碍现。 代謝物的濃度大約是100％到300％***血漿濃度。 血漿代謝物濃度的總和為N1979（O-葡萄糖醛酸）和N91288（趺准椋基葡萄糖醛酸）昼接。 N1979濃度> 95％，N91288濃度<5％悴晰。 因此慢睡，據(jù)報(bào)道代謝物PK值與N1979相同。

N1979出現(xiàn)相對(duì)較快铡溪，所有隊(duì)列的峰值濃度均在不到4.0小時(shí)內(nèi)達(dá)到.Cmax和AUCtau值以小于劑量比例的方式增加一睁。 在較低劑量下，末期半衰期（t?）較大（10.4 – 11.6小時(shí)）佃却，在較高劑量下則較小（?5小時(shí)）窘俺。 原型和代謝物之間半衰期值的相似性表明饲帅，N1979的消除受到形成速率的限制复凳。 暴露累積比率Racc（AUC）和Racc（Cmax）介于0.9到1.3之間，表明多次給藥時(shí)代謝產(chǎn)物暴露的累積量可忽略不計(jì)灶泵。 高脂食品的Tmax為5小時(shí)育八，而禁食狀態(tài)的Tmax為3小時(shí)。 然而赦邻，與禁食狀態(tài)相比髓棋，N1979 Cmax和AUC0-t值略高（106％-101％），表明食物對(duì)N1979 PK的影響最小惶洲。

在隊(duì)列2的受試者中按声，在第1天評(píng)估了***和N1979（葡糖醛酸苷代謝產(chǎn)物）的尿排泄量。 ***和N1979的腎臟清除率較低恬吕，分別為1.31 L / h和3.67L / h签则。這代表了***和N1979普通健康成年人肌酐清除率的大約20％和50％，

分別铐料〗チ眩總體而言，***劑量的55％在24小時(shí)內(nèi)排泄在尿液中钠惩，其中***占5％柒凉，代謝產(chǎn)物占50％（N1979和N91288）。由于***的腎臟清除率較低篓跛，且24小時(shí)內(nèi)***的血漿濃度相對(duì)較低膝捞，因此代謝和/或其他非腎臟清除途徑（可能是膽道清除）似乎是原型藥物總體清除的主要原因。

***血漿藥代動(dòng)力學(xué)在第1天口服***后举塔，血漿***濃度相對(duì)較快達(dá)到峰值绑警，所有人群的中位Tmax值在1.50至5.00小時(shí)之間。在所有受試者中央渣，給藥后24小時(shí)血漿中***仍可定量计盒。第2組的受試者在第1天不慎服用了25 mg，而不是計(jì)劃的50 mg芽丹；因此北启，添加了同類群組2a以接受單次50 mg劑量。幾何平均Cmax值隨劑量的增加而增加拔第，從10 mg的33.0 ng / mL增加到25 mg的111 ng / mL咕村，245 ng / mL，1810 ng / mL蚊俺，1600 ng / mL和3840 ng / mL 懈涛，50毫克，250毫克（禁食）泳猬，250毫克（禁食）和500毫克劑量水平批钠。對(duì)于10mg至500mg劑量水平宇植，Cmax的幾何平均％CV范圍為14.0％至57.8％。與Cmax相似埋心，AUC值隨劑量增加而增加指郁。幾何平均AUClast值分別為327 h * ng / mL，893 h * ng / mL拷呆，1530 h * ng / mL闲坎，12000 h * ng / mL，10300 h * ng / mL和32400 h * ng / mL分別為10毫克茬斧，25毫克腰懂，50毫克，250毫克（禁食）啥供，250毫克（禁食）和500毫克劑量悯恍。對(duì)于10mg至500mg劑量水平，幾何平均AUCinf值的范圍為357h * ng / mL至32500h * ng / mL伙狐。

第1天的***暴露參數(shù)（Cmax涮毫，AUClast和AUCinf）呈線性且略有增加在最大劑量下大于劑量成比例的方式。對(duì)于10贷屎、25和50 mg劑量水平罢防，***的表觀清除率（CL / F）似乎與劑量無(wú)關(guān)，但對(duì)于250和500 mg劑量水平唉侄，其表觀清除率（CL / F）相對(duì)較低咒吐。高脂餐后5分鐘內(nèi)給予***的平均Cmax和AUC值比空腹受試者給予***的平均Cmax和AUC值低約15％。

到第7天属划，除一名受試者外（在50毫克隊(duì)列中）恬叹，所有受試者的劑量前***濃度均可量化。由于與第1天和第14天相比同眯，在第7天收集的血漿樣品相對(duì)較少绽昼，因此第7天PK參數(shù)的估計(jì)值較不可靠。因此须蜗，第7天PK值應(yīng)用于定性而非定量目的硅确。

在10到500 mg劑量范圍內(nèi)，幾何平均Cmax值以略大于劑量比例的方式從67.9 ng / mL增加到6200 ng / mL明肮。對(duì)于10到500 mg劑量菱农，最終相半衰期（t?）的幾何平均估計(jì)值隨著劑量從8.03小時(shí)增加到4.71小時(shí)而降低。與Cmax一致柿估，AUC0-tau以大于劑量比例的方式增加循未，對(duì)于10 mg至500 mg組，其幾何平均值為442 h * ng / mL至40800 h * ng / mL秫舌。

在第14天只厘。所有受試者能獲得***的濃度烙丛。與第一天相比，***的出現(xiàn)更加迅速羔味，所有組的Tmax中位值均小于兩個(gè)小時(shí)。與第一天相反钠右， Cmax幾何均值增加與劑量成正比赋元，對(duì)10mg和500mg組，從84.3 ng/mL 增長(zhǎng)到5800 ng/mL飒房。與第一天一致搁凸，AUC0-tau以略大于劑量比例的方式增加。在低劑量最終消除半衰期的幾何平均估計(jì)值更長(zhǎng)狠毯，對(duì)10 mg和 50 mg 劑量組护糖，值分別為在14.9到10.5；對(duì)250和50 0g劑量組的值分別為5.58和5.21嚼松。

在低劑量組中較長(zhǎng)的半衰期更有可能取決于采樣時(shí)間表嫡良，因?yàn)橹挥?0 mg和 50 mg 劑量組水平采樣時(shí)間達(dá)到48小時(shí)，在穩(wěn)態(tài)狀態(tài)下所有劑量組的清除率的幾何均值范圍在13.9-23.6 L/h之間献酗，線性分析中記錄了清除率的劑量依賴性在降低寝受。在10、25罕偎、250 mg 組中暴露累計(jì)比的幾何均值是大于1.2的很澄，但是500mg組的是1.01。這表明每天重復(fù)一次后***展示了在低劑量組很低的累積值颜及，在高劑量組沒(méi)有累計(jì)值甩苛。對(duì)于所有劑量組檢測(cè)峰濃度的幾何均值累計(jì)比(Racc(Cmax)) >1.33，表明每天重復(fù)一次劑量俏站，峰濃度增加中等程度讯蒲。

代謝物N1979血漿藥代動(dòng)力學(xué)，在第1天口服***之后乾翔，N1979血漿濃度爱葵，無(wú)活性代謝物出現(xiàn)相對(duì)較快，顯示Tmax值的中位數(shù)約為4.0小時(shí)反浓。在所有受試者服藥萌丈，N1979服藥后24小時(shí)血漿中N1979仍然可測(cè)量，表明多劑量組中有累積效應(yīng)雷则。與空腹受試者相比辆雾，高脂餐后5分鐘內(nèi)服用***可使N1979 Cmax的均值和N1979的AUCinf幾何均值值均高出約6％。 空腹?fàn)顟B(tài)下N1979的出現(xiàn)較快月劈， Tmax值中位數(shù)比餐后狀態(tài)早2.0小時(shí)度迂。 總體而言藤乙，代謝物與原型的幾何均值比值≥1.40，在較低劑量（10-50 mg）下可見(jiàn)最大比例惭墓。

在第7天坛梁，除了1個(gè)受試者（50mg組）所有的受試者劑量前N1979濃度均可以被測(cè)量，由于在第7天血漿樣本數(shù)量相對(duì)較少（與第1天和第14天相比）腊凶，這個(gè)PK參數(shù)估計(jì)與其他天相比可能可靠性較低划咐。基于這個(gè)原因钧萍，這些值常常用來(lái)定性褐缠，而不是定量的目的。10和500 mg 組,Cmax值的幾何均值分別以小于劑量比例的方式從359 ng/mL 增加到 9580 ng/mL风瘦。末端半衰期的幾何均值估計(jì)值在劑量組之前是一致的队魏，值在5.61-6.09小時(shí)之間。對(duì)于 10 mg,万搔、50 mg,胡桨、250 mg、500 mg組蟹略，與Cmax一致登失，AUC0-24比劑量比例增加，其幾何均值分別是2020 h*ng/mL挖炬，8950 h*ng/mL, 47200 h*ng/mL, 83400 h*ng/mL揽浙。如第一天所見(jiàn)，根據(jù)***的低劑量（10 和50 mg）意敛，這個(gè)代謝物和原型的幾何均值比是更高的馅巷。在500mg劑量水平,代謝物與原型Cmax幾何均值比小于這個(gè)單位（0.0973），而其余組的比率均大于1草姻。

在第14天钓猬，所有受試者均可以在藥物服用前測(cè)出N1979濃度。N1979的出現(xiàn)是非沉枚溃快的敞曹，所有組中Tmax值的中位數(shù)小于4小時(shí)。10 mg 到500 mg 組综膀，Cmax值的幾何均值的增加分別小于從389 ng/mL 到 8270 ng/mL的劑量比例澳迫。10 mg 到500 mg 劑量組水平，AUCtau的的增加是小于劑量比例的增加剧劝，其幾何均值分別為2110 h*ng/mL 和 69600 h*ng/mL橄登。末端半衰期在低劑量組更長(zhǎng)，10 mg 和50mg劑量組值分別是11.6和10.4，250mg 和500mg劑量組值分別是5.77和5.74拢锹。對(duì)于低劑量組更長(zhǎng)的半衰期可能取決于采樣時(shí)間表谣妻，，因?yàn)橹挥?0 mg和 50 mg 劑量組水平采樣時(shí)間達(dá)到48小時(shí)卒稳。在原型和代謝物半衰期的值相似性表明N1979的消除受形成速率的影響蹋半。由于代謝物的末端消除半衰期不應(yīng)該短于原型的末端消除半衰期，這N1979的末端消除半衰期很有可能在大部分受試者中被低估了充坑。這暴露累計(jì)比值Racc(AUC) 的幾何均值范圍從0.88到1.09湃窍，表明多次給藥的代謝物積累量可忽略不計(jì)。這峰濃度累計(jì)率(Racc(Cmax) 范圍從0.907到1.33匪傍，進(jìn)一步表明缺乏累計(jì)。在第14天代謝物和原型的Cmax幾何均值比范圍在0.898到2.91觉痛，AUCtau幾何均值比范圍在1.22到3.14役衡。表明N1979的全身暴露是***的100% 至300%。

尿液藥代動(dòng)力學(xué)薪棒，*** 和 N1979的尿排泄手蝎，葡萄糖醛酸代謝物，在第2組受試者的第1天被評(píng)估俐芯。25 mg ***組的大約有5%（第2組第1天）被清楚棵介，因?yàn)槟蛞褐?**沒(méi)有變化，導(dǎo)致腎清除率低至1.31 L/h吧史，大約是普通健康成人的肌酐清除率的20％邮辽。由于***較低的腎清除率和24小時(shí)內(nèi)***的低血漿濃度，它表明代謝和/或其他非腎臟清除途徑（可能是膽汁清除）的清楚是原型藥物的全身清除的主要原因贸营。

尿液中排出的N1979的幾何平均質(zhì)量為19.1 mg吨述，它代表了25mg劑量組的50%。這N1979的腎臟清除率是3.67 L/h钞脂，大約是普通健康成人的肌酐清除率（7.2 L/h）的50％揣云。

這個(gè)結(jié)果表明與原型藥物相比，N1979主要經(jīng)歷了腎臟清除冰啃，正如表明的那樣通過(guò)高劑量組清除和有更大的腎臟清除估計(jì)值邓夕。

綜合，***劑量的55%在24小時(shí)內(nèi)排除到尿液中阎毅，5%是原型焚刚，50%是代謝物（N1979 和 N91288）。

安全性：49例受試者中報(bào)道中有40名（81.6%）在研究期間至少有1次發(fā)生與治療相關(guān)的不良事件净薛。在第1組和第4組的所有受試者（這些接受***和 placebo14天的）報(bào)道了1個(gè)與藥物相關(guān)的汪榔，而在第2a組（16.7%）和第5組（66.7%）只有很少的受試者報(bào)道與藥物相關(guān)，可能是由于在這兩組中***的給藥時(shí)間更短。***有很好的耐藥性痴腌，所有的與藥物相關(guān)的嚴(yán)重程度為輕度雌团，沒(méi)有觀察到與劑量相關(guān)的不良時(shí)間發(fā)生率增加，***沒(méi)有比安慰劑更廣泛的事件出現(xiàn)士聪。一個(gè)最大耐受劑量是不確定锦援，因?yàn)樵诟邉┝吭囼?yàn)中是沒(méi)有劑量限制性毒性是確定的。

第1-4組剥悟，受試者合并安慰劑治療（14天劑量）

藥物相關(guān)報(bào)道頻率最多的是接觸性皮炎灵寺、頭痛、頭暈区岗。在第1-4組中接受***或安慰劑的所有受試者中均發(fā)生接觸性皮炎略板，在第1組和第2組中有3/6（50%）的受試者發(fā)生頭痛，但是在第3組和第4組中慈缔，下降到0/6和1/6 (17%)叮称， 1/9 (11%)發(fā)生在安慰劑受試者中。在第2組中有2/6(33%)的受試者發(fā)生頭暈藐鹤，且2/9（22%）發(fā)生在安慰劑組瓤檐。在所有被報(bào)告的受試者中，對(duì)于心電圖導(dǎo)聯(lián)來(lái)說(shuō)接觸性皮炎被認(rèn)為是次要的娱节。由于接觸性皮炎和頭痛的發(fā)生頻率挠蛉，SOC皮膚和皮下組織疾病顯示出TEAE的發(fā)生頻率最高，并且SOC神經(jīng)系統(tǒng)疾病顯示了下一個(gè)TEAE最高頻率肄满，所有的TEAEs在嚴(yán)重程度上是輕度谴古。

有19例受試者（38.8%）報(bào)告了與研究藥物有相關(guān)性的TEAEs。在第1悄窃、2組（67%）這些事件百分比較第3讥电、4組（33%）更高，在最后兩個(gè)組中轧抗，發(fā)生率低于安慰劑組（56%）恩敌。由研究藥物引起的報(bào)告最常見(jiàn)的不良事件是，發(fā)生頭痛的總共有7個(gè)受試者（在第1横媚、2纠炮、3、4組中分別是2例[33%],1例[17%],0例,1例[17%]灯蝴，其中安慰劑1例[11%]）;發(fā)生頭暈的總共有4名受試者（在第2組2例[33%]恢口，安慰劑組2例[22%]）。發(fā)生口瘡性口炎總共有3例受試者（第1組2例[33%]穷躁，安慰劑組1[11%]）;發(fā)生便秘的總共有3名受試者（第2組1例[17%],安慰劑1例[11%]）耕肩。所有的其他因素相關(guān)的不良時(shí)間被報(bào)告的僅僅只有1人。

這里沒(méi)有嚴(yán)重不良事件，沒(méi)有與藥物相關(guān)的不良事件導(dǎo)致試驗(yàn)中斷和停止猿诸，并且沒(méi)有不良事件導(dǎo)致死亡婚被。

在12導(dǎo)聯(lián)ECT數(shù)據(jù)、臨床實(shí)驗(yàn)室結(jié)果和其他的安全性數(shù)據(jù)顯示沒(méi)有重大臨床意義事件梳虽。

第2a組和第5組（單次給藥組）

接觸性皮炎是報(bào)告最多的事件址芯，第5組中有4例（67%）受試者發(fā)生，安慰劑有1例（25%）受試者發(fā)生窜觉。只有一個(gè)其他事件被報(bào)告：在2a組和安慰劑各有一例受試者發(fā)生頭痛谷炸。

心血管安全，除了對(duì)心率的影響很小禀挫，ECG數(shù)據(jù)發(fā)現(xiàn)全部為陰性:所有治療組旬陡，包括安慰劑，在第14天心率增加语婴。***的500mg劑量組最高的心率和最大的增加是相關(guān)的季惩，但是這個(gè)增加與其他劑量組和安慰劑沒(méi)有明顯差異。隨著***劑量增加或*** or N1979的濃度的增加腻格，更高的變化值沒(méi)有一致的趨勢(shì)。

沒(méi)有AV傳導(dǎo)干擾是和***的給藥有關(guān)啥繁，在觀察期內(nèi)腦室內(nèi)傳導(dǎo)變化不一致菜职。心肌復(fù)極不受***給藥的影響，***, N91288, 或 N1979的QTcF和血漿濃度的改變是沒(méi)有相關(guān)性的旗闽。

除了對(duì)心率影響很小以外酬核，心電動(dòng)態(tài)檢測(cè)儀結(jié)果全部是陰性，24小時(shí)心率值的均值适室，最大值嫡意，最小值在治療期間沒(méi)有改變，雖然所有治療組平均每小時(shí)心率值顯示在第1天末與基線相比有微小增加捣辆。在第14天蔬螟，*** 500 mg組的受試者HR每小時(shí)值顯示最低高度，但是沒(méi)有注意到一致的劑量趨勢(shì)汽畴，對(duì)比安慰劑改變也沒(méi)有明顯差異旧巾。

新房異位的結(jié)果是正常的。這里有少數(shù)室上性心動(dòng)過(guò)速發(fā)作忍些，

所有22拍或更短的持續(xù)時(shí)間最大是147 bpm.鲁猩，在研究中未發(fā)現(xiàn)明顯的室性異常，除了在*** 50 mg組第二天單個(gè)受試者發(fā)生了短暫的心室發(fā)作罢坝。最大持續(xù)時(shí)間是6拍廓握，最大總體心率是99bpm。動(dòng)態(tài)心電圖診斷結(jié)果不明顯。

QTcF的均值是很窄的范圍從398.5 到 426.8 msec隙券，在觀察的整個(gè)試驗(yàn)中男应，幾乎沒(méi)有發(fā)現(xiàn)變化。對(duì)所有治療的QTcF的均值變化與基線相比是非常相似的是尔，但是在第1天2-8小時(shí)和第14天的4小時(shí)確實(shí)顯示出更大的減少趨勢(shì)殉了，變化的平均值是最小總體范圍從18.6 msec（250 mg組,14天，4小時(shí)）到 9.9 msec（10 mg組拟枚，10天薪铜，服藥前）。沒(méi)有明顯的劑量組的趨勢(shì)恩溅「艄浚回歸分析顯示QTcF的改變和***的濃度，或N1979的濃度沒(méi)有關(guān)系脚乡⊙烟玻回歸的斜率近似為0.220 和0.235，非顯著性P值為0.71和 0.65奶稠。從最低到最高的觀察濃度QTcF預(yù)測(cè)變化值幾乎相同俯艰，-0.7和 0.1 msec,***分別為-0.8和0.1msec，N1979分別為-0.8和0.1msec锌订。

心電圖和動(dòng)態(tài)心電圖檢查結(jié)果是互相補(bǔ)充的竹握，在這兩種情況下，在*** 500 mg 治療中顯示心率最小的增加辆飘，與安慰劑相比沒(méi)有顯著差異啦辐。心臟加速的趨勢(shì)僅僅與高劑量組有關(guān)，在增加時(shí)間或劑量趨勢(shì)一致的情況下沒(méi)有顯示出藥效學(xué)的效果蜈项。

結(jié)論

***-1H-01 (SNO-2)臨床研究的主要目的是評(píng)估在健康受試者中每日一次口服膠囊14天評(píng)估***的安全性和耐受性芹关。第二個(gè)目的是評(píng)估在健康受試者中***的藥代動(dòng)力學(xué)。36個(gè)受試者被隨機(jī)分配服用***，所有受試者被納入***及其代謝物N1979的藥代動(dòng)力學(xué)分析中。

***血漿PK結(jié)論

每日一次以10, 50, 250, 和500 mg劑量口服***膠囊14天诵肛，N9115的藥代動(dòng)力學(xué)結(jié)果如下：

?***經(jīng)歷了快速吸收，所有組的Tmax均小于2小時(shí)浇冰。

?在10 mg至500 mg組中Cmax幾何均值按劑量比例增加。

?同樣聋亡，對(duì)于10 mg至500 mg組肘习，穩(wěn)態(tài)時(shí)AUCtau幾何均值以略大于劑量比例的方式增加。

?較低劑量下末期半衰期的幾何平均估計(jì)值（t?）更長(zhǎng)坡倔，10和50 mg劑量組分別為14.9和10.5漂佩，而250和500 mg劑量分別為5.58和5.21脖含。

?***在第14天之前（可能在第7天或之前）達(dá)到穩(wěn)定狀態(tài)。

?所有劑量組在穩(wěn)態(tài)下的幾何平均清除率范圍在13.9至23.6 L / h之間投蝉，清除率與劑量有關(guān)养葵，可能由于新陳代謝的飽和而降低。

?在低劑量每天重復(fù)一次之后瘩缆，***顯示出最小的累計(jì)（Racc（AUC）> 1.2）关拒，而在測(cè)試的最高劑量下則無(wú)累計(jì)。

?同樣庸娱，所有試驗(yàn)劑量組的幾何平均峰濃度累積比（Racc（Cmax））> 1.33着绊，這表明，每天重復(fù)一次給藥熟尉，峰濃度會(huì)略有增加归露。

?在高脂餐中服用250 mg ***不會(huì)影響平均Cmax和AUC值，這比空腹受試者的水平低約15％斤儿。

血漿代謝物N1979藥代動(dòng)力學(xué)結(jié)論

每天一次口服10剧包、50、250和500 mg ***藥物往果，共14天疆液，導(dǎo)致其通過(guò)葡萄糖醛酸化作用快速和廣泛地代謝為兩種非活性代謝物，主要代謝為O-葡糖醛酸N1979（總代謝物的含量> 95％）陕贮，并在較小程度上（總含量的<5％）轉(zhuǎn)化為N91288的趺墩常基葡糖醛酸苷。多次口服10 至500 mg劑量N9115后主要代謝物N1979的要藥代動(dòng)力學(xué)的總結(jié)如下：

?N1979的較快的出現(xiàn)飘蚯，所有組的Tmax值中位數(shù)小于4小時(shí)。

?所有組中福也，Cmax幾何均值以低于劑量比例方式增加局骤，表明代謝可能達(dá)到飽和。

?類似的暴凑，AUCtau幾何均值隨著劑量的遞增以低于劑量比例方式增加峦甩。

? N1979末端半衰期幾何均值估計(jì)隨著劑量遞減而減小现喳；

?原型與代謝物相似的半衰期值表明劑量的增加限制了N1979的形成速率凯傲。

?通過(guò)累計(jì)暴露比值的幾何均值(Racc(AUC) 和 Racc(Cmax))顯示N1979展示的多次暴露累積曝光量可忽略不計(jì)。

?Cmax 和 AUCtau代謝物和原型的幾何均值比隨著***劑量的增加而減少嗦篱，范圍是***.的300% 到 100%冰单。

*** 和代謝物 N1979 尿液藥代動(dòng)力學(xué)

*** 和 N1979的尿液排泄，在第2組第1天受試者葡萄糖醛酸代謝物被評(píng)估灸促。

?***的腎臟清除率低至1.17 L/h,诫欠，這大約是健康受試者肌酐清除率的20％涵卵，并且24小時(shí)內(nèi)***低血漿濃度表明，對(duì)于原型藥物總體清除率荒叼，代謝和/或其他非腎臟清除率是主要原因轿偎。

???N1979腎臟清除率幾何均值是3.67 L/h。

? ***的25 mg劑量（第2組第1天）約1.17 mg的***被廓，大約5%未改變的原型藥物通過(guò)尿液排出坏晦。

?被排除的N1979的幾何平均質(zhì)量是19.1 mg，大約是25mg劑量組的50%嫁乘。

?25 mg劑量組55%（第2組昆婿，第1天）被排除在尿液中，50%是N1979亦渗，5%是沒(méi)有變化的原型藥物挖诸；

?這些結(jié)果表明***到N1979經(jīng)歷了廣泛的新陳代謝，隨后被排出在尿液中法精，約占劑量的50%多律。

安全性結(jié)論：

?多次遞增劑量的***在普通健康志愿者中有很好的耐受性；

?頻數(shù)最多的不良事件是接觸性皮炎（38例受試者）搂蜓，頭痛（8例受試者）狼荞，和頭暈（4例受試者）。SOC皮膚和皮下組織疾病的發(fā)生率最高帮碰，接觸性皮炎事件是被認(rèn)為與心電圖和遙測(cè)評(píng)估相關(guān)的導(dǎo)線放置有關(guān)相味，SOC神經(jīng)系統(tǒng)疾病顯示出下一個(gè)最高的不良事件發(fā)生頻率。

?這里沒(méi)有嚴(yán)重不良事件殉挽，或與研究藥物相關(guān)的不良事件導(dǎo)致停止和中斷丰涉，所有的不良事件在研究完成之前被解決。

?心電圖和動(dòng)態(tài)心電圖檢查結(jié)果是互補(bǔ)的斯碌，在兩種情況下一死，*** 500 mg試驗(yàn)中顯示出輕微的心率增加，與安慰劑組沒(méi)有明顯差異傻唾。心臟加速的趨勢(shì)僅僅與高劑量組有關(guān)投慈，在增加時(shí)間或劑量趨勢(shì)一致的情況下沒(méi)有顯示出藥效學(xué)的效果。

?總體而言冠骄， ***-1H-01（SNO-2）心電圖和動(dòng)態(tài)心電圖結(jié)果證明***具有強(qiáng)大的心臟安全性伪煤。

?在平均QTcF值變化中未發(fā)現(xiàn)劑量組趨勢(shì)，回歸分析顯示QTcF改變與***濃度或代謝物N1979濃度無(wú)關(guān)凛辣。

?臨床實(shí)驗(yàn)室結(jié)果抱既，肺活量測(cè)定，生命體征或體格檢查數(shù)據(jù)無(wú)臨床上顯著趨勢(shì)扁誓。

后記：我此時(shí)此刻是翻譯官蝙砌，我此時(shí)此刻只能做翻譯阳堕。沒(méi)有什么是不可能的，保持專注度择克；我目前的翻譯速度一篇文獻(xiàn)的前幾篇是8小時(shí)1頁(yè)恬总，主要耗時(shí)在專業(yè)名詞上，在累計(jì)了專業(yè)名詞后翻譯速度是在8小時(shí)3頁(yè)肚邢。

2021年5月13日星期四

專業(yè)名詞積累

P3

1壹堰、 medical review錯(cuò)誤的翻譯為醫(yī)藥回顧，正確的是醫(yī)學(xué)審查骡湖，

2贱纠、12-lead ECG measurements，12導(dǎo)聯(lián)ECG測(cè)量响蕴。

3谆焊、ambulatory：move

4、Hematology：blood

5浦夷、urinalysis:bladder（toilet,body）, the waste liquid that collects in the bladder and that you pass from your body辖试，analysis of urine, urinalysis;

6、concomitant：merge

7劈狐、hemoglobin oxygen saturation by pulse oximetry, 有沒(méi)有認(rèn)識(shí)的罐孝，oxygen，pulse

Hemoglobin：blood red egg white肥缔；

Saturation：飽和度

Oximetry：血氧儀

8莲兢、spirometry

9、telemetry：the process of using special equipment to send, receive and measure scientific data over long distances续膳。

P3

10改艇、inferential statistical analyses

11、Formal 坟岔；猜測(cè)正式的

12谒兄、performed，do

13炮车、feasibility：likely to be achieved；this plan is feasibility.

14酣溃、sufficient,錯(cuò)譯為有效性瘦穆，正譯為足夠的；

15赊豌、derived: 推導(dǎo)

16扛或、noncompartmental methods：非房室模型方法

17、plasma concentrations：血漿濃度

P3

18碘饼、Intensive：repeat

19熙兔、Triplicate：一式三份

20悲伶、Centralized：集中的

21、Cardiac：心臟病

22住涉、cardiologists：心臟病專家

23麸锉、Prematurely：in advance

24、Caucasian ：White people

25舆声、Cohort：group

26花沉、each comprising:each group

P4

Pharmacokinetics resulted in rapid absorption

27、Oral:drink

28媳握、Indicated:show

29碱屁、Peak：high

30、Rapid：quickly

31蛾找、post dose：

P5

32娩脾、the appearance of :……的出現(xiàn)

33、cohorts：group

34打毛、In contrast to Day 1：compare

35柿赊、in geometric mean：trangal and square are geometric

36、roughly：

37隘冲、proportional：ration

38闹瞧、terminal：end

P6

dependent upon the sampling chedule翻譯錯(cuò)誤，正確為取決于采樣時(shí)間表

P7

likely owing to the shorter duration of *** administration in these 2 cohorts.

Duration:during

Owing：歸咎于

and no events emerged that were more prevalent on *** than placebo

并且沒(méi)有事件出現(xiàn)更加廣泛在***超過(guò)安慰劑展辞。

The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is

formation rate-limited with increase in dose.

附上原文：

CLINICAL STUDY REPORT

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of *** in Healthy Subjects

DCR study code: 13172

Sponsor study code: ***-1H-01 (SNO-2)

IND number: 119145

***: Clinical Phase 1 Study

Indication studied: Safety, tolerability, pharmacokinetics

Studied period: 16 February 2014 (first subject screened) – 11 November 2014 (last follow-up)

SPONSOR Nivalis Therapeutics, Inc. (formerly N30 Pharmaceuticals)

3122 Sterling Circle, Suite 200

Boulder, CO 80301, USA

Sponsor’s Contact Robert Hopkins, DVM, MS

Phone: +1 (720) 945-7716

Fax: +1 (303) 440-8399

INVESTIGATOR DaVita Clinical Research

11750 W. 2nd Place, Suite 300, Lakewood, CO 80228 USA

Investigators Chris Galloway, MD

Phone: +1 (303) 566-3100

Fax: +1 (303) 542-7300

Project Manager Marla Elhard, BSN, RN

Phone: +1 (303) 566-3005

Fax: +1 (855) 544-8170

AUTHORS Christopher A. Graybill, PhD, Medical Writer (DaVita)

Scott Brantley, PhD, Pharmacokinetic Scientist (Nuventra)

Eugene R. Heyman, PhD, Senior Biostatistician (Cardiocore)

Daniel B. Goodman, MD, Vice President and Medical Director

(Cardiocore)

Greg Ginn, MS, Biostatistician (DaVita)

Date of this report: 18 September 2015

This study was performed in compliance with the principles of Good Clinical Practice

(GCP), including the archiving of essential documents. This report was written in

compliance with the International Conference on Harmonization (ICH) guidelines.

CLINICAL STUDY REPORT

Nivalis Therapeutics, Inc.; ***-1H-01 (SNO-2)

18 September 2015

Confidential

2 SYNOPSIS

Study Title A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending

Dose Study Evaluating the Safety, Tolerability, and Pharmacokinetics of *** in

Healthy Subjects

Study Code

DCR study code: 13172

Sponsor study code: ***-1H-01 (SNO-2)

IND number: 119145

Sponsor: Nivalis Therapeutics, Inc. (previously known as N30 Pharmaceuticals, Inc.)

3122 Sterling Circle, Suite 200, Boulder, CO 80301 USA

Sponsor’s Contact: Robert Hopkins, DVM, MS

Study Center: DaVita Clinical Research

11750 W. 2nd Place, Suite 300, Lakewood, CO 80228 USA

Project manager: Marla Elhard, BSN, RN

Investigator: Christopher Galloway, MD

Publication: None at time of writing this report

Study Period: Date of first screening to last follow-up: 16 February 2014 – 11 November 2014

Clinical Phase: Phase 1

Objectives

Primary Objective:

? To assess the safety and tolerability of escalating, multiple doses of *** in healthy subjects.

Secondary Objective:

? To assess the pharmacokinetics (PK) of *** and its primary metabolite, N91288, following multiple doses.

Methodology

Design:

This was planned as a double-blind, randomized, placebo-controlled, multiple ascending dose study; however, two single dose cohorts were also added. In the multiple ascending dose portion of the study, at least 4 ascending cohorts were planned with 8 subjects per cohort (6 active, 2 placebo). Each subject underwent screening (Day -28 to Day -3) and, if eligible, returned to the unit on Day -1 and eligibility was reconfirmed. Eligible subjects received an oral dose of investigational medicinal product (IMP), ***, or placebo once daily on Study Days 1 through 14 and were followed for safety while housed in the clinical research unit (CRU) until they were discharged on Day 15. Pharmacokinetics were followed from Study Day 1 through the morning of Study Day 16.Participation of an individual subject may have lasted approximately 49 days from the time of screening until the end-of-study follow-up call. A Safety Monitoring Committee (SMC) reviewed the safety data after completion of each cohort and decided whether to proceed to the next planned ascending dose cohort, modify the planned dose,repeat a dose, or stop the study according to the stopping rules outlined in the protocol.

The single dose cohorts also included 8 subjects per group (6 active, 2 placebo) and assessed single dose PK and effects of food intake, respectively.

Treatments:

? *** (10, 50, 250, and 500 mg) capsules, administered orally once daily for either 14 days (multiple dose cohorts) or one time (single dose cohorts)

? Matched placebo capsules, administered orally once daily

Procedures and Assessments:

Eligibility screening

Consisting of medical history, demographic information, prior and concomitant medications, physical examination, physical measurement (height, weight, body mass index [BMI]), 12-lead electrocardiogram (ECG) evaluation, 48-hour ambulatory ECG arrhythmia (Holter monitoring) assessment, vital signs

measurements, clinical laboratory tests (serology, hematology, blood chemistry,

urinalysis, pregnancy test for women), and drug and alcohol screen

PK assessments:

PK assessments of blood and urine for *** and N1979

Safety: 12-lead ECG recordings, adverse event (AE) monitoring, ambulatory ECG

(Holter), clinical safety laboratory tests, concomitant medications, physical

examinations, hemoglobin oxygen saturation by pulse oximetry, pregnancy testing,

spirometry, telemetry, vital signs, weight

Main Criteria for Inclusion

Age: 18-55 years, inclusive

BMI: ≥ 19.5 kg/m2 and ≤ 32.0 kg/m2

Subjects: Healthy Caucasian male and female subjects without a history of clinically

significant cardiac findings

Study Medication

Active substance: ***

Dosage form: Capsules

Strength/Lot number: 5 mg/N454451

Strength/Lot number: 25 mg/N454891

Strength/Lot number: 50 mg/N456044

Manufacturer: Norwich Pharmaceuticals (Norwich, NY)

Name: Placebo

Dosage form: Capsules

Lot number: N454450

Manufacturer: Norwich Pharmaceuticals (Norwich, NY)

Criteria for Evaluation/Endpoints

Pharmacodynamics: Not applicable.

Pharmacokinetics: This was a double-blind, randomized, placebo-controlled, multiple ascending dose study. Four ascending dose, 10, 50, 250 and 500 mg cohorts were studied with 8 subjects per cohort (6 active, 2 placebo).Each subject received an oral dose of investigational medicinal product (IMP), ***, or placebo once daily on

Study Days 1 through 14 and was followed for safety and pharmacokinetic (PK) assessments.

Plasma PK The Day 1 PK

parameters determined from the *** concentration-time data for the first dose included maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), area under the concentration-time curve calculated from time 0 to the last quantifiable concentration (AUC0-t) and to infinity (AUCinf), and terminal elimination half-life (T?). Additionally, oral clearance (CL/F) and apparent volume of distribution (Vz/F) were estimated. The steady-state PK parameters from the

*** on Day 14 concentrationtime data included: Cmax, Tmax, t?, AUC0-12, AUC0-τ, CLss/F, and accumulation ratio (Racc) were calculated.

*** undergoes glucuronidation, primarily to N1979, the O-glucuronide representing >95% of total glucuronide metabolites measured. N91288, the acyl-glucuronide was a minor component representing <3% of total. The metabolite pharmacokinetic parameters were determined from the total N1979 and N91288 plasma concentrations and are referred to as N1979, the primary metabolite in the SNO-2 PK report and throughout this document. The N1979 concentration-time data for the first dose on Day 1 included: Cmax, Tmax, t?, AUC0-24, AUCinf, and metabolite to parent (M/P) ratio. The steady-state PK parameters from the N1979 Day 14 concentration-time data included: Cmax, Tmax, t?, AUCtau, Racc, and M/P ratio. The terminal elimination half-life was estimated by log-linear regression of the plasma concentrations during the terminal phase on a logarithmic scale, using at least three time points.

Urine PK *** and metabolite (N1979) PK parameters derived from Cohort 2 on Day 1 were renal clearance (CLr) and cumulative amount of study drug recovered in urine (Ae0-t). In addition, combined parent and metabolite results are reported as total percent of dose excreted in urine.

Safety: Safety assessments were based on medical review of AE reports and the results of 12-lead ECG measurements, ambulatory ECG (Holter), clinical safety laboratory tests (including hematology, clinical chemistry with CRP, and urinalysis), concomitant medications, physical examinations, hemoglobin oxygen saturation by pulse oximetry, pregnancy testing, spirometry, telemetry, vital sign measurements, and weight.

Statistical Methods

Sample Size Determination: This was an exploratory PK study and, therefore, was not powered for inferential statistical analyses. Formal sample size calculations were not performed. The number of subjects was chosen based on feasibility and was considered sufficient to meet the study objectives.

Pharmacokinetic Parameters: PK parameters for *** and N1979 were derived using noncompartmental methods employing WinNonlin? Phoenix version 6.3 (Pharsight, St. Louis, MO). The PK parameters were estimated from the plasma concentrations using standard methods of noncompartmental analysis and were

calculated using actual collection times, and PK parameters were compared using analysis of variance.

Safety Parameters: AEs were tabulated; clinical laboratory tests, 12-lead ECG data, vital signs data, and physical examinations data were summarized descriptively and changes from Baseline were described. Analysis of ECG data (with intensive, triplicate measurements at 3 timepoints on Days 1-2 and Days 14-15 in addition to single measurements at other timepoints) included heart rate rhythm, QRS axis, PR interval, QRS duration, RR interval, and QT interval; QTcF was calculated. All ECGs were evaluated by qualified, centralized cardiac safety cardiologists.

Results

Subject Disposition

A total of 49 subjects were randomized into the study, and 47 subjects (96%) completed the study. Two subjects discontinued the study prematurely for personal reasons (unrelated to the study). Of the 49 total subjects, 37 were male and 12 were female. All subjects were Caucasian. The mean age (±SD) of subjects was 39.1 (11.4) years.

*** Exposure

The following describes the assignment of study subjects to cohort and dose:

Multiple-dose (14 days of dosing) cohorts, each comprising 6 subjects on active *** and 2 subjects on placebo, with a total of 24 subjects dosed with ***, and 9 with placebo (including 1 replacement subject).

? Cohort 1: 10 mg

? Cohort 2: 50 mg

? Cohort 3: 250 mg

? Cohort 4: 500 mg

Single dose cohorts, each comprising 6 subjects on active *** and 2 subjects on placebo:

? Cohort 2a: 50 mg

? Cohort 5: 250 mg (dosed with high-fat meal)

Pharmacokinetics

Pharmacokinetics Summary Oral administration of *** from 10 to 500 mg once daily for 14 days resulted in rapid absorption as indicated by the peak concentrations achieved within 2 hours post dose for all dose groups.

The geometric mean Cmax values increased in a roughly dose proportional manner. Similarly, the AUC0-tau increased in a slightly greater than dose proportional manner. Administration of 250 mg dose of *** with high-fat food resulted in a Tmax of 4 hours relative to 1.5 hours in fasted state. However, *** Cmax and AUC0-t values relative to those at fasted state were within 90%, indicating minimal effects of food on *** PK.Geometric mean estimates of the terminal phase half-life (t?) were longer at lower doses with values of 10.5 to 14.9 hours for the low doses, and approximately 5 hours of the high dose groups, 250 and 500 mg doses. The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance noted in the linearity analysis. The geometric mean of the exposure accumulation ratios, Racc(AUC) and Racc(Cmax), was minimal, ranging >1.2 to >1.33, respectively for all dose groups. This indicates

that *** displays minimal accumulation following repeat once-daily dosing at low doses and no accumulation at the highest dose tested.

*** underwent rapid and extensive metabolism via glucuronidation to two inactive metabolites, following oral administration of 10 to 500 mg once daily. The metabolite concentrations were approximately 100% to 300% of *** plasma concentrations. Plasma metabolite concentrations were measured as a sum of N1979, the O-glucuronide, and N91288, the acyl glucuronide. N1979 concentrations were >95% and N91288 concentrations were <5% of the total sum. Therefore, the metabolite PK values are reported as that of N1979.

N1979 appearance was relatively rapid, with peak concentrations reached in less than 4.0 hours for all cohorts.

The Cmax and AUCtau values increased in a less than dose proportional manner. The terminal phase half-life (t?) was larger (10.4 – 11.6 hours) at lower doses, and smaller (~5 hours) for the high doses. The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited. The

exposure accumulation ratios, Racc(AUC) and Racc(Cmax), ranged from 0.9 to 1.3, indicating negligible accumulation of metabolite exposure with multiple dosing. High-fat food resulted a Tmax of 5 hours relative to 3 hours in fasted state. However, N1979 Cmax and AUC0-t values were slightly greater (106% - 101%) relative to those at fasted state, indicating minimal effects of food on N1979 PK.

The urinary excretion of *** and N1979, the glucuronide metabolite, were evaluated on Day 1 in Cohort 2 subjects. *** and N1979 exhibited a low renal clearance of 1.31 L/h and 3.67L/h, respectively. This represents roughly 20% and 50% of the creatinine clearance of an average healthy adult for *** and N1979,

respectively. Overall, 55% of the *** dose was excreted in the urine over 24 hours, 5% as *** and 50% as metabolites (N1979 and N91288). Due to the low renal clearance of *** and the relatively low plasma concentrations of *** at 24 hours, it appears that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug. *** Plasma Pharmacokinetics Following oral administration of *** on Day 1, plasma *** concentrations peaked relatively rapidly with median Tmax values ranging between 1.50 and 5.00 hours across all cohorts. *** remained quantifiable in plasma 24 hours post-dose in all subjects. Subjects in Cohort 2 were inadvertently dosed 25 mg on Day 1 instead of planned 50 mg; therefore, Cohort 2a was added to receive a single 50 mg dose. The geometric mean Cmax values increased with an increase in dose from 33.0 ng/mL at 10 mg, to 111 ng/mL, 245 ng/mL, 1810 ng/mL, 1600 ng/mL, and 3840 ng/mL at the 25 mg, 50 mg, 250 mg (fasted), 250 mg (fed), and 500 mg dose levels, respectively. The geometric mean %CV for Cmax ranged from 14.0% to 57.8%, for the 10 mg to 500 mg dose levels. Similarly to Cmax, AUC values increased with an increase in dose. The geometric mean AUClast values were 327 h*ng/mL, 893 h*ng/mL, 1530 h*ng/mL, 12000 h*ng/mL, 10300 h*ng/mL, and 32400 h*ng/mL for the 10 mg 25 mg, 50 mg, 250 mg (fasted), 250 mg (fed), and 500 mg dose levels, respectively. The geometric mean AUCinf values ranged from 357 h*ng/mL, to 32500 h*ng/mL for the 10 mg to 500 mg dose levels.*** exposure parameters on Day 1 (Cmax, AUClast, and AUCinf) increased in a linear and slightly greater than dose proportional manner at the highest dose. The apparent clearance (CL/F) of *** appeared to be relatively

independent of dose for the 10, 25, and 50 mg dose levels but was slightly lower for the 250 and 500 mg dose levels. Administration of *** within 5 minutes of a high-fat meal resulted in mean Cmax and AUC values roughly 15% lower than those when *** was administered to fasting subjects.

By Day 7, all but one subject (in the 50 mg Cohort) had quantifiable pre-dose *** concentrations. Day 7 PK parameter estimates are less reliable since relatively fewer plasma samples were collected on Day 7 compared to Days 1 and 14. Therefore, the Day 7 PK values should be used for qualitative, rather than quantitative, purposes.

The geometric mean Cmax values increased in a slightly greater than dose proportional manner from 67.9 ng/mL to 6200 ng/mL over the 10 to 500 mg dose range. Geometric mean estimates of the terminal phase half-life (t?) decreased with increasing dose from 8.03 to 4.71 hours for the 10 to 500 mg doses. Consistent with Cmax, AUC0-tau increased in a greater than dose-proportional manner, with geometric means of 442 h*ng/mL to 40800 h*ng/mL for the 10 mg to 500 mg cohorts.

By Day 14, all subjects had quantifiable pre-dose *** concentrations. Compared to Day 1, the appearance of *** was more rapid, with median Tmax values less than 2.0 hours for all cohorts. In contrast to Day 1, the increase in geometric mean Cmax values was roughly dose proportional from 84.3 ng/mL to 5800 ng/mL for the 10 mg to 500 mg cohorts. Consistent with Day 1, the AUC0-tau increased in a slightly greater than dose proportional manner. Geometric mean estimates of the terminal phase half-life (t?) were longer at lower doses with values of 14.9 and 10.5 for the 10 and 50 mg doses, respectively, and 5.58 and 5.21 for the 250 and 500 mg doses, respectively. The longer half-lives at the lower dose groups are likely dependent upon the sampling schedule as the 10 and 50 mg dose levels were the only ones sampled out to 48 hours. The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance noted in the linearity analysis. The geometric mean of the exposure accumulation ratios (Racc(AUC)) was >1.2 for the 10, 25, and 250 mg cohorts, but was 1.01 for the 500 mg cohort. This indicates that *** displays minimal accumulation following repeat once-daily dosing at low doses and no accumulation at the highest dose

tested. The geometric mean peak concentration accumulation ratios (Racc(Cmax)) were >1.33 for all doses tested,indicating that peak concentrations increased to modest extent with repeat once-daily dosing.N1979 Metabolite Plasma Pharmacokinetics Following oral administration of *** on Day 1, plasma

concentrations of N1979, the inactive metabolite, appeared relatively rapidly with median Tmax values around 4.0 hours. N1979 remained quantifiable in plasma 24 hours post-dose in all subjects, indicating the potential for accumulation with multiple dosing. Administration of *** within 5 minutes of a high-fat meal resulted in roughly 6% higher mean N1979 Cmax and approximately equal mean N1979 AUCinf values compared to the values for fasting subjects. Appearance of N1979 was quicker in the fasted state, with a median Tmax value 2.0 hours earlier than the fed state. Overall, the geometric mean metabolite to parent ratios were ≥ 1.40, with the largest ratios seen at the lower (10-50 mg) doses.

By Day 7, all but one subject (in the 50 mg Cohort) had quantifiable pre-dose N1979 concentrations. Due to the relatively small (compared to Days 1 and 14) number of plasma samples on Day 7, the PK parameter estimates are likely less reliable than those on other days. For this reason, these values should be used for qualitative, rather? than quantitative, purposes. The geometric mean Cmax values increased in a less than dose proportional manner from 359 ng/mL to 9580 ng/mL for the 10 and 500 mg cohorts, respectively. Geometric mean estimates of the terminal phase half-life (t?) were consistent between doses, with values between 5.61 and 6.09 hours. Consistent with Cmax, AUC0-24 increased than dose-proportional manner, with geometric means of 2020 h*ng/mL,8950 h*ng/mL, 47200 h*ng/mL, and 83400 h*ng/mL for the 10 mg, 50 mg, 250 mg, and 500 mg Cohorts,respectively. As seen on Day 1, the geometric mean metabolite to parent ratios were higher following the lower (10 and 50 mg) doses of ***. The geometric mean metabolite to parent ratio for Cmax at the 500 mg dose level was less than unity (0.973), whereas the remainder of the ratios were greater than 1.

By Day 14, all subjects had quantifiable pre-dose N1979 concentrations. The appearance of N1979 was relatively rapid, with median Tmax values less than 4.0 hours for all cohorts. The increase in geometric mean Cmax values was less than dose proportional from 389 ng/mL to 8270 ng/mL for the 10 mg to 500 mg cohorts, respectively. AUCtau increased in a less than dose proportional manner with geometric mean values of 2110 h*ng/mL to 69600 h*ng/mL for the 10 to 500 mg dose levels, respectively. Geometric mean estimates of the terminal phase half-life (t?) were larger at lower doses with values of 11.6 and 10.4 at 10 and 50 mg doses, respectively, and 5.77 and 5.74 at the 250 and 500 mg doses, respectively. The longer half-lives for the lower dose groups are likely dependent upon the sampling schedule as the 10 and 50 mg dose levels were the only ones sampled out to 48 hours. The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited.

Since the terminal elimination half-life of a metabolite should not be shorter than the terminal elimination half-life of the parent, the terminal elimination half-life of N1979 is likely underestimated in many subjects. The geometric means of the exposure accumulation ratios (Racc(AUC)) ranged from 0.880 to 1.09, indicating negligible

accumulation of metabolite exposure with multiple dosing. The peak concentration accumulation ratios (Racc(Cmax)) ranged from 0.907 to 1.33, further indicating the lack of accumulation. The geometric mean metabolite to parent ratios on Day 14 ranged between 0.898 and 2.91 for Cmax and between 1.22 and 3.14 for AUCtau, indicating systemic exposure to N1979 is between 100% and 300% of that of ***.

Urine Pharmacokinetics The urinary excretion of *** and N1979, the glucuronide metabolite, was evaluated on Day 1 in Cohort 2 subjects. Approximately 5% of the 25 mg *** dose (Cohort 2, Day 1) was eliminated as unchanged *** in the urine, resulting in a low renal clearance of 1.31 L/h, which is roughly 20% of the creatinine clearance of an average healthy adult. Due to the low renal clearance of *** and the relatively low plasma concentrations of *** at 24 hours, it appears that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug.

A geometric mean mass of N1979 excreted in the urine was 19.1 mg, which represents approximately 50% of the 25 mg dose. The geometric mean renal clearance of N1979 was 3.67 L/h that is roughly 50% of the creatinine clearance of an average healthy adult (7.2 L/h).These results suggest that N1979 primarily undergoes renal clearance, as indicated by the high percent of dose eliminated and the greater renal clearance estimates as compared to those of the parent drug.

Overall, 55% of the *** dose was excreted in the urine over 24 hours, 5% as parent and 50% as metabolites (N1979 and N91288).

Safety

Adverse Events Forty (40) of 49 total subjects (81.6%) reported at least 1 TEAE during study participation. All subjects (those receiving *** and placebo for 14 days) in Cohorts 1 through 4 reported a TEAE, whereas fewer subjects in Cohort 2a (16.7%) and Cohort 5 (66.7%) reported TEAEs, likely owing to the shorter duration of *** administration in these 2 cohorts. *** was well tolerated, all TEAEs were mild in severity, no dose related increases in the incidence of adverse events were noted, and no events emerged that were more prevalent on *** than placebo. A maximum tolerated dose was not identified because no dose limiting toxicities were identified at the highest dose tested.Cohorts 1 – 4 and combined placebo treated subjects (14-day dosing) The most frequently reported TEAEs were contact dermatitis, headache, and dizziness. Contact dermatitis occurred in all subjects who received *** or placebo in Cohorts 1 through 4; headache occurred in 3/6 (50%) subjects in Cohorts 1 and 2 but decreased to 0/6 and 1/6 (17%) in Cohorts 3 and 4 compared with 1/9 (11%) subjects on placebo; dizziness occurred in 2/6 (33%) subjects in Cohort 2 and 2/9 subjects on placebo (22%). Of note, the contact dermatitis was considered to be secondary to the ECG leads in all subjects in which it was reported. Due to the frequency of contact dermatitis and headache, the SOC Skin and Subcutaneous Tissue Disorders displayed the highest frequency of TEAEs, and the SOC Nervous System Disorders displayed the next highest frequency of TEAEs. All TEAEs were mild in severity.Nineteen subjects (38.8%) reported TEAEs that were causally related to the study drug. A higher percentage of these events were observed in Cohorts 1 and 2 (67%) than in Cohorts 3 and 4 (33%). In the latter two cohorts, the incidence was less than on placebo (56%). The most frequently reported adverse events that were attributed to study drug were: headache occurring in a total of 7 subjects (2 [33%], 1 [17%], 0, 1 [17%], in Cohorts 1, 2, 3, and 4, respectively, and 1 [11%] on placebo); dizziness occurring in a total of 4 subjects (2 [33%] in Cohort 2 and 2 [22%] on placebo); aphthous stomatitis occurring in 3 subjects (2 [33%] in Cohort 1 and 1 [11%] on placebo); and constipation occurring in 2 subjects (1 [17%] in Cohort 2 and 1 [11%] on placebo). All other causally related TEAEs were reported by only 1 subject. There were no SAEs, no TEAEs resulting in study drug discontinuation or interruption, and no AEs resulting in death.

There were no clinically significant trends in 12-lead ECG data, clinical laboratory results, or other safety data. Cohorts 2a and 5 (single dose administration) Contact dermatitis was the most frequently reported event, occurring in 4 (67%) subjects in Cohort 5 and 1 (25%) subject on placebo. The only other event reported was headache occurring in 1 subject each in Cohort 2a and on placebo.

Cardiovascular Safety Findings for ECG data were uniformly negative, with the exception of a minimal effect on heart rate (HR): all treatment groups, including Placebo, had increases of HR on Day 14. The 500 mg dose of *** was associated with the highest HRs and greatest increases, but the increases were not markedly different from the other dose groups or Placebo. There were no consistent trends for higher values of change with increasing dose of *** or increasing concentrations of *** or N1979.No disturbance of AV conduction was associated with administration of ***. There were no consistent trends of intra-ventricular conduction to vary over the observation period. Cardiac repolarization was not affected by administration of ***. There was no relationship between change of QTcF and plasma concentrations of ***, N91288, or N1979.

Holter monitoring findings were consistently negative, again with the exception of a minimal effect on heart rate. Mean, maximum, and minimum 24-hour HR values were unchanged during treatment, although mean hourly HR values showed minor increases from Baseline late on Day 1 for all treatment groups. On Day 14, hourly values of HR showed minimal elevation for subjects in the *** 500 mg group, but no consistent dose trends were noted and changes were not clearly different from Placebo.

Findings for atrial ectopy were normal. There were a small number of supraventricular tachycardia episodes, all 22 beats or fewer in duration with a maximum rate of 147 bpm. Significant ventricular ectopy was not noted during the study, with the exception of 2 brief episodes of ventricular runs in a single subject on *** 50 mg on Day 2. The maximum duration was 6 beats and maximum overall heart rate was 99 bpm. Holter diagnostic findings were unremarkable.

Mean QTcF values were in a narrow range of 398.5 to 426.8 msec. Little variation was noted across the time course of observations. Mean changes of QTcF from Baseline were quite similar for all treatments, but did show a tendency to greater decreases on Day 1 Hour 2 to Hour 8 and on Day 14 Hour 4. The mean values of change were minimal overall ranging from -18.6 msec (250 mg group, Day 14, Hour 4) to 9.9 msec (10 mg group, Day 10, predose). No dose group trends were seen. Regression analysis showed no relationship of change of QTcF with concentration of *** or, separately, with the concentration of N1979. The slopes of the regressions were nearly flat, 0.220 and 0.235, and had non-significant p-values of 0.71 and 0.65. Value of predicted change of QTcF for the lowest to highest observed concentration were nearly identical, -0.7 and 0.1 msec, respectively for *** and from -0.8 and 0.1 msec, respectively for N1979.

The ECG and Holter heart rate findings were complementary and, in both cases, showed minor increases of heart rate during *** 500 mg treatment, not clearly different from placebo. The trend for the cardiac acceleration was associated solely with the highest dose without indication of a pharmacodynamic effect either for timing of the increases or for a consistent dose trend.

Conclusions

The primary objective of Clinical Study ***-1H-01 (SNO-2) was to evaluate the safety and tolerability of *** administered as a once daily oral capsule for 14 days in healthy subjects. A secondary objective was to evaluate the PK of *** in this subject population. Of the 36 subjects who were randomized to receive ***,

all were included in the PK analysis of *** and its metabolite, N1979.

*** Plasma PK Conclusions

The oral administration of *** at 10, 50, 250, and 500 mg once daily for 14 days results in the following *** PK:

? *** undergoes rapid absorption as indicated by a Tmax of less than 2 hours for all cohorts.

? The geometric mean Cmax values increased roughly dose proportional for the 10 mg to 500 mg cohorts.

? Similarly, the geometric mean AUCtau at steady state increased in a slightly greater than dose proportional manner for the 10 mg to 500 mg cohorts.

? Geometric mean estimates of the terminal phase half-life (t?) were longer at lower doses with values of 14.9 and 10.5 for the 10 and 50 mg doses, respectively, and 5.58 and 5.21 for the 250 and 500 mg doses, respectively.

? *** reached steady state before Day 14, possibly before or by Day 7.

? The geometric mean clearance at steady-state ranged between 13.9 and 23.6 L/h for all dose groups, with a dose dependent decrease in clearance, possibly due to saturation of metabolism.

? *** displays minimal accumulation (Racc(AUC) >1.2) following repeat once-daily dosing at low doses and no accumulation at the highest dose tested.

? Similarly, the geometric mean peak concentration accumulation ratios (Racc(Cmax)) were >1.33 for all doses tested, indicating that peak concentrations increased slightly with repeat once-daily dosing.

? Administration of 250 mg of *** with a high-fat meal did not affect the mean Cmax and AUC values, which were roughly 15% lower than the levels in fasting subjects.

N1979 Metabolite Plasma PK Conclusions

The oral administration of *** at 10, 50, 250 and 500 mg once daily for 14 days resulted in the rapid and extensive metabolism of *** via glucuronidation to two inactive metabolites, mainly to O-glucuronide N1979 (>95% of total metabolite) and, to a lesser extent (<5% of total), to N91288, the acyl glucuronide. The PK values for

the primary metabolite N1979 following repeat oral dosing of *** at 10 to 500 mg are summarized below.

? The appearance of N1979 was relatively rapid, with median Tmax values less than 4.0 hours for all cohorts.

? The geometric mean Cmax values increased in a less than dose proportional manner for all cohorts, suggesting possible saturation of metabolism.

? Similarly, the geometric mean AUCtau increased in a less than dose proportional manner with increase in dose.

? N1979 geometric mean estimates of the terminal phase half-life (t?) decreased with increase in dose.

? The similarity in half-life values between parent and metabolite suggests that the elimination of N1979 is formation rate-limited with increase in dose.

? N1979 shows negligible accumulation of exposure with multiple dosing as shown by the geometric means of the exposure accumulation ratios (Racc(AUC) and Racc(Cmax)).

? The geometric mean metabolite to parent ratios for Cmax and AUCtau decreased with an increase in N911115 dose, ranged from 300% to 100% of that of ***.

*** and N1979 Metabolite Urine PK The urinary excretion of *** and N1979, the glucuronide metabolite, was evaluated on Day 1 in Cohort 2 subjects.

? Renal clearance of *** was low 1.17 L/h, which is roughly 20% of the creatinine clearance in healthy subjects and the relatively low plasma concentrations of *** at 24 hours suggest that metabolism and/or other non-renal clearance routes of elimination (possibly biliary) are primarily responsible for the overall clearance of the parent drug.

? The geometric mean renal clearance of N1979 was 3.67 L/h.

? Approximately 1.17 mg of ***, approximately 5% of the 25 mg of *** dose (Cohort 2, Day 1) was eliminated unchanged parent drug in the urine

? The geometric mean mass of N1979 excreted was 19.1 mg, which represents approximately 50% of the 25 mg dose.

? A total of 55% of the 25 mg dose (Cohort 2, Day 1) was eliminated in the urine, with 50% as N1979 and 5% as unchanged parent drug.

? These results suggest that *** undergoes extensive metabolism to N1979 which was subsequently eliminated in the urine, representing approximately 50% of the dose.

Safety Conclusions

? Multiple, ascending doses of *** were well tolerated in normal healthy volunteers.

? The most frequently reported TEAEs were dermatitis contact (38 subjects), headache (8 subjects), and dizziness (4 subjects). The SOC Skin and Subcutaneous Tissue Disorders displayed the highest frequency of TEAEs, where contact dermatitis events were thought to be related to the lead placement associated with ECG and telemetry assessments, and the SOC Nervous System Disorders displayed the next highest frequency of TEAEs.

? There were no SAEs or TEAEs resulting in study drug discontinuation or interruption. All TEAEs were resolved prior to study completion.

? The ECG and Holter heart rate findings were complementary and, in both cases, showed minor increases of heart rate during *** 500 mg treatment, not clearly different from placebo. The trend for the cardiac acceleration was associated solely with the highest dose without indication of a pharmacodynamic effect either for timing of the increases or for a consistent dose trend.

? Overall, Protocol ***-1H-01 (SNO-2) ECG and Holter results demonstrated robust cardiac safety for ***.

? No dose group trends were seen in change in mean QTcF values. Regression analysis showed no relationship of change of QTcF with concentration of *** or, separately, with the concentration of N1979.

? There were no clinically significant trends in clinical laboratory results, spirometry, vital sign, or physical examination data.

Date of report: 18 September 2015