Antivirl Therpy 25; 2:79 79 (doi:.385/imp2874) Originl rticle Single dose permivir for the tretment of cute sesonl influenz: integrted nlysis of efficcy nd sfety from two plcebo-controlled trils Richrd Whitley, Aln Lughlin 2, Simon Crson 3, Essck Mith 4, Guy Tellier 5, Mrk Stich 6, Jenn Elder 7, W Jmes Alexnder 8, Sylvi Dobo 8, Phil Collis 8, Willim P Sheridn 8 * Peditric Infectious Diseses, University of Albm, Birminghm, AL, USA 2 Merrylnds Medicl Centre, Merrylnds, New South Wles, Austrli 3 Christchurch Southern Helth Centre, Christchurch, New Zelnd 4 Newgte Centre, Newtown, Johnnesburg, South Afric 5 Omnispec Clinicl Reserch, Mirbel, QC, Cnd 6 Jcksonville Center for Clinicl Reserch, Jcksonville, FL, USA 7 PhrPoint Reserch, Wilmington, NC, USA 8 BioCryst Phrmceuticls, Durhm, NC, USA *Corresponding uthor e-mil: bsheridn@biocryst.com Bckground: Current influenz tretment options include orl or inhled ntivirl gents. There is n unmet need for prenterl ntivirl tretments. Methods: Permivir, prenterl influenz neurminidse inhibitor (NAI), ws dministered by single-dose intrmusculr (IM) injection in two plcebo-controlled studies in dult outptients with cute, uncomplicted influenz during two consecutive influenz sesons. Results: In Phse II study, permivir tretment significntly shortened durtion of fever nd reduced virl lod in nsophryngel secretions. A subsequent Phse III study ws not fully enrolled; however, in both studies, the mgnitude of the tretment effect fvouring permivir ws consistent with tht reported for other NAIs. A post-hoc nlysis ws conducted by integrting efficcy nd sfety results of 427 subjects from both studies. The medin time to llevition of symptoms (TTAS) in subjects receiving permivir 3 mg (3.2 h) ws shorter thn for plcebo (34.8 h; P=.6 djusted for smoking behviour, influenz seson nd virus type; undjusted P=.47). The medin time to resolution of fever ws reduced by 24 h fter tretment with permivir 3 mg compred with plcebo (P=.4). The proportion of subjects shedding influenz virus ws significntly decresed over 48 h following permivir tretment (P=.9). Detection of post-tretment viruses with decresed susceptibility to NAIs ws uncommon. Permivir ws generlly sfe nd well-tolerted with types nd rtes of dverse event similr to plcebo. Conclusions: The results of these studies re consistent with previous reports of permivir dministered by intrvenous infusion, nd demonstrte positive risk benefit profile for permivir in ptients with cute uncomplicted influenz. Introduction Influenz is mjor public helth problem, cusing widespred morbidity nd significnt mortlity in nnul epidemics, prticulrly in young children nd the elderly, nd incresed helth burdens nd mortlity in pndemics cused by novel strins. Although vccines re prtilly effective in preventing influenz, it hs proven difficult to estblish high usge in mny countries nd unpredictble chnges in ntigenic determinnts of circulting influenz strins pose chllenges to timely introduction of new vccine formultions. The current clinicl prctice guidelines of the Infectious Diseses Society of Americ (IDSA) recommend ntivirl tretment for dults with lbortory confirmed or highly suspected influenz who hve onset of symptoms within 48 h before presenttion nd who wish to shorten the durtion of illness [], regrdless of immuniztion sttus. The US Centers for Disese Control nd Prevention (CDC) recommend ntivirl tretment 25 Interntionl Medicl Press 359-6535 (print) 24-258 (online) 79
R Whitley et l. s soon s possible for ny ptient with confirmed or suspected influenz who is hospitlized, hs severe, complicted or progressive illness or is t higher risk for influenz complictions [2]. Antivirl medictions recommended by the CDC re limited to neurminidse inhibitors (NAIs) tht re dministered twice dily s 5-dy courses orlly (oseltmivir) or by inhltion (znmivir). There is n ummet need for prenterl product for ptients who re unble to tolerte orl or inhled tretments. Permivir (BioCryst Phrmceuticls, Durhm, NC, USA) is n investigtionl prenterlly dministered NAI with potent ctivity ginst brod rnge of influenz A nd B subtypes, including influenz A(HN)pdm9, highly pthogenic influenz A(H5N), nd the recently described novel influenz A(H7N9) in vitro [3 5]. The phrmcology of permivir is chrcterized by high binding ffinity, slow dissocition from the neurminidse enzyme [6], high pek levels fter prenterl dministrtion nd demonstrted efficcy when dministered s single dose in niml models of influenz infection [7]. A plcebo-controlled tril conducted in Jpn demonstrted the efficcy of permivir in single doses of 3 mg nd 6 mg permivir dministered intrvenously (IV) [8]. This report presents n integrted met-nlysis of individul subject dt from two seprte plcebo-controlled clinicl trils (Studies 2 nd 3) tht evluted the sfety nd efficcy of single doses of permivir (5 mg nd 3 mg) dministered by intrmusculr (IM) injection in dults with cute, uncomplicted influenz. The two studies hd similr eligibility criteri nd identicl primry nd secondry end points, nd were conducted during successive non-pndemic influenz sesons in 26 27 nd 27 28. Methods The studies were conducted in full conformnce with the principles of the Declrtion of Helsinki. Institutionl review bords for ech prticipting centre reviewed nd pproved the protocol nd consent form prior to enrolment t given site. All prticipnts gve written informed consent prior to enrolment. Design of the studies The studies were ech designed s double-blind, rndomized, multicentre, plcebo-controlled trils. Subject ssignment to tretment in both trils ws strtified ccording to current smoking behviour. In Study 3, rndomiztion ws lso strtified ccording to influenz A or influenz B subtype by rpid ntigen test t subject presenttion. Study 2 ws conducted t multintionl sites from Jnury to September 27. Study 3 ws conducted in the United Sttes nd enrolled subjects in Jnury nd Februry 28 before the study ws terminted to focus clinicl development on more concentrted IM formultion tht would llow for evlution of higher doses of permivir. Both studies were registered on CliniclTrils.gov: Study 2 CliniclTrils.gov identifier NCT49263; Study 3 CliniclTrils.gov identifier NCT6935. Study popultions nd tretment Previously helthy mles nd non-pregnnt femles ged 8 yers who presented within 48 h of onset of influenz symptoms with positive rpid ntigen test (RAT) for influenz A or influenz B performed t the clinic site nd who hd documented fever 38. C (orl), one or more respirtory symptoms (cough, sore throt or nsl symptoms) nd one or more constitutionl symptoms (hedche, mylgi, feverishness or ftigue) were considered for enrolment. Individuls were excluded from these studies if they presented with ny of the following: receipt of ny influenz ntivirl tretment during the previous 7 dys or influenz immuniztion within 2 dys prior to enrolment; ctive, cliniclly significnt chronic illness including heptitis B or C, or HIV infection with CD4 + T-cell count <35 cells/mm 3 ; congestive hert filure meeting NYHA Clss II or greter severity; cliniclly significnt bnorml ECG; severe COPD or severe persistent sthm; clinicl findings suggesting the presence of complictions of influenz (for exmple, sinusitis, otitis, bronchitis, pneumoni); current therpy with systemic corticosteroids, other immunosuppressnts or nticogulnts; or history of lcohol or drug buse. Prticipnts were centrlly rndomized to three tretment groups in Study 2 nd to two tretment groups in Study 3. Prticipnts, clinic stff nd sponsor personnel remined blinded to tretment lloction throughout conduct of both studies. In Study 2, the tretment groups were single dose permivir 3 mg, permivir 5 mg nd plcebo in rtio of ::. In Study 3, the tretment groups were single dose permivir 3 mg nd plcebo in rtio of 2:. In both studies, permivir ws formulted t concentrtion of 75 mg/ml. Study drug ws dministered s bilterl 2-ml IM injections in ech glutel muscle ( totl of 4 ml). No more thn min elpsed between the dministrtion of the two injections. Efficcy ssessments Prticipnts were provided with subject diry crds nd recorded the severity of seven influenz symptoms (cough, nsl obstruction, sore throt, ftigue, hedche, mylgi nd feverishness) using 4-point scle (, bsent;, mild; 2, moderte; 3, severe) twice dily for 9 dys, then once dily for 5 dditionl dys. Prticipnts mesured nd recorded orl temperture 7 25 Interntionl Medicl Press
Permivir tretment for cute sesonl influenz twice dily for 4 dys, t lest 4 h fter or immeditely before dministrtion of orl cetminophen, using n electronic thermometer. Prior to tretment nd then once dily fter study tretment, prticipnts recorded their bility to perform usul ctivities on n -point scle (, not ble to perform usul ctivities;, ble to perform ll usul ctivities). Virologicl ssessments Nylon flocked swbs were used to collect smples from the posterior turbinte of ech nre nd the posterior phrynx (3 swbs) prior to tretment nd t 48 h, 96 h (±24 h) nd 96 h (±72 h) in both studies, with 24 h post-tretment smple obtined in Study 2 only. At ech collection time point, the three swbs were plced into single vil with 3. ml Universl Trnsport Medium contining lbumin (Copn Dignostics, Murriet, CA, USA), gitted nd shipped refrigerted to centrl collection repository. Upon receipt, specimens were divided into four liquots, frozen t -8 C, nd shipped to ViroClinics BV (Rotterdm, the Netherlnds). Initil virus isoltion ws performed in Mdin Drby cnine kidney (MDCK) cells. Virus type nd subtype ws determined by rel-time PCR. The titre of virus in virus-positive smples ws determined by seril dilution in MDCK cells. Titres were clculted s log tissue culture infective dose (TCID 5 )/ml of virl trnsport medium. In Study 2, the pretretment nd lst positive post-tretment isoltes recovered from ech subject were tested for susceptibility to permivir, oseltmivir nd znmivir by 2 -(4-methylumbelliferyl)- -D-N-cetylneurminic cid (MUNANA) ssy [9]. In Study 2, virl isoltes were sequenced from smples of subjects with positive virus cultures t dy 5 posttretment, nd in ny post-bseline virus isolte with n IC 5 tht ws 2 sd greter thn the men IC 5 of the respective subtype t bseline. Sttisticl methods Originl subject-level dt ws combined from both studies for nlysis. The primry efficcy nlysis included subjects with lbortory-confirmed influenz infection, defined s positive virus culture, positive PCR ssy or fourfold or greter increse in HAI ntibody titre t dy 4 (Study 2 only). The primry efficcy end point ws time to llevition of symptoms of influenz (TTAS), which ws defined s the number of hours from the time of the first injection of study drug to the strt of the period in which the subject hd chieved llevition of symptoms. A subject ws considered to hve llevition of symptoms if ll of the seven symptoms of influenz, s recorded in the subject diry, were either bsent or were present t no more thn mild severity level nd this symptom sttus ws mintined for t lest 24 h. As only one study included 5 mg permivir rm, substntilly fewer subjects received this dose compred with 3 mg permivir. Response to tretment with permivir 3 mg versus plcebo ws designted s the primry comprison of interest. Secondry efficcy vribles for the integrted nlysis were time to resolution of fever, time to resumption of usul dily ctivities, nd chnge in influenz virus titre by TCID 5 /ml. Descriptive sttisticl methods were used to summrize the integrted dt from both studies. The tretment groups were defined s permivir 5 mg, permivir 3 mg or plcebo. Unless specified otherwise, ll sttisticl tests were two-sided nd were performed using significnce () level of.5. The sttisticl nlyses were conducted with the SAS softwre pckge (version 9..3; SAS Institute Inc., Cry, NC, USA). The popultions for the integrted nlyses included the intent-to-tret (ITT), defined s ll subjects rndomized, the intent-to-tret infected (ITTI), defined s ll subjects rndomized with n influenz infection confirmed by lbortory culture, PCR or fourfold rise in ntibody titre who received dose of study drug, nd the sfety popultion, defined s ll subjects rndomized who received dose of study drug. The ITT popultion ws the primry popultion for nlyses of demogrphics nd subject ccountbility. The ITTI popultion ws used for nlyses of efficcy. The sfety popultion ws used for nlyses of sfety. TTAS ws estimted for ech tretment group using the Kpln Meier method. Subjects who did not experience llevition of influenz symptoms were censored t the dte of their lst non-missing ssessment. For the primry nlysis of the primry efficcy end point in the integrted nlyses, differences between permivir 3 mg nd plcebo tretment groups were ssessed using the Wilcoxon Gehn sttistic djusted for current smoking behviour, influenz seson nd influenz virus type. Hzrd rtios were determined using Cox regression model with effects for tretment group, current smoking behviour, influenz seson nd influenz virus type. A secondry nlysis ws conducted by performing the sme nlyses without the djustments for current smoking behviour, influenz seson nd influenz virus type. The time (h) to resolution of fever ws estimted using the Kpln Meier method using temperture nd symptom relief mediction use informtion obtined from the subject diry dt. Temperture mesurements tken within 4 h fter dose of cetminophen were excluded from nlysis. Subjects who did not hve resolution of fever were censored t the dte of their lst non-missing temperture ssessment. The time (dys) to resumption of usul ctivities ws estimted using the Kpln Meier method. Subjects who did not return to their pre-study level of Antivirl Therpy 2.7 7
R Whitley et l. performnce of usul ctivities were censored t the dte of their lst non-missing visul nlogue scle vlue. Sttisticl testing for time to resolution of fever nd time to resumption of usul ctivities ws performed in the sme mnner s for the primry end point. For subjects with positive culture for influenz virus nd with TCID 5 /ml dt t bseline, the chnge in virus titres ws evluted using the time-weighted chnge from bseline in log TCID 5 /ml. The difference between the permivir tretment groups nd plcebo ws evluted using vn Elteren Test djusted for current smoking behviour, influenz seson nd influenz virus type. A secondry nlysis ws conducted using the Wilcoxon rnk-sum test with no djustment for current smoking behviour, influenz seson nd influenz virus type. Differences between study groups in the proportion of subjects shedding influenz virus t dys 2, 3 nd 5 ws exmined using the Cochrn Mntel Henszel generl ssocition sttistic (djusted nlysis) nd the c 2 sttistic (undjusted nlysis). Figure. Screening, enrolment, virology sttus nd study completion Ptients screened for eligibility Study 2: n=2,5 Study 3: n=6 Totl: n=2,23 ITT popultion: ptients rndomized Study 2: n=344 Study 3: n=83 Totl: n=427 Sfety popultion: ptients received study drug Study 2: n=342 Study 3: n=82 Totl: n=424 ITTI popultion: confirmed influenz infection Study 2: n=39 Study 3: n=82 Totl: n=4 Screen filures Study 2: n=,77 Study 3: n=33 Totl: n=,84 Did not receive study drug Study 2: n=2 Study 3: n= Totl: n=3 Influenz infection not confirmed Study 2: n=24 Study 3: n=2 Totl: n=26 Permivir 3 mg Study 2 Study 3 Totl Permivir 5 mg Study 2 Plcebo Study 2 Study 3 Totl ITT popultion 5 57 72 4 5 26 4 Sfety popultion b 5 57 72 3 4 25 39 ITTI popultion c 6 57 63 4 9 25 34 Discontinued from study due to: Adverse event Lost to follow-up Other d d 2 2 e 3 All subjects who were rndomized. b All subjects who were rndomized nd received t lest one dose of study drug. c All subjects who were rndomized, received t lest one dose of study drug nd hd lbortory-confirmed influenz infection. d Withdrew consent. e Study discontinued by sponsor. ITT, intent-to-tret; ITTI, intent-totret infected. 72 25 Interntionl Medicl Press
Permivir tretment for cute sesonl influenz Results Subject disposition nd nlysis popultions A totl of 2,5 nd 6 potentil subjects were evluted for enrolment in Study 2 nd Study 3, respectively (Figure ). In both studies, the most common reson for exclusion ws negtive RAT t screening. In Study 2, 344 of the 2,5 potentil subjects were rndomized from 6 sites, of whom 342 subjects received study drug (permivir 3 mg, n=5; permivir 5 mg, n=3; plcebo, n=4). Two subjects were not treted when n error in RAT interprettion ws detected. In Study 3, 83 of 6 potentil subjects were rndomized from 38 sites, with 82 subjects receiving study drug (permivir 3 mg, n=57; plcebo, n=25). One subject ws rndomized in error nd did not receive study drug. The popultions for the integrted nlyses of the efficcy of permivir included the ITT popultion (427 subjects), sfety popultion (424 subjects) nd the ITTI popultion (4 subjects; Figure ). The mjority of subjects in the ITTI were confirmed on the bsis of virl culture nd/or positive PCR (n=397). Four subjects were included on the bsis of >4-fold rise in postbseline ntibody titre. Subjects ssigned to ech tretment group hd similr demogrphic chrcteristics (Tble ). Slightly more femles thn mles received permivir tretment nd the overll prevlence of smoking ws pproximtely 2%. Becuse Study 3 ws only conducted in the US, the mjority of subjects receiving tretment with permivir 3 mg cross both studies resided in North Americ. Distribution of influenz virus subtype ws similr cross the three groups nlysed: 73% of subjects were infected with n influenz A virus with 49% of subjects hving influenz due to A(H3N2) virus infection. The durtion of illness before tretment ws 36 h in 66 7% of subjects nd the severity of the cute illness, bsed on composite severity scores for the seven symptoms of influenz, ws similr cross tretment groups. Demogrphics seprted by individul study re provided in Additionl file. Tble. Demogrphics of ll enrolled subjects Chrcteristic Permivir 3 mg (n=72) Permivir 5 mg (n=4) Plcebo (n=4) Men ge, yers (sd) 35 (3.) 37 (5.5) 34 (.5) Mle, n (%) 82 (48) 47 (4) 7 (5) Men BMI, kg/m 2 (sd) 27.9 (6.25) 27.4 (6.2) 26.6 (6.3) Current smoker, n (%) 39 (23) 22 (9) 3 (2) Geogrphic region North Americ, n (%) 4 (6) 45 (39) 7 (5) Jpn/Southest Asi, n (%) () () 3 (2) Europe, n (%) 2 () Austrli nd New Zelnd, n (%) 4 (23) 43 (38) 42 (3) South Afric, n (%) 27 (6) 25 (22) 24 (7) Influenz seson Northern Hemisphere 26 27, n (%) 47 (27) 45 (39) 46 (33) Southern Hemisphere 27, n (%) 67 (39) 68 (6) 66 (47) Northern Hemisphere 27 28, n (%) 58 (34) () 29 (2) Influenz infection Positive culture, n (%) 6 (94) (88) 32 (94) Negtive culture, n (%) (6) 4 (2) 9 (6) Influenz type b A/HN (wild type), n (%) 37 (22) 32 (28) 35 (25) A/H3N2, n (%) 9 (52) 5 (44) 68 (48) B, n (%) 3 (8) 9 (7) 28 (2) A/indeterminte type, n (%) 2 () 3 (3) 3 (2) Type indeterminte, n (%) 3 (2) Influenz not confirmed, n (%) 9 (5) (9) 7 (5) Durtion of illness t rndomiztion 24 h, n (%) 48 (28) 36 (32) 45 (32) >24 to 36 h, n (%) 66 (38) 43 (38) 53 (38) >36 to 48 h, n (%) 58 (34) 34 (3) 4 (29) Men severity of illness score c (sd) 4.5 (3.7) 4.4 (3.6) 4.3 (3.93) Intention-to-tret popultion. b Influenz type ws determined bsed on PCR nd/or serology results where vilble. A/indeterminte type the influenz A/ subtype could not be determined; Type indeterminte the influenz type (A or B) could not be determined. c Severity of illness score ws bsed on the sum of individul severity scores ( 3) for the 7 symptoms of influenz from the first complete subject diry entry. BMI, body mss index. Antivirl Therpy 2.7 73
R Whitley et l. Tble 2. Clinicl end points in subjects with confirmed influenz End points Permivir 3 mg (n=63) Permivir 5 mg (n=4) Plcebo (n=34) Time to llevition of symptoms Men, h (sd) 3.6 (6.89) 36.2 (8.5) 48.2 (7.25) Medin, h (95% CI) 3.2 (88.4, 3.4) 4. (95.2, 45.5) 34.8 (3.5, 63.8) Difference compred with plcebo, h -2.6-2.7 Primry comprison P-vlue b.6 HR (95% CI) c.838 (.648,.85) Secondry comprison P-vlue d.47 HR (95% CI) e.846 (.657,.89) Time to resolution of fever Men, h (sd) 54.3 (3.8) 7.5 (6.5) 79.9 (5.66) Medin, h (95% CI) 42.8 (4.3, 46.) 5.7 (43.5, 6.7) 66.8 (56., 75.9) Difference compred with plcebo, h -24. -5. Primry comprison P-vlue b.4 HR (95% CI) c.648 (.494,.848) Secondry comprison P-vlue d <. HR (95% CI) e.63 (.472,.797) Time to resumption of usul ctivities Men, dys (sd) 9.4 (.3) 9.9 (.39).2 (.3) Medin, dys (95% CI). (8.,.). (9., 2.). (., 2.) Difference compred with plcebo, dys Primry comprison P-vlue b.65 HR (95% CI) c.867 (.653,.5) Secondry comprison P-vlue d.2 HR (95% CI) e.867 (.658,.42) Intent-to-tret infected popultion. b P-vlue bsed on the Wilcoxon-Gehn sttistic for the comprison of permivir 3 mg versus plcebo, controlling for smoking sttus, influenz seson nd influenz virus type. c Hzrd rtio (HR) bsed on the Cox regression model, including prmeters for tretment, current smoking behviour, influenz seson nd influenz virus type. d P-vlue bsed on the Wilcoxon-Gehn sttistic for the comprison of permivir 3 mg versus plcebo. e HR bsed on the Cox regression model, which included tretment s prmeter. Clinicl outcomes The time to llevition of symptoms ws shorter for subjects treted with permivir 3 mg compred with plcebo (Tble 2). The medin time to llevition of symptoms ws 3.2 h for permivir 3 mg tretment compred with 34.8 h for plcebo; difference of 2.6 h, P=.6, djusted nlysis, nd P=.47, undjusted nlysis. A difference of 2.7 h ws observed in subjects treted with permivir 5 mg. The mjority of subjects in these two studies hd infection due to influenz A (A[HN] or A[H3N2]). The medin times to llevition of symptoms for subjects with confirmed influenz A infection treted with permivir 3 mg or plcebo were. h nd 37.7 h (P=.29, undjusted), respectively, demonstrting shortening of illness by 26.7 h. A slightly smller difference of 22. h ws observed for the 5 mg group (5.7 h versus 37.7 h plcebo, P=.288, undjusted). The medin time to resolution of fever decresed in dose-dependent mnner with significnt reduction in the durtion of fever fter tretment with permivir 3 mg compred with plcebo: 42.8 h versus 66.8 h respectively, difference of 24. h (P=.4 djusted, P<. undjusted; Tble 2). The medin time to resumption of usul ctivities ws the sme cross ll tretment groups (. dys), lthough the shortest men time to resumption of usul ctivities ws reported fter permivir 3 mg tretment, 9.4 dys, compred with.2 dys for plcebo (P=.65 djusted, P=.2 undjusted; Tble 2). Results for ll of the clinicl end points broken out by individul study re provided in Additionl file. Virologicl outcomes The medin chnge (decrese) in virus titre, s mesured by the time-weighted chnge in log TCID 5 /ml t dy 3 showed decrese in virus titre fter tretment with permivir 3 mg of -.63 log TCID 5 /ml, which ws 74 25 Interntionl Medicl Press
Permivir tretment for cute sesonl influenz Tble 3. Virl end points mong subjects with confirmed influenz Permivir 3 mg (n=58) Permivir 5 mg (n=98) Plcebo (n=29) Time-weighted chnge from bseline in log TCID 5 /ml Tretment to dy 3, n 56 98 28 Men (sd) -.6 (.863) -.6 (.967) -.36 (.882) Medin -.63 -.78 -.38 Min, mx -3.75,.94-3.94,.3-3.88,.38 Primry comprison P-vlue.9 Secondry comprison P-vlue b <. Virl shedding in subjects with positive influenz culture t bseline Dy 2, n/totl n (%) 83/ (82) 78/97 (8) 97/3 (94) Primry comprison P-vlue c.8 Secondry comprison P-vlue d.8 Dy 3, n/totl n (%) 68/54 (44) 5/98 (52) 77/27 (6) Primry comprison P-vlue c.9 Secondry comprison P-vlue d.9 Dy 5, n/totl n (%) 35/56 (22) 26/98 (27) 28/26 (22) Primry comprison P-vlue c.96 Secondry comprison P-vlue d.966 P-vlue bsed on the vn Elteren sttistic djusted for current smoking behviour, influenz seson nd influenz virus type compring permivir 3 mg to plcebo. b P-vlue bsed on the Wilcoxon rnk-sum test compring permivir 3 mg to plcebo. c P-vlue bsed on the Cochrn-Mntel-Henszel Generl Assocition sttistic djusted by current smoking behvior, influenz seson nd influenz virus type compring permivir 3 mg to plcebo. d P-vlue bsed on the c 2 test compring permivir 3 mg to plcebo. TCID 5, log tissue culture infective dose. significntly greter thn the reduction with plcebo of -.38 log TCID 5 /ml (P=.9, djusted; Tble 3). The reduction in virus titre t 48 h of -.78 log TCID 5 /ml in subjects who received permivir 5 mg ws similr to the 3 mg group. The proportion of subjects shedding influenz virus who received permivir 3 mg ws significntly lower thn for plcebo on study dy 2 (82% versus 94%, P=.8) nd dy 3 (44% versus 6%, P=.9; Tble 3), respectively. Proportions of subjects shedding virus t dy 2 (8%) nd dy 3 (52%) in subjects who received permivir 5 mg were similr to those in the 3 mg group. Results for the virologicl end points broken out by individul study re provided in Additionl file. All influenz virus isoltes recovered by culture prior to tretment (bseline) from subjects enrolled in Study 2 were exmined for susceptibility to permivir, oseltmivir nd znmivir by fluorometric ssy performed on virus MDCK culture superntnts. Comprison of the IC 5 vlues demonstrted tht permivir ws the most potent NAI for A(HN) nd A(H3N2) viruses with medin IC 5 vlues <.5 nm, which were severl-fold lower thn for oseltmivir nd znmivir (Tble 4). The medin IC 5 of permivir for influenz B viruses ws similr to tht of znmivir nd severl-fold lower thn for oseltmivir. In Study 2, influenz viruses recovered by culture from post-tretment smples were exmined for chnges in IC 5 of permivir. The men pretretment permivir IC 5 ws used s mesure of susceptibility t bseline nd isoltes with n IC 5 >3 sd bove the men permivir IC 5 for the respective virus were identified for exmintion. Of the 68 subjects treted with permivir for whom pired bseline nd post-tretment IC 5 dt were vilble, totl of 7 (4.2%) subjects hd post-tretment isoltes with n IC 5 3 sd from the men permivir IC 5 for the respective virus, nd t lest twofold increse over the bseline IC 5 vlue (Tbles 4 nd 5). One out of 98 (%) subjects treted with plcebo hd post-tretment isolte with n IC 5 3 sd from the men permivir IC 5 for the respective virus, nd t lest twofold increse over the bseline IC 5 vlue. Tretment-emergent genotypic NA mino cid substitutions were detected in isoltes from two subjects who received permivir. A chnge in permivir IC 5 from.2 nm t bseline to 8.34 nm on dy 5 fter tretment ws present for one A(HN) isolte with H275Y substitution. A chnge in permivir IC 5 from.5 nm t bseline to.43 nm on the first dy fter tretment ws present for n A(H3N2) isolte with tretment-emergent mixture of sprgine nd serine t position 294 (N294N/S). No tretment emergent substitutions were identified in the remining posttretment isoltes with elevted IC 5 vlues. Sfety nlyses Among the 285 subjects who received single doses of permivir in either study, 72 (6%) were treted Antivirl Therpy 2.7 75
R Whitley et l. Tble 4. Virus subtype nd IC 5 of neurminidse inhibitors for pretretment influenz viruses cultured from subjects enrolled in Study 2 Virus subtype nd prmeter n Permivir IC 5,nM Oseltmivir IC 5, nm Znmivir IC 5, nm A/HN 68 Men (sd).47 (.995) 3.28 (8.29) 2.92 (7.93) Medin.5.3.59 Min, mx., 5.52.3, 64.42.2, 42.33 A/H3N2 36 Men (sd).2 (.38).78 (2.78).58 (.755) Medin.4.42.4 Min, mx., 3.38.3, 3.67., 6.52 A/indeterminte 6 Men (sd).35 (2.32).87 (4.26) 3.7 (3.878) Medin.68 5.84.92 Min, mx., 5.26.54, 36.72.4, 8.93 B 56 Men (sd) 2.73 (2.229) 8.58 (3.364) 4.3 (2.85) Medin 2.36 5.42 3.7 Min, mx.4,.27.5, 8.49.3, 4.33 Tble 5. Virus subtype nd IC 5 of neurminidse inhibitors for pretretment influenz viruses cultured from subjects enrolled in Study 2: post-tretment isoltes with incresed permivir IC 5 Bseline Post-tretment, Dy TE NA Subject ID Tretment Virus subtype IC 5, nm IC 5 nm post-tretment b Fold chnge substitutions 6627 PVR 5 mg A/HN.2 8.34 5 69.5 H275Y 42 PVR 5 mg A/H3N2.5.43 2 28.6 N294N/S 262 PVR 5 mg A/H3N2.24.78 2 7.42-2424 PVR 3 mg A/HN.2 3.52 9 29.3-6647 PVR 3 mg A/HN 2.95 9.68 3 3.28-4556 PVR 3 mg A/H3N2.8 3.2 5 37.75-462 PVR 3 mg A/H3N2.26 4.65 3 7.88-4645 Plcebo A/H3N2.4.5 3.8 - Isoltes with post-tretment IC 5 >3 sd from men IC 5 of the virus subtype (Tble 4) nd t lest twofold increse over the pired bseline IC 5. b Dy post-tretment on which virus isolte with incresed IC 5 ws detected. PVR, permivir; TE NA, tretment emergent neurminidse. with the 3 mg dose nd 3 subjects received the 5 mg dose; 39 subjects received plcebo. Permivir ws generlly sfe nd well-tolerted, with dverse event rtes similr to plcebo. Most (82 9%) dverse events were mild or moderte in severity. The incidence of ny dverse event following tretment with either dose of permivir (5 mg, 38% nd 3 mg, 4%) ws comprble to the incidence in subjects who received plcebo (45%; Tble 6). The most common dverse events were gstrointestinl disorders, with nuse occurring in 8% of subjects receiving permivir 3 mg, 6% of subjects treted with permivir 5 mg nd 7% of subjects who received plcebo. Dirrhoe nd vomiting occurred in 4 6% of subjects in ech tretment group. Mny of the reported dverse events, for exmple, gstrointestinl events, mylgi, proteinuri nd sthm/bronchospsm, were likely relted to influenz virus infection or underlying conditions. Injection site pin or bruising ws reported by 3% of subjects who received permivir 3 mg, in none of the subjects who received the lower dose of permivir, nd by one subject receiving plcebo. Two subjects hd serious dverse events. One subject who received permivir 3 mg ws withdrwn with meningitis (presumed bcteril) from Study 2 pproximtely dys fter study drug tretment, with subsequent ftl outcome. Another subject in Study 2 who received plcebo ws reported with serious dverse event of pyelonephritis, nd recovered. No subjects in Study 3 hd serious dverse events. Two dditionl subjects in Study 2, both of whom received plcebo, were reported with Grde 4 dverse events of hyperglycemi nd neutropeni, respectively. Severe dverse events were slightly more common mong subjects who received plcebo (n=9/39, 5%) 76 25 Interntionl Medicl Press
Permivir tretment for cute sesonl influenz Tble 6. Tretment emergent dverse events: gretest severity nd dverse events reported for 2% of subjects in ny tretment group Permivir Permivir 3 mg 5 mg Plcebo (n=72) (n=3) (n=39) Subjects with ny event, n (%) 7 (4) 43 (38) 62 (45) By severity Mild, n (%) 37 (53) 27 (63) 26 (42) Moderte, n (%) 25 (36) 2 (28) 25 (4) Severe, n (%) 9 (3) 4 (9) 9 (5) Life-thretening, n (%) () 2 (3) Gstrointestinl disorders Dirrhoe, n (%) (6) 5 (4) 6 (4) Nuse, n (%) 3 (8) 7 (6) 9 (7) Vomiting, n (%) 6 (4) 4 (4) 8 (6) Nervous system disorders Dizziness, n (%) 9 (5) 3 (3) 4 (3) Vsovgl syncope, n (%) 7 (5) Renl nd urinry disorders Proteinuri, n (%) 7 (4) (9) 8 (6) Infections nd infesttions Herpes simplex or zoster, n (%) () 3 (3) Phryngitis/tonsillitis, n (%) 4 (3) Urinry trct infection, n (%) 2 () 2 (2) Respirtory disorders Asthm/bronchospsm, n (%) 2 () () 4 (3) Epistxis, n (%) 3 (2) () () Musculoskeletl disorders Mylgi, n (%) 4 (2) () Metbolism disorders Hyperglycemi, n (%) 3 (2) Psychitric disorders Insomni, n (%) 5 (4) 2 (2) Administrtion site disorders Injection site pin/bruising, n (%) 5 (3) () Two serious dverse events were reported in Study 2. A cse of meningitis in subject who received permivir 3 mg ws rted s life-thretening. A cse of pyelonephritis in subject who received plcebo ws rted s severe. nd these events included hedche, phryngitis nd tonsillitis, pyelonephritis, sthm nd hyperglycemi. Severe events reported mong subjects who received the permivir 3 mg tretment (n=9/72, 3%) were incresed blood cretinine, mylgi, injection site pin, chest pin, urticri, hypersensitivity, extremity pin nd decresed neutrophil count. Influenz-relted complictions were ssessed proctively in both studies nd were recorded somewht less frequently for the subjects who received permivir 3 mg (% of subjects) compred with subjects who received permivir 5 mg (9%) or plcebo (8%). As noted bove, the only ftlity in either study occurred in subject with presumed bcteril meningitis with onset dys fter permivir tretment. Discussion The NAIs vilble in the US, orl oseltmivir nd inhled znmivir, were pproved for mrketing over decde go fter clinicl trils demonstrted tht tretment could shorten the course of cute, uncomplicted influenz illness [ 2]. Both drugs re self dministered, twice dily, for 5 dys. A recent met nlysis concluded tht therpy with oseltmivir or znmivir my provide net benefit over no tretment of influenz [3]. At present, no single-dose or prenterl gent for tretment of influenz is vilble in the US. The clinicl end point of TTAS hs been ccepted by regultory uthorities s vlid ssessment of symptom improvement in otherwise helthy persons with cute uncomplicted influenz, nd the clinicl dt required to ssess this end point cn generlly be esily mesured. In the evlution of drugs for cute influenz, the use of plcebo control is pproprite becuse the risk of serious consequences of non-tretment in otherwise helthy individuls with uncomplicted influenz is smll [4]. Bsed on this integrted nlysis of dt from two similrly designed, well controlled studies, conducted in both northern nd southern hemispheres, the prenterl dministrtion of single dose of permivir 3 mg ws ssocited with reduction in TTAS of.9 dys (2.6 h) compred with plcebo. In these studies, the mjority of prticipnts hd influenz A infection, nd for these subjects the improvement in TTAS compred with plcebo ws. dys (26.7 h). In met-nlysis of rndomized controlled trils in helthy dults with influenz, orl oseltmivir tretment reduced the medin durtion of symptoms by.9 dys (95% CI.3,.4) while inhled znmivir reduced the medin durtion of symptoms by.8 dys (.3,.3) [5]. Thus, the mgnitude of reduction in durtion of influenz symptoms fter single-dose IM permivir tretment observed in the combined nlyses presented here is similr to tht for tretment with 5 dys of therpy with either orl oseltmivir or inhled znmivir. This integrted nlysis focused on two studies tht evluted permivir when given by IM dministrtion. A prllel clinicl development progrmme focused on the evlution of IV permivir. In plcebo-controlled tril conducted in Jpn, permivir 3 mg nd 6 mg dministered s single IV doses were both effective, with sttisticlly significnt reductions of the medin TTAS to 2.5 dys (59. h) nd 2.5 dys (59.9 h), respectively, compred with 3.4 dys (8.8 h) for plcebo [8]. In forml humn bioequivlence studies the bsolute biovilbility of single IM permivir doses from 75 mg to 6 mg ws high, rnging from 92% to % of the exposure when dministered IV, with dose proportionl Antivirl Therpy 2.7 77
R Whitley et l. increse in exposure (AUC) tht ws bioequivlent to the sme doses dministered IV. Evlution of secondry end points in this integrted nlysis found tht time to resolution of fever ws significntly shortened with permivir 3 mg. Likewise, there ws greter reduction in virl titre, nd lower proportion of subjects shedding virus 48 h fter tretment for subjects who received permivir 3 mg compred with plcebo. A trend ws seen in reduction of time to resumption of usul ctivities with permivir 3 mg tretment, compred with plcebo. A less beneficil effect on secondry end points with the 5 mg dose ws noted, indicting possible dose response effect. In the virologicl nlyses of Study 2, permivir ws confirmed to be the most potent NAI when tested ginst pretretment viruses recovered from subjects, nd development of resistnce in post-bseline isoltes ws uncommon. The sfety observtions in the present integrted nlysis indicte tht permivir is generlly welltolerted when given s single-dose tretment nd ws not ssocited with n incresed incidence of gstrointestinl-relted dverse events reported with the use of oseltmivir. Since permivir ws pproved for mrketing in Jpn in 2, it is estimted tht more thn,, ptients hve sfely received permivir IV. The currently reported studies support the conclusion tht single dose of prenterl permivir demonstrtes positive benefit risk profile in ptients with cute uncomplicted influenz. Acknowledgements The conduct of these studies ws supported in whole or in prt with funding from the Office of Public Helth Emergency Prepredness, Office of Public Helth Emergency Countermesures, Wshington, DC, USA, under contrct number HHSO2732C. Additionl funding ws provided by the study Sponsor, BioCryst Phrmceuticls, Durhm, NC, USA. The uthors would like to thnk Amy McCullough nd Julie Dves for study mngement oversight, prticipting ptients, study site stff, nd the study investigtors listed in Additionl file 2. Disclosure sttement RW is Director of Giled Sciences. AL, SC, EM, GT nd MS received reserch support from BioCryst. JE hs been pid consultnt for BioCryst, Biot, Giled Sciences nd Tobir Therpeutics. WJA, SD, PC nd WPS re previous or current employees of BioCryst nd received slry, stock nd stock options. Additionl files Additionl file : Supplementry informtion on the demogrphics of enrolled subjects by study, nd clinicl nd virl end points in subjects with confirmed influenz cn be found t http://www.intmedpress.com/uplods/ documents/3268_whitley_add_file.pdf Additionl file 2: Full uthor cknowledgements cn be found t http://www.intmedpress.com/uplods/ documents/3268_whitley_add_file2.pdf References. Hrper SA, Brdley JS, Englund JA, et l. Sesonl influenz in dults nd children dignosis, tretment, chemoprophylxis, nd institutionl outbrek mngement: clinicl prctice guidelines of the Infectious Diseses Society of Americ. Clin Infect Dis 29; 48:3 32. 2. Centers for Disese Control nd Prevention. Influenz ntivirl medictions: summry for clinicins. (Updted 2 Jnury 2. Accessed 9 August 25.) Avilble from http://www.cdc.gov/flu/professionls/ntivirls/summryclinicins.htm 3. Bnti S, Prker CD, Annth SL, et l. Comprison of the nti-influenz virus ctivity of RWJ-272 with those of oseltmivir nd znmivir. Antimicrob Agents Chemother 2; 45:62 67. 4. Gubrev LV, Trujillo AA, Okomo-Adhimbo M, et l. Comprehensive ssessment of 29 pndemic influenz A (HN) virus drug susceptibility in vitro. Antivir Ther 2; 5:5 59. 5. Co RY, Xio J-H, Co B, Li S, Kumki Y, Zhong W. Inhibition of novel ressortnt vin influenz H7N9 virus infection in vitro with three ntivirl drugs, oseltmivir, permivir nd fvipirvir. Antivir Chem Chemother 23; 23:237 24. 6. Bbu YS, Chnd P, Bnti S, et l. BCX-82 (RWJ-272): discovery of novel, highly potent, orlly ctive, nd selective influenz neurminidse inhibitor through structure-bsed drug design. J Med Chem 2; 43:3482 3486. 7. Bnti S, Arnold CS, Prker CD, Upshw R, Chnd P. Antiinfluenz virus ctivity of permivir in mice with single intrmusculr injection. Antivirl Res 26; 69:39 45. 8. Kohno S, Kid H, Msshi M, Shimd J, S-282 Clinicl Study Group. Efficcy nd sfety of intrvenous permivir for tretment of sesonl influenz virus infection. Antimicrob Agents Chemother 2; 54:4568 4574. 9. Wetherll NT, Trivedi T, Zeller J, et l. Evlution of neurminidse enzyme ssys using different substrtes to mesure susceptibility of influenz virus clinicl isoltes to neurminidse inhibitors: report of the Neurminidse Inhibitor Susceptibility Network. J Clin Microbiol 23; 4:742 75.. Trenor JJ, Hyden FG, Vroomn PS, et l. Efficcy nd sfety of the orl neurminidse inhibitor oseltmivir in treting cute influenz: rndomized controlled tril. JAMA 2; 283:6 24.. Nicholson KG, Aoki FY, Osterhus ADME, et l. Efficcy nd sfety of oseltmivir in tretment of cute influenz: rndomised controlled tril. Lncet 2; 355:845 85. 2. Monto AS, Fleming DM, de Groot R, et l. Efficcy nd sfety of the neurminidse inhibitor znmivir in the tretment of influenz A nd B virus infections. J Infect Dis 999; 8:254 26. 3. Hsu J, Sntesso N, Mustf R, et l. Antivirls for tretment of influenz: systemtic review nd met-nlysis of observtionl studies. Ann Intern Med 22; 56:52 524. 78 25 Interntionl Medicl Press
Permivir tretment for cute sesonl influenz 4. US Food nd Drug Administrtion. Guidnce for industry influenz: developing drugs for tretment nd/ or prophylxis. (Updted April 2. Accessed 9 August 25.) Avilble from http://www.fd.gov/drugs/ GuidnceComplinceRegultoryInformtion/Guidnces/ defult.htm 5. Cooper NJ, Sutton AJ, Abrms KR, Wiloo A, Turner D, Nicholson KG. Effectiveness of neurminidse inhibitors in tretment nd prevention of influenz A nd B: systemtic review nd met-nlyses of rndomized controlled trils. BMJ 23; 326:235. Accepted 4 September 24; published online 5 October 24 Antivirl Therpy 2.7 79