Facts About Chronc Fatgu Syndrom - sample thereof

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1 Cardac Toxcty n Chronc Fatgu Syndrom: Rsults from a Randomzd 40-Wk Multcntr Doubl-blnd Placbo Control Tral of Rntatolmod Bruc C. Stouch, Ph.D 1 Davd Strayr, M.D 2. Wllam Cartr, M.D 2. 1 Phladlpha Collg of Ostopathc Mdcn Phladlpha, PA Hmsphrx Bopharma, Inc. Phladlpha, PA KEY WORDS: Chronc Fatgu Syndrom (CFS), rntatolmod ABSTRACT Th sdntary lf-styl causd by xtrm fatgu s a sgnfcant rsk factor for hart dsas whch s a ladng caus of dath n Chronc Fatgu Syndrom (CFS) patnts. AMP-516, a 40-wk doubl-blnd, placbocontrolld study n CFS patnts to valuat th ffctvnss of rntatolmod (Amplgn ) ncludd rpatd QT ntrval masurmnts. A 5 ms post-tratmnt man ncras n QT prolongaton was obsrvd n th placbo group, whl a <5 ms man post-tratmnt ncras n QT prolongaton was obsrvd n th rntatolmod patnts. A gratr proporton of th placbo patnts wr found to hav sgnfcant QT prolongaton, compard to patnts rcvng rntatolmod. Th ncras n QT n th placbo group was assocatd wth contnud us of concomtant mdcatons known to prolong QT; patnts randomzd to rcv rntatolmod wr abl to sgnfcantly rduc thr dpndnc on ths sam mdcatons. Rducng th rsk of cardac toxcty by rducng fatgu and th us of concomtant mdcatons wth srous sd ffcts s an mportant clncal objctv and undrscors th srousnss of CFS. Introducton Chronc Fatgu Syndrom (CFS) s a svr dsordr consstng of profound fatgu and a varty of othr dbltatng symptoms that affcts up to 4 mllon Amrcans 1, 2. Hart falur s a major caus of dath wth CFS, vn n th fmal populaton whr th ag of dsas onst s typcally yars of ag 3. Currntly, thr ar no approvd tratmnts for ths dsas, and svrly afflctd patnts oftn bcom sdntary and bdrddn. To valuat th nvstgatonal drug rntatolmod (a TLR3 agonst, whch modulats nnat and adoptv mmunty) for CFS, Study AMP-516 was conductd as a 40-wk doubl-blnd, randomzd, multcntr, placbo-controlld tral (n=234) 4. Tabl 1 contans a summary of th patnts nrolld and tratd n AMP-516. Th man duraton of symptoms of CFS was Vol.10, No.3, 2010 Th Journal of Appld Rsarch.

2 Tabl 1: Summary of Onst Hstory and Duraton of CFS Symptoms (AMP-516) Paramtr Rntatolmod (n=117) Placbo (n=117) All (n=234) Ag at onst, yars n Man (sd) 34.0 (9.33) 34.1 (9.83) 34.0 (9.56) Mdan Rang 11 to to to 54 Duraton of symptoms of chronc fatgu syndrom, yars n Man (sd) 9.56 (5.36) 9.73 (6.08) 9.64 (5.72) Mdan Rang 1.4 to to to 35.6 Tm from dagnoss of chronc fatgu syndrom, yars n Man (sd) 5.93 (3.56) 5.90 (3.66) 5.92 (3.60) Mdan Rang 0.3 to to to 14.9 sd=standard dvaton. yars, and patnts had bn suffrng wth CFS for ovr 5 yars pror to nrollmnt. Th profound nablty of CFS patnts to xrcs and th chronc duraton of thr sdntary lf-styl s a sgnfcant rsk factor for hart dsas. Hart falur s a ladng caus of dath n patnts wth CFS 3. Ovr 20% of th total daths of CFS subjcts nvstgatd by Jason, t al. wr scondary to hart falur, whch s known to nduc QT prolongaton most lkly through uprgulaton of KCNE1 5. For patnts wth CFS, mor than twc as many womn d from hart falur compard to mn. Matrals and Mthods A comprhnsv analyss of QT ntrval assssmnts ncludng th QTc ntrval was prformd n AMP-516 pr ICH E14 Gudanc: Clncal Evaluaton of QT/QTc Intrval Prolongaton and Proarrhythmc Potntal for Non-Ant-arrhythmc Drugs (Octobr 2005, ICH). In AMP-516, th Safty Populaton valuatd for QT prolongaton consstd of 190 subjcts (91 rcvd rntatolmod (Poly I : Poly C 12 U) and 99 placbo) wth a basln and post-basln QT ntrval dtrmnaton prformd undr standardzd condtons. Th clncal ECG databas consstd of ovr 1, lad surfac ECGs obtand durng basln (twc) and at wks 20, 34, and 40. All ECGs wr obtand by an xprncd tam hadd by an xrcs physologst. Th tam travld to ach st and obtand th ECGs pror to admnstrng th tradmll tolranc tst. Th sam ECG analyss qupmnt (Puls Bomdcal, Inc., Norrstown, Pnnsylvana USA) was utlzd for all subjcts at all study sts throughout th duraton of th AMP-516 study. Data was rcordd and dffrncs n proportons wr analyzd usng a 2-tald Fshr s xact tst. Intra-arm dffrncs from basln n contnuous paramtrs wr analyzd usng a pard-dffrnc t-tst. Th Journal of Appld Rsarch Vol.10, No. 3,

3 Fgur 1: QT Prolongaton Obsrvd n th Placbo Group, Basd on th Uppr On-Sdd 95% Confdnc Lmts from th Intra-Patnt Man Dffrncs from Basln QT (mllsconds) Valus. Probablty valus < 0.05 wr consdrd to b sgnfcant; valus <0.1 but 0.05 wr consdrd hghly suggstv of a sgnfcant dffrnc. All statstcal tsts wr prformd usng th SAS Systm (Cary, NC). Rsults Thr was no sgnfcant dffrnc n th man QT valus rcordd at basln, basd on th actual rcordd valus, or th corrctd valus usng thr th Baztt s or Frdrca s formula. Th dffrncs at basln btwn th placbo and rntatolmod randomzd tratmnt groups (rntatolmod placbo) was -6.4, -3.0, and -4.2 for QT, Baztt s, and Frdrca, rspctvly. Although suggstv of hghr masurmnts n th placbo group, non of th dffrncs wr sgnfcant at th alpha = 0.05 lvl. Th ntra-patnt avrag QTc (Bazzt) basln valus wr xamnd rlatv to th E14 gudanc usng th catgorcal classfcaton of QTc valus. Basd on th lowst thrshold valu (>450 msc), ovr 8% of th patnts n th QTc analyss had an avrag basln QTc valu of >450 msc (95% CI: 4.9% to 13.3%). Ths fndng suggsts that a rcognzabl populaton of CFS patnts who partcpatd n AMP-516 wr at ncrasd rsk of cardovascular dsas and cardac-rlatd vnts. Th QTc valus from th placbo group from AMP-516 wr analyzd to dtrmn th man QTc ntrval basd on th ntra-patnt changs from basln (rf. Fgur 1). Ths rsults ar commnsurat wth th E14 gudanc for valdaton of th dsgn usd to assss QT prolongaton. Spcfcally, patnts tratd wth placbo had a man QTc ncras of 5.4 ms; slghtly gratr than th mnmum rqurd by th gudanc for prformng a vald QT study. Th maxmum on-study QTc ntrval (QTcB) was dtrmnd for ach patnt and catgorzd usng th cutoff ponts spcfd n th E14 Gudanc Documnt, QTc ntrvals > 500, > 480, and > 450 msc. In gnral, thr wr mor placbo patnts ovr th rspctv thrsholds, compard to patnts randomzd to rcv rntatolmod. Th post-basln rsults for th QT valus, obsrvd and corrctd ar prsntd n Fgur 2. Patnts randomzd to rcv placbo had a sgnfcantly longr QT ntrval, compard to patnts randomzd to rcv rntatolmod (p=0.049). Although 82 Vol.10, No.3, 2010 Th Journal of Appld Rsarch.

4 Fgur 2: No Evdnc of Incrasd QT Prolongaton wth Rntatolmod Compard to Placbo, Basd on th Uppr On-Sdd 95% Confdnc Lmts from th Intra-Patnt Man Dffrncs n QT (mllsconds) Valus by Randomzd Tratmnt Assgnmnt M l l s c o n d s Probablty valu from th 2-sampl t-tst of th man valus. P= P= Patnts randomzd to rcv placbo had a longr QT ntrval, compard to patnts randomzd to rcv Rntatolmod. P= Rntatolmod Placbo Rntatolmod Placbo Rntatolmod Placbo QT QTc (Baztt) QTc (Frdrca) Fgur 3: No Evdnc of Incrasd QT Prolongaton wth Rntatolmod Compard to Placbo, Basd on th Uppr On-Sdd 95% Confdnc Lmts from th Intra-Patnt Man Dffrncs n QT (mllsconds) Valus by Randomzd Tratmnt Assgnmnt D f f r n c In all cass for Rntatolmod, th lngth of th on-sdd 95% lmt s approxmatly 10 mllsconds, whch s at th pr-spcfd thrshold statd n Scton of Gudanc Documnt E P= Rntatolmod Placbo QTc (Baztt) A Pror Boundary: 10 mllsconds Probablty valu from th 2-sampl t-tst of th man valus. 4.3 P= Rntatolmod Placbo QTc (Frdrca) Th Journal of Appld Rsarch Vol.10, No. 3,

5 Fgur 4: Man (95% CI) of th Intra-Patnt Dffrncs n QT (mllsconds) Valus Btwn Placbo Patnts Who Ethr Dd or Dd Not Rcvd Concomtant Mdcatons Known to Prolongd th QT Intrval 20 M l l s c o n d s P=0.304 NO MEDICATIONS TAKEN KNOWN TO PROLONG QT 7.0 P<0.001 Probablty valus from th Wlcoxon Sgnd Rank tst <=1 MEDICATION TAKEN KNOWN TO PROLONG QT Th chang from basln was sgnfcantly dffrnt from zro (p<0.05) for placbo patnts who wr xposd to 1 or mor concomtant mdcatons known to prolong th QT ntrval P=0.175 NO MEDICATIONS TAKEN KNOWN TO PROLONG QT 7.3 P=0.001 <=1 MEDICATION TAKEN KNOWN TO PROLONG QT Fgur 5: Arthmtc Avrag QTc (Baztt) from Placbo Patnts Who Rcvd 0, 1, and 2 or Mor Dffrnt Concomtant Mdcatons Known to Prolong QT by Randomzd Tratmnt Assgnmnt 12 Avrag Chang (ms) n QT from Basln Placbo Incrasd xposur to mdcatons known to prolong QT ar assocatd wth ncrasd prolongaton n th patnts randomzd to rcv placbo >=2 NUMBER OF MEDICATIONS TAKEN INTRA-PATIENT THAT PROLONG QT Vol.10, No.3, 2010 Th Journal of Appld Rsarch.

6 Fgur 6: Prcntag of Patnts Who had a Dcras n th Numbr of Days of Exposur to Mdcatons Known to Prolong QT by Study and Randomzd Tratmnt Assgnmnt PERCENTAGE OF PATIENTS AMP-502 P=0.013 (Ch-squar tst) Rntatolmod Placbo AMP-516 P=0.048 (Ch-squar tst) DECREASED USE OF MEDICATIONS NO DECREASED USE OF MEDICATIONS. DECREASED USE OF MEDICATIONS NO DECREASED USE OF MEDICATIONS trndng n th sam drcton, th corrctd QT valus wr not sgnfcantly dffrnt at th alpha = 0.05 lvl btwn patnts randomzd to rcv thr placbo or rntatolmod. QT Rsults Basd on th Chang from Basln Patnts randomzd to rcv placbo had a slghtly longr QT ntrval, compard to patnts randomzd to rcv rntatolmod, howvr th dffrnc was not sgnfcant at th alpha = 0.05 lvl. Basd on ths rsults, thr s no vdnc that patnts tratd wth rntatolmod ar at an ncrasd rsk of cardo-toxcty. Th ntra-patnt post-basln mnus basln rsults for th QT valus, obsrvd and corrctd ar prsntd graphcally n Fgur 3. Th lngth of th on-sdd 95% confdnc lmt from th arthmtc avrag, basd on th ntra-patnt dffrncs, s prsntd n Fgur 4. For patnts randomzd to rcv rntatolmod, th lngth of th on-sdd 95% lmt s approxmatly 10 mllsconds, qual to th pr-spcfd thrshold statd n Scton of Gudanc Documnt E14. Th corrctd QT prolongaton data from th rntatolmod tratmnt group dos not xclud 10 ms, howvr th uppr on-sdd 95% confdnc lmt s lss than obsrvd n th placbo arm. Addtonally, th man chang from basln n th rntatolmod tratmnt group s lss than 5 ms, whl th man chang obsrvd n th placbo group xcds 5 ms. Many of th concomtant mdcatons utlzd by th CFS subjcts ar known to prolong th QT ntrval or nduc Torsads d Ponts (TdP). No drugs ar currntly approvd for th tratmnt of CFS. Accordngly, CFS patnts utlz numrous concomtant mdcatons n a largly unsuccssful ffort to rlv th chroncally dbltatng symptoms of CFS. Bcaus of th mportanc of studyng th potntal proarrhythmc ffct of rntatolmod n th actual populaton bng chroncally xposd to ths vast array of concomtant mdcatons ncludng many known to prolong th QT ntrval, a QT study conductd pr th E14 Gudanc n a CFS populaton s substantally supror to a QT study conductd n a normal halthy voluntr populaton. Th cumulatv xposur to rntatolmod ovr 40 wks n ths svrly dbltatd populaton takng an array of QT ntrval prolongng drugs can not b rplcatd n a normal halthy populaton. Th us of concomtant mdcatons n AMP-516 was prmttd to trat th symptoms and morbdty assocatd Th Journal of Appld Rsarch Vol.10, No. 3,

7 wth CFS. Although approvd for gnral us, svral of th concomtant mdcatons hav an assocatd product warnng that xposur to th mdcaton may caus QT prolongaton, translatng to an ncrasd rsk of cardo toxcty. Wthn th placbo group, th chang from basln was not sgnfcantly dffrnt from zro for patnts who wr not xposd to concomtant mdcatons known to prolong th QT ntrval. Howvr, th chang from basln was sgnfcantly dffrnt from zro (p<0.05) for placbo patnts who wr xposd to 1 or mor concomtant mdcatons known to prolong th QT ntrval. Fgur 5 provds a graphcal dpcton of th ncrasd QT ntrvals n th placbo patnts takng 0, 1, and 2 mdcatons wth a known rsk for prolongng QT. An addtonal analyss was prformd to dtrmn f patnts randomzd to rcv rntatolmod xprncd a sgnfcant rducton n th cumulatv xposur to mdcatons that prolong QT, compard to patnts randomzd to rcv placbo. Sxty-ght of th 100 patnts (68.0%) randomzd to rcv rntatolmod xprncd a rducton n xposur to concomtant mdcatons wth a known rsk of prolongng QT, compard to 59 of th 108 patnts (54.6%) randomzd to rcv placbo. Comparng th proporton of patnts btwn randomzd tratmnt assgnmnt and dcrasd xposur rvald a sgnfcant dffrnc n favor of rntatolmod (p=0.048). Patnts randomzd to rcv rntatolmod wr on and thr-quartrs tms mor lkly to hav rducd xposur to mdcatons known to prolong QT, compard to placbo (Odds rato: 1.76 [95% CI: 1.00 to 3.11] rf. Fgur 6). Ths fndngs wr also found n an arlr doubl-blnd, randomzd, placbo controlld study (AMP-502) of 92 CFS patnts 6. Twnty-sx of th 45 patnts (57.8%) randomzd to rcv rntatolmod xprncd a rducton n xposur to concomtant mdcatons wth a known rsk of prolongng QT, compard to 15 of th 47 patnts (31.9%) randomzd to rcv placbo. Comparng th proporton of patnts btwn randomzd tratmnt assgnmnt and dcrasd xposur rvald a sgnfcant dffrnc n favor of rntatolmod (p=0.013). Patnts randomzd to rcv rntatolmod wr approxmatly 3 tms mor lkly to hav rducd xposur to mdcatons known to prolong QT, compard to patnts randomzd to rcv placbo (Odds rato: 2.92 [95% CI: 1.25 to 6.84]). Concluson Th QT ntrval prolongaton rsults from th AMP-516 study provd a had-to-had comparson btwn patnts randomzd to rcv thr rntatolmod or placbo. Th ncras n QT prolongaton obsrvd n th placbo group provds concurrnt valdaton of th dsgn, gvn a 5 ms post-tratmnt ncras was obsrvd n th placbo group of CFS patnts. Th ncras obsrvd n th placbo patnts can b drctly attrbutabl to th us of concomtant mdcatons known to prolong QT, coupld wth a sdntary lf-styl known to b a rsk factor for hart dsas. Incrasd stamna and tolranc to xrcs ar mportant factors n rducng th cardovascular rsk assocatd wth CFS. In both AMP-502 and AMP-516, rntatolmod rsultd n a statstcally sgnfcant (p<0.05) ncras n moblty and stamna (xrcs tolranc). Rducng th sdntary nflunc of CFS through ncrasd stamna, coupld wth th rducd dpndnc on mdcatons that can prolong QT, s an mportant stp n th managmnt of ths chronc dsas. Th analyss of th ntrapatnt QT ntrval data from AMP-516, whr ovr 1,000 EKGs wr rcordd durng th cours of th study rvald vdnc of an ncrasd rsk of proarrhythmc potntal n th placbo group, compard to th rntatolmod tratd group. Gvn mor patnts n th placbo group contnu wth thr us of mdcatons, compard to patnts rcvng rntatolmod, t s ndtrmnat as to th xact contrbu- 86 Vol.10, No.3, 2010 Th Journal of Appld Rsarch.

8 ton th ncras n xrcs tolranc had on abrogatng QT prolongaton n th rntatolmod group. Rgardlss, basd on th thrsholds publshd n th FDA gudlns for all nw drugs, thr wr sgnfcantly mor ntra-patnt masurmnts n placbo patnts that wr prolongd, compard to th rntatolmod tratd patnts. Rntatolmod tratmnt allowd CFS subjcts to rduc thr dpndnc on concomtant mdcatons usd to trat dbltatng symptoms of CFS, concdntally rducng xposur to drugs known to prolong th QT ntrval. Ths may suggst a nw thraputc stratgy to potntally mtgat th ncdnc of hart falur/suddn dath n ths rlatvly young, prdomnantly fmal, populaton by rducng thr dpndncy on pallatv mdcatons assocatd wth ncrasd rsk of TdP/suddn dath. Furthr clncal studs should provd mor nsght nto th potntal rlatonshp btwn polypharmacy (as practcd n allvatng CFS symptomatology), QT ntrval prolongaton, and th rlatv ncdnc of catastrophc cardovascular vnts n ths populaton. Rfrncs 1) Fukuda K, Straus S, Hck I, t al. Th Chronc Fatgu Syndrom: A Comprhnsv Approach to Its Dfnton and Study. Annals of Intrnal Mdcn 1994; 121: ) Dr. Grbrdng s Addrss at CFS Awarnss Campagn Launch 3) Jason L, Corrad K, Grss S, t al. Causs of Dath Among Patnts wth Chronc Fatgu Syndrom. Halth Car for Womn Intrnatonal 2006; 27: ) Mtchll W, Strayr D and Cartr W. Targtng Toll-Lk Rcptor 3 (TLR3) for Human Thrapy (Pag 42). In: Procdngs of th Dath, Dangr & Immunty Confrnc, March 8-9, ) Watanab E, Yasu K, Kamya K, t al. Uprgulaton of KCNE1 Inducs QT Intrval Prolongaton n Patnts wth Chronc Hart Falur. Crc J 2007; 71: ) Strayr D, Cartr W, Brodsky I, t al. A Controlld Clncal Tral wth a Spcfcally Confgurd RNA Drug, Poly (I) Poly (C 12 U), n Chronc Fatgu Syndrom. Clncal Infctous Dsas 1994; 18 (S):S Th Journal of Appld Rsarch Vol.10, No. 3,