CADTH Canadian Drug Expert Committee Recommendation

Transcription

1 CADTH COMMON DRUG REVIEW CADTH Canadian Drug Expert Cmmittee Recmmendatin (Final) DUPILUMAB (DUPIXENT SANOFI-AVENTIS CANADA INC.) Indicatin: Atpic dermatitis RECOMMENDATION The CADTH Canadian Drug Expert Cmmittee (CDEC) recmmends that dupilumab nt be reimbursed fr the treatment f adult patients with mderate-t-severe atpic dermatitis (AD) whse disease is nt adequately cntrlled with tpical prescriptin therapies r when thse therapies are nt advisable. Service Line: CADTH Drug Reimbursement Recmmendatin Versin: 1.0 Publicatin Date: July 2018 Reprt Length: 7 Pages

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3 DUPILUMAB (DUPIXENT SANOFI-AVENTIS CANADA INC.) Indicatin: Atpic dermatitis Recmmendatin: The CADTH Canadian Drug Expert Cmmittee (CDEC) recmmends that dupilumab nt be reimbursed fr the treatment f adult patients with mderate-t-severe atpic dermatitis (AD) whse disease is nt adequately cntrlled with tpical prescriptin therapies r when thse therapies are nt advisable. Reasns fr the Recmmendatin: 1. N evidence was available that cmpared dupilumab with ther drugs cmmnly used in the treatment f AD. The fur phase III, placeb-cntrlled, randmized cntrlled trials (RCTs) (three 16-week trials [SOLO 1, SOLO 2, and LIBERTY AD CAFÉ] and ne 52-week trial [LIBERTY AD CHRONOS]) reviewed were nt designed t cmpare dupilumab with ther drugs cmmnly used in the treatment f atpic dermatitis. Althugh these trials demnstrated that a statistically significantly greater percentage f patients had imprvements in AD severity, symptms, and quality f life with dupilumab treatment cmpared with placeb, the magnitude f clinical benefit with dupilumab cmpared with existing alternative treatments is unknwn. 2. There are several ntable gaps in the clinical evidence regarding dupilumab, including data t assess the lng-term safety f dupilumab, cncerns with the generalizability f the trial results t patients wh wuld be expected t use dupilumab in clinical practice, and an absence f efficacy and safety data fr the use f dupilumab in patients where tpical prescriptin therapies are nt advisable. Discussin Pints: CDEC nted that fr patients with AD wh d nt achieve disease cntrl with apprpriate skin care measures, tpical crticsterids (TCS) and/r tpical calcineurin inhibitrs (TCIs) r phttherapy, the standard f care typically cnsists f treatment with intermittent curses f immunsuppressive drugs. The Cmmittee recgnized that dupilumab is the first Health Canada apprved drug fr use in patients with mderate-t-severe AD wh are nt adequately cntrlled with tpical therapies, and nted that dupilumab wuld likely be used as an alternative treatment ptin fr patients wh are inadequately cntrlled with immunsuppressive drugs r have cntraindicatins t such drugs. Hwever, the Cmmittee cncluded that the ptential advantages f using a Health Canada apprved drug in this ppulatin did nt ffset the disadvantages assciated with using a drug that lacks cmparative efficacy and safety data. CDEC nted that AD is a chrnic, relapsing cnditin where patients ften experience episdes f wrsening symptms thrughut their lives. The included trials were limited t 16 weeks (three trials) and 52 weeks (ne trial) duratin; therefre, there are n safety data fr dupilumab beynd ne year f treatment. Lnger-term safety data were needed fr the Cmmittee t apprpriately assess the benefit versus risk prfile f dupilumab. CDEC nted that patients wh were using TCS, a standard treatment f AD, r TCIs within ne week f the baseline visit were excluded frm SOLO 1, SOLO 2, and LIBERTY AD CHRONOS, while the LIBERTY AD CAFÉ trial excluded patients wh used TCIs within ne week f the screening visit. The LIBERTY AD CHRONOS trial als excluded patients wh experienced imprtant side effects t tpical medicatins (e.g., intlerance, hypersensitivity). These exclusin criteria limit the generalizability f the efficacy and safety results reprted in the trials t patients wh wuld be expected t use dupilumab in clinical practice and wuld frequently use TCS r a TCI regularly t treat their AD. CDEC nted that nly 2.2% and 1.7% f patients randmized in the SOLO 1 and SOLO 2 trials, respectively, were cnsidered t be intlerant t TCS. Therefre, there is a paucity f efficacy and safety data fr the use f dupilumab in the subset f patients fr whm tpical prescriptin therapies are nt advisable. CDEC nted that the patient-grup input fr this review indicated that patients with AD ften experience difficulty with their tpical treatment plans, including challenges with adherence t tpical therapies. The clinical expert cnsulted by the CADTH Cmmn Drug Review (CDR) nted that the use f tpical treatments between flares is intended t keep a patient s AD under cntrl, and effrts t vercme the challenges assciated with adherence t tpical therapies has the ptential t reduce the need fr systemic medicatins such as dupilumab fr sme patients. 3

4 Backgrund: Dupilumab has a Health Canada apprved indicatin fr the treatment f adult patients with mderate-t-severe AD whse disease is nt adequately cntrlled with tpical prescriptin therapies r when thse therapies are nt advisable. Dupilumab can be used with r withut TCS. Dupilumab is a recmbinant human IgG4 mnclnal antibdy. It is available as a subcutaneus injectin, and the Health Canada apprved dse is 150 mg/ml. Summary f CDEC Cnsideratins: The Cmmittee cnsidered the fllwing infrmatin prepared by CDR: a systematic review f RCTs f dupilumab and a critique f the manufacturer s pharmacecnmic evaluatin. The Cmmittee als cnsidered input frm a clinical expert with experience treating patients with AD and patient grup submitted infrmatin abut utcmes and issues imprtant t patients with AD. Patient Input Infrmatin: The Eczema Sciety f Canada (ESC) prvided input fr the CDR submissin fr dupilumab. Patient perspectives were btained by ESC frm an nline survey and ne-n-ne interviews. The fllwing is a summary f key input frm the perspective f the patient grup: AD has a significant impact n patients daily lives. Patients describe an intense itch that can persist all day and ften wrsens at night, thereby affecting sleep. Living with chrnic itch, pain, and chrnic cycles f flares (acute wrsening f the disease) takes a significant tll n quality f life. Apprximately 87% f patients reprted that their day-t-day quality f life is negatively impacted by interrupted and/r lss f sleep, anxiety, depressin, scial islatin, pr self-esteem, and suicidal thughts. Caregivers are als impacted and reprted feelings f helplessness and frustratin, while the patient is suffering with a cnditin that cannt be cntrlled and cntinues t flare. The caregivers indicated they als experienced sleep lss, alng with anxiety and depressin. Respndents nted the fllwing issues with their current AD treatment: difficulty dressing after applying treatments (52% f respndents); feeling uncmfrtable (49%); difficulty finding time during the day t apply the medicatins (44%); difficulty adhering t a tpical treatment plan (38%); tpical medicatins causing interference with wrk and/r day-t-day life (38%); and physical pain when applying treatments (32%). Apprximately 63% f respndents wh have tried ff-label systemic therapies reprted the therapies did nt wrk well in managing their AD. Patients are seeking a treatment that will break the cycle f flares and manage the itch. Patients als expect the new medicatin t imprve their quality f life. Clinical Trials The CDR systematic review included fur phase III, duble-blind, parallel-grup, placeb-cntrlled RCTs f patients with mderatet-severe AD. SOLO 1 (N = 671) and SOLO 2 (N = 708) randmized patients with AD in a 1:1:1 treatment rati f: dupilumab 600 mg n day 1 fllwed by 300 mg weekly; dupilumab 600 mg n day 1 fllwed by 300 mg every ther week; r weekly subcutaneus injectins f placeb, respectively, fr 16 weeks. LIBERTY AD CHRONOS (N = 740) randmized patients with AD in a 3:1:3 rati fr treatment with the fllwing: 300 mg f dupilumab weekly fllwing a lading dse f 600 mg n day 1; 300 mg f dupilumab every ther week fllwing a lading dse f 600 mg n day 1; r weekly subcutaneus injectins f placeb, respectively, fr 52 weeks. LIBERTY AD CAFÉ randmized patients with AD wh had either a histry f prir cyclsprine-a (CSA) expsure and either inadequate respnse t CSA r intlerance and/r unacceptable txicity, r a histry f being CSA-naive and nt eligible fr CSA due t medical cntraindicatins r ther reasns, in a 1:1:1 rati fr treatment with the fllwing: dupilumab 600 mg n day 1 fllwed by 300 mg weekly; dupilumab 600 mg n day 1 fllwed by 300 mg every ther week; r weekly subcutaneus injectins f placeb, respectively, fr 16 weeks. Patients in LIBERTY AD CHRONOS and LIBERTY AD CAFÉ were cncmitantly treated with medium-ptency TCS daily n areas f the skin with active lesins. N active cmparatr trials met the CDR review criteria. 4

5 Outcmes Outcmes were defined a priri in the CDR systematic review prtcl. Of these, the Cmmittee discussed the fllwing: Severity f AD was assessed using the Investigatr Glbal Assessment (IGA) scre, the Eczema Area and Severity Index (EASI), and the Scring Atpic Dermatitis (SCORAD) tl. The IGA is a five-pint scale ranging frm 0 t 4 that prvides a glbal clinical assessment f AD severity (where 0 indicates clear, 2 is mild, 3 is mderate, and 4 indicates severe AD). N minimal clinically imprtant difference (MCID) was identified fr patients with AD. The EASI assesses fur disease characteristics f AD (erythema, infiltratin/papulatin, excriatins, and lichenificatin). These were assessed fr severity by the investigatr n a scale f 0 (absent) t 3 (severe) fr each f fur bdy regins (head, arms, trunk, and legs), and weighted by bdy surface area fr each regin. A ttal EASI scre can range frm 0 t 72 pints, with higher scres indicating greater severity. An MCID f 6.6 pints has been reprted fr patients with AD. The SCORAD assesses three cmpnents f AD: the affected bdy surface area, the severity f clinical signs, and the symptms and results, prviding a maximum scre f 103, with a higher scre indicating a mre severe cnditin. An MCID f 8.7 pints has been reprted fr patients with AD. Symptm reductin was assessed using the Pruritus Numerical Rating Scale (NRS) and the Patient-Oriented Eczema Measure (POEM). The Pruritus NRS was used fr patients t reprt, in a daily diary, the verall and maximum intensity f their itch n a scale f 0 t 10. N MCID was identified fr patients with AD. The seven-item POEM was used t assess the frequency f ccurrence during the past week f the fllwing using a five-pint scale: dryness, itching, flaking, cracking, sleep lss, bleeding, and weeping. Higher scres n a scale frm 0 t 28 indicate pr quality f life and increasing severity f eczema. The MCID fr the POEM was determined t be 3.4 pints in patients with AD. Health-related quality f life was assessed using the Dermatlgy Life Quality Index (DLQI) and the EurQl 5-Dimensins (EQ-5D) 3-Levels questinnaire (EQ-5D-3L). The DLQI assessed the impact f a (general) dermatlgical disease n a patient s quality f life ver a ne-week perid by assessing the fllwing six dimensins: symptms and feelings, daily activities, leisure, wrk/schl, persnal relatinships, and treatment. Scres range frm 0 t 30, with higher scres indicating prer quality f life. N MCID was identified fr patients with AD. The EQ-5D is a generic quality-f-life instrument that includes the fllwing five dimensins: mbility, self-care, usual activities, pain/discmfrt, and anxiety/depressin. The EQ-5D-3L was used t assess these dimensins acrss three levels f severity (n prblem, sme prblems, severe prblems). N MCID was identified fr patients with AD. Adverse events (AEs), serius adverse events (SAEs), withdrawal due t adverse events (WDAEs), ntable harms (AD flares, cnjunctivitis), and use f rescue medicatin. Acrss all studies, the prprtin f patients with EASI-75 (a 75% r greater imprvement frm baseline) at week 16 was the primary efficacy end pint. The prprtin f patients with an IGA scre f 0 r 1 (n a five-pint scale) and a reductin frm baseline f tw r mre pints at week 16 was an additinal primary end pint fr the SOLO trials and LIBERTY AD CHRONOS, and a secndary end pint fr LIBERTY AD CAFÉ. Efficacy The prprtin f patients with EASI-75 was greater in the dupilumab grup cmpared with the placeb grup acrss all trials, with a range in difference f prprtin acrss trials frm 32.3% (95% cnfidence interval [CI], 24.75% t 39.94%) t 45.7% (95% CI, 35.72% t 55.66%). Each trial yielded statistically significant (P < ) findings. The prprtin f patients with an IGA scre f 0 r 1 and a reductin frm baseline f tw r mre pints at week 16 was greater in the dupilumab grup cmpared with the placeb grup, with a range in difference f prprtin acrss trials f 26.3% (95% CI, 14.95% t 37.65%) t 27.7% (95% CI, 20.18% t 35.17%). Each trial yielded statistically significant findings (P < ). While n relevant MCID was fund in the literature fr the IGA fr patients with AD, the clinical expert cnsulted fr this review indicated that the findings were relevant clinically. The least 5

6 squares mean percentage change in SCORAD frm baseline was greater in the dupilumab grup cmpared with the placeb grup. Acrss trials, the least squares mean difference in SCORAD scre between the dupilumab and placeb grups ranged frm 27.7 (95% CI, t 21.90) t 32.9 (95% CI, t 26.06), and these differences were statistically significant (P < ) acrss all trials at week 16. The LIBERTY AD CHRONOS trial included an additinal assessment at week 52; all efficacy results remained cnsistent and statistically significant (P < ). The prprtin f patients with an imprvement (reductin in scre) in their weekly average peak daily Pruritus NRS scre f fur r mre pints frm baseline t week 16 was statistically greater (P < ) fr patients in the dupilumab grup cmpared with placeb acrss all trials, with a range in difference between grups f 26.5% (95% CI, 19.13% t 33.87%) t 39.1% (95% CI, 28.53% t 49.65%). Similar findings were seen fr the prprtin f patients with an imprvement in their weekly average peak daily Pruritus NRS scre f three r mre pints frm baseline t week 16. The LIBERTY AD CHRONOS trial included an additinal assessment at week 52 fr the Pruritus NRS end pints, which shwed findings that were statistically significant (P < ) and cnsistent with week 16 findings. The least squares mean change in POEM scre frm baseline t week 16 was greater in the dupilumab grup cmpared with the placeb grup, ranging frm 6.5 (95% CI, 8.02 t 5.01) t 7.6 (95% CI, 9.29 t 5.97). These findings were statistically significant (P < ) and clinically significant (MCID = 3.48) acrss all trials. The least squares mean change in DLQI scre frm baseline t week 16 was greater in the dupilumab grup cmpared with the placeb grup, ranging frm 4.0 (95% CI, 5.16 t 2.80) t 5.7 (95% CI, 6.86 t 4.47). These findings were bth statistically significant (P < ) and ptentially clinically relevant based n an MCID range f 2.2 t 6.9. The LIBERTY AD CHRONOS trial included an additinal assessment at week 52 fr the DLQI end pint, which shwed findings that were statistically significant (P < ) and cnsistent with week 16 findings. Acrss the SOLO 1, SOLO 2, and LIBERTY AD CHRONOS trials, the difference in least squares mean change frm baseline in EQ-5D-3L index utility scre between the dupilumab and placeb grups ranged frm (95% CI, 0.02 t 0.10) t (95% CI, 0.12 t 0.21). Harms (Safety and Tlerability) Overall AEs were similar cmpared with placeb. The mst cmmn class f AEs was infectins and infestatins. Cnsistently acrss trials, cnjunctivitis (and general eye disrders) affected mre patients in the dupilumab grup cmpared with the placeb grup. In the SOLO 1, SOLO 2, LIBERTY AD CHRONOS, and LIBERTY AD CAFÉ trials, there were fewer SAEs with dupilumab cmpared with placeb; acrss trials at week 16, SAEs were reprted in 1.7% t 4.7% f patients in the dupilumab grup and 3.5% t 9.3% in the placeb grup. The mst cmmn SAEs related t vv vv vvvvvv vvvvvvvvvv vv vvvvvvvvvvv vvvv vvvvvvvv vv vvvvvvvvv vvvvvvvvvvvvvvvv Rescue medicatin was used in mre patients in the placeb grup cmpared with dupilumab. Rescue medicatin was used in 21.0% and 16.1% f patients in the dupilumab grup, and in 51.8% and 52.1% f patients in the placeb grup in the SOLO trials. In LIBERTY AD CHRONOS and LIBERTY AD CAFÉ, rescue medicatin was used in 10.9% and 3.7% f patients in the dupilumab grup, and 34.6% and 14.8% f patients in the placeb grup. Acrss all trials, the mst cmmn frm f rescue medicatin was ptent (grup III) TCS. Cst and Cst-Effectiveness Dupilumab is available as a 150 mg/ml slutin in a pre-filled syringe at a manufacturer-submitted price f $1, per 300 mg dse. The first-year cst f dupilumab is $31,154 and $30,000 annually thereafter. The manufacturer submitted a cst-utility analysis f dupilumab as an add-n t current standard f care (SOC) in patients with mderate-t-severe AD whse disease is nt adequately cntrlled with tpical prescriptin therapies. The cmparatr was current SOC, which was defined as mid-ptency TCS r TCIs. The mdel structure included a shrt-term (ne-year) phase in which efficacy was mdelled in terms f respnder status, based n the results f the LIBERTY AD CHRONOS trial and a lng-term maintenance phase cnsisting f three health states: n maintenance treatment with dupilumab and SOC; n treatment with SOC alne; and death. 6

7 The analyses were cnducted frm the perspective f the publicly funded health care system in Canada ver a lifetime time hrizn, with csts and benefits discunted at an annual rate f 1.5%. The manufacturer reprted that dupilumab plus SOC was assciated with an incremental cst-utility rati (ICUR) f $89,723 per quality-adjusted life-year (QALY) cmpared with SOC alne. CDR identified the fllwing key limitatins with the manufacturer s ecnmic submissins: The manufacturer s analysis excluded relevant cmparatrs (such as alitretinin, immunsuppressants, and phttherapy). The effects f cmpliance were nt fully incrprated within the ecnmic mdel. The manufacturer assumed that pr cmpliance with dupilumab wuld reduce drug treatment csts withut any effect n quality f life r treatment respnse. Adjusting cmpliance rates t reflect the values reprted in the LIBERTY AD CHRONOS trial resulted in a higher ICUR, given the increased csts assciated with dupilumab. Treatment-specific utility values were applied based n a regressin analysis, with respnders n dupilumab plus SOC assumed t maintain quality f life thrughut their lifetime, while treatment waning fr SOC was assumed after the first year. The mdel was sensitive t changing the treatment-utility values and t varying the assumptins arund treatment waning. An annual discntinuatin rate f 2.4% fr dupilumab was applied, which was lwer than reprted fr ther bilgics and lwer than bserved in the SOLO trial. Applying a discntinuatin rate f 6.3% based n the SOLO trial did nt significantly impact the results. The cst-effectiveness f dupilumab plus SOC in patients where tpical prescriptin therapies are nt advisable is unknwn. CDR undertk a reanalysis, revising the discntinuatin rate, the cmpliance rate, and the apprach t mdelling health state utility values. Based n the CDR reanalysis, the ICUR fr dupilumab plus SOC cmpared with SOC alne in patients nt adequately cntrlled by tpical prescriptin therapies was $579,672 per QALY gained. Based n the CDR reanalysis, a price reductin f 84% is required t achieve an ICUR f $50,000 per QALY. CDEC Members: April 11, 2018 Meeting Dr. James Silvius (Chair), Dr. Silvia Alessi-Severini, Dr. Ahmed Bayumi, Dr. Bruce Carletn, Dr. Alun Edwards, Mr. Bb Gagne, Dr. Ran Gldman, Dr. Allan Grill, Dr. Peter Jamiesn, Dr. Anatly Langer, Mr. Allen Lefebvre, Dr. Kerry Mansell, Dr. Yvnne Shevchuk, and Dr. Adil Virani. Regrets: Nne Cnflicts f Interest: Nne June 20, 2018 Meeting Dr. James Silvius (Chair), Dr. Silvia Alessi-Severini, Dr. Ahmed Bayumi, Dr. Bruce Carletn, Dr. Alun Edwards, Mr. Bb Gagne, Dr. Ran Gldman, Dr. Allan Grill, Dr. Peter Jamiesn, Mr. Allen Lefebvre, Dr. Kerry Mansell, Dr. Yvnne Shevchuk, and Dr. Adil Virani. Regrets: Nne Cnflicts f Interest: Nne 7