Systematic Literature Review and Indirect Treatment Comparison Of

Home , Bisacodyl, Functional constipation, Linaclotide

PGI8 Systematic literature review and indirect treatment comparison of linaclotide versus other oral constipation treatments in patients with chronic constipation H Okumura,1 W Tang,2 K Iwasaki,2 S Shoji,1 T Odaka,3 A Nakajima4 1Astellas Pharma Inc., Tokyo, Japan; 2Milliman Inc., Tokyo, Japan; 3Odaka Medical and Gastrointestinal Clinic, Chiba, Japan; 4Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

INTRODUCTION Figure 2. Treatments included in NMA. Figure 3. Risk of bias of included trials. ●● Chronic constipation (CC), including functional constipation, irritable bowel CC Naloxegol 12.5Naloxegol mg 5 mg IBS-C syndrome with constipation (IBS-C), and opioid-induced constipation (OIC), Naloxegol 25 mg OIC [12w] [4w] [12w] 1 Naloxegol[4w, 50 12w] mg [12w] [3w, 12w] CC and IBS-C negatively affects patients’ quality of life and has a prevalence rate of [3w, 12w]Alvimopan 0.5 mg [12w] Random sequence generation Alvimopan 1 mg Methylnaltrexone 450 mg 2,3 [4w] Methylnaltrexone 300 mg CC and OIC (selection bias) approximately 14% and 28% worldwide and in Japan, respectively. Methylnaltrexone 150 mg Lactitol[2w] 20 g Naloxone 2.5 mg Lactitol[7d] 10 g Allocation concealment ●● The most commonly recommended treatments are polyethylene glycol [3w] Wheat (triticum) 20 g (selection bias) Naloxone 5 mg [4w] (PEG), lubiprostone, linaclotide, prucalopride, lactulose, bisacodyl, and [3w] Naloxone 10 mg Ispaghula 20 g 4 [4w] Blinding of participants and personnel [3w] Ispaghula 10.8 g dietary fibre ; in Japan, magnesium oxide followed by stimulant laxatives Naloxone 20 mg [14d] (performance bias) [3w] 5 Bisacodyl 10 mg are commonly used. Tegaserod 4 mg [3d, 4w] [12w] Tegaserod 12 mg Lactulose 20 g Blinding of outcome assessment ●● Linaclotide, a first-in-class, minimally absorbed oligo peptide with guanylate [4w, 12w] [2w, 3w, 4w] (detection bias) Lactulose 10 g cyclase-C agonistic activity, is approved for chronic idiopathic constipation Placebo [7d, 3w] Prucalopride 4 mg Incomplete outcome data 6 [4w] (72 μg and 145 μg) and IBS-C (290 μg) in the United States and for CC and Prucalopride 2 mg (attrition bias) 7 [4w] IBS-C in Japan (500 µg). [2w, 2m] Prucalopride 1 mg Linaclotide 62.5 μg [4w] Selective reporting PEG 26 g (reporting bias) ●● Most treatments for CC have limited efficacy and are associated with Linaclotide[4w, 12w]72/75 μg [4w] PEG 20 g 8 Linaclotide[5d, 2w] 100 μg [4w] unwanted side effects. Moreover, selection of the most appropriate PEG 11.8 g Linaclotide[2w, 2m] 125 μg Other bias therapeutic option is limited by a lack of direct comparisons between PEG 10/10.35[4w] g PEG 5.9 g [4w, 12w] [4w] the available drug classes. Linaclotide 133/145/150Linaclotide[2w, 2m] μg250 μg Plecanatide[4w] 6 mg Plecanatide 3 mg 0% 25% 50% 75% 100% [4w, 12w] [12w] ●● A recently conducted network meta-analysis (NMA) showed that most Linaclotide 266/290/300Linaclotide[2w, 12w, μg500 2m] μg [12w] [4w, 12w] [5d] LinaclotideLinaclotide 579/600 μg 1000 μg pharmacological therapies for functional constipation have similar efficacy; [1w, 2m] [1w] Lubiprostone 16 µg Lubiprostone 48 µg however, this meta-analysis did not include patients with IBS-C.9 Lubiprostone 32[1w, µg 2w, 4w, 12w] Low risk of bias Unclear risk of bias High risk of bias The nodes represent the treatment modalities compared and the lines represent the comparison arms in each trial analysed. The size of each node represents the number of patients pooled for each treatment and the thickness of the lines represents the number of trials for each comparison. CC, chronic constipation; d, days; IBS-C, inflammatory bowel syndrome with constipation; m, months; OIC, opioid-induced OBJECTIVE constipation; w, weeks. Primary objective ●● To compare the efficacy of linaclotide with other medications for CC, ●● A total of 47 treatments/16 drugs (different doses of the same drug were ●● After screening, selected trials were assessed for risk of bias using the including functional constipation, IBS-C, and OIC, by conducting a defined as separate treatments), including placebo, were included in the NMA. Cochrane’s Risk of Bias Tool; 4 trials had at least 1 domain for high risk systematic literature review and NMA. Treatment duration ranged from 3 days to 12 weeks (Figure 2). of bias (Figure 3).

METHODS RESULTS Table 1. Study design highlights. ●● In terms of the change in weekly spontaneous bowel movements (SBM; Figure 4), the approved dose of linaclotide 500 µg in Japan was statistically significantly more effective (mean difference, 95% credible interval [CI]) than placebo (-1.906; 95% CI, -2.672 to -1.197), lubiprostone 16 µg (-1.903; -3.254 to -0.704), Study design ●● Systematic literature review and NMA of randomized trials of 43 oral drugs approved for CC methylnaltrexone 150 mg (-1.805; -3.207 to -0.397), methylnaltrexone 300 mg (-1.413; -2.771 to -0.016), methylnaltrexone 450 mg (-1.407; -2.796 to -0.003), ●● The trials for analysis included those conducted globally and naloxegol 12.5 mg (-1.322; -2.403 to -0.240), tegaserod 4 mg (-1.148; -2.139 to -0.172), and tegaserod 12 mg (-1.023; -1.909 to -0.182). in Japan ●● Linaclotide 500 µg was statistically significantly less effective than the non-approved dose of linaclotide 600 µg (1.156; 0.025-2.281) and bisacodyl 10 mg (2.997; Databases searched ●● PubMed, Cochrane CENTRAL, and ClinicalTrials.gov 1.652-4.359). ●● Ichushi-web (database of Japanese medical studies maintained by the Japan Medical Abstracts Society) ●● Sensitivity analyses showed that findings for linaclotide 500 µg were generally consistent when the following trials were excluded: IBS-C and OIC Figure( 5), and clinical trials of linaclotide in Japan and mild-to-moderate constipation (Figure 6).

Eligibility criteria ●● All approved oral drugs identified from WHO Anatomical Therapeutic Chemical classification system, World Figure 4. Overall mean difference in the number Figure 5. Sensitivity analysis: 26 trials of patients Figure 6. Sensitivity analysis: 30 trials of patients Gastroenterology Organization Global Guidelines, and of weekly SBM before and after treatment with CC (IBS-C and OIC were excluded). with average baseline SBM <3 (mild-to-moderate Japanese guidelines for the treatment of constipation compared with linaclotide 500 µg. constipation was excluded). ●● Patients with CC, including IBS-C and OIC ●● Controlled clinical trials (randomized and quasi-randomized) Constipation Patients Constipation Patients Constipation Patients treatments (n) treatments (n) treatments (n) ●● Patients with constipation due to organic disease and

observational studies were excluded Placebo 8692 Placebo 3838 Linaclotide 500 µg 511 Linaclotide 500 µg 164 Placebo 4340 Linaclotide 62.5 µg 181 Linaclotide 62.5 µg 78 Linaclotide 500 µg 511 Efficacy endpoint ●● Change from baseline in weekly number of SBM was Linaclotide 72/75 µg 603 Linaclotide 72/75 µg 524 Linaclotide 62.5 µg 181 Linaclotide 100 µg 24 Linaclotide 100 µg 12 Linaclotide 72/75 µg 470 Linaclotide 125 µg 172 Linaclotide 125 µg 69 Linaclotide 100 µg analysed Linaclotide 133/145/150 µg 772 Linaclotide 133/145/150 µg 690 Linaclotide 125 µg 172 ● Linaclotide 250 µg 175 Linaclotide 250 µg 72 Linaclotide 133/145/150 µg 639 ● Mean differences of SBM were compared between linaclotide Linaclotide 266/290/300 µg 2004 Linaclotide 266/290/300 µg 697 Linaclotide 250 µg 175 Linaclotide 579/600 µg 202 Linaclotide 579/600 µg 113 Linaclotide 266/290/300 µg 1040 500 µg (standard dose in Japan) and other treatments Linaclotide 1000 µg 12 Linaclotide 1000 µg Linaclotide 579/600 µg 62 Linaclotide 1000 µg Lubiprostone 16 µg 431 Lubiprostone 16 µg 41 ●● Mean difference and 95% credible intervals for SBM were Lubiprostone 16 µg Lubiprostone 32 µg 43 Lubiprostone 32 µg 43 Lubiprostone 32 µg Lubiprostone 48 µg 1200 Lubiprostone 48 µg 416 Lubiprostone 48 µg 550 calculated by analysing the probability of each drug having Placanatide 3 mg 453 Placanatide 3 mg 453 Placanatide 3 mg 453 Placanatide 6 mg 441 the best outcome (increased SBM) Placanatide 6 mg 441 Placanatide 6 mg 441 PEG 5.9 g 67 PEG 5.9 g PEG 5.9 g 67 PEG 10/10.35 g 86 PEG 10/10.35 g PEG 10/10.35 g 86 PEG 11.8 g 69 PEG 11.8 g PEG 11.8 g 69 NMA method ●● Multivariate, random-effects meta-analysis based on the PEG 20 g 99 PEG 20 g PEG 20 g 67 PEG 26 g 10 PEG 26 g 67 PEG 26 g 67 methodology proposed by White et al. (2012) using Bayesian Prucalopride 1 mg 113 Prucalopride 1 mg 113 Prucalopride 1 mg Prucalopride 2 mg 141 Prucalopride 2 mg 75 Prucalopride 2 mg 66 modelling Prucalopride 4 mg 143 Prucalopride 4 mg 79 Prucalopride 4 mg 64 Lactulose 10 g 165 Lactulose 10 g Lactulose 10 g Lactulose 20 g 152 Lactulose 20 g Lactulose 20 g Bisacodyl 10 mg 274 Bisacodyl 10 mg 274 Bisacodyl 10 mg Sensitivity analysis ●● Limited to CC Ispaghula 10.8 g 91 Ispaghula 10.8 g 91 Ispaghula 10.8 g 91 Ispaghula 20 g 10 Ispaghula 20 g 10 Ispaghula 20 g 10 for NMA ●● Limited to trials with average baseline weekly SBM <3 Wheat (triticum) 20 g 12 Wheat (triticum) 20 g 12 Wheat (triticum) 20 g 12 Lactitol 10 g 63 Lactitol 10 g Lactitol 10 g Lactitol 20 g 30 Lactitol 20 g Lactitol 20 g CC, chronic constipation; IBS-C, irritable bowel syndrome with constipation; NMA, network meta-analysis; OIC, opioid-induced Methylnaltrexone 150 mg 201 Methylnaltrexone 150 mg Methylnaltrexone 150 mg 201 Methylnaltrexone 300 mg 201 Methylnaltrexone 300 mg Methylnaltrexone 300 mg 201 constipation; SBM, spontaneous bowel movements; WHO, World Health Organization. Methylnaltrexone 450 mg 200 Methylnaltrexone 450 mg Methylnaltrexone 450 mg 200 Alvimopan 0.5 mg 393 Alvimopan 0.5 mg Alvimopan 0.5 mg 335 Alvimopan 1 mg 388 Alvimopan 1 mg Alvimopan 1 mg 332 Naloxegol 5 mg 31 Naloxegol 5 mg Naloxegol 5 mg 31 Naloxegol 12.5 mg 439 Naloxegol 12.5 mg Naloxegol 12.5 mg 439 Naloxegol 25 mg 467 Naloxegol 25 mg Naloxegol 25 mg 467 ●● A total of 1577 publications/trials were retrieved for screening; Naloxegol 50 mg 30 Naloxegol 50 mg Naloxegol 50 mg 30 Naloxone 2.5 mg 8 Naloxone 2.5 mg Naloxone 2.5 mg 8 Naloxone 5 mg 8 Naloxone 5 mg Naloxone 5 mg 8 52 publications (54 trials) were included in the NMA (Figure 1). Naloxone 10 mg 8 Naloxone 10 mg Naloxone 10 mg 8 Naloxone 20 mg 7 Naloxone 20 mg Naloxone 20 mg 7 Tegaserod 4 mg 867 Tegaserod 4 mg 867 Tegaserod 4 mg ●● The 4 trials identified by hand searching were published phase 2 and 3 Tegaserod 12 mg 2125 Tegaserod 12 mg 1186 Tegaserod 12 mg studies of linaclotide in Japan. -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 Mean di erence (95% CI) Mean di erence (95% CI) Mean di erence (95% CI) Favours linaclotide 500 µg normalized to Favours other Favours linaclotide 500 µg normalized to Favours other Favours linaclotide 500 µg normalized to Favours other treatments treatments treatments Figure 1. Flow chart. linaclotide 500 µg linaclotide 500 µg linaclotide 500 µg Linaclotide 500 μg Significantly worse than linaclotide 500 μga Significantly better than linaclotide 500 μga No significant difference from linaclotide 500 μg

a PubMed Cochrane CENTRAL Ichushi-web ClinicalTrials.gov Hand search Mean differences were considered significantly different from linaclotide 500 µg when the 95% CI did not contain 0. N=697 N=798 N=29 N=49 N=4 CI, credible interval; PEG, polyethylene glycol.

N=1495

Duplication CONCLUSIONS N=488 ●● This is the first study to compare the Japanese standard dose of linaclotide (500 µg) indirectly with other treatments for CC, including IBS-C and OIC. N=1007 ●● Linaclotide 500 µg was statistically significantly more effective than placebo, low-dose lubiprostone (16 µg), methylnaltrexone, naloxegol (12.5 mg), and tegaserod, but statistically significantly less effective than bisacodyl and linaclotide 600 µg (which is a non-approved dose) with regard to improving weekly SBM. Excluded by 1st Excluded by 1st Excluded by 1st screening: N=713 screening: N=23 screening: N=31 ●● In general, these findings provide relative efficacy data that may contribute to clinical decision-making for patients with CC.

N=294 N=6 N=18

Excluded by 2nd Excluded by 2nd Excluded by 2nd Acknowledgements screening: N=252 screening: N=5 screening: N=13 LIMITATIONS ●● This study was sponsored by Astellas Pharma Inc. Medical writing assistance was provided by Sandra N=42 N=1 N=5 Kurian, Mpharm and Serina Stretton, PhD, CMPP of ProScribe – Envision Pharma Group and was ● There were insufficient data among studies to include other efficacy (44 trials) (1 trial) (5 trials) ● funded by Astellas Pharma Inc. endpoints and an analysis of adverse events. References ●● Treatment duration varied widely (3 days to 12 weeks) among the included studies. N=52 1. Sun SX, et al. Dig Dis Sci 2011;56:2688-95. (54 trials) 2. Suares NC, Ford AC. Am J Gastroenterol 2011;106:1582-91. ●● OIC is not an approved indication for linaclotide but was included because 3. Tamura A, et al. J Neurogastroenterol Motil 2016;22:677-85. it is an approved indication for some treatments (eg, lubiprostone). 4. Ford AC, et al. Am J Gastroenterol 2014;109 Suppl 1:S2-S26. 5. Hirose T, et al. Biomed Rep 2016;5:497-500. ●● Clinically equivalent doses of linaclotide and PEG were pooled for analysis. Disclosures 6. Linaclotide (LINZESS®) [prescribing information]. Cambridge, MA, USA: Ironwood ●● Treatments under development and treatments administered rectally Pharmaceuticals, Inc.; 2017. ●● H Okumura was involved in study design/concept, analysis, and interpretation and is an employee of were excluded. 7. Linaclotide (LINZESS®) [package insert]. Tokyo, Japan: Astellas Pharma Inc.; 2018. Astellas Pharma Inc.; W Tang and K Iwasaki were involved in acquisition of data and statistical analysis, ● Limited and low-quality information about older treatments are employees of Milliman, and received funding from Astellas Pharma Inc.; S Shoji was involved in 8. Johanson JF, Kralstein J. Aliment Pharmacol Ther 2007;25:599-608. ● statistical analysis and is an employee of Astellas Pharma Inc.; T Odaka and A Nakajima were involved 9. Nelson AD, et al. Gut 2017;66:1611-22. (eg, magnesium oxide) was available. in analysis and interpretation and received an advisory contract fee from Astellas Pharma Inc. 10. White IR, et al. Res Synth Methods 2012;3:111-25.