Safety and Effectiveness of Combining Biologics and Small Molecules in IBD: Systematic Review With Meta-Analysis

Background: Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis (SRMA) to assess the safety and effectiveness of dual biologic therapy (DBT) or small molecule combined with a biologic therapy (SBT) in IBD patients.  Methods: MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Clinical trials.gov were reviewed from inception to Nov 3, 2020. Studies with two or more IBD patients on DBT or SBT were included while single-case reports were excluded. The main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination category. Effectiveness was reported as pooled rates of clinical, endoscopic and/or radiographic response and remission. Random-effects modeling was performed for between-study heterogeneity using the I² statistic. The SRMA was registered with PROSPERO (CRD4202018361).  Findings: Of the 3,688 publications identified, 13 studies involving 266 patients on seven different combinations were included. Median number of prior biologics ranged from 0-4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-Tumour Necrosis Factor (aTNF, n=56) or tofacitinib (Tofa, n=57), respectively. Pooled rates of SAE for these were 9·6% (95% CI, 1·5 – 21·4; 8 studies; I2 0%) for VDZ-aTNF and 1·0% (95% CI, 0·0 – 7·6; 5 studies; I2 0%) for Tofa-VDZ. Pooled clinical remission rates for these were 55·1% (95% CI, 19·6 – 88·5; 8 studies; 53 TTs; I2 81%) for VDZ-aTNF and 47·8% (95% CI, 19·0 – 77·4; 5 studies; 49 TTs; I2 69%) for Tofa-VDZ. No new safety signal was reported for any combination. There was considerable heterogeneity across studies (I2, 0 to 87%). Interpretation: DBT or SBT appears to be generally safe and effective in IBD patients with conclusions on effectiveness limited by between-study heterogeneity. This data needs to be confirmed in prospective studies.   Registration: The SRMA was registered with PROSPERO (CRD4202018361). Funding Statement: None. Declaration of Interests: Kindra Clark-Snustad: Dr. Clark-Snustad reports personal fees from BMS, personal fees from Pfizer, outside the submitted work; Anish Patel: Dr. Patel reports personal fees from JANSSEN, personal fees from TAKEDA, personal fees from ABBVIE, outside the submitted work; Andres Yarur: Dr. Yarur reports personal fees from Takeda, personal fees from Prometheus Bioscience, personal fees from Arena Pharmaceutical, personal fees from Bristol Myers Squibb, during the conduct of the study; Benjamin L. Cohen: Dr. Cohen reports personal fees from Abbvie, personal fees and nonfinancial support from Pfizer, personal fees from Bristol Myers Squibb, personal fees from Janssen, personal fees from Target RWE, personal fees from Sublimity Therapeutics, outside the submitted work; Matthew A. Ciorba: Dr. Ciorba reports grants and personal fees from Pfizer, grants and personal fees from Takeda, outside the submitted work; Scott D. Lee MD: Dr. Lee reports grants and personal fees from Abbvie, grants and personal fees from UCB, grants and personal fees from JANSSEN, grants and personal fees from TAKEDA, grants from BMS, grants from ABGENOMICS, grants and personal fees from ELI LILLY, grants from ARENA, outside the submitted work; Edward V. Loftus, Jr.: Dr. Loftus reports grants and personal fees from AbbVie, personal fees from Allergan, grants and personal fees from Amgen, personal fees from Arena, personal fees from Boehringer Ingelheim, grants and personal fees from Bristol-Myers Squibb, personal fees from Calibr, grants and personal fees from Celgene, personal fees from Celltrion Healthcare, personal fees from Eli Lilly, grants and personal fees from Genentech, grants and personal fees from Gilead, personal fees from Iterative Scopes, grants and personal fees from Janssen, personal fees from Ono Pharma, grants and personal fees from Pfizer, grants from Receptos, grants from Robarts Clinical Trials, personal fees from Sun Pharma, grants and personal fees from Takeda, grants from Theravance, grants and personal fees from UCB, outside the submitted work; David Fudman: Dr. Fudman reports personal fees from Pfizer, outside the submitted work; Bincy P. Abraham: Dr. Abraham reports personal fees from Abbvie, personal fees from Ferring, grants and personal fees from Takeda, personal fees from Janssen, personal fees from Pfizer, personal fees from Medtronics, personal fees from Samsung bioepis, personal fees from Bristol-Myers Squibb, outside the submitted work; Jean-Frederic Colombel: Dr. Colombel reports grants and personal fees from Abbvie, personal fees from Amgen, personal fees from Allergan, personal fees from Arena Phramaceuticals, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers-Squibb, personal fees from Celgene Corporation, personal fees from Celltrion, personal fees from Eli Lilly, personal fees from Enterome, personal fees from Ferring Phramaceuticals, personal fees from Genentech, personal fees from Gilead, personal fees from Iterative Scopes, personal fees from Ipsen, personal fees from Immunic, personal fees from Imtbio, personal fees from Inotrem, grants and personal fees from Janssen Pharmaceuticals, personal fees from Landos, personal fees from Limmatech, personal fees from Medimmune, personal fees from Merck, personal fees from Novartis, personal fees from OMass, personal fees from Otsuka, personal fees from Pfizer, personal fees from Shire, grants and personal fees from Takeda, personal fees from Tigenix, personal fees from VielaBio, outside the submitted work; Parakkal Deepak: Dr. Deepak reports personal fees from Janssen, personal fees from Pfizer, personal fees from Prometheus Biosciences, other from Boehringer Ingelheim, personal fees from Arena Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Arena Pharmaceuticals, grants from Bristol Myers Squibb-Celgene, grants from Boehringer Ingelheim, outside the submitted work; All other authors declare no competing interests.