Drugs for Bugs: The Next Generation of Pharmaceuticals Mark Pimentel, MD, FRCP(C) Executive Director, Medically Associated Science and Technology (MAST) Program Cedars-Sinai Medical Center
Microbiome The microbiome can t cause everything Patients
How to Treat the Microbiome? Antibiotics Kill or inhibit bacteria Probiotics Replace a deficiency of one or more bacteria Take advantage of a benefit provided by certain bacteria Fecal microbial transplant (FMT) Who is normal? Genetically engineered bacteria Produce a product that can treat human disease or promote health Drugs for bugs Not meant to kill but rather affect the production pathways of bacteria
Bugs as Drugs A. Probiotics - Finding bacteria that naturally produce something that is beneficial (e.g. anti-inflammatory) - Finding bacteria or sets of bacteria that restore balance Pros Simple Promising basic science Cons No magic bullets yet FDA hurdles Too many products
What Probiotic Should I Use? 64 different probiotics listed Refridgerated/dessicated $19.99-69.99
Some of the Benefits Bifidobacter Reduces TNF Enhances mucosal IL-10 (anti-inflam) Diminishes LPS Affects toll receptors Inhibits pathogenic bacteria Improves epithelial tight junctions Promotes MMC s Increased acetate production Inhibits biofilm production Increases CD4+ T cells Decrease CD4+/CD8+ cells Many other effects
Bugs as Drugs B. Fecal Transplant -Replacing the whole gut microbiome Pros Simple Very promising (e.g. C diff) Cons Complications FDA hurdles What is normal feces?
SER-109 Not FMT but a cocktail of spores isolated from normal human stool To establish normal flora in the treatment of recurrent C. difficile infection Then 2016 happened
Bugs as Drugs C. Genetically modified bacteria -Contains desired gene (eg anti-tnf biologic) -Also needs kill switch Pros Simple Very promising (e.g. C diff) -Incorporates in gut microbiome to produce product (absorbed or local) Cons Complications FDA hurdles What is normal feces?
Kill Switches 1. Deficiency Switch Probiotic Beneficial Product/effect AA Engineered such that cannot produce an essential amino acid
Kill Switches 2. Deadman Switch Probiotic Toxin Beneficial Product/effect Inhibitor Blocks the production of toxin
Kill Switches 3. Passcode Switch Probiotic Toxin Beneficial Product/effect Multiple agents Very complex because its like a combination lock All the agents need to be there or the bacteria dies Benefit: Hard to imagine the environment might figure it out and all the bacterium escape
Elafin Producing Bacteria ViThera Pharmaceuticals developing VT301 for Crohn s disease Engineered Lactococcus lactis and lactobacillus caseii to produce elafin Elafin is a protease inhibitor that is produced by normal human epithelium and deactivates elastase and proteinase-3 In IBD elafin is reduced and this could allow elastase and proteinase to damage the gut wall Success in animal models Motta JP, et al. Sci Transl Medicine, 2012
Bacterial Injection Injecting solid tumor with bacteria Strong quorum sensing Bacteria are microaerophilic so die when in oxygen so stay in blood starved tumor Bacteria draws inflammation and kill of tumor cells Zheng, et al. Sci Translat Med, 2017
Protecting Good Bugs iv antibiotics Gut penetration Beta lactamase SYN-004 Pros Simple Proven effective Cons B-lactams only
Why is Rifaximin a Microbiome Drug? 1. Not systemic 2. Soluble in bile in small bowel, precipitates in the colon 3. Works only in the small bowel 4. No yeast accumulation 5. 98% of stool flora unchanged after 3 courses of rifaximin 6. No development of bacterial resistance Kim, et al. Dig Dis Sci 2013 Pimentel, et al. Dig Dis Sci 2017
TARGET 1 and 2 Trials for IBS Primary Primary Efficacy Outcome Efficacy Outcome SGA-IBS Weekly SGA-IBS Weekly Study TARGET Study TARGET 1 TARGET TARGET 2 Odds Odds Ratio Ratio 1.53 1.53 1.45 1.45 1.49 1.49 (95% CI) p-value (1.10,2.12) (95% CI) p-value 0.0125 (1.10,2.12) 0.0125 (1.05,2.01) 0.0263 (1.05,2.01) 0.0263 (1.18,1.88) 0.0008 (1.18,1.88) 0.0008 Key Key Secondary Secondary IBS Bloating Weekly IBS Bloating Weekly TARGET TARGET 1 TARGET TARGET 2 1.62 1.62 1.49 1.49 1.56 1.56 (1.16,2.27) (1.16,2.27) (1.08,2.06) (1.08,2.06) (1.23,1.96) (1.23,1.96) 0.0045 0.0045 0.0167 0.0167 0.0002 0.0002 Other Other Secondary Secondary SGA-IBS Daily SGA-IBS Daily IBS Bloating IBS Bloating Daily Daily IBS Ab Pain IBS Ab Pain Daily Daily TARGET TARGET 1 TARGET TARGET 2 TARGET TARGET 1 TARGET TARGET 2 TARGET TARGET 1 TARGET TARGET 2 1.76 1.76 1.59 1.61 1.59 1.61 1.41 1.41 1.76 1.76 1.52 1.52 1.45 1.45 1.46 1.46 1.42 1.42 (1.26,2.47) (1.26,2.47) (1.13,2.24) (1.28,2.04) (1.13,2.24) (1.28,2.04) (1.01,1.97) (1.01,1.97) (1.26,2.44) (1.26,2.44) (1.21,1.92) (1.21,1.92) (1.05,2.02) (1.05,2.02) (1.05,2.03) (1.05,2.03) (1.13,1.78) (1.13,1.78) 0.0009 0.0009 0.0072 <0.0001 0.0072 <0.0001 0.0486 0.0486 0.0008 0.0008 0.0004 0.0004 0.0255 0.0255 0.0232 0.0232 0.0028 0.0028 FDA FDA Proposed Proposed Ab Pain Stool Ab Pain & Stool Daily (FDA) Daily (FDA) Ab Pain Daily Ab Pain Daily (FDA) (FDA) Stool Consist. Stool Consist. Daily (FDA) Daily (FDA) TARGET TARGET 1 TARGET TARGET 2 TARGET TARGET 1 TARGET TARGET 2 TARGET TARGET 1 TARGET TARGET 2 1.40 1.40 1.55 1.55 1.47 1.47 1.48 1.48 1.46 1.46 1.46 1.46 1.80 1.80 1.57 1.57 1.67 1.67 (1.02,1.92) (1.02,1.92) (1.12,2.13) (1.12,2.13) (1.17,1.84) (1.17,1.84) (1.08,2.03) (1.08,2.03) (1.06,2.00) (1.17,1.83) (1.06,2.00) (1.17,1.83) (1.25,2.59) (1.25,2.59) (1.12,2.21) (1.12,2.21) (1.31,2.14) (1.31,2.14) 0.0401 0.0401 0.0077 0.0077 0.0009 0.0009 0.0157 0.0157 0.0194 0.0009 0.0194 0.0009 0.0015 0.0015 0.0096 0.0096 <0.0001 <0.0001 Pimentel, et al NEJM, 2011 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 Odds Ratio and 95% CI Odds Ratio and 95% CI Favors Placebo Favors Rifaximin Favors Placebo Favors Rifaximin
TARGET 1 and 2 Durable IBS Response Primary Efficacy Outcome SGA-IBS Weekly Study TARGET 1 TARGET 2 Odds Ratio 1.35 1.52 1.44 (95% CI) (1.00, 1.82) (1.13, 2.03) (1.17, 1.77) p-value 0.0477 0.0053 0.0007 Key Secondary IBS Bloating Weekly TARGET 1 TARGET 2 1.28 1.56 1.42 (0.95, 1.73) (1.16, 2.09) (1.15, 1.75) 0.1042 0.0031 0.0011 Other Secondary SGA-IBS Daily IBS Bloating Daily IBS Ab Pain Daily TARGET 1 TARGET 2 TARGET 1 TARGET 2 TARGET 1 TARGET 2 1.60 1.47 1.48 1.50 1.67 1.53 1.35 1.35 1.31 (1.18, 2.18) (1.09, 1.99) (1.20, 1.83) (1.10, 2.04) (1.24, 2.25) (1.24, 1.89) (1.00, 1.83) (1.01, 1.81) (1.06, 1.61) 0.0025 0.0127 0.0003 0.0103 0.0008 <0.0001 0.0495 0.0435 0.0118 FDA Proposed Ab Pain & Stool Daily (FDA) Ab Pain Daily (FDA) Stool Consist. Daily (FDA) TARGET 1 TARGET 2 TARGET 1 TARGET 2 TARGET 1 TARGET 2 1.36 1.44 1.40 1.31 1.37 1.33 1.70 1.48 1.58 (1.01, 1.83) (1.08, 1.92) (1.14, 1.72) (0.98, 1.75) (1.03, 1.83) (1.09, 1.64) (1.24, 2.33) (1.09, 2.00) (1.27, 1.97) 0.0396 0.0141 0.0014 0.0725 0.0298 0.0058 0.0009 0.0114 <0.0001 0.0 0.5 1.0 1.5 2.0 2.5 Odds Ratio and 95% CI Pimentel, et al NEJM, 2011 Favors Placebo Favors Rifaximin
Effect of Rifaximin (10 years later) Increasing rifaximin use 40% reduction in D-IBS Oh SJ, et al DDW 2017
Drugs for Bugs -Proteins -Gases -Toxins -Adhesins -Flagellae -Sterols -Obesity -IBS -IBD -Constipation -Others Block pathway for these human harmful byproducts Pros Simple Very promising (e.g. C diff) Cons Complications FDA hurdles What is normal feces?
Non-Antibiotic Drugs Block adhesion (Prevent retention) Dozens of products that could affect host
Statins and Methane Lovastatin was later discovered from Aspergillus spp Akiro Endo (1971) discovered mevastatin which is a chemical produced by certain fungi to defend against other organisms Mevastatin was toxic to humans
How Lovastatin Would Help Hydrogen (H 2 ) Lovastatin Syntroph F420 Methane (CH 4 ) M. smithii F420 is the key enzyme in path that makes methane in M. smithii
Lovastatin Lactone and F420 Enzyme Muskal SM, et al. F1000 2016;5:606.
Lovastatin Timed Release Phase 2 Trial Study 1 Study 2 SYN-010 42 mg (19) SYN-010 42 mg (54) CH 4 >10 ppm SYN-010 21 mg (22) Placebo (22) Subjects who successfully completed Study 1 were transferred to active drug at Day 29 Screen 1 7 14 21 28 35 42 49 56 63 70 77 84 Day Gottlieb K, et al. DDW 2016. Lactulose breath test (LBT)
Breath Methane AUC at Week 12 (ppm*h) Methane Correlates with Improved Symptoms on Lovastatin 300 250 200 150 100 50 p = 0.0259 Gottlieb K, et al. DDW 2016. 0 0 1 2 3 4 5 6 7 Weekly No. Complete Spontaneous Bowel Movements (CSBMs)
Clinical Responders by Month Month 1 2 3 Month 1 2 3 Month 1 2 3 Month -- 2 3 Dose Month 1 Dose Months 2,3 Gottlieb K, et al. DDW 2016.
No. Subjects Using Rescue Medication % Subjects Using Rescue Medication in Study Lovastatin Timed Release 8 7 6 5 4 3 2 1 Daily use of RLax (bisacodyl; 5 mg) Placebo SYN-010 21 mg SYN-010 42 mg in Study 1 0 0 4 8 12 16 20 24 28 Study Day 100% % Subjects using RLax (bisacodyl; 5 mg) 90% 80% 70% 60% 50% 40% 30% 20% 10% 0 54.5% in Study 1 18.2% *p=0.013 vs Placebo p=0.03 vs Placebo Fisher s exact test 21.1% Placebo SYN-10 21 mg SYN-10 42 mg Gottlieb K, et al. DDW 2016.
Company Product Indication Stool Open biome Stool CDI RBX2660 Rebiotix Purified stool bacteria CDI, IBD MET-1 Nubiyota 33 bacteria probiotic CDI SER-109 Seres Spores to re-establish flora CDI SER-287 Seres Spores IBD VE-202 Vedanta Clostridium that restores IBD CBM-588 Osel Clostridium butyricum CDI, IBD L plantarum Optibiotix L plantarum Obesity CNDO-201 Fortress Trichuris suis Crohns Blautix 4D pharma Bacterial blend IBS Thetanix - Anti-inflam protein from bacteroides IBD AG-014 Intrexon Genetic modified lactobac secreting anti-inflam chemicals IBD SHP-01 Symbiotic Lysin antimicrobial enzyme CDI VT-301 ViThera Elafin producing lactobacillus IBD SGM-1019 2 nd Genome Molecule inhibits host microbe interaction IBD SYN-004 Synthetic Biologics Β-lactamase CDI prevent SYN-010 Synthetic Biologics Block methane production Constip Rifaximin Salix Gut specific microbial modulator D-IBS Early phase Failing Phase II+ Approved
Conclusion 1. There are emerging therapeutics directed at the gut microbiome to treat human disease 2. Most are using bugs as drugs 3. Future therapies will include drugs for bugs 4. There needs to be an increased tolerance load for investment in this area of work