SMT19969: A Selective Therapy for C. difficile Infection One Bug, One Drug 25 th September 2012
SMT19969: A Selective Therapy for CDI SMT19969 is a novel antibiotic for the specific treatment of Clostridium difficile infection (CDI) Positioned for treatment of initial infection and reducing rates of recurrent disease Compound meets early stage target product profile Potent growth inhibition of C. difficile Narrow spectrum of activity Low rate of resistance development Oral dosing yet retained in the GI tract Well tolerated in GLP toxicology studies Programme supported by a Seeding Drug Discovery Grant Phase I clinical trial to start Q4 2012 2 One Bug One Drug September 2012
Clostridium difficile: A Significant Healthcare Problem Significant increase in the global prevalence of CDI since the late 1990s Partly driven by the emergence of hyper-virulent strains BI/NAP1 (ribotype 027) strain accounts for 35% of US cases Surveillance data suggests approximately 900,000 cases p.a. across North America and EU Recent reports suggest CDI prevalence is significantly under-estimated * Potentially up to 30,000 deaths associated with CDI each year in the USA twice federal estimates * Accounts for >80% of deaths due to gastroenteritis CDI Cases and Mortality in USA Up to 30% of patients now presenting with severe disease Cases being reported in previously low risk groups CDC recently reported that: 94% of cases associated with healthcare system contact 75% of cases have disease onset outside of hospital Combined US and EU healthcare cost $ 7bill p.a. 3 One Bug One Drug September 2012 *Eur J Clin Micro Inf Dis 2012p2439; USA Today 2012 Aug 16 Healthcare Cost and Utilization Project; CDC NVSR Reports
CDI: Disease Progression and Key Issues Antibiotics Gut flora perturbation Patient ingests spores Asymptomatic colonisation C. difficile negative Patient colonised with C. difficile following exposure to the healthcare system Discharge of spores Symptom resolution CDI antibiotic treatment Recurrent disease Spore germination Toxin production Inflammation of colonic mucosa Mild diarrhoea Life threatening pseudomembranous colitis, toxic megacolon and bowel perforation Recurrent disease (relapse or re-infection) remains the main clinical issue Each episode associated with: Increased risk of further recurrent disease Increased disease severity Increased mortality rate Risk of Recurrent Disease* After initial episode 25-30% After third episode >60% 4 One Bug One Drug September 2012 * Am J Gastro 2002 p1769 ; CID 1997 p324
Current Treatment Issues Established antibiotics limited and of sub-optimal efficacy Eroding Efficacy of Mainstay Antibiotics * Vancomycin and metronidazole: Recurrent disease Eroding efficacy Emerging resistance Alternative therapies are impractical or of limited efficacy IV Ig, toxin sequestering, probiotics Limited efficacy Toxin antibodies, faecal biotherapy Second line therapies Novel antibiotic Fidaxomicin has recently launched Superior sustained clinical response to 25 days post EOT Significant step forward in CDI management Reduced C. difficile sporulation and sparing of gut flora Potentially less effective against BI/NAP1/027 strains Fidaxomicin US Phase III Results Clinical Response Sustained Response Fidaxomicin 88% 70% Vancomycin 86% 57% 5 One Bug One Drug September 2012 *Lancet Inf Dis 2005 p549; Astellas Superbugs Conference 2012 CID 2012 55 Suppl 2
SMT19969: Potent Activity Against C. difficile SMT19969 screened against a panel of C. difficile clinical isolates comprised of: 30 genotypically distinct strains includes emerging strains such as ribotype 078 Common EU ribotypes 027 (BI/NAP1), 106 and 001 21 recently isolated strains with reduced susceptibility to metronidazole C. difficile Group (N o Isolates) SMT19969 Metronidazole Vancomycin MIC Range MIC 90 MIC 90 MIC 90 Overall Total (82/82) 0.06-0.25 0.125 8 2 Genotypically distinct group (30) 0.06-0.125 0.125 2 2 Ribotype 001 (10) 0.06-0.125 0.125 1 4 Ribotype 027 (11) 0.125-0.25 0.125 2 2 Ribotype 106 (10) 0.125-0.25 0.125 2 2 Reduced MET susceptibility (21) 0.06-0.125 0.125 8 2 6 One Bug One Drug September 2012
Gut Flora: Key to Addressing Recurrent Disease CDI caused by a disruption of the natural gut flora allowing overgrowth of C. difficile * Recurrent CDI associated with even more dramatic disturbances in the natural balance of the gut flora CDI antibiotics invariably cause continued disruption to gut flora This on-going collateral damage during treatment increases patient susceptibility to recurrent disease Central role of gut flora in preventing recurrent CDI shown by success of faecal biotherapy Procedure results in the restoration of the entire gut flora 90-95% cure rate achieved in treating severe chronic recurrent and antibiotic recalcitrant CDI Although effective, procedure is not suitable for front line use Additional concerns with infection control Therefore, a narrow spectrum antibiotic for CDI is desirable: Allows gut flora recovery whilst treating the initial C. difficile infection Thereby removing the niche C. difficile can exploit Minimise rates of recurrent disease by allowing colonisation resistance to re-establish 7 One Bug One Drug September 2012 * JID 2008 p435; CID 2003 p580 and Anaerobe 2009 p285; CID 1997 p729
SMT19969: Minimal Impact on Gut Flora SMT19969 screened for effects on gut flora at therapeutically relevant concentrations Screening concentration range 0.25 to 512 µg/ml Typical peak gut levels of vancomycin 500 µg/ml Bacterial Group (N o Isolates) MIC 50 MIC 90 MIC 90 MIC 90 SMT19969 Vancomycin * Fidaxomicin * Bacteroides spp. (16) >512 >512 128 >1,024 Clostridium spp. (8) 16 512 16 128 Lactobacillus spp. (9) 128 >512 2 32 Peptostreptococcus spp. (12) 64 128 0.5 1.0 Enterococcus spp. (8) >512 >512 4 8 Bifidobacterium spp. (7) 64 128 2 32 Eubacterium spp. (5) 256 512 2.0 0.03 E. coli (7) >512 >512 >128 >128 Other Proteobacteria (14) >512 >512 >128 >128 8 One Bug One Drug September 2012 * Optimer Pharma. AAC 2004 p4433 and AAC 2004 p4898
SMT19969: Resistance Potential C. difficile shown to have a low propensity to develop resistance to SMT19969 1. Serial passage No increase in SMT19969 MIC vs. C. difficile following 14 passages at 0.5xMIC Fidaxomicin s MIC increases to 2µg/mL after 14 passages * 2. Frequency of resistance No spontaneous resistant mutants isolated Mutation Frequency C. difficile Strain 4 x MIC 8 x MIC NCTC13307 <6.9 x 10-9 <6.9 x 10-9 NCTC13366 <3.17 x 10-9 <3.17 x 10-9 9 One Bug One Drug September 2012 * Optimer Pharma. ICAAC 2004 E-2047
SMT19969: Kill Curves and PAE SMT19969 results in a 4 log reduction in CFU after 24 hours Increased killing compared to vancomycin Post antibiotic effect (PAE) of 2 hours at 8xMIC following 3 hour initial incubation PAE increases with both increased incubation time and drug concentration Incubation Time SMT19969 Conc. PAE (hours) 1 hour 4 x MIC 0.2 8 x MIC 1.2 3 hours 4 x MIC 0.7 8 x MIC 2 10 One Bug One Drug September 2012
SMT19969: Low Faecal Binding SMT19969 MIC against C. difficile in the presence of faeces determined Faecal material causes no significant increase in MIC Comparable to vancomycin controls No significant dose adjustment required to account for MIC in the presence of faeces Drug MIC vs. C. difficile (µg/ml) 0% Faeces 5% Faeces 10% Faeces 20% Faeces SMT19969 0.125 0.125 0.25 0.5 Vancomycin 2 4 4 8 11 One Bug One Drug September 2012
Recurrent Disease Initial Disease SMT19969: In vivo Efficacy Demonstrated C. difficile Clindamycin Dosing d-1 d0 d1 SMT19969 assessed in the standard hamster model of CDI i. Infection with C. difficile: 10 5-10 6 CFU (day -1) ii. 24 hours later, SC dose of clindamycin (10 mg/kg) to disrupt gut flora (day 0) iii. 24 hours later, start dosing with agents (day 1 5) Model endpoints monitor for: Dosing ends d5 1. Antibiotic effect during course of dosing Typically 100% mortality by day 3 in untreated, infected animals 2. Ability of a compound to prevent recurrence Recurrent disease observed in vancomycin treated animals 7-9 days after last dose d13 Group Treatment n Dose Route Frequency 1 SMT19969 10 20 mg/kg PO SID 5 days 2 SMT19969 10 10 mg/kg PO SID 5 days Surviving animals sacrificed d21 3 Vancomycin 10 20 mg/kg PO SID 5 days 4 Vehicle 10 - PO SID 5 days 12 One Bug One Drug September 2012
SMT19969: In vivo Efficacy SMT19969 shows complete protection during through to day 21 at 20 mg/kg 100% survival during course of dosing with vancomycin but only 40% survival by day 21 High concentrations of SMT19969 in the caecum No drug accumulation during dosing or systemic exposure observed in infected animals Initial Disease Recurrent Disease 13 One Bug One Drug September 2012
SMT19969: ADMET Profile SMT19969 is to be dosed orally and is retained in the GI tract Maximise exposure of SMT19969 at the site of infection Studies with 14 C labelled SMT19969 show 99.8% of compound excreted in faeces No radioactivity detected in any tissue outside of GI tract GI levels above MIC following single oral dose Data supports compound being stable during GI transit No degradation by intestinal contents No significant metabolism by intestinal CYPs No metabolism by gut flora MIC Compound is not a substrate for efflux pumps CDI patients invariably have underlying co-morbidities Drug-drug interactions an important consideration 14 One Bug One Drug September 2012
SMT19969: ADMET Profile Formal toxicology studies complete and no significant issues identified Well tolerated in 28 day repeat oral dosing GLP studies in rat and dog at 1,000 mg/kg >150 fold higher than anticipated clinical dose No adverse effects, post dosing observations or clinical signs noted in any animals No adverse findings on necropsy and histopathology of tissues No adverse findings from any other in-life parameter No GI disturbances Not detected in plasma in any TK sample (LOQ=1ng/mL) No safety pharmacology, ADME or other issues Genotox (Ames & Chrom Abs ±S9) herg Rat Irwin Dog CVR No off target issues from CEREP s in vitro pharmacology panel 15 One Bug One Drug September 2012
SMT19969: First-in-Human Phase I Trial First dose in Phase I clinical trial planned for Q4 2012 Randomised, double-blind, placebo-controlled study in healthy male volunteers Single and multiple ascending dose phases Examine safety, tolerability and PK of oral SMT19969 in healthy subjects SAD Phase: Six cohorts of eight male subjects, aged 18-55 years (6 receiving SMT; 2 placebo) Anticipated dose escalation - 20mg, 100mg, 400mg, 1000mg and 2000mg Cohort examining effect of dietary state on PK to be included MAD Phase: Two cohorts of eight male subject, aged 18-55 years (6 receiving SMT; 2 placebo) Will receive oral doses BID for 10 days Faecal samples collected at baseline, mid point of dosing, end of dosing and two weeks post dosing 16 One Bug One Drug September 2012
SMT19969: A Selective Therapy for CDI SMT19969 is a novel antibiotic for the specific treatment of Clostridium difficile infection (CDI) Positioned for treatment of initial infection and reducing rates of recurrent disease Compound meets early stage target product profile Potent growth inhibition of C. difficile Narrow spectrum of activity Low rate of resistance development Oral dosing yet completely retained in the GI tract Well tolerated in GLP toxicology studies Phase I clinical trials to start Q4 2012 17 One Bug One Drug September 2012
Contact Dr Richard Vickers Summit PLC 91 Milton Park, Abingdon, Oxon OX14 4RY, UK + 44 (0)1235 443939 richard.vickers@summitplc.com