Susan Dorman, MD December 02, Medical Consultant Meeting. San Antonio, TX

Transcription

1 Success/Failure of TBTC Study 31: Rifapentine containing treatment shortening regimens for pulmonary tuberculosis: A randomized, open label, controlled phase 3 clinical trial Susan Dorman, MD December 02, 2016 Medical Consultant Meeting December 02, 2016 San Antonio, TX EXCELLENCE EXPERTISE INNOVATION Susan Dorman, MD has the following disclosures to make: No conflict of interests No relevant financial relationships with any commercial companies pertaining to this educational activity 1

2 Treatment shortening for (drugsusceptible) pulmonary TB: Building a case for rifapentine Susan Dorman, MD Johns Hopkins University School of Medicine Heartland National TB Center December 2, 2016 Development of the modern short course regimen s 1980 s Schatz & Waksman discover streptomycin: antibiotic era begins Use of isoniazid prevents acquired drug resistance: enduring cure becomes possible Use of rifampin shortens treatment duration from 18 months to 9 months Use of PZA shortens treatment duration to 6 months Replacing streptomycin with ethambutol enables a less toxic, oral 4 drug regimen 2

3 Current TB treatment intensive phase continuation phase isoniazid rifampin pyrazinamide ethambutol isoniazid rifampin 10 mg/kg months Need for Shorter TB Treatments (in addition to improving access to, delivery of TB care) Shorter, highly potent regimens have potential to: Increase adherence, decrease default rates Decrease drug resistance Decrease TB Control Program costs Strategies for developing shorter regimens New drugs Optimize use of existing drugs 3

4 Existing drugs that may not be used optimally Rifamycins Is 10 mg/kg the optimal dose for rifampin? Is rifampin the optimal drug in its class? Fluoroquinolones Which fluoroquinolone? As replacement for ethambutol? As replacement for isoniazid? Pyrazinamide How to get drug into more bacteria How to minimize toxicity and maximize activity Linezolid, β lactams, others Rifamycins Rifamycins Inhibit bacterial DNA dependent RNA polymerase Key sterilizing component of TB tx Rifampin, rifapentine, rifabutin, rifalazil 4

5 Current use of rifampin and the case for pharmacodynamic (PD) optimization A lot of bacteria PD in mice Evidence of MED in humans Early bactericidal activity 2 RIF dose n EBA mg mg mg Few/no bacteria In DAILY combo therapy with INH: 3 Doses <9 mg/kg associated with positive sputum cx at 8, 16, 20 wks 1 Jindani et al, Am Rev Respir Dis 1980;121:939 2 Long et al, Am Rev Respir Dis 1970;119;879 3 Jayaram et al, AAC (2003); 47:2118 Current use of rifampin and the case for pharmacodynamic (PD) optimization A lot of bacteria PD in mice Evidence of MED in humans Early bactericidal activity 2 RIF dose n EBA mg mg Few/no bacteria Range of human AUC/MIC after 600 mg oral dose 1200 mg In DAILY combo therapy with INH: 3 Doses <9 mg/kg associated with positive sputum cx at 8, 16, 20 wks 1 Jindani et al, Am Rev Respir Dis 1980;121:939 2 Long et al, Am Rev Respir Dis 1970;119;879 3 Jayaram et al, AAC (2003); 47:2118 5

6 Existing drugs that may not be used optimally Rifamycins Is 10 mg/kg the optimal dose for rifampicin? Is rifampicin the optimal drug in its class? Fluoroquinolones Which fluoroquinolone? As replacement for ethambutol? As replacement for isoniazid? Pyrazinamide How to get drug into more bacteria How to minimize toxicity and maximize activity Linezolid, β lactams, others Rifapentine (RPT, P) MIC 90 = 0.06 g/ml (vs for RIF) Half life = h (vs. 2 4 for RIF) Developed as a rifamycin for highly intermittent (600 mg once or twice per week) active TB treatment; US FDA approved for this indication in 1998, but activity of these intermittent regimens is not sufficient for their use in patients at high risk for treatment failure 6

7 Preclinical: DAILY rifapentine is highly active in mouse model of TB Log 10 CFU per Lung R, rifampin 8 P, rifapentine R 10 HZ 7 R 20 HZ 6 R 40 HZ 5 P 10 HZ P 20 HZ Treatment duration (weeks) From Nuermberger et al Proportion (%) of mice relapsing after Rx for: Regimen 8 wks 10 wks 12 wks R 10 HZ Not Done Not Done 100% (15/15) R 20 HZ Not Done 100% (15/15) 67% (10/15) R 40 HZ Not Done 27% (4/15) 0% (0/15) P 10 HZ 100% (15/15) 33% (5/15) 0% (0/15) P 20 HZ 40% (6/15) 0% (0/15) Replacing RIFAMPIN 10 mg/kg/d with RIFAPENTINE 10 mg/kg/d: increases bactericidal & sterilizing activity halves the time needed for cure Stages in the clinical testing of a new TB drug EARLY (1) Pre clinical Safety, tolerability, PK, drug drug interactions, food effects Single doses, repeated doses Typically in healthy adults MID (2) Efficacy, assessed using surrogate markers Additional information about safety & tolerability PK and pharmacodynamics LATE (3) Efficacy, assessed through definitive cure/lack of cure FDA Review Synergy and antagonism in regimens Additional information about safety, tolerability Population: TB patients 7

8 (Re ) Development of Rifapentine for TB: Does higher rifamycin exposure, accomplished by daily rifapentine, result in increased anti TB activity that is sufficient to shorten TB treatment? Preclinical (mouse model of TB) Phase 1 dose escalation study EARLY (1) Phase 2 clinical trial with surrogate endpoint MID (2) Phase 3 clinical trial of shortened treatment regimen LATE (3) Clinical Phase 1: Safety and PK of escalating rifapentine daily doses in healthy volunteers TBTC S29B: Multiple dose RPT PK Mean concentration (mcg/ml) mg/kg RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RPT No evidence of dose dependent increase in frequency of known rifamycin associated toxicities, such as hepatotoxicity or cytopenias. Maximum tolerated dose at least 20 mg/kg/d Time from dose (h) Dooley et al; Clin Pharmacol Ther 2012;91:881 8

9 (Re ) Development of Rifapentine for TB: Does higher rifamycin exposure, accomplished by daily rifapentine, result in increased anti TB activity that is sufficient to shorten TB treatment? Preclinical (mouse model of TB) Phase 1 dose escalation study EARLY (1) Phase 2 clinical trial with surrogate endpoint MID (2) Phase 3 clinical trial of shortened treatment regimen LATE (3) Clinical Phase 2: TBTC Study 29X STUDY OBJECTIVE For regimens that include RPT at a dose higher than 10 mg/kg/d (in addition to H+Z+E) administered daily during intensive phase treatment of smear positive, drug susceptible pulmonary TB: Determine safety & tolerability Estimate antimicrobial activity, using a surrogate endpoint for cure PK/PD relationships Which PK parameter is associated with effect or toxicity? For the key PK parameter, what range should we target? Are there covariates that influence that PK parameter? What strategies can we use to get the most people at that PK parameter target 9

10 Sputum smear (+) PTB suspect Phase 2 Randomization (n=320) RPT 20 mg/kg INH+PZA+EMB 7/7 for 8 weeks RPT 15 mg/kg RPT placebo INH+PZA+EMB 7/7 for 8 weeks RPT 10 mg/kg RPT placebo INH+PZA+EMB 7/7 for 8 weeks Study visits every 2 weeks for safety assessments & sputum culture Double blind with respect to RPT dose, but not RPT vs RIF RPT given with high fat food to maximize absorption RIF 10 mg/kg INH+PZA+EMB 7/7 for 8 weeks ASSESS FOR PRIMARY ENDPOINTS: Tolerability/safety: discontinuations, AEs Efficacy (surrogates): % culture neg at week 8, time to stable cx conversion ATS/CDC/IDSA recommended continuation phase regimen Sites enrolling in Setting TBTC Study 29 and 29x Phase 2 10

11 Enrollment Phase 2 Inclusion criteria (summary) Age 18 years or older Sputum smear (+) PTB suspect < 5 days TB tx, prior 6 months HIV testing; those on ART excluded (drug-drug interactions) Karnofsky > 60 AST < 3x ULN Informed consent Randomization stratified by Enrollment site baseline cavitation, yes vs. no 801 Not enrolled: Refused (127) Not eligible (573) Other or unknown (101) 1135 Screened 334 Enrolled Phase 2 80 not eligible for MITT: Did not grow Mtb (6) Resistant to INH, rifamycins and/or PZA (44) Other (30) 19 not eligible for Per Protocol: Drug toxicity led to d/c regimen (5) Died (2) Withdrew consent or physician advised to d/c regimen (7) Contaminated week 8 cx (1 Other (2) 334 Intention to Treat analysis 254 Modified Intention to Treat analysis 235 Per Protocol analysis 11

12 Clinical Phase 2: TBTC Study 29X Results: Study Population (ITT) Phase 2 Assigned treatment arm > RIF 10 N=85 RPT 10 N=87 RPT 15 N=81 RPT 20 N=81 Median age (range) 33 (19,78) 29 (19,66) 31 (18,69) 31 (19,70) Median weight (range) 54 (41,77) 54 (40,76) 55 (40,81) 54 (41,82) Male (%) 55 (65) 63 (72) 58 (72) 54 (67) Cavitary pulmonary TB (%) 69 (81) 67 (77) 61 (75) 60 (74) HIV positive (%) 5 (6) 6 (7) 4 (5) 11 (14) Enrolled at African site (%) 45 (53) 49 (56) 48 (59) 48 (59) Clinical Phase 2: TBTC Study 29X Results: Tolerability (ITT) *A well tolerated regimen was pre defined as one for which the 90% one sided confidence limit of the % of participants who permanently discontinued that regimen was < 30% Assigned treatment arm > RIF CTRL N=85 RPT 10 N=87 RPT 15 N=81 RPT 20 N=81 Regimen permanently discontinued Upper bound of 90% one sided CL* 11 (12.9%) (5.7%) (6.2%) (11.1%) 17.1 based on microbiology death toxicity other than death w/draw consent, refuse to continue Other Safety: No differences in adverse events (number, type, severity) between arms 12

13 The % of participants converting sputum cultures to negative by week 8 is higher for those taking a RPT regimen than for those taking a RIF regimen % with culture conversion by week Solid culture MGIT culture RIF RPT What is driving the overall difference in culture conversion between the RPT and RIF regimens? RIF RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RIF RPT 600 mg RPT 900 mg RPT 1200 mg RIF RPT low RPT med RPT high Is it the mg/kg dose given? (as randomized) Is it the mg dose given? Is it the drug exposure (AUC)? No... No... Yes! 13

14 What is driving the overall difference in culture conversion between the RPT and RIF regimens? RIF RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RIF RPT 600 mg RPT 900 mg RPT 1200 mg RIF RPT low RPT med RPT high Is it the mg/kg dose given? (as randomized) Is it the mg dose given? Is it the drug exposure (AUC)? No... No... Yes! What is driving the overall difference in culture conversion between the RPT and RIF regimens? RIF RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg RIF RPT 600 mg RPT 900 mg RPT 1200 mg RIF RPT low RPT med RPT high Is it the mg/kg dose given? (as randomized) Is it the mg dose given? Is it the drug exposure (AUC)? No... No... Yes! 14

15 Clinical Phase 2:TBTC Study 29X Arm vs. Dose vs. Exposure Response Phase 2 PD outcome Description Stable culture conversion, solid media Stable culture conversion, liquid media P value Arm effect P value Dose effect P value Exposure (AUC) effect Is 20 mg/kg better than 15 mg/kg better than 10 mg/kg? Is 1200 mg better than 900 mg better than 600 mg? Is AUC driving the effect? Efficacy: PKPD relationship is steep Emax curve Phase 2 Maximal effect effect 50% effect Legend: Median exposure: 600 mg group Median exposure: 900 mg group Median exposure: 1200 mg group 30 AUC (mcg*h/l) 15

16 Key Findings from Phase 2 Studies of RPT The RPT regimens were well tolerated and appeared safe; there were no specific toxicities that increased with increasing RPT dosage Efficacy, whether assessed by % culture negative at end of intensive phase or time to stable culture conversion, was greater for the highest RPT dosages than for RIF Exposure (AUC) was the strongest driver of the efficacy response; AUCresponse curve is steep PK and PK/PD analyses support flat dosing using 1200 mg with food Pulmonary cavitation is an important covariate presence of cavity(s) increases by almost 3 fold the RPT AUC required for half maximal response Conclusion from Phase 2 Studies of RPT For rifapentine, the robust antimicrobial activity and observed good tolerability and safety justify assessment of daily high dose rifapentine in regimens of shorter than 6 months duration in a phase 3 clinical trial 16

17 Clinical Phase 3: TBTC S31/ACTG 5349 Primary Objectives Evaluate efficacy of a rifapentine containing regimen to determine whether the single substitution of RPT for RIF makes it possible to reduce to 4 months the duration of treatment (direct follow on to S29X) 2PHZE/2PH Evaluate efficacy of a 4 month regimen that substitutes a) RPT for RIF and b) MOX for EMB to determine whether reduction to 4 months duration is possible (optimized regimen using existing drugs) 2PHZM/2PHM DESIGN: multicenter 3 arms (1:1:1) Open label Non inferiority design Screen for eligibility Consent, enroll Randomize 1:1:1 Notes: All treatment: daily 7/7 Flat P dose of 1200 mg M dose of 400 mg Food guidance: food with RPT, no food with RIF Regimen 1 (control) 2RHZE/4RH (26 wks) Regimen 2 (investigational) 2PHZE/2PH (17 wks) Regimen 3 (investigational) 2PHZM/2PHM (17 wks) Evaluation for primary outcome (cure) at 12 months after randomization SECONDARY: Evaluate safety and tolerability of the regimens, intensive PK of ALL TB drugs and EFV, biobanking 17

18 CDC / NIH Partnership Sites enrolling in TBTC Study 29 and 29x TBTC Study Sites Phase 3 Target: 2,500 participants Smear positive and/or is Xpert positive with semiquantitative result of medium or high Age 12 or older HIV w/ CD4 100 ACTG Clinical Research Sites Eligibility (summary) Phase 3 Inclusion Sputum that is smear positive and/or is Xpert positive with semiquant result of medium or high Age 12 or older HIV testing CD4 100 Usual lab parameters Informed consent Exclusion More than 5 days of treatment directed against active TB TB or suspected TB involving CNS, bones/joints, miliary Wt less than 40 kg Karnofsky score of 50 or less Known drug resistant TB 18

19 TBTC Community Research Advisor s Group International community driven advisory board Works to ensure meaningful representation & engagement of affected communities in the TBTC by: Raising awareness of TB and TBTC research among communities and policymakers Ensure that community priorities are reflected in TBTC research priorities and study design Help ensure that communities understand the TBTC research, and are informed of and understand the research results Augment TB research literacy Study 31 / A5349 Status Phase 3 First patient in: January 2016 Current enrollment approx 500 participants Targets Last patient enrolled: Q Last patient out: Q Results: Q

20 What else is on the horizon? DS TB: high dose rifampin for treatment shortening DS PTB: identification of subpopulations of patients that can be cured reliably with <6 months tx, and subpopulations that require >>6 months tx DS and DR TB: PaMZ, B PaMZ DR TB Shortened regimens Injection sparing regimens Optimization of drug use for EPTB (e.g. TBM) Site coordinators & clinicians, and participants Thank you The S29X Protocol Team: Neil Schluger, Jason Stout, Lorna Bozeman, Stefan Goldberg, John Johnson, Betial Haile, Emily Hecker, Grace Muzanye, Masa Narita, Payam Nahid, Susan Ray, Chad Heilig, Andrew Vernon, Marc Weiner The S31 Protocol Team: Payam Nahid, Sue Swindells, Stefan Goldberg, Ekaterina Kurbatova, Richard Chaisson, Kwok Chiu Chang, Michael Chen, Mark Cotton, Dalene von Delft, Kelly Dooley, Melissa Engle, Courtney Fletcher, Phan Ha, Lara Hosey, John Johnson, Daniel Johnson, Marilyn Marone, Cynthia Merrifield, Jose Miro, Sachiko Miyahara, Nguyen Viet Nhung, April Pettit, Anthony Podany, Kathleen Robergeau, Wadzanai Samaneka, Andrew Vernon, Mark Weiner, Lisa Wolf The TBTC Data Center: Pei Jean Feng, Ruth Moro, Chad Heilig, Lorna Bozeman, Stefan Goldberg, Bill Mac Kenzie, Erin Sizemore, Kimberly Chapman, Deron Burton, Anne Purfield, Nicole Brown Ekaterina Kurbatova Sanofi Aventis (for donation of rifapentine and support for PK analyses) Others: Rada Savic, Kelly Dooley, Chuck Peloquin for PK/PD analyses; Bill Burman, Eric Nuermberger, Jacques Grosset FUNDERS: CDC TB Trials Consortium, NIH AIDS Clinical Trials Group, FDA Orphan Products R01 20

21 Supplementary Slides FDA/EMA recommend blindingwhy open label? Differential recommendations re: food Yes for rifapentine / no for rifampin Evidence of decreased absorption concerns for rifapentine with higher pill burden Complexity and pill burden double dummy for both rifampin and rifapentine, double dummy for both ethambutol and moxifloxacin, placebo for blinding moxifloxacin and pyrazinamide in the third and fourth months, and placebo for blinding use of isoniazid and rifampin in last two months Inability to blind effectively (?) Discoloration of urine beyond 4 months in control arms Delays in acquisition and distribution of placebos (and cost) Hard endpoints of failure/relapse (microbiologic) and death Extensive sputum samples for individuals in whom a treatment change is being considered 21

22 Allow age 12 yrs or older S31 team perspective is that inclusion of 12 yrs is a reasonable approach that balances issues Important population there is good reason to include children PK expected to be similar in adolescents and adults based on available data (Weiner AJRCCM 2004; Marshall Ped Infect Dis 1999) Adult type disease (based on age and S31 requirement for sputum bacillary burden) will minimize issues around endpoint assessments Seems reasonable to allow for site issues: IRB norms may allow adults but not children Site investigator expertise or recruitment population may not include pediatric TB Therefore, enrollment of adolescents at sites at which capacity and expertise exists Enrolling even younger children may not be wise: Less certainty about dosing of RPT Pill burden is quite high with present formulations Allow CD4 100 Important population there is good reason to understand how the investigational regimens perform in patients with HIV/AIDS CD4 cut off for eligibility: 50 vs 100 vs 200 <50: increased risk of death (major implications for NI margin); clear indication for prompt ART; risk for IRIS; risk for other OI s that complicate care and introduce drug drug interactions/overlapping side effects Stride ACTG study of ART initiation at 2 vs 8 weeks for HIV pos adults with new dx of TB: Survival markedly worse for CD4 <50 Survival slightly worse at early time points for CD Survival no different for CD vs. CD4 >200 Disseminated TB more common with lower CD4, but implications for TB tx duration not clear Will stratify enrollment: HIV negative vs. HIV positive Will allow for DSMB monitoring of efficacy No perfect solution. Emerging consensus that allowing CD4 100 balances complicated set of clinical, pragmatic, programmatic, scientific, ethical issues. 22

23 Rifapentine dosing: rationale for flat dose of 1200 mg S29X: clear AUC response relationship S29X and ACTG 5911 toxicity not clearly related to AUC or dose Clearance not meaningfully affected by weight Using mg/kg dosing when clearance not influenced by weight results in systematic under dosing of lightest weight people R. Savic, unpublished PD in mice Range of human exposures after 600 mg oral dose Jayaram et al, AAC (2003); 47:

24 Covariates: presence of pulmonary cavity(s) increases by almost 3 fold the rifapentine AUC required to achieve half maximal effect No cavity effect Half maximal effect Cavity(s) AUC (mcg*h/l) Spatial distribution of TB drugs in intact lesions PZA diffused favorably and rapidly into the necrotic cores MXF accumulated in cellular regions, it did not diffuse well into acellular caseum Prideaux, Nature Med

25 Stable culture conversion (MITT) LIQUID MEDIA, BY ASSIGNED TREATMENT ARM Probability that stable culture conversion has been observed RPT 20 mg/kg (n=61)* RPT 15 mg/kg (n=71) RPT 10 mg/kg (n=80)* RIF 10 mg/kg (n=74) Weeks on treatment RPT 3 rd tertile RPT 2 nd tertile RPT 1st tertile RIFAMPIN Stable culture conversion MITT SOLID MEDIA BY RIFAPENTINE AUC TERTILE 25

26 RPT 3 rd tertile RPT 2 nd tertile RPT 1st tertile RIFAMPIN Stable culture conversion MITT LIQUID MEDIA BY RIFAPENTINE AUC TERTILE Re developing rifapentine: getting the dose right How much is safe and well tolerated? What are the pharmacokinetics at higher doses? Pharmacodynamics Which PK parameter is associated with effect or toxicity? For that key PK parameter, what range should we target to maximize effect and minimize toxicity? Are there covariates that influence that PK parameter What strategies can we use to get the most people at that PK parameter target? 26

27 MALDI-MSI and H&E Staining of lung tissue : single dose of RPT 2h 3h 6h cellular lesion cavitary lesion cavitary lesion Courtesy Dalin Rifat and Kelly Dooley Re developing rifapentine: getting the dose right How much is safe and well tolerated? What are the pharmacokinetics at higher doses? Pharmacodynamics Which PK parameter is associated with effect or toxicity? For that key PK parameter, what range should we target to maximize effect and minimize toxicity? Are there covariates that influence that PK parameter What strategies can we use to get the most people at that PK parameter target? 27

28 Endpoints Efficacy endpoints (MITT) Stable culture conversion (on solid and on liquid media, considered separately) % with conversion at completion of intensive phase (i.e. at week 8) Tolerability and Safety Endpoints (ITT) Discontinuation of assigned intensive phase (first 8 weeks) therapy Adverse events Pharmacokinetics (PK): What the body does to the drug Absorption Distribution Metabolism Elimination Pharmacodynamics (PD): What the drug does To the human body (e.g. toxicity) To a microbe or disease process 28

29 Sample Size Primary objective focuses on Tolerability & Safety Primary endpoint: discontinuation of assigned regimen during intensive phase Define well tolerated as regimen for which the 90% one sided CI of the % of participants failing to complete regimen excludes 30% (~twice rate observed in recent TBTC phase 2 studies) H0: π 0.30 H1: π < 0.30 If 70 participants/arm and 15 (21.4%) d/c assigned regimen during intensive phase 90% one sided CI for true d/c rate is (0%, 29.8%) Since CI excludes 30%, it is c/w alternative hypothesis Plan for 70 microbiologically eligible participants/arm Will enroll 80/arm Unpublished, Rada Savic, UCSF 29

30 Clinical Phase 2: TBTC Study 29X Primary Efficacy Result: % of participants with negative cultures at the end of intensive phase treatment (MITT), RIF in S29: solid 79.2%, liquid 62.6% by ASSIGNED TREATMENT ARM RIF CTRL RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg SOLID CX % (n/n) 81.3 (52/64) 92.5 (62/67) 89.4 (59/66) 94.7 (54/57) % difference vs. RIF (95% CI) P value 11.3 ( 1.7, 24.3) ( 5.5, 21.8) (0.7, 26.3) 0.05 LIQUID CX % (n/n) 56.3 (36/64) 74.6 (50/67) 69.7 (46/66) 82.5 (47/57) % difference vs. RIF (95% CI) P value 18.4 (0.8, 35.9) ( 4.5, 31.4) (8.9, 43.5) <0.01 Clinical Phase 2: TBTC Study 29X Primary Efficacy Result: % of participants with negative cultures at the end of intensive phase treatment (MITT), RIF in S29: solid 79.2%, liquid 62.6% by ASSIGNED TREATMENT ARM RIF CTRL RPT 10 mg/kg RPT 15 mg/kg RPT 20 mg/kg SOLID CX % (n/n) 81.3 (52/64) 92.5 (62/67) 89.4 (59/66) 94.7 (54/57) % difference vs. RIF (95% CI) P value 11.3 ( 1.7, 24.3) ( 5.5, 21.8) (0.7, 26.3) 0.05 LIQUID CX % (n/n) 56.3 (36/64) 74.6 (50/67) 69.7 (46/66) 82.5 (47/57) % difference vs. RIF (95% CI) P value 18.4 (0.8, 35.9) ( 4.5, 31.4) (8.9, 43.5) <

31 Unpublished, Rada Savic, UCSF RPT clearance is not meaningfully affected by participant weight RPT bioavailability decreases somewhat with increasing dose Flat dosing (i.e. NOT mg/kg ) is justified 31

32 Rifapentine dosing: rationale for flat dose of 1200 mg S29X: clear AUC response relationship S29X and ACTG 5911 toxicity not clearly related to AUC or dose Clearance not meaningfully affected by weight Using mg/kg dosing when clearance not influenced by weight results in systematic under dosing of lightest weight people Is the magnitude of the effect sufficient to warrant proceeding to phase 3? 32

33 Biomarker vs. Surrogate Marker Biomarker a lab measurement that reflects the activity of the disease process Surrogate Marker a test that is a substitute for a clinically meaningful endpoint and is expected to predict the effect of the therapy Validated surrogate marker: One for which there is evidence that a drug induced effect on the surrogate predicts (results in) the desired effect on the clinical outcome of interest Unvalidated surrogate marker: A surrogate that is reasonably likely to predict the clinical outcome of interest, but for which there is insufficient evidence to establish that this relationship exists Start Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 EBA TB TREATMENT Early Bactericidal Activity (EBA) as a surrogate marker Fall in viable colony forming units of Mtb in sputum early in therapy (first 2 to 14 days) Information that EBA studies can provide Whether a drug kills metabolically active bacilli found in sputum Can guide dose selection Provides information about relationship between PK and bactericidal activity Can study a single drug, or that drug as a component of a regimen(s) Limitations Does not adequately assess drug activity against metabolically less active bacilli or bacilli not in sputum Technically challenging 33

34 Start Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 EBA TB TREATMENT First 8 weeks????? Good activity necessary but not sufficient biologically or as surrogate? Antimicrobial activity over the first approx. 8 weeks % of participants with negative cultures at end of intensive phase Time to culture conversion to negative (time to event) Serial sputum colony counts over 8 weeks (increase in) time to detection by MGIT liquid culture Limitations Do not adequately assess drug activity against metabolically less active bacilli Technically challenging Larger sample sizes required and/or desired (typically >50/arm) LATE (3) Efficacy, assessed through definitive cure/lack of cure Accepted outcome measure: absolute difference, between arms, in % of participants who either fail to respond to treatment or relapse after completing treatment, assessed at 1 to 2 years after randomization (durable cure or lack thereof) Non inferiority design Interested in determining if a new treatment is not worse than that of an active control by more than a specified margin Poor discriminatory power can lead to a false conclusion of noninferiority: NI trials require high degree of rigor, quality 34

35 Thanks to Study 31 / A5349 Protocol team Payam Nahid, Chair Susan Dorman, Chair Stefan Goldberg, TBTC Project Officer Janet Anderson* Patricia Bessler Richard Chaisson*, ** Kwok Chiu Chang Michael Chen, Statistician Mark Cotton Dalene von Delft (CRAG) Kelly Dooley*, ** Melissa Engle Pei Jean Feng Courtney Fletcher Phan Ha Chad Heilig John L. Johnson Daniel Johnson* Marilyn Maroni (Sanofi) Cynthia Merrifield Jose M. Miro Sachiko Miyahara Nguyen Viet Nhung April Pettit Anthony Podany Kathleen Robergeau (Westat) Wadzanai Samaneka* Susan Swindells*, ACTG Chair Andrew Vernon Mark Weiner Lisa Wolf Suria Yesmin 69 CDC TB Trials Consortium Study 29: multicenter, randomized, open label phase 2 trial (efficacy & safety) Sputum smear (+) PTB suspect RIF 10 mg/kg INH+PZA+EMB 5 d/wk x 8 weeks Empty stomach Randomization stratified by cavitation study visits weekly: safety sputum culture DOT RPT 10 mg/kg INH+PZA+EMB 5 d/wk x 8 weeks; Empty stomach Hypothesis: antimicrobial activity of RPT regimen superior to that of RIF regimen End of intensive phase ( wk 8): assess for primary endpoints (cx status at week 8; discontinuations; AEs ATS/CDC/IDSA recommended continuation phase regimen 35

36 RESULTS OF TBTC S29: In adults with drug S pulmonary TB, efficacy (by surrogate endpoint of week 8 culture conversion) of rifapentine 10 mg/kg daily regimen not superior to that of standard rifampin regimen; rifapentine regimen safe and well tolerated % of participants having negative sputum cultures at end of intensive phase (week 8) Culture Medium RIFAMPICIN 10 mg/kg RIFAPENTINE 10 mg/kg P value Difference (95% CI) Liquid 62.6% 122/ % 152/ ( 5.0, 13.2) Solid 79.2% 167/ % (193/233) ( 3.6, 11.0) JID 2012 Endpoints and Sample Size Primary TB disease free survival at 12 months after study treatment assignment % of participants with grade 3 or higher AEs during study tx Sample size 2500 NI margin 6.6% Type 1 error, alpha=0.05 Type 2 error=