# Presentation: 885491

## Ketek (telithromycin) NDA Background

**Janice Soreth, M.D.**
**Director**
**Division of Anti-Infective Drug Products**
**CDER/FDA**

## Telithromycin - Background

**Regulatory History**
**Overview of First Advisory Committee**
**FDA Action Letter**
**New Studies**

## Telithromycin - Regulatory History

**NDA submitted to FDA February 28, 2000**
**First Advisory Cmte. met April 26, 2001**
**FDA issued approvable letter June 1, 2001**
**Amendment submitted July 24, 2002**

## Telithromycin - April 2001 Advisory Committee

**Four indications proposed:**
**community-acquired pneumonia***
**acute exacerbations of chronic bronchitis***
**acute sinusitis***
**tonsillopharyngitis**
- 	*** ****including penicillin- and erythromycin-resistant ****	****	*****Streptococcus pneumoniae***

## Telithromycin- April 2001 Advisory

**Phase III Clinical Database by Type of Study and Indication**

## CAP: Clinical Response -TOC 

- April 2001 AC

## AECB: Clinical Response -TOC 

- April 2001 AC

## Sinusitis: Clinical Response - TOC

- April 2001 AC

## Tonsillopharyngitis

**Primary efficacy based on microbiologic eradication**
**Comparative study: success rates were 84% telithromycin v. 89% pen [-14,5]**
**FDA guidance: 85% success for “first line”**
**Further discussion tabled**

- April 2001 AC

## Drug Resistant Streptococcus pneumoniae

- April 2001 AC

##  Telithromycin - PRSP CAP *

- April 2001 AC

## Telithromycin - ERSP CAP*

- April 2001 AC

## April 2001 - Efficacy Summary

**FDA’s efficacy analyses consistent with those of the company for pneumonia, bronchitis, and sinusitis**
**Substantial evidence for approval entails both efficacy and safety**

- April 2001 AC

## Telithromycin- Phase 3 Safety Data

- April 2001 AC

## Deaths

- No deaths in phase I trials
- 11 deaths in phase III (10 CAP, 1 pharyngitis)
- 7 deaths in telithromycin pts, 4 in comparator pts
- None directly attributed to drug
- 6 deaths (4 Ketek, 2 comp) scored as tx failures
- 6/7 telithromycin-treated patients who died had CV cause
- 0/4 comparator patients who died had CV cause
- Most CAP deaths occurred in high-risk patients (Fine category III or higher)

- April 2001 AC

## Serious AEs - Phase 3

**4 drug-related SAEs in uncontrolled trials: gastroenteritis, vasculitis, hepatitis, leukopenia**

- April 2001 AC

## AEs - Phase 3

- April 2001 AC

## Telithromycin - April 2001 Advisory Focus on Safety

**Cardiac**
**Hepatic**
**Visual**

## QTc effects: in vitro and preclinical data

- Inhibits IKr channel (major repolarization current)
- Ki 42.5 μM (moxifloxacin 129 μM)
- Mean serum Cmax 2.4 μM (Phase 1); observed maximum Conc. 12 μM (Phase 3)
- Rat myocardial:serum conc. ratio = 6
- Prolongs action potentials in isolated fibers
- >75% increase in APD90 at Ki
- Potentiates sotalol-induced APD prolongation
- Prolongs QTc and increases HR in dogs
- 30 ms  1 min after single IV dose (17 ms for clari)
- 27-30 ms after multiple oral doses (100 mg/kg/d)

- April 2001 AC

## QTc with telithromycin: Phase 1

*** p<0.05 vs. placebo**

- April 2001 AC

## CYP3A4 inhibitor interactions

** ****Telithromycin C****max**** increased by 52% with ketoconazole**
** ****Telithromycin AUC increased by 95% with ketoconazole**

***comparison with placebo**

- April 2001 AC

## Telithromycin - Concentration Variation

- Phase 1
- Nonlinear pharmacokinetics
- Single dose (800 mg)
- mean Cmax: 1.99 mg/L
- maximum Cmax: 5.13 mg/L (renally impaired subject)
- Multiple dose (800 mg)
- mean Cmax: 2.07 mg/L
- maximum Cmax: 6.66 mg/L (elderly subject)
- Phase 3
- Maximum observed concentration: 7.6 - 9.9 mg/L

- April 2001 AC

## Telithromycin pharmacokinetics in special populations

- Elderly subjects: Cmax and AUC  by 100%
- Hepatic impairment
- AUC and Cmax similar to healthy subjects, but renal clearance increases to compensate
- Potential accumulation if CrCl with hepatic impairment
- Renal impairment (single dose)
- Moderate impairment (CrCl 40-80 mL/min):
- Cmax  by 33%; AUC  by 42%
- Severe impairment (CrCl <40 mL/min):
- Cmax  by 44%; AUC  by 59%

- April 2001 AC

## QTc: Phase 3

**Telithromycin increased QTc in phase 3**
**Small but consistent increase in controlled trials**
**Possible interactions with CYP3A4 and CYP2D6 substrates in exploratory analyses**
**Mean with CYP3A4 + CYP2D6: 11.5 msec (clarithromycin 5.4 msec)**

- April 2001 AC

## Telithromycin - Hepatic Data

- Pre-Clinical
- Hepatotoxicity in Dogs, Rats, Monkeys
**(Increased AST & ALT; liver necrosis in 4-week rat study; hepatocellular hypertrophy, multinucleated hepatocytes)**
- Phase I
- Clustering of hepatic AEs in elderly at 2000 mg x1
- No clear dose-response for hepatic AEs
- Phase III
- Similar AE rates telithromycin and comparators
- No apparent drug-induced hepatic deaths

- April 2001 AC

## Telithromycin - Hepatic Data

- Phase III (cont’d)
- 2 Hepatic SAEs plausibly assoc. with telithromycin
- Liver biopsy in 1 pt: centrilobular necrosis and  eosinophilic infiltration (ALT & Eos  Day 1)
- More AST and ALT elevations in telithromycin-treated CAP patients with normal baseline values
- Not seen in Non-CAP patients
- Concomitant low-level AST / ALT & T.Bili. elevations only in telithromycin-treated patients

- April 2001 AC

## Telithromycin - Visual Data

- Phase 1
- 40/1003 (0.4%) subjects reported blurred vision with supratherapeutic doses
- Phase 3
- 14/2045 (0.7%) Ketek v. 1/1672 (0.1%) comparator
- Majority of patients female and < 40 years
- Transient but variable time course (minutes to hours to days)

- April 2001 AC

## April 2001 AC- Safety Summary

- Potential confluence of multiple risk factors
- (1) QTc prolongation
- (2) Concentration dependence of QTc effect
- (3) Concentration variation in special populations
- (4) Potential for hepatotoxicity
- (5)  exposure in elderly pts, hepatic/renal disease
- (6)  exposure with concomitant medications
- Limited data on at-risk subjects
- Potential for wide population exposure

## Outpatient Antimicrobial Therapy, U.S. 

**(millions of courses in 1992)**

**McCaig LF and Hughes JM. JAMA 1995; 273:214-9**

**Otitis media**

**URI (non-specific)**

**Bronchitis**

**Pharyngitis**

**Sinusitis**

**All other diagnoses**

**23.6**

**17.9**

**16.3**

**13.1**

**12.9**

**26.5**

## Telithromycin - April 2001 AC Vote

- Do the efficacy and safety data presented support the use of Ketek in
- community-acquired pneumonia  	7 yes   3 no
- exacerbation of chronic bronchitis	0 yes  10 no
- acute sinusitis				2 yes   8 no
- Are the data sufficient for a claim of pneumonia due to pen-resistant *S. pneumoniae*?	3 yes  7 no
- If approved, should Ketek have a specific indication for erythro-resistant *S. pneumoniae*?	3 yes  7 no

## April 2001 AC Recommendations

- Recommendations for additional studies:
- Safety
- Larger number of patients need to be enrolled in studies to determine safety.
- Special populations should be targeted (elderly, patients with hepatic impairment, renal impairment); more PK
- Drug interactions need to be evaluated.
- Efficacy
- More data requested in patients with drug-resistant *S. pneumoniae *(including bacteremia)

## Telithromycin - June 2001 Action Letter

**NDA approvable for pneumonia, bronchitis, and sinusitis**
**Additional safety and efficacy data requested to assess risks/benefits**
**large safety trial in respiratory tract infections**
**PK studies in special populations**
**additional experience with drug-resistant *****S. pneumoniae, H. influenzae***

- June, 2001

## Telithromycin NDA Amendment - New Studies

**Safety/Phase 3**
**Study 3014:**
**Randomized, open-label multi-center trial comparing  telithromycin to amoxicillin/clavulanate in outpatients with CAP, AECB, or AS in a usual care setting**
**24,000 patients enrolled**
**Designed as a large safety study to examine adverse events of special interest (cardiac, hepatic, visual)**

## Telithromycin NDA Amendment - New Studies

**Efficacy/Phase 3**
**To address request for additional data in CAP on drug-resistant S. pneumoniae**
**study 4003: randomized, double-blind, comparative trial of telithromycin (800 mg qd, 5 v. 7d)  versus clarithromycin (500 mg bid, 10d))**
**study 3012: non-comparative CAP trial, 800 mg x 7d**
**study 3107 (Japan)**
**To address request for more data in AECB **
**study 3013: r, db, telithromycin versus clari**

## Telithromycin NDA Amendment- New Studies

**Safety/Phase I Studies**
**Cardiac**
**1062: multiple dose telithromycin; assessed PK and QT interval changes in subjects with renal impairment**
**1063: multiple dose telithromycin + ketoconazole; assessed effect by ketoconazole on PK of telithromycin in elderly subjects with renal impairment. Included assessment of QT.**

## Telithromycin NDA Amendment- New Studies

**Safety/Phase I Studies**
**Visual**
**1059: single dose,randomized,placebo-controlled,double-blind,cross-over study in young subjects with normal vision and subjects (50-65 yo) with presbyopia.  Telithromycin given as single 800 and 2400 mg dose. Ophthalmologic evaluations performed; telithromycin concentration measured in plasma and tears.**
**1064: single dose (2400 mg),randomized,placebo-controlled,double-blind,cross-over study in healthy subjects 18-65 yo.  Assessments similar to study 1059 above.**

## Telithromycin NDA Amendment- New Studies

**Safety/Phase I Studies**
**Hepatic**
**1060****: ****Multiple-dose study (800 mg daily for 7 days) of telithromycin in patients with hepatic impairment and healthy subjects**

## Telithromycin NDA Amendment -Additional Data

**Post-marketing experience from 1-1.5 million exposures (as of October 2002) in Europe and Latin America**

## In the Best Interest of the Public

**Review of a new class of drugs presents opportunities and challenges**
**Potential benefit to increase our armamentarium of agents to treat infections, including resistant pathogens**
**Potential risks of toxicities**
**Balance of risk/benefit in setting of wide usage**