1

Factive® (gemifloxacin)

NDA 21-158

March 4, 2003

Anti Infective Drugs Advisory Committee Meeting

Edward Cox, M.D., M.P.H.

Deputy Director, Office of Drug Evaluation IV

Center for Drug Evaluation and Research

U.S. Food and Drug Administration

2

FDA Presentations• Microbiology

Peter Dionne, MS• Community-Acquired Pneumonia

Regina Alivisatos, MD• Acute Bacterial Exacerbation of Chronic Bronchitis

Eileen Navarro, MD• Safety

Maureen Tierney, MD, MSc• Summary

Edward Cox, MD, MPH

3

MICROBIOLOGY OF FACTIVE ®

GEMIFLOXACIN MESYLATE

NDA 21-158

Peter A. DionneMicrobiologist DSPIDP

4

OVERVIEW

• Activity compared to other Quinolones

• Activity against Resistant S. pneumoniae

• Activity against S. pneumoniae Mutants

• Efficacy against S. pneumoniae in Rat Pneumonia model

5

In vitro Activity of Gemifloxacin and

Comparators {MIC90s}Organism GEMI CIPRO LEVO MOXI GATIStreptococcus pneumoniae 0.03 2.0 1.0 0.25 0.5Staphylococcus aureus MS 0.06 1.0 0.5 0.12 0.25Haemophilus influenzae 0.03 0.03 0.03 0.06 <0.03Haemophilusparainfluenzae

0.06 0.06 0.06 0.25 0.12

Moraxella catarrhalis 0.015 0.06 0.06 0.06 0.03Escherichia coli 0.25 0.5 0.5 0.06 0.06Klebsiella pneumoniae 0.5 1.0 1.0 1.0 1.0Mycoplasma pneumoniae 0.12 --- 0.5 0.12 0.25Legionella pneumophila 0.015 0.03 0.015 0.125 0.03MS = methicillin-susceptible

6

Comparative PK Data for Quinolones

Antimicrobial Dose Cmax AUC0-24

(mcg/mL) (mcg.h/L)Gemifloxacin 320 mg QD 1.6 8.4Levofloxacin 500 mg QD 5.7 47.5Ciprofloxacin 500 mg BID 2.97 26.2Gatifloxacin 400 mg QD 4.2 51.3Moxifloxacin 400 mg QD 4.5 48.0Ofloxacin 400 mg QD 4.6 61.0

7

• Gemi MICs are Lower against Gram positive bacteria compared to other quinolones

• Gemi MICs are about equal to other quinolones against Gram negative bacteria

• Gemi PK parameters weaken the significance of lower MICs against Gram +

• Gemi PK parameters may affect efficacy against Enterobacteriaceae

8

Activity Against PEN-R S. pneumoniae

Compound No. ofIsolates

MIC Range(mcg/mL)

Range of MIC90s(mcg/mL)

MedianMIC90

(mcg/mL)S. pneumoniae (Pen-S)Gemifloxacin 261 <0.004-0.25 0.03-0.08 0.06Moxifloxacin 196 0.06-0.25 0.25 0.25Levofloxacin 239 0.06-4 1-2 2Ciprofloxacin 261 0.12-8 1-4 2S. pneumoniae (Pen-I)Gemifloxacin 72 <0.008-0.12 0.03-0.12 0.03Moxifloxacin 39 0.06-0.25 0.12-0.25 0.12Levofloxacin 59 0.12-4 1-2 2Ciprofloxacin 72 0.25-4 1-4 2S. pneumoniae (Pen-R)Gemifloxacin 51 <0.004-1 0.03-0.12 0.03Moxifloxacin 0 0.06-0.12 0.12 NALevofloxacin 41 0.5->16 1->16 1Ciprofloxacin 51 0.25->8 1->8 1Data compiled from NDA 21-158

9

Activity Against Quinolone-R

S. pneumoniaeCompound No. of Isolates

MIC Range (mcg/mL)

Range of MIC90s

(mcg/mL)

Median MIC90

(mcg/mL) S. pneumoniae (Quin-S) Gemifloxacin 332 < 0.008-0.25 0.06 0.06 Moxifloxacin 3603 < 0.002-2 0.25 0.25 Levofloxacin 332 0.12-4 2 2 Ciprofloxacin 207 0.25-4 4 NA S. pneumoniae (Quin-R) Gemifloxacin 160 < 0.03-2 0.25-1 0.5 Moxifloxacin 75 0.12-8 4 NA Levofloxacin 160 0.5->32 16->32 >16 Ciprofloxacin 103 4->32 32->32 32 NA = Not applicable—Data is from one study Data compiled from NDA 21-158 Quin-R was defined in each individual study. Ciprofloxacin MIC > 4 g/mL and/or Levofloxacin MIC > 8 g/mL

10

MICs of Selected S. pneumoniae

MutantsMutation MIC (mcg/mL)GEMI MOXI LEVO CIPRO

Wild-type 0.016 0.064 0.038 0.5ParC S79Y 0.064 0.125 1.5 4.0ParC S79F 0.032 0.125 1.0 2.0ParC S79Y,gyrA S81Y

0.25 2.0 >32 >32

GyrA S81Y 0.023 0.125 0.75 1.0ParC S79Y 0.064 0.125 1.0 6.0ParC S79Y 0.047 0.064 1.0 4.0

11

Susceptibility of Cipro-R

S. pneumoniaeStrain MIC (mcg/mL)Cip Levo Gati Moxi Gemi ParC

ChangeGyrA

ChangeEfflux

2680 2 1 0.5 0.25 0.03 No No No4610 4 1 0.5 0.25 0.06 Yes No No16702 4 1 0.5 0.25 0.06 No No Yes18705 4 2 0.5 0.25 0.03 Yes No Yes16701 16 8 4 2 0.25 Yes Yes No17012 16 8 4 2 0.12 Yes Yes No18410 16 8 4 2 0.12 Yes Yes No

12

Activity Against 44 S. pneumoniae

Second Step Mutants [# at each MIC]MIC (mcg/mL) GEM MOX GAT LEV CIP

0.016 10.03 00.06 30.125 15 10.25 22 10.5 3 1 11 5 1 12 25 6 1 14 11 26 2 38 10 14 116 22 1232 ` 4 1264 14

128 1MIC90 0.25 4 8 16 64MIC50 0.25 2 4 16 32

13

• S. pneumoniae MICs against Pen-R = MICs against Pen-S as with all quinolones

• Gemi MICs against Quin-R S. pneumoniae are in the range of 0.25-1 mcg/mL; Moxi MICs about 4 mcg/mL

• S. pneumoniae double-mutants have Gemi MICs 0.25 mcg/mL; Moxi ~ 2 mcg/mL; Levo ~32 mcg/mL

• Gemi PK values about 6 times lower than Moxi PK

14

Efficacy of Gemifloxacin Compared to Levofloxacin in

RTI in Rats (Gemi MIC < 0.03 mcg/mL]Strain Resistance MIC (mcg/mL) Log10 CFU/lungs

Profile GEMI Levo NTC GEMI Levo 1629 Pen-S < 0.03 0.25 6.8 + 1.2 <1.7a,b 4.0 + 1.6a

10127 Pen-S < 0.03 1 6.4 +1.9 1.9 + 0.5a,b 4.1 + 1.3a L11259 Pen-S < 0.03 1 6.4 + 1.9 <1.7a,b 5.7 + 1.1 406081 MAC-R < 0.03 0.5 5.0 + 0.9 2.2 + 0.6a,b 4.5 + 1.8 N1387 MAC-R < 0.03 0.5 5.1 + 0.9 2.5 + 1.1a,b 3.5 + 0.8a 404053 Pen-R < 0.03 0.5 5.9 + 2.9 1.8 + 0.2a,b 4.0 + 1.4a

205118 Pen-R < 0.03 NT 6.3 + 0.6 3.6 + 1.9a,b 6.3 + 0.7 MAC-R = macrolide-resistant Pen-S = penicillin-susceptible; Pen-R = penicillin-resistant GEMI = gemifloxacin; LEVO = levofloxacin; NTC = not-treated control; NT = not tested a Significant difference compared with untreated controls (p < 0.01) b Significant difference compared with levofloxacin (p < 0.01) Dosing was once daily and started 24 hours post-infection

15

Efficacy of Gemifloxacin Compared to Levofloxacin in

RTI in Rats [Gemi MICs > 0.125 mcg/mL]Strain Resistance MIC (mcg/mL) Log10 CFU/lungs

Profile GEMI Levo NTC GEMI Levo 305313 CIP-R 0.125 1 7.9 + 0.4 3.3 + 1.3a,b 5.7 + 1.3a

622286 CIP-R/MAC-R 0.125 4 6.4 + 1.3 2.5 + 1.1a,b 5.1 + 1.3 PT94254123 CIP-R 0.25 16 8.1 + 0.8 4.4 + 0.7a,b 6.8 + 0.6a

402123 CIP-R 0.25 8 8.3 + 0.8 5.7 + 0.9a,b 7.3 + 1.2 509063 CIP-R 0.25 8 6.2 + 1.6 3.5 + 1.1a,b 6.2 + 0.7 214152 CIP-R 0.5 16 6.6 + 1.6 3.8 + 1.4a 5.0 + 1.4 TPS 3 CIP-R 0.5 16 6.7 + 0.4 5.5 + 1.8 5.9 + 1.3 TPS 5 CIP-R 0.5 32 6.2 + 0. 5 4.5 + 1.2a,b 5.7 + 0.5 703316 CIP-R 0.5 >16 6.6 + 0.4 6.2 + 0.9 6.5 + 0.3 42064 CIP-R 0.5 16 6.7 + 0.3 5.4 + 1.9 5.2 + 1.1 CIP-R = ciprofloxacin-resistant; MAC-R = macrolide-resistant GEMI = gemifloxacin; LEVO = levofloxacin; NTC = not-treated control a Significant difference compared with untreated controls (p < 0.01) b Significant difference compared with levofloxacin (p < 0.01) Dosing was twice daily and started one hour post-infection

16

Efficacy of Gemifloxacin Compared to Moxifloxacin and

Gatifloxacin in RTI in Rats Strain GEMI MOXI GATI NTC GEMI MOXI GATI 404053 <0.03 0.06 0.125 6.5 + 1.5 <1.7 <1.7 <1.7 406081 <0.03 0.125 0.25 6.8 + 1.0 <1.7 <1.7 <1.7 205118 <0.03 0.25 1.0 6.3 + 1.1 1.9 + 0.6* ** 2.9 + 1.6 3.7 + 1.1 305313 0.125 2.0 4.0 6.1 + 1.5 4.0 + 0.8 3.5 + 1.4 4.1 + 1.4 509063+ 0.25 2.0 4.0 7.0 + 0.4 3.8 + 1.6 * 4.6 + 1.3 6.1 + 1.2c

PT9424123 0.25 2.0 4.0 6.8 + 1.4 3.1 + 0.7 3.6 + 1.9 4.0 + 1.4 622286 0.125 1.0 1.0 7.4 + 1.4 2.6 + 1.2** 4.6 + 2.0 3.6 + 2.3 402123+ 0.25 2.0 4.0 6.1 + 2.2 3.6 + 1.1 3.9 + 1.3 3.1 + 1.1 GEMI = gemifloxacin; MOXI = moxifloxacin; GATI = gatifloxacin; NTC = not-treated control * Significant difference compared with GATI (p<0.05) ** Significant difference compared with MOXI (p<0.05) c Not significantly different from control (p>0.05) + Genetically-defined second step mutants Dosing was b.i.d. and started 1 hour post-infection

17

In rat S. pneumoniae RTI infection model • Isolates with Gemi MICs < 0.03 mcg/mL

once daily dosing is effective and CFU/lung reaches close to level of detection (< 1.7 CFU/lung]

• Isolates with Gemi MICs > 0.125 mcg/mL must be dosed BID for efficacy and CFU/lung is > level of detection

• Gemi better than Levo; Gemi about same as Moxi and Gati

18

Summary

GEMI ~ MOXI > LEVO

19

Community Acquired Pneumonia

Factive (gemifloxacin)

NDA 21-158

Regina Alivisatos, MD

20

Sponsor’s Proposed Indication

• Community-acquired pneumonia caused by Streptococcus pneumoniae (including penicillin-, clarithromycin- and cefuroxime-resistant strains), Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella catarrhalis; Mycoplasma pneumoniae; Chlamydia pneumoniae; Legionella pneumophila; Staphylococcus aureus

• Proposed Dose: One 320 mg tablet daily for 7 days

21

Overview

Efficacy in relation to• Duration of Treatment• Severity of disease• Streptococcus pneumoniae

Penicillin-resistant

Macrolide-resistant

Cefuroxime-resistant

Quinolone-resistant

22

Clinical StudiesStudy Treatment Regimen Duration N* Geographic Region

Controlled studies011 Gemifloxacin 320 mg qd 7 days 168 Europe, S. Africa

Amoxicillin /clavulanate 10 days 1561g/125 mg tid

012 Gemifloxacin 320 mg qd 7 or 14 days 319 U.S. Canada, Europe,Cefuroxime 500 mg 7 or 14 days 322 S. Africa

/Clarithromycin 500 mg bid049 Gemifloxacin 320 mg qd 7 or 14 days 290 U.S., Mexico, Spain

Trovafloxacin 200 mg qd 7 or 14 days 281185 Gemifloxacin 320 mg qd 7-14 days 172 Australia, Europe,

IV Ceftriaxone 2g qd + 1-7 days + 173 Guatemala, Lebanon,oral Cefuroxime 500 mg bid 1-13 days Philippines, Singapore

and North AmericaUncontrolled studies

061 Gemifloxacin 320 mg qd 7 days 216§ World-Wide (ExceptN. America)

287 Gemifloxacin 320 mg qd 7 days 188 Asia, U.S., MexicoPhilippines

23

FDA Analyses - Duration of Treatment

Statistical issues with the combining of all 7 day patients

because• 1 controlled study (011) and 2 uncontrolled were of 7

days duration a priori• in studies 061, 049, and 185, the duration of treatment

was determined at the on-therapy visit and was investigator-driven

• FDA performed additional analyses based on a stricter division of studies into those with a priori duration of 7 days and those where duration could vary

24

Patient Disposition- CAP

GemifloxacinN

ComparatorsN

Controlled Studies 947 927

7 days fixed (011) 167 153

7-14 days (012, 049, 185) 7 days 14 days

780468312

774457317

Uncontrolled Studies 402

7 days fixed (061, 287) 402

Total 1349 927

25

FDA Analysis of Clinical Response by Duration of Treatment

Clinical PP Gemifloxacin

n/N (%) Comparators

n/N (%)7 day fixed Controlled (011) Uncontrolled (061, 287) Combined

102/115 (88.7)286/315 (90.8)388/430 (90.2)

99/113 (87.6)-

7-14 days (012, 049, 185) 7 days 14 days Combined

329/363 (90.6)200/219 (91.3)529/582 (90.9)

319/348 (91.7)218/237 (92.0)537/585 (91.8)

26

Severity• Severity was determined by retrospective application

of Fine criteria with the exception of study 287 where the Fine criteria were applied prospectively

• Patients assigned to a risk class (I - V) according to demographic, clinical and laboratory characteristics that stratified them by risk of mortality within 30 days

• Based on assigned risk class, patients were classified as having mild (I, II), moderate (III) or severe (IV, V) disease

• Patients in risk classes I, II and III can often be managed as outpatients, whereas those in classes IV and V are at higher risk of death and often require hospitalization*

*mortality risk class IV = 9 - 12%, class V = 30%

27

Severity DemographicsGemifloxacin ITT

DurationGender Age 7 to 14 day

Severity(FineClass) Male Female Mean

Range7 dayfixed

7 day 14 day

Mild(I, II) n=996

473 (47.4) 523 (52.5) 46.618-80

440 345 211

Moderate(III) n=224

156 (69.6) 68 (30.4) 69.428-89

88 78 58

Severe(IV, V) n=129

93 (72.1) 36 (27.9) 76.346-97

41 45 43

28

FDA Analysis of Clinical Response by Severity

7 to 14 day7 day fixed 7 day 14 day

CPP Gemi Comp Gemiuncont

Gemi Comp Gemi Comp

Mild 73/84(86.9)

57/67(85.1)

236/257(91.8)

246/272(90.1)

241/261(92.3)

130/141(92.2)

155/165(93.9)

Moderate 16/18(88.9)

32/35(91.4)

39/45(86.7)

53/58(91.4)

56/61(91.8)

39/44(88.6)

38/42(90.5)

Severe 13/13(100.0)

10/11(90.9)

11/13(84.6)

30/31(96.8)

22/26(84.6)

31/34(91.2)

25/30(83.3)

29

Clinical Response in Hospitalized Patients

• Hospitalization used as a criterion to assess the effectiveness of gemifloxacin in severe cases CAP

• Questions regarding appropriateness of using hospitalization as a sole determinant of severity

• Decision to hospitalize was investigator-driven and may have varied according to geographic location

• Only in study 185 were all patients hospitalized as per protocol for at least 24 hours

• Comparable efficacy between treatment arms

30

FDA Analysis of Clinical Response in Bacteremic Patients

Clinical PPGemifloxacin

n/N (%)Comparators

n/N (%)7 day fixed Controlled (011) Uncontrolled (061, 287) Combined

8/8 (100.0)9/13 (69.2)

17/21 (81.0)

10/11 (90.9)-

7-14 days (012, 049, 185) 7 days 14 days Combined

4/4 (100.0)22/23 (95.7)26/27 (96.3)

9/12 (75.0)14/14 (100.0)23/26 (88.5)

31

Severity and Mortality

For All Patients – Risk Class Specific Mortality Rates - CAP studies/ITTFine

Class(score)*

Finepneumoniavalidation

cohort

Comparative Studies Non-Comparative

Studies

Mortality gemifloxacin comparators gemifloxacin% who died # of

patients% who

died# of

patients% who

died# of

patients% who

diedn % n % n %

I 0.1% 347 1 (0.3%) 369 3 (0.8%) 154 0II (<70) 0.6% 330 2 (0.6%) 287 2 (0.7%) 166 3 (1.8%)

III (71-90) 0.9% 164 4 (2.4%) 181 3 (1.7%) 63 2 (3.2%)IV (91-130) 9.3% 104 5 (4.8%) 90 4 (4.4%) 21 0

V (>130) 27% 4 0 5 1 (20.0%) 0 0Total 5.2% 949 12 (1.3%) 932 13 (1.4%) 404 5 (1.2%)

* Inclusion in risk class I was based upon the absence of all predictors identified in step 1 of the Fine prediction rule.Inclusion in risk classes II, III, IV, and V was determined by a patient ’s total risk score, which was computed according to the Fine scoring system.Table design adapted from Table 3. in Fine MJ et al. N Engl J Med 1997;336:243-50.

32

Severity and Precedents

• Two quinolones, levofloxacin and moxifloxacin have a severe disease claim; both with PO and IV formulations

• Criteria for determining severity differed but were applied at the time of randomization in both applications that received an approval.

• Criteria were used to determine mode of treatment as well as duration.

• Most of the severe patients in the levofloxacin NDA received IV treatment.

• Moxifloxacin claim was granted after FDA review of the IV formulation.

33

Streptococcus pneumoniae• Sponsor is requesting approval for penicillin,

macrolide, and cefuroxime resistant S. pneumoniae Data also submitted on quinolone-resistant S. pneumoniae

• Levofloxacin and moxifloxacin have the indication of PRSP

• No antimicrobial currently has an MRSP indication

• PRSP and MRSP discussed at January 2003 AIDAC

• No previous claims for cefuroxime-resistant PRSP

• What is the clinical relevance of Macrolide- and Cefuroxime-resistant S. pneumoniae in the setting of penicillin resistance?

34

Penicillin Resistant Streptococcus pneumoniae

Agency and sponsor in agreement that:• 12 BPP gemifloxacin-treated patients had

Streptococcus pneumoniae isolates with penicillin MICs of 2mcg/mL (3 of these had MICs of

4 mcg/mL)• Clinical success and bacteriological eradication

rates in the PP patients with PRSP were 100% • Four (4) comparator arm patients had PRSP with

100% clinical success and bacteriological eradication rates

35

Macrolide Resistant Streptococcus pneumoniae

25 gemifloxacin-treated PP patients with Streptococcus

pneumoniae had macrolide resistant isolates

(clarithromycin MIC 1mcg/mL)• Clinical success and bacteriologic eradication rates were

22/25 (88%) PP• 10 isolates (40%) were also penicillin-resistant

12 comparator-treated PP patients had macrolide resistant

Streptococcus pneumoniae• Clinical success and bacteriologic eradication rates were

11/12 (91.6%) PP

• 3 isolates (25%) were also penicillin-resistant

36

Cefuroxime-resistant Streptococcus pneumoniae

• 18 patients had cefuroxime -resistant Streptococcus pneumoniae isolates (MIC 4 mcg/mL)

• Clinical success and bacteriological eradication rates at follow-up were 17/18 (94.4%)

• 12 out of the 18 cefuroxime-resistant isolates were also PRSP (67%)

• 15 of the 18 cefuroxime-resistant isolates were also clarithromycin resistant (83%)

• On the comparators arm there were 7 patients with Streptococcus pneumoniae isolates (PP) resistant to cefuroxime that were all successfully treated (ITT 8)

37

Quinolone-resistant Streptococcus pneumoniae

• In the gemifloxacin group of the combined studies population, there were no pathogens resistant to ofloxacin and levofloxacin

• 1 resistant isolate on the all comparators arm (failure)

• In the gemifloxacin group there were 4 isolates of Streptococcus pneumoniae with an MIC against ciprofloxacin of 4 mcg/mL (clinical success and bacteriological eradication rate: 100%)

38

Acute Bacterial Exacerbation of Chronic Bronchitis

Factive (gemifloxacin) NDA 21-158

Eileen Navarro, MD

39

ABECBApplicant’s Proposed Label Indication and

Claim

“FACTIVE is effective for the treatment of acute exacerbations of chronic bronchitis due to H. influenzae, M. catarrhalis, S. pneumoniae, H. parainfluenzae and S. aureus.”

“earlier eradication of H. influenzae from the sputum”

40

Issues in Applicant’s Additional Findings :

“Superior clinical efficacy” “Prolonged exacerbation-free intervals” “Efficacy in hospitalized severe ABECB”

- “no requirement for an IV to oral switch”- results in earlier time to hospital discharge- reduces RTI related hospitalization

LIMITATIONS: Study design issues Adjustments for multiple comparisons Clinical relevance

41

Efficacy in Principal Studies

Successful Outcome

Study Factive Comparator*Difference %

(95% CI)

% (n/N) % (n/N)

ClinicalStudy 068 86.0 (239/278) 84.8 (240/283) 1.2 (-4.7, 7.0)

Study 070 93.6 (247/264) 93.2 (248/266) 0.3 (-3.9, 4.6)

Study 212 88.2 (134/152) 85.1 (126/148) 3.0 (-4.7, 10.7)

Microbiologic

Study 068 85.0 (34/40) 85.0 (34/40) 12.3 (-4.9, 29.5)

Study 070 90.9 (40/44) 90.9 (40/44) 11.4 (-3.3, 26.0)

Study 212 78.4 (29/37) 78.4 (29/37) -7.3 (-23.8, 9.2)

*Comparators; Study 068 clarithromycin; Study 070 Augmentin; Study 212 levofloxacin

42

Early Bacterial Eradication in ABECB

•Patients with H. influenzae represent only a small proportion of patients with ABECB in the clinical studies

• In patients with H. influenzae, no clear correlation of early eradication with clinical benefit • Early eradication related to pharmacokinetics

• Eradication favored comparators in some pivotal studies

43

Clinical Success - ITT AnalysisSupportive Studies

Success Rate (%)

FACTIVE Comparator Difference

ClinicalOutcome

ITT Population % (N) % (N) % (95% CI)

Study 069 89.4 (302) 83.1 (314) 6.3 (0.9, 11.7)

Study 207 82.6 (138) 72.1 (136) 10.5 (0.7, 20.4)

44

Applicant’s Finding: Superiority over Comparators ITT - Considerations

• A finding limited to the ITT population of Supportive Studies 069 and 207– Primary analysis of clinical efficacy (PP) - non-

inferiority – Similar response rates in the secondary analyses of

Bacterial Efficacy in the BPP and BITT

• Pivotal ABECB studies do not show superiority for Clinical Efficacy in ITT and PP population.

45

Efficacy in Severe ABECBStudy 207- Considerations

• Non-inferior to parenteral therapy in hospitalized ABECB

– open label, non-US study

– hospitalized patients able to tolerate oral therapy limits applicability to ALL hospitalised patients requiring parenteral therapy

• Earlier time to discharge (mean difference of 0.5 days)

– clinical significance of a 0.5 day difference

– multiple secondary endpoints

– no difference in primary outcome

– no difference in other related outcomes (time to resolution, indirect costs)

46

Prolonged Time to Next Exacerbation & Reduced Respiratory Tract Related

Hospitalization - Considerations

Prolonged Time to Next Exacerbation • 3 studies - contradictory outcomes • one showed a trend favoring FACTIVE (Study 139),

one favored the comparator (Study 105)• Study 112 -primary analysis showed no difference

Reduced Respiratory Tract Related Hospitalization • Analyses not adjusted for multiple comparisons• No difference in other related outcomes (e.g.

indirect costs)

47

Partial List of Approved Products for ABECB

Quinolone:

levofloxacin

ofloxacin

moxifloxacin

ciprofloxacin

gatifloxacin

Macrolide:

clarithromycin

azithromycin

Beta lactam:

amoxicillin/clavulanate

cefaclor

ceftibuten

cefuroxime axetil

cefdinir

cefditoren pivoxil

cefixime

cefpodoxime

loracarbef

48

Anti-infective Use in ABECB- Considerations

Age in Years % of totalSCOTT-LEVIN ANTIBIOTIC UTILIZATION DATA*

<40 years of age 33.5

>40 years of age+ 66.5PIVOTAL AECB STUDIES

<40 years of age 0.8

>40 years of age 99.2*Appendix 1 Applicant's background package +includes ubnsoecified ages

49

Summary

• FACTIVE clinical efficacy non-inferior to comparators in ABECB

• Unresolved questions regarding clinical relevance or applicability of other findings

• Limited evidence supporting other findings

• Potential impact of broader use in the community

50

Safety of Factive(gemifloxacin)

NDA 21-158

Maureen R. Tierney, MD, MSc.

Medical Officer

FDA

51

Safety Population

• Phase II and III clinical trials– Gemifloxacin 320 mg po=6775– All Comparators (beta lactams, macrolides,

and quinolones)=5248

• ABECB~45%

• CAP~17.5%

• ABS, uUTI, cUTI, SSSI, NGU

• Study 344 & other special Clin. Pharm.

52

Demographics of Safety Population

AgeGemifloxacin

N=6775Comparators

N=5248

<40 1711 (25.2%) 1037 (19.8%)

40-65 3000 (44.3%) 2398 (45.7%)

>65 2064 (30.5%) 1813 (34.5%)

53

Demographics of Safety Population

GenderGemifloxacin

N=6775Comparators

N=5248

Male 3278 (48.4%) 2511 (47.8%)

Female 3497 (51.6%) 2737 (52.2%)

54

Demographics of Safety Population

RaceGemifloxacin

N=6775Comparators

N=5248

White 5871 (86.7%) 4825 (91.9%)

Black 298 (4.4%) 192 (3.7%)

Oriental 227 (3.4%) 43 (0.8%)

Other 379 (5.6%) 188 (3.6%)

55

Adverse Events of Special Interest

• Withdrawals and Serious Adverse Events• QT Prolongation• Hepatic Safety Profile• Rash

56

Withdrawals Due to Adverse Events

GemifloxacinN=6775

All ComparatorsN=5248

Rash 64 (0.9%) 15 (0.3%)

Nausea 23 (0.3%) 20 (0.4%)

Diarrhea 22 (0.3%) 25 (0.5%)

Urticaria 15 (0.2%) 4 (0.1%)

Vomiting 15 (0.2%) 16 (0.3%)

Pneumonia 12 (0.3%) 12 (0.2%)

57

Serious Adverse Events with Suspected Relationship

GemifloxacinN=6775

All ComparatorsN=5248

Rash 7 (0.1%) 1 (<0.1%)

LFTsIncreased

3 (<0.1%) 0

Pneumonia 3 (<0.1%) 2 (<0.1%)

Diarrhea 0 3 (<0.1%)

58

QT Effects

• Known side effect for quinolone class• Some mild prolongation noted in database• Serious event if occurred

59

QT Effects

IC50 for Inhibition of hERG

sparfloxacin 37 um

grepafloxacin 93 um

gemifloxacin 260 um

gatifloxacin 329 um

moxifloxacin 354 um

levofloxacin 827 um

60

Mean Change in QTc

• Clinical Pharmacology 4.9 msec• Combined Clinical Population 2.6 msec

61

Changes in QTc

Change fromOff-Therapy QTc

GemifloxacinN=407

ComparatorsN=380

>30 to <40 23 (5.7%) 19 (5.0%)

>41 to <50 17 (4.2%) 11 (2.9%)

>51 to <60 5 (1.2%) 0

>60 5 (1.2%) 2 (0.5%)

62

Gemifloxacin Dose and QTc

320 mg 480 mg 680 mg

Dose of Gemifloxacin

Man

ual Q

Tc

(mse

c)re

peat

dos

e :

Gem

iflo

xaci

n-P

lace

bo40

30

20

10

0

-10

-20

63

Drug Interactions and QTc

• No inhibition or induction of CYP450 enzymes• Not dependent upon metabolism by CYP450

enzymes• Dual route of elimination

64

Hepatic Safety Profile of Gemifloxacin

• Pre-clinical Findings• LFT increases with 480 and 640 mg doses• LFT increases in those with hepatic

impairment or more comorbidity• ALT and/or BR elevations

65

Pre-clinical Hepatic Findings in Dogs

• Cholangitis/pericholangitis with hepatocellular degeneration and single cell necrosis at high doses

• crystalline deposits of drug in bile canaliculi• elevated ALT and Alk Phos

66

LFT Elevations at Higher Doses• Uncomplicated UTI Study

– gemifloxacin 640 mg x 1 – ciprofloxacin 250 mg BID x 3 days

• 9/592 (1.6%) of gemifloxacin group ALT>2xULN with 4 >6xULN

• No ALT elevations >2xULN for comparator• No bilirubin elevations >2xULN in either group

• Similar results seen in 480mg and 640mg dose clinical pharmacology studies

• Study 005 4/16 elderly withdrawn with high LFTs (ALT 121-333)

67

AEs of the Liver and Biliary System in Patients with Baseline Liver Disease*

Gemifloxacin320mgN=235

ComparatorsN=168

HepaticEnzymesIncreased

8 (3.4%) 0

Alk PhosIncreased 10 (4.3%) 0

BilirubinIncreased

5 (2.1%) 1 (0.6%)

* history of liver disease and elevated LFTs at screening

Source: Sponsor Safety Table 17.35

68

LFT Elevations in Patients with Higher Comorbidity

• Study 185 – 6 with LFT elevations to >3xULN with 4

withdrawals from Gemifloxacin arm – 3 with LFT elevations >3xULN but no

withdrawals from comparator arm

• Study 287– 2 with ALT>3xULN + BR>1.5mg/dl

69

Combined ALT and Bilirubin Elevations

• ALT>3xULN + BR >1.5 mg/dl • 2 patients in Study 287 Non comparative CAP • 1 in comparator in combined clin pop

• ALT>2xULN + BR>1.5 mg/dl in range • additional 3 for gemifloxacin from comparative

clinical trials• none for comparator

70

Bilirubin Elevations

• One healthy male BR 0.8 to 7.5 mg/dl during clin pharm study (previously had an elevation of BR to 1.7mg/dl on oflox)

• 3 BR elevations >2xULN <4xULN in patients in range at screening (none for comparator) in the combined clinical population (all in comparative studies)

71

ALT Elevations

• No patient in range at screening had ALT elevation >8xULN on 320 mg

• 1 patient in total safety population had treatment emergent ALT elevations to >8xULN on therapy-ALT 110 to 501 IU

• 2 patients on 640 mg dose who were in range at screening had ALT elevations >8xULN

72

RASH

• Higher incidence than all comparators• Higher number of serious AEs and

withdrawals than all comparators• Markedly high incidence in an enriched

population (31.7% Study 344)– Large % BSA, more urticaria, 6% mucus

membrane involvement

• Issues affecting clinical practice

73

RASH-Incidence of Events

GemifloxacinN=6775

ComparatorsN=5248

OverallIncidence 241(3.6%) 59(1.1%)

SeriousAdverse Events 7(0.1%) 1(<0.1%)

Urticaria 36(0.5%) 11(0.2%)

Withdrawals 64(0.9%) 15(0.3%)

74

Severity of Rash

GemifloxacinN=6775

ComparatorsN=5248

Patients withAE of Rash

241* 59

Mild 123 (51%) 34 (57.6%)

Moderate 90 (37.3%) 22 (37.3%)

Severe 33 (13.6%) 4 (6.7%)

*some rashes categorized twice because of multiple rash terms

75

Time and Rash

• Two-thirds of rash in gemifloxacin patients began after day 7 of therapy

• Two-thirds of rash in comparator patients began Day 7 or before

• days 8,9,10 most likely for gemifloxacin rash

76

Risk Factors for Rash Development

• Gender (female)

• Age (<40)

• Planned duration of treatment (>7 days)

• Indication

• HRT in Women >40 years of age

77

Rash by Age, Gender, and Duration of Therapy - Combined Population

0

5

10

15

20

25

3 5 7 10 14 3 5 7 10 14

Duration of Therapy (days)

Per

cen

t R

epo

rtin

g R

ash

(%

)

Males ≥ 40y

Males <40y

Females ≥ 40y

Females <40y

gemifloxacin comparators

78

Rash by Indication

Gemifloxacin Comparators

ABECB 44/2847 (1.5%) 21/2591 (0.8%)

CAP 55/1160 (4.7%) 19/926 (2.1%)

79

Rash in ABECB by Gender, Age and Duration

5 days 7 days 10 days Total

Females <40 0/42/2

(100%)0/2

2/8(25%)

Females >4016/1046(1.5%)

7/218(3.2%)

1/23(4.3%)

24/1287(1.9%)

Males <40 0/51/2

(50%)1/7

(14.3%)

Males >408/1190(0.7%)

8/319(2.5%)

1/36(2.8%)

17/1545(1.1%)

80

Rash in CAP by Age, Gender, and Duration

7 days 14 days Total

Females <408/98

(8.2%)7/31

(22.6%)15/129(11.6%)

Females >409/284(3.2%)

10/126(7.9%)

19/410(4.6%)

Males <406/138(4.3%)

3/39(7.7%)

9/177(5.1%)

Males >409/328(2.7%)

3/116(2.6%)

12/444(2.7%)

81

HRT use and Risk of Rash

HRT use inFemales>40

Presence of Rashdue to

Gemifloxacin

Yes 5.6%

No 2.8%

82

Prior or Subsequent Quinolone Usage

• 3/181 (1.7%) patients who had received a prior quinolone developed a rash

– selection bias - no rash on prior exposure

• 0/12 patients developed a rash upon receiving a subsequent quinolone after experiencing a rash on gemifloxacin

– selection bias (?) - rash probably not severe

83

Study 344

84

Demographics Study 344

Race Study Participants

White 929 (91.9%)

Black 2 (0.2%)

Oriental 20 (2.0%)

Hispanic 49(4.8%)

Other 11(1.9%)

85

Study 344 Part A

SubjectsWithRash

PointEstimate

95% CI

GemiN=819 260 31.7% (28.5, 35)

CiproN=164 7 4.3% (0.9, 7.7)

86

Withdrawals and SAEs Due to Rash Study 344 Part A

• Withdrawals– 26/819 from Gemifloxacin– 0/164 from Ciprofloxacin

• Serious AEs– No rash related serious AEs in either arm

• Severe cutaneous AE’s – 20/260 for gemifloxacin– 0/7 for ciprofloxacin

87

Time and Rash-Part A

Gemifloxacin Ciprofloxacin

Mean Day ofOnset

9 7

MedianDuration(Days)

7 4

88

Severity of Rash-Part A

Gemifloxacin Ciprofloxacin

Total with rash N = 260 N = 7

Mild 161 (62%) 6 (85.7%)

Moderate 80 (31%) 1 (14.3%)

Severe 19 (7%) 0

89

Extent of Gemifloxacin RashPart A (N=260)

% of Body Surface Number (%)*

0-5 40 (15.4)

6-10 27 (10.4)

11-20 39 (15.0)

21-40 35 (13.5)

41-60 47 (18.1)

>60 67 (25.8)

*unknown for 5 cases

90

Characteristics of Gemifloxacin Rash-Part A

Characteristic Number (%)

Macules 209 (80.4%)

Papules 210 (80.4%)

Pruritus 180 (69.2%)

Plaques 29 (11.2%)

Tenderness 22 (8.5%)

Urticaria 30 (11.5%)

91

Mucus Membrane InvolvementPart A

• None in Ciprofloxacin rash (n=7)• Gemifloxacin - 16/260 (6.2% of rash)

– Eyes 3/260– Genitalia 1/260– Mouth 12/260

92

Mouth Mucus Membrane Lesions in Gemifloxacin Rash Part A

• 5 with one to a few ulcerations, erosions, papules, or vesicles inside mouth or on lips

• 2 with erythema on lips or inside mouth• 2 with petechiae on lips• 3 unavailable description of mouth lesions• no pictures taken

93

Treatment of Gemifloxacin Associated Rash

• Antihistamines• Topical steroid preparations• Systemic Steroids

– 12/260 rashes in Study 344– 27/241 rashes in combined clinical population

94

Case 1 344-025-1471

• 24yo WF with no PMH• Onset day 8 with fever• Pruritic rash with erythematous macules and

papules >60%BSA• Lesions in mouth (?type)• Treatment with Zyrtec and Medrol pack• Duration of rash 6 days• Quality of Life - very much affected

95

025-01471

96

Case 2 344-020-00844

• 20 yo WF no PMH• Onset day 8• Pruritic rash with erythematous macules and

papules >60%BSA with plaques and mild facial edema

• Erythematous macules on lips • Treatment Benadryl and oral Prednisone• Duration of rash 12 days• Quality of Life - moderately affected

97

020-00844

98

Case 3 -344-025-01318

• 21 yo WF with h/o child asthma • Onset Day 6• Pruritic urticarial rash with erythematous

macules and papules >60% BSA • Treatment Benadryl and oral Solumedrol• Duration of rash 6 days• Quality of Life - some aspects very much

affected

99

025-01318

100

Case 4 344-030-1420

• 21 yo WF no PMH• Onset day 8 • Non pruritic rash with erythematous macules and

papules >60%BSA with ulcers in mouth and pharyngitis

• Not withdrawn • No systemic therapy • Duration of rash 7 days• Quality of Life-minimally affected

101

030-01420

102

Case 5 344-028-1374

• 39 yo WF with a h/o hives to sulfa• Onset day 9• Morbilliform urticarial eruption 40-60% BSA

with erythema on labial mucosa• Acetaminophen only

• Duration of rash 30 days • Quality of Life-no assessment made

103

028-01374

104

Case 6 344-029-01399

• 20 yo WF no PMH• Onset Day 6• Pruritic rash with erythematous macules 20-40%

BSA• Duration of rash 4 days• No photographs of rash taken

• Biopsy - Linear deposition of IgM along dermal basement membrane

• Quality of Life-moderately affected

105

106

Histopatholgy of Gemifloxacin Rash

• Most-mild superficial perivascular infiltrate• Moderate or deep perivasular infiltrate in 10

specimens• Eosinophils noted in 10 cases• No pattern for CD-4 or CD-8 cells• IF faint deposits of IgM and/or C3 in dermal

vessel lumina with 1 along BM• No evidence of vasculitis, bulla or necrosis

107

Study 344 Part B

108

Study 344 Part B Excluding Center 027

Regimen Subjectswith

Rash/Total

Rash 95%CI Rate

Gemi/rash/cipro 8/136 5.9% (1.6,10.2)

Gemi/rash/placebo 1/50 2.0% (0.0,6.9)

Gemi/N rash/gemi 6/248 2.4% (0.3,4.5)

Gemi/Nrash/placebo 5/256 2.0% (0.6,4.5)

109

Summary Study 344 - Part B

• Suggestion of minor cross-sensitization with ciprofloxacin (not conclusive)

• Cannot extrapolate about cross sensitization with other quinolones

• No evidence of subclinical sensitization with gemifloxacin

110

Quinolones and Severe Cutaneous Reactions

• Roujeau et al NEJM 1995;333:1600-7.– Multivariate Crude RR for SJS/TEN

• quinolones 10 (2.6-38)• aminopenicillins 6.7 (2.5-18)• sulfonamides 173 (75-396)

• Literature Review– 13 case reports SJS/TEN with a variety of

fluoroquinolones

111

Summary of Safety

• Minor increase in Mean QTc• Some LFT elevations particularly in those

with liver disease or more comorbidity• Rash

– Increased overall incidence– Large %BSA involved– Some severe rashes with mucus membrane

involvement in Study 344

112

Risk Benefit

113

Risk Benefit Considerations - ABECB

• Efficacy

• Length of therapy

• Chronic condition often requiring recurrent therapy

• Rash rates in population prescribed drug

• Possible limitation of future quinolone availabilty in those who experience rash

• Small increases in LFTs

• Minor increase in mean QTC

114

Risk Benefit Considerations - CAP

• Efficacy

• Oral therapy

• Prescriber compliance with 7 day regimens

• Possible limitation of future quinolone availability in those who experience rash

• Possibly more hepatic effects in those with more comorbidity

• Minor increase in mean QTc

115

116

Summary - 1• Microbiology

– in vitro and animal model data– pharmacokinetic parameters

• Community Acquired Pneumonia– duration of treatment– severity of disease– Streptococcus pneumoniae

• Acute Bacterial Exacerbation of Chronic Bronchitis– principal studies support efficacy– statistical and clinical considerations for other findings– population differences clinical trial vs. usage data

117

Summary - 2

• Safety– rash - rates, risk factors, remaining questions

• risk for more serious dermatologic manifestations?• likelihood of cross-sensitization to other

fluoroquinolones?• practical considerations?

– hepatic safety - findings at daily doses >320 mg– cardiac repolarization– risk benefit considerations for the proposed indications

• CAP• ABECB