# Presentation: 570782

## Safety and Efficacy of Gemifloxacin  for ABS in Clinical Studies 

***Maureen R. Tierney, MD, MSc.***** **
***Senior Medical Officer***
***Division of Special Pathogen and Transplant  Products***
***CDER***

**Anti-Infective Drugs Advisory Committee Meeting**
**September 12, 2006**

## Points for Discussion

**Efficacy in ABS**
**Cutaneous AEs in ABS Studies**
**Cutaneous AEs in NDA 21-158**
**QT Issues**
**Liver AEs**
**Analysis of Risk Benefit**

## ABS Studies

| Study | Type | Drug(s)/duration  |  |
| --- | --- | --- | --- |
| 009 | R, C, DB
Sinus puncture | Gemi 7 day vs. Cefuroxime 10 day |  |
| 010 | R, C, DB | Gemi 7 day vs. Trovofloxacin 10 day  |  |
| 186 | R, C, DB | Gemi 5 day vs. Gemi 7 day |  |
| 206  | OL, single arm 
Sinus puncture | Gemi 5 day  |  |
| 333 | OL, single arm
Sinus endoscopy  | Gemi 5 day  |  |

**ABS** **Studies**

## Inclusion Criteria

**Symptoms >7 <28 days with purulent/mucoid nasal discharge plus**
**X-Ray (opacification or A/F level) +**
**1 Major: pain/pressure over sinuses, facial congestion, or nasal blockage  **_**OR**_
**2 Minor: tooth pain, earache, non-vascular HA, cough, halitosis, fever, change in smell, periorbital swelling**
**Sinus puncture required in 009 and 206**
**2003 AC recommends sinus puncture in all ABS clinical studies**

## Outcome Criteria

**Primary-investigator determination of sustained improvement or resolution of signs and symptoms as seen at follow-up Days 18-24 such that no further antibiotic treatment required. **
**Bacteriologic success = clinical cure with presumed eradication or documented eradication with persistent symptoms **
**	****(**_**no**_** f/u sinus puncture required unless clinically indicated).**

## % Clinical Success at Follow up

## Summary of CI ABS Clinical Trials

| Study Number | PP | ITT |
| --- | --- | --- |
| 009 | -6.4, 4.1 | -9.4, 1.6 |
| 010 | -7.1, 5.4 | -6.5, 8.1 |
| 186 | -6.5, 7.6 | -8.0, 6.4 |
| 206 | noncomparative |  |
| 333 | noncomparative |  |

## Study 186 at Follow-up

| 
 | Gemifloxacin
5 days | Gemifloxacin
7days |
| --- | --- | --- |
| PP Population | 178 | 171 |
| Success | 155 (87.1) | 148 (86.5) |
| 95% CI | -6.51, 7.63 |  |
| ITT Population | N=212 | N=198 |
| Success | 176 (83.0) | 166 (83.8) |
|      95% CI | -8.02, 6.38 |  |

**Study 186 at Follow-up**

## Study 186 at End of Therapy

|  | Gemifloxacin
320 mg qd for 5 days | Gemifloxacin
320 mg qd for 
7 days |  |
| --- | --- | --- | --- |
| PP Population | N=186 | N=180 |  |
| Success, n (%) | 173 (93%) | 173 (96%) |  |
|  95% CI
 | -7.7, 1.5 |  |  |
| ITT Population | N=212 |  | N=198 |
| Success, n (%)  | 188 (88.7) |  | 189 (95.5) |
|  95% CI | -11.9, -1.6 |  |  |
|  |  |  |  |

**Notes:**
No culture required

##  Microbiological Results for Study 009 at FU

|                                          |  | Bacteriological ITT |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  |  | Gemifloxacin (7 day) |  | Cefuroxime (10 day) |  |
|  Follow-Up  |  | N=165 n/N* %  |  | N=156 n/N* %  |  |
| All Pathogens  |  | 157/185 | (84.9) | 152/173 | (87.9) |
| S. pneumoniae  |  | 58/66 | (87.9) | 57/64 | (89.1) |
| H. influenzae  |  | 29/37 | (78.4) | 33/36 | (91.7) |
| K. pneumoniae  |  | 15/18  | (83.3)  | 18/19  | (94.7)  |
| S. aureus |  | 14/17 | (82.4) | 8/11 | (72.7) |
| M catarrhalis  |  | 9/9 | (100.0) | 6/6 | (100.0) |

## In vitro Activity of Gemifloxacin

| Organism | Gemi | Cipro | Levo | Moxi | Gati |  |
| --- | --- | --- | --- | --- | --- | --- |
| S. pneumoniae | 0.03 | 2.0 | 1.0 | 0.25 | 0.5 |  |
| S. aureus | 0.06 | 1.0 | 0.5 | 0.12 | 0.25 |  |
| H. Influenzae | 0.03 | 0.03 | 0.03 | 0.06 | <0.03 |  |
| H. parainfluenzae | 0.06 | 0.06 | 0.06 | 0.25 | 0.12 |  |
| M. catarrhalis  | 0.015 | 0.06 | 0.06 | 0.06 | 0.03 |  |
| E. coli | 0.25 | 0.5 | 0.5 | 0.06 | 0.06 |  |
| K. pneumoniae | 0.5 | 1.0 | 1.0 | 1.0 | 1.0 |  |
| M. pneumoniae | 0.12 | -- | 0.5 | 0.12 | 0.25 |  |
| L. pneumophila | 0.015 | 0.03 | 0.015 | 0.125 | 0.03 |  |
|  |  |  |  |  |  |  |

## Comparative PK Data for Quinolones

## Microbiology

**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**** **

## Efficacy Summary

_**7 Day 2 Non-inferiority DB,R studies**_
**Clinical outcome @FU-82% ITT to 90%PP. similar trend at end of Rx**
**Bacteriologic Outcome in 1 study @85% ALL Pathogens (88% Pneumo, 79% HI)**
**Comparators’ effect size not determined**
_**5 Day 1 Non-inferiority DB, R study**_
**Clinical Outcome @FU-ITT 83% **
**Comparators’ effect size not determined**
**Results not consistent at end of therapy and followup**
**No randomized bacteriologic data **

## Safety

## Cutaneous Adverse Events in ABS Studies

**7 day studies**
**009**
**010**
**5 day studies**
**186**
**206**
**333**
**Combined 5 vs 7 day **

## Study 009 Skin AEs

|  | Gemi 7 D (n = 338) | Cefurox. (n = 337) |
| --- | --- | --- |
| Rash | 29  | 2 |
| Erythem.Rash | 0 | 1 |
| Urticaria | 5 | 0 |
| Mac-Pap Rash | 1 | 0 |
| Photosensitivity | 2 | 1 |
| Total (1 overlap) | 36 (10.6%) | 4 |
| Severe Rash | 5 | 0 |
| Withdrawal | 8 | 0 |
|  |  |  |

## Study 010 Skin AEs

|  | Gemifloxacin
 7day (n= 202) | Trovafloxacin 
10 day (n=199) |
| --- | --- | --- |
| Rash | 11 | 1 |
| Erythem.Rash | 8 | 1 |
| Urticaria | 2 | 0 |
| Mac-Pap Rash | 1 | 0 |
| Total  | 22 (10.9%) | 2 |
| Severe Rash | 9 | 0 |
| Withdrawal | 9 | 0 |

**Study 010 Skin AEs**

## Slide 19

| Study 009 Rash by Age and Gender |  |  |  |
| --- | --- | --- | --- |
|  | <40 | > 40 | Total |
| Female  | 13/104 (12.5%) | 5/83 (6.0%)  | 18/187 (9.6%) |
| Male | 4/78 (5.1%) | 2/66 (3.0%) | 6/144 (4.2%) |
| Total  | 17/182(9.3%) | 7/149 (4.7%) | 24/331 (7.3%) |

## Study 010 Rash by Age and Gender

|  | <40 | > 40 | Total |
| --- | --- | --- | --- |
| Female  | 10/58 (17.2%) | 4/58  (6.9%)  | 14/116 ( 12.1%) |
| Male | 2/48  (4.2%) | 3/31  (9.7%) | 5/79 ( 6.3%) |
| Total | 12/106 ( 11.3%) | 7/89 ( 7.9%) | 19/195  (9.7%) |

##  Study 186 - Incidence of Rash

|  | Gemifloxacin
for 5 days | Gemifloxacin
for 7 days |
| --- | --- | --- |
|  | N = 218 | N=203 |
| Rash | 1 (0.5%) | 1 (0.5%) |
| Rash Maculo-papular | 2 (0.9%) | 4 (2.0%) |
| Rash erythematous  | 0 | 7 (3.4%) |
| Urticaria | 1 (0.5%) | 5 (2.5%) |
| Dermatitis | 2 (0.9%) | 1 (0.5%) |
| Total | 6 (2.8%) | 18(8.9%) |
| Withdrawn due to rash  | 1 | 0 |
| Severe Rash | 0 | 2 |
| Rash in Women | 69% |  |

- Adapted from data in original submission NDA 21-376.

## Study 206 Cutaneous Adverse Events

|  | N=461 | % |
| --- | --- | --- |
| Patients with Any Cutaneous Adverse Event* (5 overlaps) | 12 | 2.6 |
| Rash Maculo-papular | 8 | 1.7 |
| Urticaria | 3 | 0.6 |
| Pruritus | 3 | 0.6 |
| Rash Pustular | 1 | 0.2 |
| Rash | 1 | 0.2 |
| Severe Rash  | 0 |  |
| Rash in Women  | 6/8 | 75% of rash |

- Source: Adapted from Study Report 206, NDA 21-376

**Study 206 Cutaneous Adverse Events**

## Study 333-Incidence of Rash

|  | N=451 | % |
| --- | --- | --- |
| Rash Mac-Pap | 12 |  |
| Rash | 5 |  |
| Urticaria | 4 |  |
| Dermatitis | 2 |  |
| Photosenstivity | 2 |  |
| Rash erythematous | 2 |  |
| Severe Rash  | 2 (10.5%) |  |
| Total | 23 | 5.1% |
| Withdrawal | 4 |  |

## Cutaneous Adverse Events in Combined ABS Studies

| Preferred Term | Gemi 5 Day
N=1122 | Gemi 7 Day
N=724 | All Comparators
N=521 |
| --- | --- | --- | --- |
| Total | 35(3.1%) | 62 (8.6%) | 5 (1.0%) |
| Urticaria | 8 (0.7%) | 12(1.7%) | 0 |
| Rash | 7 (0.6%) | 38 (5.2%) | 3 (0.6%) |
| Rash Mac-pap | 22 (2.0%) | 6 (0.8%) |   0 |
| Rash erythem | 2 (0.2%) | 18 (2.5%) | 2 (0.4%) |
| Rash pustular | 1 (0.1%) |   0 |   0 |
| Severe rash | 2 (0.2%) | 16 (2.2%) |   0 |

**Cutaneous Adverse Events in Combined ABS Studies**

## Original NDA 21-158 (N=6775) Total Clinical Trial Database (N=8119)	(6775 +CAP studies + ABS 333)

**Evaluation of Rash**

## RASH

**Higher incidence than all comparators**
**Higher number of serious AEs and withdrawals than all comparators**
**Markedly high incidence in an enriched population of women under 40 (31.7%)**
**Higher incidence in any subgroup at any duration of therapy**

## RASH-Incidence of Events

## Severity of Rash

****some rashes categorized twice because of multiple rash terms***

##   Number (%) of Patients With Rash by Gender, Age

|  | Gemifloxacin 320mg qd |  | All Comparators |  |
| --- | --- | --- | --- | --- |
| Gender |  |  |  |  |
| Male | 78/3278 | (2.4) | 20/2511 | (0.8) |
| Female | 163/3497 | (4.7) | 39/2737 | (1.4) |
| Age, yrs |  |  |  |  |
| <40 | 115/1711 | (6.7) | 13/1037 | (1.3) |
| >40 | 126/5064 | (2.5) | 46/4211 | (1.1) |

##  Rash Incidence by Decade 

|  | Total population | Females only |
| --- | --- | --- |
| < 19 | 7/147 (4.8) | 4/92 (4.3) |
| 20-29 | 54/787 (6.9) | 40/455 (8.8) |
| 30-39 | 54/776 (7.0) | 37/445 (8.3) |
| 40-49 | 40/1124 (3.6) | 24/658 (3.6) |
| 50-59 | 30/1211 (2.5) | 22/638 (3.4) |
| 60-69 | 31/1294 (2.4) | 22/591 (3.7) |
| 70-79 | 18/1110 (1.6) | 10/461 (2.2) |
| 80-89 | 6/292 (2.1) | 3/133 (2.3) |
| > 90 | 1/32 (3.1) | 1/22 (4.5) |

## Day of Rash Onset

|  | 
Gemifloxacin
320 mg qd |  | All Comparators |  |
| --- | --- | --- | --- | --- |
| Patients with Rash* | N = 241 (overall N = 6775) |  | N = 59 (overall N = 5248) |  |
| Time to Rash Onset (days) | n | (% of rash) | n | (% of rash) |
|  1 | 9 | (3.7) | 6 | (10.7) |
|  2 | 19 | (7.9) | 9 | (15.3) |
|  3 | 14 | (5.8) | 10 | (16.9) |
|  4 | 10 | (4.1) | 6 | (10.2) |
|  5 | 12 | (5.0) | 3 | (5.1) |
|  6                      (29.4%) | 7 | (2.9) | 2 | (3.4) |
|  7 | 6 | (2.5) | 2 | (3.4) |
|  8 | 36 | (14.9) | 1 | (1.7) |
|  9 | 46 | (19.1) | 4 | (6.8) |
| 10 | 38 | (15.8) | 3 | (5.1) |
| 11 | 19 | (7.9) | 1 | (1.7) |
| 12-14 | 11 | (4.6) | 2 | (3.4) |
| 15-19 | 7 | (2.9) | 5 | (8.5) |
| >19 | 7 | (2.9) | 5 | (8.5) |

**Day of Rash Onset**

## Number (%) of Patients With Rash by Therapeutic Indication

|  | 
Treatment Group |  |  |  |
| --- | --- | --- | --- | --- |
|  | Gemifloxacin 320mg qd |  | All Comparators |  |
|  | N=6775 |  | N=5248 |  |
| Indication | n | (%) | n | (%) |
| AECB | 44/2847 | (1.5) | 21/2591 | (0.8) |
| CAP | 55/1160 | (4.7) | 19/926 | (2.1) |
| ABS | 73/1397 | (5.2) | 5/521 | (1.0) |
| cUTI | 48/758 | (6.3) | 11/729 | (1.5) |
| uUTI | 14/430 | (3.3) | 2/444 | (0.5) |
| uSSSI | 5/39 | (12.8) | 1/37 | (2.7) |
| NGU | 2/144 | (1.4) | 0/0 | (0.0) |
| Data Source: Tables 105a, 105b, 105c, 105d, 105e, 105f, 105g. |  |  |  |  |

- Source: Applicant’s Table 14.20 from NDA 21058 18 month Safety Update

## Study 344 Part A

## Severity of Rash-Part A

## Extent of Gemifloxacin RashPart A (N=260)

****unknown for 5 cases***

## Characteristics of Gemifloxacin Rash-Part A

## Mucus Membrane InvolvementPart A

**None in Ciprofloxacin rash (n=7)**
**Gemifloxacin - 16/260 (6.2% of rash)**
**Eyes 3/260**
**Genitalia 1/260**
**Mouth 12/260**

## Treatment of Gemifloxacin Associated Rash

**Antihistamines**
**Topical steroid preparations**
**Systemic Steroids**
**12/260 rashes in Study 344 ~5%**
**27/241 rashes in combined clinical population ~9%**

## 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

## 025-01471

## 025-01471

**025-01471**

## Case 2 -344-025-01318

**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**

**Case 2 -344-025-01318**

## Case 2 - 344-025-01318

**Case 2 - 344-025-01318**

## Case 2 - 344-025-01318

**Case 2 - 344-025-01318**

## Source of Rash Slides

**Study 344 Report **
**Resubmission NDA 21-158**

## Preclinical QTc Potential

**Preclinical QTc Potential**

## Mean Change in QTc

**Clinical Pharmacology Population**
**4.9msec**
**Clinical Studies Population**
**2.3msec**

## Hepatic Safety Profile of Gemifloxacin

**Preclinical Findings**
**LFT increases with 480 and 640 mg dose **
**ALT and/or  BR elevations**

## 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**

## ALT Elevations

**No patient in range at screening had ALT elevation >8xULN on 320 mg **
**1 patient 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**
**Postmarketing Events**

## Safety Conclusions

**Higher incidence of rash and urticaria even at 5 days (minimum of 2.5 times greater than comparators)**
**Higher incidence of severe rash**
**Higher incidence of withdrawals due to rash**
**Low grade liver and QT signal**
**No Tendon signal at this time**

## Risk Benefit

**Mild-Moderate Rash**
**Labeled Q Allergic **
**	****(~2-3%) **
**?Sensitization**
**Severe Rash**
**Meds for Rx of Rash (~10%)**
**? Serious Rash**
**? QT Prolongation**
**? Liver**

**Small  and ? Effect size-No demonstrated advantage**
**No demonstrated randomized bacteriologic benefit at 5 days**