# Presentation: 617341

## Injectafer® (Iron Carboxymaltose Injection) NDA 22-054

**Min Lu, M.D., M.P.H.**
**Division of Medical Imaging and Hematology Products**
**Office of Oncology Drug Products**
**FDA **
**February 1, 2008**

## Outline

-  **Proposed Indication **
** ****Efficacy Results**
** ****Safety Results**
** ****Mortality**
** ****Serious Adverse Events/Cardiac Events**
** ****Hypophosphatemia**
**Summary**

## Indication

**June, 2006: Treatment of iron deficiency anemia in:**
-  **heavy uterine bleeding **
** ****post-partum**
** ****inflammatory bowel disease**
** ****hemodialysis**
**November, 2007: Tre****atment of iron deficiency anemia in:**
** ****heavy uterine bleeding **
** ****post-partum patients**

## Clinical Program

**Injectafer exposure: n = 2080**
**14 studies with various designs**
**8 were multicenter, randomized, active controlled:  **
**6 oral iron-controlled & used proposed Injectafer dose regimen of maximum single dose of 1000 mg**
**2 Venofer/placebo-controlled & used Injectafer 200 mg per dose regimen**

## Clinical Program

**Study populations in 14 clinical studies:**
**Heavy uterine bleeding (HUB)**
**Postpartum (PP)**
**Inflammatory bowel disease **
**Chronic kidney disease**
** ****Non-dialysis **
** ****Hemodialysis **
**Multifactorial iron deficiency **
**Chronic heart failure**

**Notes:**
The study populations in the 14 clinical studies included patients with heavy utering bleeding, post-partum anemia, inflammatory bowel disease, chronic kidney disease including non-dialysis and hemodialysis patients, and patients with multifactorial iron deficiency anemia as well as patients with chronic heart failure.

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## Efficacy Results

** ****4 studies (1 in HUB and 3 in PP) **
** ****Primary endpoints:**
**Change from baseline in hemoglobin, or**
**Proportions of patients achieving anemia correction**
** ****2 superiority; 2 non-inferiority**
** ****All open label**
** ****Oral iron control**
** ****6 to 12 week duration**

## Heavy Uterine Bleeding: 1VIT-4002/4003Proportion of subjects who achieved an increase in hemoglobin ≥ 2 g/dL from baseline at anytime during 6-week study*

|  | Injectafer | Oral Iron |
| --- | --- | --- |
| Combined analysis | 187/228 
(82%) | 139/225a 
(62%) |
| VIT-4002 | 99/120
(83%) | 80/126
(64%) |
| VIT-4003 | 88/108
(82%) | 59/99
(60%) |

***modified ITT population**
**a**** p< 0.001**

**Heavy Uterine Bleeding: 1VIT-4002/4003****Proportion of subjects who achieved an increase in hemoglobin ****≥ 2 g****/dL from baseline at anytime ****during 6-week study***

## Post-partum Anemia Efficacy Results in 3 Trials in Modified ITT Population 

| Studies/
Primary Efficacy Endpoints |  | 
Injectafer | 
Oral Iron |
| --- | --- | --- | --- |
| 1VIT03001
Hb Increase ≥2g/dL 
during 6 weeks  | 
N
(%) | 
162/168
(96.4%) | 
159/169
(94.1%) |
| VIT-IV-CL-009 
Mean change (SD)
in Hb at Week 12 | 
N
g/dL | 
216
3.34 (1.79) | 
109
3.18 (1.76) |
| 1VIT06011
Hb ≥12 g/dL
during 6 weeks | 
N
(%) | 
127/139
(91.4%) | 
98/147*
(66.7%) |

***p<0.05**

## Safety Results 

**Potential Mortality Signal**** **
**Numeric imbalance in deaths/clinical ****	****presentation suggestive of cardiac ****	****events**
**Numeric imbalance in serious adverse ****	****event rates/cardiac events**
**Hypophosphatemia**

## Mortality Imbalance

**10 deaths after Injectafer exposure**
**5 deaths in randomized, controlled studies**
**1 death in a randomized, cross-over study**
**4 deaths in uncontrolled studies**
**1 death after Venofer exposure in a   randomized, controlled study**
**0 deaths after oral iron exposure in  randomized, oral iron-controlled studies**

## Deaths after Injectafer Exposureby Dose Regimen in Multicenter Studies

| Maximum 
single dose | Deaths | Study 
population |
| --- | --- | --- |
| 1000 mg
(proposed dose regimen) | 
7/1739 
(0.4%)
 | ND-CKD: 4
Postpartum: 1
IBD: 1
Multi-factorial: 1 |
| 200 mg
 | 3/311 
(1.0%) | HD: 3 |

## Deaths after Other Iron Exposure

**1 death after Venofer **
** ****200 mg x 2 doses **
** ****Died of worsening heart failure per      **
**Investigator**
** ****CHF study**

## Deaths after Injectafer ExposureCardiac Causes

| Apparent “cause” | Days post last exposure | Events |
| --- | --- | --- |
| Cardiac arrest | 1 | Died at workplace |
| PP cardiomyopathy with heart failure | 8 | Unresponsive at home and was dead on arrival to hospital |
| Acute MI | 9 | Extensive AMI on Day 4 |
| Resp failure/TB | 15 | Discharge summary: “developed acute cardiac insufficiency, and at 21:30 patient died” |
| Cardio-respiratory arrest | 19 | Died suddenly at home |

## Deaths after Injectafer ExposureOther Causes

| Apparent “cause” (investigator) | Days post last exposure |
| --- | --- |
| MVA/trauma | 15 |
| Pneumonia/sepsis | 27 |
| Urosepsis/pneumonia | 35 |
| Anoxic encephalopathy/GI bleed | 46 |
| Colon perforation | 98 |

## Deaths in Multicenter, Randomized, Controlled Studies

| Data Pool | Injectafer | Control |
| --- | --- | --- |
| All Studies (8) | 5/1206 
(0.4%) | 1/994* 
(0.1%) |
| Oral Iron-controlled Studies (6) | 4/1057 
(0.4%) | 0/834
(0%) |

***oral iron, Venofer or placebo**

## SAE in Multicenter, Randomized, Controlled Studies

| Data Pool | Injectafer | Control |
| --- | --- | --- |
| All Studies (8) | 43/1206 
(3.6%) | 36/994* 
(3.6%) |
| Oral Iron-controlled Studies (6) | 34/1057 
(3.2%) | 21/834
(2.5%) |

***oral iron, Venofer or placebo**

## SAE by Term in Multicenter, Randomized, Controlled Studies

| Term | Injectafer | Control |
| --- | --- | --- |
| All Studies (8)  |  |  |
| Cardiac | 13/1206 (1.1%) | 8/994* (0.8%) |
| Infection | 11/1206 (0.9%) | 5/994* (0.5%) |
| Oral Iron-controlled Studies (6) |  |  |
| Cardiac | 9/1057 (0.9%) | 3/834 (0.4%) |
| Infection | 10/1057 (0.9%) | 3/834 (0.4%) |

*******oral iron, Venofer or placebo**

## Non-fatal Cardiac SAEs: Oral Iron-Controlled Studies

| Major events in each patient | Study | Days after last Injectafer dose |
| --- | --- | --- |
| CHF/CAD | CKD-ND | 2 |
| Pulmonary edema with mitral valve regurgitation | PP | 3 |
| MI/resp arrest | CKD-ND | 9 |
| CHF | CKD-ND | 9 |
| Tachycardia | IBD | 21 |
| Worsening CAD | CKD-ND | 46 |
| Palpitation | CKD-ND | 47 |
| CHF/fluid retention | PP | Oral iron |
| Demand cardiac ischemia | CKD-ND | Oral iron |
| CHF | CKD-ND | Oral iron |

## Hypophosphatemia

**Nature Clinical Practice: Nephrology, 2006:**
** “...****implicated as a cause of rhabdomyolysis, respiratory failure, hemolysis and left ventricular dysfunction”**
**“****The high rate of sepsis... might result, in part, from acquired dysfunctions in leukocyte chemotaxis and phagocytosis, secondary to hypophosphatemia”**
**“****Patients with severe hypophosphatemia (< 1.0 mg/dL) are treated to avoid potential detrimental consequences...”**
**After Injectafer exposure: **
**One subject (HUB): nadir phosphate < 1 mg/dL  (CTC Grade 4)**
**CTC Grade 3 hypophosphatemia common**

## CTC Grade 3 Hypophosphatemia Serum Phosphate <2.0-1.0 mg /dL

| Studies | Injectafer | Oral iron/other |
| --- | --- | --- |
| Post-partum |  |  |
|   1VIT03001 | 14/174 (8.0%) | 0/178 (0%) |
|   1VIT06011 | 12/142 (8.5%) | 0/147 (0%) |
| Heavy uterine bleeding |  |  |
|   1VIT04002/1VIT04003 | 156/224 (70.0%) | 0/219 (0%) |
| Cross-over safety study |  |  |
|   1VIT05006 | 81/505 (16.0%) | 48/487 (9.9%)
(placebo) |
| CKD-ND |  |  |
|   1VIT04004 | 4/105 (3.8%) | 0/75 (0%) |
|   1VIT05005 | 7/98 (7.1%) | - |

## Hypophosphatemia and AE

-  **Phosphate not rigorously measured in**
**	**** ****all available studies**
** ****Categorical analyses:**
**AE: trend toward higher rates with    lower phosphate nadir.**
**SAE: no trend**
** ****No phosphate data available after   **
**    ****Injectafer exposure for all 5 cardiac  **
**    ****deaths described**

## Summary

** ****Efficacy: increased hemoglobin concentrations**
** ****Safety: **
**1) ****Imbalance in mortality:**
**Randomized, oral iron-controlled studies: **
** ****4/1057 (0.4%) Injectafer vs. 0/834 (0%) oral  **
**    ****iron**
**Overall: **
** ****10 deaths Injectafer-exposed subjects**
** ****1 death in a Venofer-exposed subject**
** ****0 deaths in oral iron-exposed subjects**
**2) Small imbalance in SAE/cardiac and infections**
**3) Imbalance in hypophosphatemia**

## Introductions to Questions

**Discuss the risk, if any, for mortality.  **
**Vote upon the overall risk-benefit profile for marketing**
**If you recommend marketing approval, what are the major features of any clinical studies that should be performed as post-marketing commitments?**
**If marketing is not recommended, discuss features of additional studies**