# Presentation: 848018

## Hepatitis B Immune Gobulin Intravenous (Human)(Nabi-HBTM Intravenous) to Prevent HBV Recurrence after Orthotopic Liver Transplantation (OLT) for Hepatitis B disease

- Charles Maplethorpe, M.D., Ph.D.
- FDA/CBER/OBRR/DH/CRB
- 87th BPAC, July 13, 2006

## STN125073

- Claim:
- Intravenous administration of Hepatitis B Immune Globulin Intravenous (Human) (HBIGIV; Nabi-HBTM Intravenous) will prevent HBV recurrence after orthotopic liver transplantation (OLT) for hepatitis B disease when given with anti-HBV antiviral therapy

## Current Indications for Hepatitis B Immune Gobulin Intravenous (Human)(Nabi-HB®)

- Acute exposure/needle-stick to blood containing HBsAg
- Sexual exposure to HBsAg-positive persons
- Perinatal exposure of infants born to HBsAg-positive mothers
- Household exposure to persons with acute HBV infection

## Order of Presentation

- Background on IND studies conducted
- Failed attempt to use University of Virginia data (McGory study) as pivotal study for licensure
- Current attempt to retrospectively analyze Nabi’s data for maintenance of HBsAg Seronegativity

## IND 8452 Chronology

- Submitted June 1999; Objective: intravenous administration for OLT for HBV disease
- Conducted 4 studies
- 1.  **Study 2906**.	Pharmacokinetics in 21 OLT subjects more than 3 months after OLT (i.e., at the earliest time when PK parameters have stabilized after OLT).  The product was Nabi HB (CANGENE), a version of the product made at Cangene Corp.  Dose: 180 IU/kg i.v.
- 2.  **Study 4406**.	An open-label extension of study 2906 for 10 subjects, to provide product to these subjects.

## IND 8452 Chronology (cont.)

- 3.  **Study 4203.**	Pharmacokinetics in 21 OLT subjects more than 6 months after OLT (i.e., at a time when PK parameters have stabilized after OLT).  The product was Nabi HB (Boca), the current version of the product manufactured in Boca Raton, FL.  Dose: 10,000 IU i.v. monthly for 3 months.
- 4.  **Study 4409.**	An open protocol for use of the product in 153 HBV OLT subjects; dose schedules and monitoring were not standardized

## Nabi Proposal to Use a non-IND Study of another HBIG i.m. product to Demonstrate Efficacy

- McGory et al, *Transplantation* **61**(9):1358-1364(1995)
- 27 HBsAg+; 17/27 HBeAg+ for OLT
- Dose: 10,000 IU
- 			anhepatic
- 			daily d1-6
- 			then target trough > 500 IU/L
- FDA Response:
- A clinical benefit must be demonstrated
- Data must show that a similar result would be expected if the Nabi HBIGIV had been used

## No Formal Demonstration of Clinical Benefit in Submitted McGory Study

- Control database not submitted
- Analysis was descriptive
- No hypothesis tested
- No prospectively described plan for analysis

## Disparity in Serum anti-HBs Levels achieved in McGory(4404) vs. Study 4203

## 2003 Nabi proposed use of surrogate endpoint:HBsAg seronegativity

- Claimed HBsAg seronegativity is the clinical goal of therapy
- Requested retrospective analysis of data from past Nabi studies for licensure
- FDA brought HBsAg endpoint issue to March 2004 BPAC, which endorsed this endpoint with 2 provisions:
- HBIGIV monotherapy needs 1 year follow-up
- HBIGIV + Lamivudine needs 2 years follow-up

## 4204

**4409**

- Dr. Roland Dickson PK study

- Open Protocol

## Slide 12

## 4204

**4409**

- Dr. Roland Dickson PK study

- Open Protocol

## Historical Control for HBIGIV + Lamivudine

| Table 2.1-1 Meta-analysis of 2-year HBV-Liver Disease Recurrence With
Lamivudine Monotherapy |  |  |
| --- | --- | --- |
| Study | N | Recurrence |
| Anselmo | 13/20 | 65% |
| Bain | 2/3 | 67% |
| Chan | 6/20 | 30% |
| Mutimer | 5/12 | 42% |
| Perrillo | 16/39 | 41% |

## Nabi states that their meta-analysis results in an HBV 2-year recurrence rate (θA) of 45% for lamivudine monotherapy with a lower bound of the 95% confidence interval at 35%. 

## Prevention of HBV Recurrence using Lamivudine MonotherapyAnna Lok, M.D,.U. of Michigan, March 2004 BPAC

- More economical and convenient compared to HBIG
- Recurrence at 1 yr 10%-30%, increases to 30%-40% at 3 yr due to emergence of resistant mutations
- Lamivudine resistant mutants can result in rapidly progressive liver disease and death
- Lamivudine monotherapy is insufficient for the prevention of recurrent hepatitis B post-LT.

**Notes:**
Lamivudine is orally administered, has negligible side effects and is more economical than HBIG. 
It has also been shown to be effective in reducing HBV recurrence to 10-30% at 1 year post-LT, but the rate of recurrence increases to 30-40% at 3 year due to emergence of resistant mutations. 
Although most patients with lamivudine resistance have mild liver enzyme elevation initially, some develop rapidly progressive liver disease and death. 
Thus, lamivudine monotherapy is insufficient for the prevention of recurrent hepatitis B post-LT. 

## Liver Transplantation for Hepatitis B – 2004 Anna Lok, M.D,. U. of Michigan, March 2004 BPAC

- Recurrence rate < 10 % using combination prophylaxis of HBIG + lamivudine
- Graft and patient survival similar if not better than patients transplanted for other liver disease

**Notes:**
Thus, HBV recurrence rate can be reduced to <10% using combination prophylaxis of HBIG+lam. 
In addition, graft and patient survival is similar if not better than patients transplanted for other liver disease. 

## Sponsor’s Analysisof Studies 4204 & 4409(Clinical Stability Endpoint)

| Table 3.3-1: Database for Efficacy of Nabi-HB with Lamivudine Compared to Lamivudine Monotherapy
(New OLT patient with = 2 years of Clinical Follow-up or Death > 30 days post transplantation) |  |  |
| --- | --- | --- |
| Study | Recurrences
Relative efficacy assuming θA = 0.45 | p-value |
| 4204 | 0/24
100% | <0.0001 |
| 4409 | 1/17
86.9% | 0.0012 |
| pooled | 1/41
94.6% | <0.0001 |

## Sponsor’s Analysisof Studies 4204 & 4409(HBsAg Serological Endpoint)

| Table 3.3-2: Database for Efficacy of Nabi-HB with Lamivudine
Compared to Lamivudine Monotherapy
(New OLT patient with = 2 years of Clinical Follow-up or
 Death > 30 days post transplantation) |  |  |
| --- | --- | --- |
| Study | Recurrences
Relative efficacy assuming θA = 0.45 | p-value |
| 4204 | 0/18
100% | <0.0001 |
| 4409 | 1/11
79.8%% | 0.028 |
| pooled | 1/29
92.3% | <0.0001 |

## FDA Analysis of Study 4204

**30 subjects**
- 2 subjects died within 30 days
**	****28 subjects**
- 	2 subjects were lost to follow-up **	****	**
**	****	****26 subjects**
- 		2 subjects died in the interval 30 days 	to 2 yrs not HBV-related
**	****	****	****24 subjects**
- 			5 subjects inadequately 			monitored for HBsAg to 2 yrs
**	****	****	****	****19 subjects**

## FDA Analysis of Study 4409

**32 subjects **(which includes 22 subjects on HBIGIV monotherapy, i.e. no Lamivudine)
- 3 died within 30 days **	**
**	****29** **subjects** (19 HBIGIV monotherapy)
- 		Excluded the following 4 subjects:
- 		1.	4409-003013 discovered to be HBsAg neg at 				transplant
- 		2.	4409-010005 not HBV infected but rec’d HBV+ liver
- 		3.	4409-010007 not HBV infected but rec’d HBV+ liver
- 		4.	4409-028004 no evidence of HBsAg pos prior to 				transplant
**	****	****	****25 subjects** (15 HBIGIV monotherapy)
- 			2 subjects died between 30 days and 2 yrs **	****	****	****	****	****23 subjects** (14 HBIGIV monotherapy)
- 				12 subjects excluded for less than 2 				yrs follow-up 								**11 subjects **(3 HBIGIV monotherapy)
- 						**8 Subjects** on combined 					HBIGIV + Lamivudine therapy

## FDA Evaluable Database for Studies 4204 and 4409

- 19 subjects from study 4204
- 8 subjects from study 4409
- 27 subjects in pooled database
- If 3 HBIGIV monotherapy subjects from study 4409 are included, 30 subjects in pooled database

## FDA Analysis

- 8/27 HBsAg seroconversions in HBIGIV + Lamivudine group
- 	29.6% HBsAg seroconversion, 95% CI (14%,50%)
- 8/30 HBsAg seroconversions if 3 HBIGIV monotherapy subjects included
- 	27% HBsAg seroconversion, 95% CI (12%, 46%)

## FDA: 8 HBsAg Seropositives

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

## Comparison of FDA/NabiApproach to Data Analysis (1)

**	****Deaths.**  FDA removed HBV non-related deaths from the database.  Nabi included HBV non-related deaths in the database and counted them as successes if the previous HBsAg measurement was negative.

## Comparison of FDA/NabiApproach to Data Analysis (2)

**	****Missing Data.**  If HBsAg measurements were not available to satisfy the requirement for at least 2 yrs HBsAg monitoring for combined HBIGIV + Lamivudine therapy, Nabi counted subjects as successes if they were monitored clinically for at least 2 years and judged to be clinically stable.  FDA removed these subjects from the database due to missing data. FDA’s approach was consistent with Nabi’s analysis plan submitted on September 3, 2003.

## Comparison of FDA/NabiApproach to Data Analysis (3)

**	****HBIGIV Discontinuation.**  Seven subjects discontinued HBIGIV therapy prior to 2 yrs.  Two of these seven HBsAg-seroconverted.  Nabi _excluded_ the 2 of 7 subjects who were HBsAg seroconverters and _included_ the 5 of 7 subjects who remained HBsAg negative.  FDA used an intent-to-treat approach, and did not exclude any of the 7 subjects for the reason of HBIGIV early discontinuation.

## Alternative Failure Analyses

|  | Current
Failures | Current
and
Deaths 
after 1 month | Current
and all
Deaths 
 | Current
and 
Missing
Data 
subjects | Current
And
Both |
| --- | --- | --- | --- | --- | --- |
| Fail =  | 8 | 12 | 17 | 31 | 40 |
| N =  | 27 | 31 | 36 | 50 | 59 |
| Fail
Rate | 30% | 39% | 47% | 62% | 68% |

## FDA/Nabi Discrepancies

| Subject ID | FDA Inclusion
Reason | FDA Exclusion
Reason | Nabi Inclusion
Reason | Nabi Exclusion
Reason |
| --- | --- | --- | --- | --- |
| 4204-002003 | HBsAg pos
At month 13 |  |  | HBsAg less than 2 yrs |
| 4204-002005 | HBsAg pos
At month 37
(day 906) |  |  | HBIGIV 
Discontinued
Day 249
HBsAg pos
Day 906 |
| 4204-015001 | HBsAg pos
At month 22 |  |  | HBIGIV 
Discontinued
Day 252
HBsAg pos
Day 635 |
| 4409-005007 | HBsAg pos
At all times |  |  | HBIGIV 
Discontinued
After 10 doses |
| 4409-003002 | HBV DNA pos
Month 10
1080 pg/ml |  |  | No HBsAg
measurements |

## FDA/Nabi Discrepancies (cont.)

| Subject ID | FDA Inclusion
Reason | FDA Exclusion
Reason | Nabi Inclusion
Reason | Nabi Exclusion
Reason |
| --- | --- | --- | --- | --- |
| 4409-001002 |  | HBIGIV monotherapy
not accepted | HBIGIV monotherapy
accepted |  |
| 4409-005010 |  | HBIGIV monotherapy
not accepted | HBIGIV monotherapy
accepted |  |
| 4409-018001 |  | HBIGIV monotherapy
not accepted | HBIGIV monotherapy
accepted |  |
| 4204-004001 |  | Died before
2 yrs
Not HBV-related | HBsAg neg
Prior to death |  |
| 4204-004003 |  | Died before
2 yrs
Not HBV-related | HBsAg neg
Prior to death |  |
| 4409-003009 |  | Died before
2 yrs
Not HBV-related | HBsAg neg
Prior to death |  |
| 4409-002005 |  | Died before
2 yrs
Not HBV-related | HBsAg neg
Prior to death |  |

## Summary

- No prospectively-designed clinical trial of Nabi-HB to demonstrate safety and efficacy for the HBV immunoprophylaxis indications in patients undergoing OLT for HBV disease
- Attempt to use McGory data failed because
- Serum anti-HBs levels not comparable
- HBsAg Seronegativity endpoint failed due to unacceptably high HBsAg seropositivity rate