# Presentation: 821837

## Blood Product Advisory Committee Meeting - July 13, 2006

- Nabi Biopharmaceuticals
**Hepatitis B Immune Globulin (Human),**
**Intravenous**
**(Nabi-HB IV)**
- Henrik Rasmussen, MD, PhD
- Senior Vice President Clinical Research, Medical & Regulatory Affairs

## Purpose

- To present substantial evidence that the safety and efficacy data, derived from the Nabi-HB IV clinical trials, support approval of BLA 125073 for the indication of:
- “prevention of hepatitis B clinical disease in HBsAg-positive liver transplant recipients.”

## Regulatory History

- 1994: Initial IND submitted
- 1995: Orphan Drug Designation
- 1997: FDA rejects suggested prospective, randomized, comparative 		study between Nabi-HB and Abbott H-BIG (not virally inactivated)
- 2001: Nabi-HB approved for post-exposure prophylaxis
- End of 2002: BLA for liver transplant indication submitted
- May 2003, May 2004, and June 2005: Complete Response Letters
- Aug. 2003, Dec. 2004, and Feb. 2006: Nabi Responses
**March 2004: BPAC Outlines Criteria for Approval**
- Dec. 2005 and April 2006: Meetings to discuss Nabi-HB IV database vs. 	BPAC criteria
**July 2006: FDA seeks BPAC advice**

## Development Limitations 

- Orphan Drug Designation: life threatening disease for very small patient population - 200 hepatitis B positive liver transplants in the US annually in ~125 transplant sites - limits size of clinical trials that can be performed
- As HBIG had become standard of care, a placebo-controlled study was not feasible
- No approved comparator
- Continuous evolving standard of care with introduction of antivirals; however, no antivirals approved for this indication
- Nabi started working with the FDA in the 90s; however, criteria for approval unclear until March 2004 BPAC meeting - retrospective data collection agreed upon with FDA after BPAC meeting

## Rationale for Approval

- Two studies demonstrating efficacy and safety of Nabi-HB IV in new transplant patients (Nabi-4204 and Nabi-4409)
- Nabi-HB has been the standard of care for HBV liver transplants in the US for 7 years - 60,000 infusions administered establishing a favorable risk/benefit profile
- HBIG efficacy is well documented in literature, has been the standard of care in the US and ROW for 15 years, and is approved for prevention of recurrence of hepatitis B post-liver transplant in the EU and ROW
- Support for efficacy from studies in maintenance-phase patients

## Rationale for Approval

| Study  | Study Type | Recurrence Rate (%) |
| --- | --- | --- |
| Nabi-4204 | New OLT | 0/24 (0 %) |
| Nabi-4409 | New OLT | 1/17 (6%) |
| Nabi-4409 | Maintenance-Phase | 0/121 (0%) |
| Nabi-4203 | Maintenance-Phase | 0/21 (0%) |
| Nabi-2906 | Maintenance-Phase | 0/21 (0%) |
| Nabi-4406 | Maintenance-Phase | 0/10 (0%) |

**Summary of Clinical Studies**

## Rationale for Approval

- Lack of guidance in US Label has resulted in numerous examples of recurrence after premature discontinuation of Nabi-HB IV (Dickson et al. 2006; Hayashi et al. 2006)
- Approval would be consistent with FDA policy encouraging companies to seek label indications for drugs that are used off-label
- Orphan drug considerations
**Meets standards in FDA guidance, “Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products”**

## Pharmacokinetics data should be captured that can be used to guide therapeutic dosing.
A historical control can be used for comparison in pivotal study.
The pivotal study should start dosing from the time of transplantation, and should not be solely based on data from the “maintenance-phase” (i.e. 6 months or more after transplantation). 
In the case of HBIG monotherapy, a minimum of 1 year of follow-up time will be necessary.
For HBIG / Lamivudine combination therapy, a minimum of 2 years of follow-up time will be necessary.

- A historical control can be used for comparison in pivotal study.
- The pivotal study should start dosing from the time of transplantation, and should not be solely based on data from the “maintenance-phase” (i.e. 6 months or more after transplantation).
- In the case of HBIG monotherapy, a minimum of 1 year of follow-up time will be necessary.
- For HBIG / Lamivudine combination therapy, a minimum of 2 years of follow-up time will be necessary.

**March 2004 BPAC Recommendations and****May 2004 FDA Letter **

## Nabi-4204 (Dickson)Pharmacokinetics

- 30 New Liver Transplant Recipients
- Lamivudine 100 mg/day started pre-surgery & continued indefinitely
- Nabi-HB base dose schedule:
- 20,000 IU day of surgery
- 10,000 IU daily days 1-7
- 10,000 IU once weeks 4 and 8
- 5,000 IU monthly from weeks 12 to 36
- Additional doses or modification based on trough anti-HBs levels
- After 2004 BPAC meeting, follow-up was extended beyond week 36 to comply with BPAC recommendations

## Nabi-HB Pharmacokineticswith Concomitant Lamivudine

| Number of Patients Below Specified Anti-HBs Levels |  |  |
| --- | --- | --- |
| Study Period | Anti HBs Titer | Patients |
| Day 1-2 | < 300 | 19/27 (70%) |
| Day 3-4 | < 300 | 10/26 (38%) |
| Day 5 | < 300 | 2/25 (8%) |
| Day 6-7 | < 300 | 2/26 (8%) |
| Day 8-30 | < 200 | 2/25 (8%) |
| Day 31-Week 12 | < 200 | 2/23 (9%) |
| Weeks 13-24 | < 100 | 1/21 (5%) |
| Weeks 25-36 | < 100 | 1/21 (5%) |
| Dickson, RC, et al., Liver Transplantation 12:124-133, 2006 |  |  |

## Dosing Recommendation for Nabi-HB IV

| Weeks Post-Transplant | Minimum Trough anti-HBs Level | Recommended Dose |
| --- | --- | --- |
| 0 - 2 | 500 IU/L | 10,000 IU anhepatically
 and then daily |
| 2 - 12 | 250 IU/L | 10,000 IU weekly
 or every 2 weeks |
| > 12 | 100 IU/L | 10,000 IU monthly
 |

## Nabi-4204 Pharmacokinetics

**BPAC Recommendation**: Pharmacokinetics data should be captured that can be used to guide therapeutic dosing:
- Target trough levels are generally achieved with the dose schedule suggested, although adjustments based on trough anti-HBs levels may be required.

## Pharmacokinetics data should be captured that can be used to guide therapeutic dosing.
A historical control can be used for comparison in pivotal study.
The pivotal study should start dosing from the time of transplantation, and should not be solely based on data from the “maintenance-phase” (i.e. 6 months or more after transplantation). 
In the case of HBIG monotherapy, a minimum of 1 year of follow-up time will be necessary.
For HBIG / Lamivudine combination therapy, a minimum of 2 years of follow-up time will be necessary.

- A historical control can be used for comparison in pivotal study.
- The pivotal study should start dosing from the time of transplantation, and should not be solely based on data from the “maintenance-phase” (i.e. 6 months or more after transplantation).
- In the case of HBIG monotherapy, a minimum of 1 year of follow-up time will be necessary.
- For HBIG / Lamivudine combination therapy, a minimum of 2 years of follow-up time will be necessary.

**March 2004 BPAC Recommendations and****May 2004 FDA Letter **

## Recurrence Rates - Literature Review

| 1-Year Recurrence Rates |  |  |
| --- | --- | --- |
| Study | No or Short-term
 (<3 months) Treatment
# Patients (%) | HBIG Monotherapy # Patients (%) |
| Samuel (1993) | 111/150 (74%) | 75/209 (36%) |
| Terrault (1996) | 21/28 (75%) | 4/24 (17%) |
| Muller (1991) | 11/11 (100%) | 6/23 (26%) |
| McGory (1996) | --- | 2/27 (7%) |
| Grazi (1996) | 8/10 (80%) | 4/25 (16%) |
| Nyman (1997) | 4/4 (100%) | 3/14 (21%) |
| Overall | 155/203 (76%) | 94/322 (29%) |
| 95% CL | (68%, 80%) | (24%, 34%) |

## Recurrence Rates – Literature Review

| 2-Year Recurrence Rates |  |  |
| --- | --- | --- |
| Study | Lamivudine Only | Lamivudine + HBIG |
| Anselmo (2002) | 13/20 (65%) | 10/89 (11%) |
| Bain (1996) | 2/3 (67%) | --- |
| Chan (2004) | 6/20 (30%) | --- |
| Mutimer (2000) | 5/12 (42%) | --- |
| Perrillo (2001) | 16/39 (41%) | --- |
| Marzano (2001) | --- | 1/25 (4%) |
| Markowitz (1998) | --- | 0/14 (0%) |
| Starkel (2002) | --- | 0/8 (0%) |
| Overall | 42/94 (45%) | 11/136 (8%) |
| 95% CL | (35%, 54%) | (4%, 14%) |

## Historical Recurrence Rate

- No evidence that baseline risk factors have substantially changed from those in published literature
- Nabi assigned a conservative estimate of recurrence (45%, 2-year recurrence rate) on lamivudine monotherapy for analyses – if anything, the recurrence rate on chronic use of lamivudine has increased

## Pharmacokinetics data should be captured that can be used to guide therapeutic dosing.
A historical control can be used for comparison in pivotal study.
The pivotal study should start dosing from the time of transplantation, and should not be solely based on data from the “maintenance-phase” (i.e. 6 months or more after transplantation). 
In the case of HBIG monotherapy, a minimum of 1 year of follow-up time will be necessary.
For HBIG / Lamivudine combination therapy, a minimum of 2 years of follow-up time will be necessary.

- A historical control can be used for comparison in pivotal study.
- The pivotal study should start dosing from the time of transplantation, and should not be solely based on data from the “maintenance-phase” (i.e. 6 months or more after transplantation).
- In the case of HBIG monotherapy, a minimum of 1 year of follow-up time will be necessary.
- For HBIG / Lamivudine combination therapy, a minimum of 2 years of follow-up time will be necessary.

**March 2004 BPAC Recommendations and****May 2004 FDA Letter **

## Nabi-4204 (Prospective Study of Nabi-HB IV + Lamivudine)

- Nabi-4204 was a prospective study that assessed the pharmacokinetics, efficacy and safety of Nabi-HB IV with concomitant lamivudine in new liver transplant recipients, conducted under investigator held IND and funded by the NIH
- Following the 2004 BPAC meeting, follow-up was extended from 36 weeks to greater than 2 years (median follow-up of 3.0 years for serology)

## Assumptions for Efficacy Analysis Based on BPAC Recommendations and Agreed upon with FDA

**HBsAg can be used as a surrogate marker for efficacy as it correlates well with clinical liver disease**
- the corollary is that if the patient is clinically well, it is reasonable to assume that the patient is sero-negative (if no measurements of HBsAg). Because of this, HBsAg measurements are not standard clinical practice in patients who are clinically well
**HBV DNA is **_**not**_** a good marker and should not be used**
- it will always be present if the assay is sufficiently sensitive
- no correlation has been demonstrated between DNA status and prognosis

## Assumptions for Efficacy Analysis Based on BPAC Recommendations

- Retrospective analysis plan was submitted to FDA, and  after the March 2004 BPAC meeting was discussed on numerous occasions
- Patients included in the analysis were HBsAg negative after OLT and had a minimum of at least two years follow-up data on Nabi-HB and lamivudine
- Two analysis populations were evaluated:
- At least two years follow-up data with serology
- At least two years clinical follow-up (this is consistent with clinical practice; if patients are clinically well without signs of liver disease, serology is not monitored)

## Nabi-4204Nabi’s Analysis, Based on Clinical Data

- 30 new liver transplant recipients:
- Nabi excluded the following patients from the analysis:
- 2 patients died within 30 days of transplant (4204-002006 and 4204-004002)
- 2 patients had Nabi-HB discontinued for economic reasons from 8 to 17 months post-transplants (4204-015001 and 4204-002005)
- 2 patients followed for less than 2 years (4204-015004 and 4204-002004)
- Therefore, **24** patients were included in Nabi’s clinically evaluable analysis.
**0/24 (0%) recurrences is statistically significantly better than 42/94 (45%) recurrences on lamivudine monotherapy (p<0.0001)**
- FDA also excluded 2 patients who died between days 30 and 730 (4204-004001 and 4204-004003) – that would make 22 evaluable patients
**0/22 (0%) recurrences is still statistically significantly better than 42/94 (45%) recurrences on lamivudine monotherapy (p<0.0001)**
- An additional 6 patients did not have 2-year serology data and were excluded from the serology database

## Disputed Patients - Nabi-4204

**Four patients were classified by FDA as treatment failures – Nabi disagrees**
_**Patient (#4204-015001)**_
- Discontinued Nabi-HB on day 252 (HBsAg negative) for economic reasons, but continued on lamivudine monotherapy
- Recurrence of Hep. B on day 636, that is >1 year after discontinuation of Nabi-HB
**FDA counted this patient as a failure of Nabi-HB in their analysis, even though this patient demonstrates the need for concomitant Nabi-HB **
- Nabi excluded the patient from analysis
_**Patient (#4204-002005)**_
- Discontinued Nabi-HB on day 249 (HBsAg negative) for economic reasons; continued on lamivudine monotherapy
- Recurrence of Hep. B on day 906, that is >2 years after discontinuation of Nabi-HB.
**The FDA counted this patient as a failure of Nabi-HB in their analysis, even though this patient demonstrates the need for concomitant Nabi-HB**
- Nabi excluded the patient from analysis

## Disputed Patients - Nabi-4204

_**Patient (#4204-001004)**_
- Died from bacterial sepsis on day 56
- HBsAg negative at time of death
- Therefore, should be censored at day 56
_**Patient (#4204-002003)**_
- HBsAg negative for 14 measurements up through day 532 with exception of one positive value on day 375
- As all measurements before and after were negative, and as the patient was clinically well without signs of recurrence throughout day 1159, the positive value on day 375 represents a lab error
**Therefore, the patient should be classified as a treatment success, not failure**

## Nabi-4409 (Expanded Access Study of Nabi-HB + Lamivudine)

- Nabi-4409 was an expanded access study to assess the pharmacokinetics, efficacy and safety of Nabi-HB IV with concomitant lamivudine in new (n = 32) as well as maintenance (n = 121) liver transplant recipients
- Following the 2004 BPAC meeting follow-up was extended to greater than 2 years (median follow-up of 4.8 years for serology)

## Nabi-4409 – New Liver Transplant Patients

**32 new liver transplant recipients:**
- Nabi excluded the following patients from the analysis:
- 3 patients died within 30 days of transplant (4409-002001, 4409-028005, 4409-020002)
- 2 patients were discovered on the day of transplant to have been HBsAg negative pre-transplant (4409-003013, 4409-028004)
- 2 patients received a HBV-positive donor liver, but was not HBV positive pre-transplantation (4409-010005, 4409-010007)
- 1 patient only received 10 doses of Nabi-HB with last dose given two weeks after transplant (4409-005007)
- 7 patients had less than 2 years of follow-up data available (4409-011001, 4409-016005, 4409-016015, 4409-079001, 4409-218001, 4409-219008, 4409-221001)
- Hence, **17 patients that were treated with Nabi-HB + lamivudine and had at least 24 months follow-up** were included in Nabi’s analysis. There was 1 recurrence among these patients (94% efficacy)
**1/17 (6%) recurrence is statistically significantly better than 42/94 (45%) recurrences on lamivudine monotherapy (p = 0.012)**
- An additional 6 patients did not have 2-year serology data and were excluded from the serology database

## Disputed Patients - Nabi-4409

**The following 4 patients were classified by the FDA as treatment failures:**
_**Patient (#4409-005007)**_
- Only received 10 doses of Nabi-HB, the last one two weeks after liver transplantation. Continued on lamivudine monotherapy.
- Developed recurrence of HBV 548 days post-LT. Died 852 days post-LT from ESLD.
**The FDA counted this patient as a failure of Nabi-HB in their analysis, **even though this patient demonstrates the need for concomitant Nabi-HB.
**Nabi excluded the patient from analysis.**
_**Patient (#4409-016010)**_
- Discontinued Nabi-HB for economic reasons on day 184;
- HbSAg negative on day 534.
- Seroconverted on day 730; ~ 30 months after discontinuation of Nabi-HB.
**Again, the FDA counted this patient as a failure of Nabi-HB in their analysis**, when this case actually demonstrates the need for concomitant Nabi-HB.
- .

## Disputed Patients - Nabi-4409

_**Patient (#4409-003002)**_
- Patient was clinically well through day 1874, no HBsAg data were recorded. Positive for HBV DNA at month 10.
- Although FDA agreed that HBV DNA should not be used as it does not correlate to prognosis, **the FDA counted this** **patient as a failure in their analysis**.
- As the patient was clinically well throughout 6 yrs, **Nabi believes the patient should be counted as a clinical success**.
_**Patient (#4409-002003)**_
- This patient was the only true failure on Nabi-HB.
- Despite treatment with Nabi-HB + lamivudine, the patient became HBsAg positive 146 days after LT.
**Nabi agrees with the FDA that this is a treatment failure**.

## Efficacy Based on Serology

**Efficacy in New Liver Transplant Patients With at Least 2 Years of HBsAg Serology or Death > 30 Days Post-Transplant**

| Study | Recurrence Rate (%) | Efficacy (relative to lamivudine monotherapy) | p-value* |
| --- | --- | --- | --- |
| Nabi-4204
 | 0/18 (0%) | 100% | <0.0001 |
| Nabi-4409 | 1/11 (9%)
 | 80% | 0.028 |
| Pooled
 | 1/29 (3%) | 92% | <0.0001 |
| * p-value is based on one-sample comparison of efficacy rate compared to lamivudine monotherapy recurrence rate of 45%
 |  |  |  |

## Efficacy Based on Clinical Status 

**Efficacy in New Liver Transplant Patients With at Least 2 Years of Clinical* Follow-up or Death > 30 Days Post-transplant**

| Study | Recurrence Rate
(%) | Efficacy (relative to lamivudine monotherapy) | p-value** |
| --- | --- | --- | --- |
| Nabi-4204
 | 0/24 (0%) | 100% | <0.0001 |
| Nabi-4409
 | 1/17 (6%) | 87% | 0.0012 |
| Pooled
 | 1/41 (2%) | 95% | <0.0001 |
| * It is assumed that if clinically well with normal liver enzymes, patient would be HBsAg negative, and therefore, a treatment success
** p-value is based on one-sample comparison of efficacy rate compared to lamivudine monotherapy recurrence rate of 45% |  |  |  |

## Recurrence Rates

| 2-Year Recurrence Rates
 |  |  |
| --- | --- | --- |
| Study | Lamivudine + Nabi-HB IV | Lamivudine + HBIG |
| Anselmo (2002) | --- | 10/89 (11%) |
| Marzano (2001) | --- | 1/25 (4%) |
| Markowitz (1998) | --- | 0/14 (0%) |
| Starkel (2002) | --- | 0/8 (0%) |
| Nabi-4204 | 0/24 (0%) | --- |
| Nabi-4204 | 0/18 (0%) | --- |
| Nabi-4409 | 1/17 (0%) | --- |
| Nabi-4409 | 1/11 (0%) | --- |
| Overall (rate, 95% CI) | 1/41 (2%, 0 – 13)
1/29 (3%, 0 -18%) | 11/136 (8%, 4 – 14%) |

## Additional Supporting Clinical Data 

**Hayashi et al.: *****Importance of Continued Hepatitis B Immunoglobulin in Prevention of Reinfection Following Liver Transplantation*****.  Liver Transplantation (submitted 2006) **
- Analysis of **20** hepatitis B positive patients, who underwent liver transplantation in UCI Medical Center between 1994 – 2001
**3** died in immediate post-operative period and **1** was lost to follow-up, leaving 16 patients with at least 2 years of follow-up data
**16** patients were followed for a mean of ~84 months (~7 years)
**10** continued on Nabi-HB + lamivudine for a mean of ~80 months.  None developed recurrence of hep. B
**6** discontinued Nabi-HB (1 due to side effects, 5 due to cost of treatment or logistics)
**Of the 6 patients who discontinued Nabi-HB, 3/6 developed recurrence of hepatitis B**

## Additional Supporting Information

**Narratives for 3 Patients Who Showed Recurrence of Hepatitis B ****in Hayashi Study**
_**Patient 1:**_** **
- Received Nabi-HB + lamivudine ~ 38 months post-liver transplant and was well with no signs of recurrent Hep. B.
- Discontinued Nabi-HB as he returned to his native country.
- When he returned to the US six months later, he had sero-converted and was HBsAg positive.
- Started high dose Nabi-HB and became sero-negative.
- Patient is still on Nabi-HB + antivirals 91 months post-liver transplant and is doing well.
_**Patient 2:**_
- Received Nabi-HB + lamivudine for ~ 22 months post-liver transplant and did well with no signs of Hep. B.
- Discontinued Nabi-HB treatment as insurance carrier stopped reimbursement due to off-label, but continued on lamivudine.
- 24 months later (46 months post-transplant), patient sero-converted (HBsAg positive) and developed severe liver disease.
**Died 62 months post-liver transplant.**

## Additional Supporting Information

**Narratives for 3 Patients Who Showed Recurrence of Hepatitis B ****in Hayashi Study *****(continued)***
_**Patient 3:**_** **
- Received Nabi-HB + lamivudine for ~ 12 months post-liver transplant and was well with no signs of recurrent Hep. B.
- Left the area and discontinued Nabi-HB as well as lamivudine.
**Returned 24 months later with clinical signs and symptoms of fulminant liver failure and HBsAg positive. **
_**Note:**_**  All three patients who showed recurrence were non-replicators,   indicating that it is very difficult to predict who are at risk.**

## Differences in FDA/Nabi Approach

- Nabi and FDA met on several occasions to discuss the analysis.
- The following were agreed upon: use of HBsAg as surrogate for efficacy, exclusion of deaths within 30 days of OLT, retrospective data collection, and meta-analysis approach to historical recurrence rate on lamivudine.
- Remaining differences:
- Deaths
- Missing data
- Nabi-HB discontinuation

## Differences in FDA/Nabi Approach to DEATHS

- FDA excluded all non-HBV related deaths that occurred < 2 years.  Nabi censored four non-HBV related deaths that were surface antigen negative at time of death.
- If non-HBV-related deaths are excluded (as FDA did), this changes results for clinical analysis from 1/41 to 1/37 (p < 0.0001) and the serology database from 1/29 to 1/25 (p < 0.0001) and does not affect overall outcome relative to the lamivudine monotherapy.

## Differences in FDA/Nabi Approach to MISSING DATA

- Nabi made every effort to follow the 2004 BPAC recommendations and collected clinical and serology data on subjects who participated in Nabi-4204 and Nabi-4409.  Some missing data are to be expected in retrospective databases.
- Nabi included subjects who were clinically stable in the _clinical database_.  We agree that this could be viewed as reflecting clinical practice rather than rigorous scientific research; however, this is standard of care, and therefore relevant.
- FDA’s comment regarding missing data does not apply to the serology data base.

## Differences in FDA/Nabi Approach to Nabi-HB DISCONTINUATION

**FDA counted subjects who sero-converted after discontinuing Nabi-HB for economic or logistical reasons as failures; this is not appropriate. Excluding these subjects, as Nabi did, is the right scientific approach and is not anti-conservative.**

## Summary

- Nabi’s BLA submission positively responds to _all_ BPAC recommendations:
**Pivotal study should be from time of transplantation**
**Nabi provided data on new transplant patients**
**Pharmacokinetics data should be captured that can be used to guide therapeutic dosing**
**pK data from Nabi-4204 provides guide to dosing**
**Historical control can be used for comparison in pivotal study**** **
**      ****	**** ****Meta-analysis of lamivudine monotherapy was used for historic**** control, using a conservative 45% recurrence rate**
**Two-year follow-up required for subjects receiving concomitant lamivudine**
**Follow-up data in new transplant patients well exceed the 2 year recommendation**

## Summary – Risk/Benefit

- Favorable Adverse Event profile – 30 AEs in over 60,000 infusions since 1999
- No reports of off-label efficacy failure (based on MedWatch forms)
- Approximately 80% recurrence prior to HBIG; 45% recurrence with lamivudine monotherapy
- In clinical trials, less than 3% failure rate in 41 new transplant patients with Nabi-HB and concomitant lamivudine; 0% failure rate in 173 maintenance patients

## Questions for BPAC - #1

***“******Post hoc inclusion and exclusion criteria”***
- Inclusion and exclusion criteria were based on BPAC recommendations.
- Nabi met with the Agency several times to discuss the analyses.  Many issues were resolved.
- Remaining issues are subject of today's meeting; e.g., inclusion of subjects who discontinued Nabi-HB as failures and relevance of clinical database.

## Questions for BPAC-  #2

***Observational nature of information, data limitations, and lack of analysis plan***
- The clinical database, while observational in nature, follows standard of care, and is therefore relevant.
- HBsAg has been accepted as surrogate by FDA and BPAC.**  Therefore, the serology database is not observational and stands on its own merits.**
- Analysis plan based on BPAC recommendations.

## Questions for BPAC - #3

***Are retrospective data, including from an expanded access program and pK study sufficient to ******demonstrate efficacy?***
- Nabi and FDA agreed to retrospective data collection.
- Efficacy was demonstrated in the pooled serology database (p<0.0001).
- Clinical database and data from maintenance patients support serology findings (p<0.0001).
**The statistical analysis should not be invalidated by counting subjects who sero-converted after discontinuing Nabi-HB as failures, as FDA did.**

## FDA Issue Summary

## Questions for BPAC - #3 (Cont.)

**Sensitivity Analysis**
- If assuming a 35% recurrence rate on lamivudine, Nabi’s pooled recurrence rate of 1/29 patients (3%--Serology) or 1/41 patients (2%--Clinical) is still highly statistically significantly superior p < 0.0001
- Even assuming a 35% recurrence rate on lamivudine, and if you exclude patients who died before 2 years of non-HBV related disease (n=4) and patients who received monotherapy (n=3), the combination of Nabi-HB + lamivudine is still highly statistically superior to lamivudine alone (p = 0.002 for serology, p < 0.0001 clinical)

## Questions for BPAC - #3 (cont.)

- Approval of Nabi-HB IV is warranted and not anti-conservative given that:
- Despite retrospective nature of databases, Nabi-4204 and Nabi-4409 clearly demonstrate efficacy
- BPAC recommendations were followed
- Nabi-HB is standard of care and has been so for years
- This is an Orphan Drug Indication
- Myozyme was recently approved as a treatment for Pompe Disease based on an open-label study in 19 patients; there are 300 new cases per year in the US of this disease
- FDA’s stated desire to bring standard of care off-label uses on label
**The need to prevent premature discontinuation, which puts patients at significant risk; doing the study the FDA requests will delay the labeled indication by 5 years**

## Post-approval Commitment

- Nabi is willing to conduct a Phase 4 study to assess efficacy of Nabi-HB and concomitant anti-viral in new liver transplant recipients (similar in design to Nabi-4204) – however, requiring this study pre-approval would delay label recommendations by 5 years:
-  0.5 year study planning and initiation
-  1 year enrollment
-  2 years follow-up
-  0.5 year data analysis and BLA preparation
-  1 year FDA review and approval
**During this time period, patients will continue to be at significant risk for recurrences and death (Hayashi et.al. 2006; Dickson et al. 2006)**

## Conclusion

- Non-standardized dose administration is not in the public health interest and places patients at risk for HBV liver re-infection and subsequent risk of death
- Nabi study data supports the following labeling claim:
**	****“****Nabi-HB is indicated for the prevention of hepatitis B clinical disease in HBsAg-positive liver transplant recipients”**