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Remune 2015 FDA BLA Clinical Dossier   Remune Full Prescribing Draft

REMUNE is a therapeutic vaccine designed to elicit immune responses against a variety of HIV antigens in patients with HIV. It consists of a suspension of killed HIV-1 virus particles that have

been emulsified with Incomplete Freund’s Adjuvant (IFA, a mixture of mannide mono-oleate and a highly purified mineral oil). Each dose is given by IM injection and contains 10 μg of p24 antigen in approximately 100 μg of total protein.

REMUNE® is derived from Zairian HIV-1 strain HZ-321, composed of gp 120-depleted HIV-1 propagated in HUT-78 cells and inactivated in beta-propiolactone and irradiation. The inactivated material is emulsified with mineral oil (Incomplete Freund's Adjuvant) at 1:1 ratio. Each 1 ml dose (at least 100μg or 10 units) has viral protein and p24.

REMUNE FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1  Remune is prescribed for Adults 18 and older with diagnosed HIV/AIDS 

2 DOSAGE AND ADMINISTRATION

REMUNE® is derived from Zairian HIV-1 strain HZ-321, composed of gp 120-depleted HIV-1 propagated in HUT-78 cells and inactivated in beta-propiolactone and irradiation. The inactivated material is emulsified with mineral oil (Incomplete Freund's Adjuvant) at 1:1 ratio. Each 1 ml dose (at least 100μg or 10 units) has viral protein and p24.

Remune is administered every 3 months IM intramuscularly via vaccine injection into the arm.

Dosing is every 3 months intramuscularly. The product for clinical use is 10 μg/mL p24 (10 μg/mL p24 antigen approximately equivalent to 100 μg total protein).

The dosage of the Drug Substance is based on total protein content. Dosages tested included 50, 100, 200, 300, and 400 μg total protein (5, 10, 20, 30, and 40 μg/mL p24 antigen) delivered intramuscularly as a 1 mL water-in-oil emulsion. The product for clinical use is 10 μg/mL p24 (10 μg/mL p24 antigen approximately equivalent to 100 μg total protein).

 

Clinical development has established that REMUNE is best given in a prime and boost regimen with an interval of 12 weeks between injections.

3 DOSAGE FORMS AND STRENGTHS

The product for clinical use is 10 μg/mL p24 (10 μg/mL p24 antigen approximately equivalent to 100 μg total protein).

The dosage of the Drug Substance is based on total protein content. Dosages tested included 50, 100, 200, 300, and 400 μg total protein (5, 10, 20, 30, and 40 μg/mL p24 antigen) delivered intramuscularly as a 1 mL water-in-oil emulsion. The product for clinical use is 10 μg/mL p24 (10 μg/mL p24 antigen approximately equivalent to 100 μg total protein).

4 CONTRAINDICATIONS

None

Minor irritation at the local injection site maybe caused by IFA contained in the Remune vaccine which is relieved by Benadryl within 48-72 hours

5 WARNINGS AND PRECAUTIONS

IFA Incomplete Freunds Adjuvant is a very irritating substance that disperses vaccine throughout the body.

Incomplete Freund’s Adjuvant (IFA) Placebo is prepared as a 1:1 mixture of 0.9% Sodium Chloride

For Injection and IFA (Incomplete Freund’s Adjuvant: 10% surfactant Montanide 80, 90% Drakeol 6 VR light mineral oil supplied by Seppic, Inc, France). IFA Placebo is provided in a single-use USP

Type I borosilicate clear glass syringe. IFA Placebo is emulsified with IFA in a water-in-oil emulsion and supplied at nominal volume of 1mL.

6 ADVERSE REACTIONS

Adverse events have primarily been of mild to moderate severity and most frequently consist of  injection site reactions. The most frequently reported adverse events following REMUNE or IFA

treatment include: pain at injection site, fatigue, hypokinesia (difficulty moving arm), myalgia, headache, diarrhea, nausea, mass at injection site, upper respiratory infection and general site injection

site reactions. Typically, the injection site reactions related to treatment lasted less than three days. REMUNE–treated patients had more severe injection site reactions such as pain at injection site, mass at

injection site, inflammation at injection site, general injection site reactions, myalgia and hypokinesia than IFA-treated patients. There have also been reports of granuloma and granuloma-like injection

site reactions associated with study drug treatment. There have been no allergic reactions attributable to the vaccine. Overall, REMUNE appears to be safe and well-tolerated.

In addition, three serious adverse events were reported as IND Safety Reports to BB-IND 8723. A safety report was submitted by the Division of AIDS (DAIDS) of a subject in ACTG sponsored study A5057 who experienced a probable gastrointestinal (GI) bleed. Upon unblinding, it was determined

that the subject was in the IFA treatment group. The GI bleed was assessed as unrelated to the study medication. Additionally, a subject in the ACTG study A5058 was hospitalised for myocardial infarction that occurred approximately 3.5 months after initiation of study treatment (either blinded

REMUNE, IFA, ALVAC or placebo). Subsequently, the myocardial infarction was assessed as not related to the study treatment. A third subject, also in Study A5058, experienced cardiomegaly, decreased ventricular function, and left bundle branch block. This subject’s blinded treatment was

either REMUNE, IFA, ALVAC or placebo. The ACTG investigator and DAIDS medical officer were unable to judge the relationship of the events to the study drugs.

The most commonly reported adverse event was injection site reactions. This is not surprising given the mode of action of REMUNE and the fact that it contains Incomplete Freund’s Adjuvant, a potent but irritating immune co-stimulator.


7 DRUG INTERACTIONS

No Known Drug Interactions

No pharmacodynamic interaction of REMUNE with other AIDS medications that patients may be taking are expected and none have been observed in clinical studies performed to date.

 

REMUNE is a vaccine and is not co-administered with any medication other than Amplivax an unapproved experimental adjuvant in combination with Remune called IR103.

No interactions with other medications that patients are receiving are expected.

8 USE IN SPECIFIC POPULATIONS

Remune is prescribed only for adults age 18 and older with diagnosed HIV or AIDS disease

 

 

Special Patient Populations: Study 808 a pediatric study was investigated doses of 2.5 μg or 10 μg p24 antigen in children but requires more studies for this indication to be approved. No other special patient populations have yet been studied

9 DESCRIPTION

REMUNE is a whole killed vaccine sterile therapeutic vaccine designed to elicit immune responses against a variety of HIV antigens in patients with HIV. It consists of a suspension of killed HIV-1 virus particles that have been emulsified with Incomplete Freund’s Adjuvant (IFA, a mixture of mannide mono-oleate and a highly purified mineral oil). Each dose is given by IM injection and contains 10 μg of p24 antigen in approximately 100 μg of total protein.

REMUNE® is derived from Zairian HIV-1 strain HZ-321, composed of gp 120-depleted HIV-1 propagated in HUT-78 cells and inactivated in beta-propiolactone and irradiation. The inactivated material is emulsified with mineral oil (Incomplete Freund's Adjuvant) at 1:1 ratio. Each 1 ml dose (at least 100μg or 10 units) has viral protein and p24.

 

Virus Inactivation:

Viral Inactivation Validation - βPL Inactivation Validation

Validation of the βPL inactivation process for HIV-1 has been performed.

Gamma Irradiation Inactivation Validation

The validation for the gamma irradiation process was originally performed at the SteriGenics facility

(Tustin, CA).

 

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action    The mechanism of action of REMUNE is to stimulate the immune system’s response to HIV antigens

and no secondary pharmacological effects are expected from its mechanism of action.

 

REMUNE is a vaccine designed to stimulate the immune system in patients with AIDS.

 

This type of drug preparation does not lend itself to studies of pharmacokinetics, pharmacodynamics or metabolism in humans; therefore, no studies of these types were performed.

 

No specific safety pharmacology studies have been conducted, but since the active component is a mixture of proteins and lipids, there is an extremely low probability of there being any significant

responses which would be detected by the standard battery of safety pharmacology tests. This is also true for the adjuvant, though some local and possibly systemic effects might be detected by some routes of administration, but which would be wholly unrepresentative of how the product is to be used.

Although not extensive, the toxicity tests that have been conducted have provided support for this conclusion.

REMUNE is a therapeutic vaccine designed to elicit immune responses against a variety of HIV antigens in patients with HIV. It consists of a suspension of killed HIV-1 virus particles that have been emulsified with Incomplete Freund’s Adjuvant (IFA, a mixture of mannide mono-oleate and a

highly purified mineral oil). Each dose is given by IM injection and contains 10 μg of p24 antigen in approximately 100 μg of total protein.

Development studies have shown that an adjuvant is required in order to elicit a high enough immune response when a challenge of HIV virus is given to previously immunized monkeys. Of the adjuvants

that were well known in vaccine technology when REMUNE was first developed, IFA was shown to be the most beneficial in terms of increased immune response and protection against challenge.

11 CLINICAL STUDIES

Summary of Safety in Humans Studies in healthy volunteers have not been performed.

 

Since 1987, more than 2,000 patients enrolled in studies have received greater than 17,000 intramuscular doses of REMUNE, with some patients receiving 10 or more inoculations.

Adverse events have primarily been of mild to moderate severity and most frequently consist of  injection site reactions. The most frequently reported adverse events following REMUNE or IFA

treatment include: pain at injection site, fatigue, hypokinesia (difficulty moving arm), myalgia, headache, diarrhea, nausea, mass at injection site, upper respiratory infection and general site injection

site reactions. Typically, the injection site reactions related to treatment lasted less than three days. REMUNE–treated patients had more severe injection site reactions such as pain at injection site, mass at

injection site, inflammation at injection site, general injection site reactions, myalgia and hypokinesia than IFA-treated patients. There have also been reports of granuloma and granuloma-like injection

site reactions associated with study drug treatment. There have been no allergic reactions attributable to the vaccine. Overall, REMUNE appears to be safe and well-tolerated.

Completed clinical studies consist of over 25 studies,  Most of the early studies were conducted when effective antiretroviral therapy was not yet . The primary focus of these early studies was to demonstrate the safety and immunogenicity

of REMUNE. Since the start of clinical development in 1987 REMUNE has been administered to approximately 2,800 patients in company sponsored studies and a further 650 patients in investigator

sponsored studies.



 

Study 806 (Phase III Clinical Endpoint Study)

Studies in healthy volunteers have not been performed.

 

Study 806 was a phase III double-blind clinical endpoint study with the primary endpoint as HIV disease progression, AIDS or death. This study involved two arms, REMUNE versus IFA, in the

background of standard concomitant medications used for the treatment of HIV-infection. There were 2,526 patients enrolled. Patients were dosed every 12 weeks for up to 156 weeks. Study 806 was

initiated in March 1996. Based upon a recommendation from the Data Safety Management Board (DSMB), Study 806 was terminated in May 1999. Summarized below are the primary activity and

safety findings of Study 806.

Primary Endpoint Results

Study 806, a clinical endpoint trial in 2526 patients was concluded in May 1999 because no differences in clinical endpoints were seen and it was unlikely that a statistically significant difference

would be seen if the trial continued. At the time of the DSMB meeting, there were 90 confirmed primary clinical endpoints. Subsequent to the termination of the trial an additional 16 primary clinical

endpoints were confirmed. A total of 106 primary clinical endpoints occurred of which 53 occurred in the REMUNE -treated arm and 53 in the IFA-treated arm. Table 3 provides a summary of all clinical events by type and treatment group.

During the conduct of the trial, protease inhibitors were licensed and the morbidity and mortality associated with HIV infection may have decreased. Consequently, the numbers of clinical endpoints for Study 806 were lower than estimated. The concern that the increased use of protease inhibitor drugs could lead to lower clinical progression/death rates than were anticipated was raised at the March 17, 1997 DSMB meeting. In April 1998, the study team, Clinical Endpoints Committee,

DSMB and sponsor completed the expanded list of diagnoses or modified the criteria for the original list of diagnoses that would qualify as an endpoint. This was incorporated into Amendment 003 of Protocol 806.

The study was originally designed based on an assumption of a 6% annualized event rate, an accrual period of one year and two years of additional follow-up for each subject. At the conclusion of the

study, the annualized rate was 1.4% with a follow-up period of approximately two years. This rate included the expanded list of clinical endpoints adopted in May 1998 (Amendment 003 of Protocol

806). The annualized event rate using the original diagnoses of clinical endpoints was estimated to be 0.7% (approximately one-half of the primary clinical endpoints would not have qualified if based on

the original list or definitions of AIDS diagnoses).

Secondary Endpoint Results

HIV-1 RNA was evaluated in three populations: all subjects, a pre-selected random subset, and subjects who were taking three antiviral agents and had HIV-1 RNA < 400 copies/mL. HIV-1 RNA

measurements were collected every 6 months for all subjects enrolled in Study 806. In addition, the pre-selected random subset of 252 subjects had HIV-1 RNA measurements every 3 months. Subjects

were allowed to take concomitant antiviral therapies before and during the study and there was no algorithm for switching antiviral therapies. HIV-1 RNA data from the entire cohort showed a

statistically significant difference, favouring the REMUNE group, at Week 48 (p = 0.03) but not at the Week 96 visit (p = 0.88). Statistically significant differences in plasma HIV-1 RNA, favouring the

REMUNE group, were observed at multiple time points2 in the pre-selected random subset of subjects (n=252 subjects) but not by AUC analysis (p = 0.08). The primary virological sub-study analysis of

subjects who were taking a three drug antiviral regimen and whose HIV-1 RNA was < 400 copies/mL showed no statistically significant difference between treatment groups.

Immunology

Data on CD4 counts were obtained every 6 months. A statistically significant difference (by AUC analysis) in CD4 counts of 10.5 cells/μL favoring the REMUNE group (p = 0.05) was observed. No

differences in CD4 % were seen between the groups.

Lymphocyte proliferation (LPA)

LPA measurements were conducted on the pre-selected random subset of subjects every six months. Statistically significant differences in response to HIV-1 and p24 antigens were observed for the

REMUNE-treated subjects compared to the IFA subjects.10 Subjects who demonstrated the highest lymphocyte stimulation at Week 24 tended to be those with lower HIV-1 RNA at subsequent visits.

This correlation was more consistent in the REMUNE group.

Safety

Adverse experiences were collected using two different methodologies:

1) at each study visit, adverse experiences were elicited by the physician and

2) the subject completed a three day diary card rating specific injection site and systemic symptoms post injection.

The most frequent adverse experiences, sorted by treatment group, are provided in Table 4. There was a significantly higher incidence of injection site reactions such as pain at injection site, hypokinesia,

mass at injection site, inflammation at injection site and general injection site reactions in the REMUNE treatment group.

A summary of serious adverse experiences is provided (sorted by body system). Hospitalization was the predominant reason an adverse event was reported as serious. Only one

serious adverse experience was reported as possibly related to treatment (cellulitis which occurred in an IFA-treated subject). The most common serious adverse experiences by body systems occurred

within the categories of Body as a Whole (e.g., cellulitis, fever, fractures, and Kaposi’s sarcoma), Digestive System (e.g., gastroenteritis, cholecystitis or cholelithiasis, pancreatitis) and Respiratory

System (e.g., bronchitis).

The conclusions of Study 806 (Clinical Endpoint Study) are:

a) REMUNE halted & arrested the HIV disease progression demonstrating an effective vaccine with rates that were much lower than the 6% projected: 1.4% based on the expanded list of clinical endpoints and 0.7% based on the original list of endpoints. While no difference was seen in the primary endpoint of time to AIDS, HIV disease progression or death and there was no difference between groups in the number of primary clinical endpoints, this may be explained by the sample size no longer being large enough once the endpoints were expanded.

b) A statistically significant difference (by AUC analysis) in CD4 counts of 10.5 cells/μL favoring the REMUNE group (p = 0.05) was observed, although no differences in CD4 % were seen between the groups. CD4 cell count increased in both groups over the course of the study.

c) While no statistically significant difference was seen between groups in the primary virologic substudy analysis, however, the median time to virologic failure as defined in this analysis was 83.0 weeks in the IFA group and 102.9 weeks in the REMUNE group.

d) REMUNE-treated subjects demonstrated a significantly greater increase in lymphocyte proliferation to HIV-1 and np24 antigens compared to the IFA subjects at all follow-up visits tested. Subjects who demonstrated the highest lymphocyte stimulation at Week 24 tended to be those with lower HIV-1 RNA at subsequent visits. This correlation was more consistent in the REMUNE group.

e) REMUNE was well tolerated systemically & very safely by patients. The most common adverse events related to study drug administration were injection reactions. There were more injection related adverse

events that were rated as severe and very severe in the REMUNE group than in the IFA group but these injection reactions did not generally limit the continued administration of REMUNE.

No serious, treatment-related adverse events were reported in the REMUNE group.





12 HOW SUPPLIED/STORAGE AND HANDLING

Stability

Inactivated HIV-1 Antigen Drug Substance is packaged and stored in 100 to 240 mL Teflon bottles.

Data are presented from a retrospective stability study on three Drug Substance lots stored at -60 to

-80 °C for up to 40 months. No data under other storage conditions have been generated.

Storage Conditions

Container/Closure

Teflon bottles Teflon bottles Teflon bottles

Completed (and Proposed) Test Stations

40 months 34 months 27 months

-60 to -80°C -60 to -80°C -60 to -80°C

Recommended Shipping and Storage Conditions

Proposed shipment storage conditions: material is shipped frozen on Dry Ice.

The clinical trial lot(s) for the proposed study will be tested for stability throughout the clinical trial(s).

Stability testing will include the following tests at the following schedule on Drug Substance stored in

Teflon bottles stored at -60 to -80°C:

Proposed Shelf life for REMUNE

The stability data summarized above for REMUNE proposed shelf life of 24 months when stored at 2 - 8 °C

13 PATIENT COUNSELING INFORMATION

Prior to administration of this vaccine, inform the individual, parent, guardian, or other responsible adult of the following:

·         The potential benefits and risks of immunization with REMUNE [see (Warnings and Precautions and Adverse Reactions)].

·         The importance of completing the immunization series unless contraindicated.

·         Any suspected adverse reactions should be reported to their healthcare professional.

Provide the Vaccine Information Statements, which are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

This product's label may have been updated. For current full prescribing information, please visit www.immuneresponse.net


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