Status: approved; controlled/government distribution

Organizations involved:

California Department of Health Services – Manuf. other; R&D; Tech.; World mark.

Massachusetts Biological Labs. – Manuf.

Cangene Corp. – Manuf. other

FFF Enterprises – USA mark.

New York Blood Center, Inc. – Tech.

Cross ref.: See also the entry below for a biodefense botulinum toxin immune globuline product, and the entries for Botulism antitoxin (#911, #912) or equine (horse)-derived botulinum toxin immune globulin. See the entry for Immune Globulin Products (#743) and Botulinum Toxin Products (#600).

Description: Botulism Immune Globulin Intravenous (Human) or BabyBIG is a lyophilized (freeze-dried) formulation of human botulism immune globulin intravenous (BIG-IV), a highly purified immunoglobulin G (IgG) preparation derived from the pooled plasma of adults immunized with pentavalent botulinum toxoid (vaccine containing inactivated botulinum toxins from Clostridium botulinum types A, B, C, D, E and F; see the Botulinum Toxoids entry, #413), with manufacturing including viral inactivation/removal by the solvent-detergent process and nanofiltration. The immune globulin is stabilized with 5% sucrose and 1% Albumin (Human), and contains no preservatives.

BabyBIG contains polyclonal IgG antibodies representative of those of the immunized donors who contributed to the plasma pool from which the product is derived. The titer of antibodies in the reconstituted product against type A botulinum toxin is at least 15 IU/mL and against type B toxin is at least 4 IU/mL. For toxin types A and B, by definition, 1 IU of botulinum antitoxin neutralizes 10,000 intraperitoneal mouse LD50 of botulinum toxin. The titers of antibody against botulinum neurotoxins C, D, and E have not been determined. These are not relevant for infant botulism, which is exclusively of types A and B in the U.S.

BabyBIG is packaged in vials, with fill volume calculated based on the IgG concentration and potency of the bulk material to achieve 100 mg ± 20 mg of product. After reconstitution with 2 mL Sterile Water for Injection USP, each BabyBIG contains milliliter) contains approximately 50 ± 10 mg immunoglobulin per mL, primarily as IgG, with trace amounts of IgA and IgM; 50 mg sucrose; 10 mg Albumin (Human); and 20 x 10-3 mEq sodium. BabyBIG is stored at 2-8 °C (refrigerated), with a dating period of 24 months from the date of manufacture, defined as the date of final sterile filtration of the formulated drug product.

Nomenclature: Botulinum immune globulin [BIO]; Botulism Immune Globulin Intravenous (Human) [FDA]; BabyBIG [TR]; botulism immune globulin intravenous [SY]; Clos-tridium botulinum toxin human immune globulin [SY]; BIG-IV [SY]

Biological.: The rationale for BIG-IV therapy in infant botulism is to neutralize toxin in the circulation and extracellular fluid prior to binding at the neuromuscular junction. Inactivation of toxin subsequently absorbed from the large intestine (site of production) is also expected. In infants exposed to botulinum toxin types A or B, BabyBIG provides the toxin-specific antibodies at levels sufficient to neutralize the expected levels of circulating neurotoxin.

Companies.: The California Department of Health Services (Berkeley, CA), CBER/FDA est. no. 1622, an agency of the State of California, received approval for BabyBIG and officially holds the manufacturing license. The license includes bulk immune globulin manufacture by the Massachusetts Public Health Biologic Labs. (CBER/FDA est. no. 0064), i.e,. bulk immune globulin is manufactured for the California Department of Health Services under contract by MBL. Further formulation is performed by Cangene Corp. (CBER/FDA est. no. 1201). Further finishing and filling into vials are performed back at MBL. FFF Enterprises distributes the product for the State of California.

Dr. Stephen S. Arnon, M.D., Chief Infant Botulism Treatment and Prevention Program, California Department of Health Services (and collaborators) deserves the most credit for development of BabyBIG, having championed and worked on the product’s development for decades.

Manufacture: The purified immunoglobulin is derived from pooled plasma obtained by plasmapheresis (see Plasma Products entry, #798) from adults immunized with pentavalent botulinum toxoid (because they work with C. botulinum) and selected for their high titers of neutralizing antibody against botulinum neurotoxins type A and B. Pooled plasma is fractionated by cold ethanol precipitation of proteins according to the Cohn-Oncley method, modified to yield a product suitable for intravenous administration; subjected to solvent-detergent viral inactivation, with purification includes hydrophobic chromatography, and nanofiltration through one 75 nm and two 35 nm filters Solvent-detergent viral inactivation typically involves incubation of the product with low concentrations of solvent and detergent, e.g., with the solvent tri-n-butyl phosphate (TNBP) and deter-gent(s), octoxynol-9 (Triton X-100) and/or polysorbate 80 (Tween 80) for at least six hours, with the solvent and detergent removed by precipitation, filtration, diafiltration, and ultrafiltration.

Several steps in the manufacturing process have been validated for their ability to reduce virus titers by inactivation and removal – Cohn/Oncley fractionation (Fraction I through Supernatant III Filtrate); nanofiltration; and solvent-detergent viral inactivation. These viral reduction steps have been validated in a series of in vitro experiments for their capacity to inactivate and/or remove HIV-1 and model viruses: bovine viral diarrhea virus (BVDV; model for hepatitis C virus); mouse encephalomyelitis virus (MEMV; model for hepatitis A virus); and pseudorabies virus (PRV), feline calicivirus (FCV), and Sindbis virus. Total mean log10 reductions range from 6.07 to >16 log10. Mean log10 reductions for Cohn/Oncley fractionation are 6.6 for Sindbis virus; >9.44, HIV-1; PRV, >10.37; BVDV, 6.25; MEMV, 4.06; and FCV (not available; N.A.). Mean reductions for nanofiltration steps are ≥6.84 Sindbis; HIV-1 (N.A.); PRV, >5.53; BVDV, ≥5.4; MEMV, N.A.; and FCV, ≥6.92. Mean reductions for solvent-detergent inactivation are Sindbis (N.A.); HIV-1, >4.51; PRV, >5.53; BVDV, >4.85; MEMV, 0.57; and FVC, N.A. Mean cumulative manufacturing reductions are Sindbis, ≥13.44; HIV-1, >13.95; PRV, >15.9; BVDV, ≥16.5; MEMV, 4.63; and FCV, ≥6.92. A mean reduction of 2.55 for parvovirus is associated with nanofiltration. Testing with bovine parvovirus (model for parvovirus B19) resulted in a mean cumulative reduction of 7.34 for Cohn-Oncley fractionation followed by solvent-detergent inactivation and hydrophobic chromatography.

The product is manufactured on a relatively small scale, with limitations including the supply of plasma from pentavalent botulinum toxoid-vaccinated persons. New lots are needed and manufactured about every 6-8 years.

FDA class: Biologics BLA

CBER class: Antitoxins, Antivenins, Enzymes and Venoms

Approvals: Date = 20031023; BLA (BL 125034/0), first approval; orphan designation (expires 10/23/2010)

Indications: [full text of the "INDICATIONS AND USAGE” of product insert/labeling]:

BabyBIG is indicated for the treatment of patients below one year of age with infant botulism caused by toxin type A or B.

Status: BabyBIG can only be obtained with permission from the California Department of Health Services (CDHS), because of the need for government authorities (including federal authorities, e.g., CDC) to track cases of botulism and due to concerns about use by those potentially developing or manufacturing botulinum toxin-based weapons. Prior to FDA approval, BabyBIG was available from the state health department as needed under an Investigational New Drug (IND) protocol.

BabyBIG is a very specialized therapeutic with no commercial market. Prior to approval, only two lots of the product had been manufactured.

[As the highest quality botulinum immune globulin available and presumably useful for biological warfare/bioterrorism defense against botulinum toxins types A-E, BabyBIG would appear to be a prime candidate for inclusion in the nation’s biodefense pharmaceutical stockpile. However, the California Dept. of Health Services indicates that this is not the case, and that the product is solely manufactured for and used by infants].

Trials: Two lots of BabyBIG were manufactured and studied in clinical trials. The State of California conducted two clinical studies: a well-controlled 5-year study that evaluated the safety and efficacy of BabyBIG in 129 infants, and an open label study in 293 infants. In the first study, BabyBIG, given within the first 3 days of hospital admission to 59 patients with laboratory-confirmed infant botulism reduced the average length of hospital stay from 5.7 weeks (placebo group) to 2.6 weeks (p <0.0001); and mean hospitalization costs per case were reduced by ~$70,000 (p < .001). Other statistically significant improvements included reduction in average time on mechanical ventilation and average time on tube feeding. Since its approval, BabyBIG had been given to 366 infants, shrinking the typical hospital stay from nearly 6 weeks to 3 and cutting hospital charges by $88,600 per patient. Dr. Arnon noted, “The treatment of just a few hundred patients has averted more than 20 years of time in the hospital and $30 million in cost since the drug was approved in Oct. 2003.” Results from this study were published in the Jan. 5, 2006, New England Journal of Medicine. The authors suggested that because botulism is now classified as a category A biological weapon, a larger supply of human antitoxin than can be derived from blood plasma is needed, e.g., from development of recombinant botulinum toxin antibodies or other products.

Traditional pharmacokinetic studies of BabyBIG have not been performed.

Disease: Of the three forms of human botulism (food poisoning, wound, and infant), infant botulism is the most recently recognized (in 1976) and is the most common form in the U.S. Infant botulism is caused by ingestion of spores of Clostridium botulinum which germinate, colonize the infant colon, and in it produce C. botulinum neurotoxin. The infant colon is more prone to an anaerobic or microaerophilic (lacking air/oxygen) environment than in older children and adults. The intestinal microflora of adult animals ordinarily prevent colonization of the gut by C. botulinum. The toxin then is absorbed, binds to peripheral cholinergic synapses, and causes flaccid paralysis. As discussed in the Botulinum Toxin Products entry, botulinum toxin is the most poisonous substance known. By extrapolation from studies with adult primates, the lethal dose in the human bloodstream is ~1 nanogram (10-6 mg)/kg body weight, and the toxicity for infants may even be higher because of the narrowness of their pharyngeal airway. Several other Clostridium species are known to less commonly also cause similar “intestinal toxemias of infancy.”

Infant botulism can range from mild, outpatient cases to sudden unexpected death indistinguishable from typical sudden infant death syndrome. Mean hospital costs in California (1984-1991) exceeded $88,000 per case (1996 dollars). Almost all cases of infant botulism in the U.S. have been caused by Group I proteolytic Clostridium botulinum type A or type B strains. Adults and older children may rarely become susceptible to infant-type botulism after broad-spectrum antibiotic treatment and intestinal surgery, inflammatory bowel disease, or procedures associated with bone marrow transplantation. The most important factor associated with risk for infant-type botulism is the intestinal flora, particularly the range of bacteria colonizing the intestines, with less diversity (e.g., in infants not yet exposed to diverse bacteria) increasing risk. Infrequent bowel movements, e.g., less than one/day in infants, is associated with increased risk.

The incidence of reported infant botulism reported by states in the U.S. from 1997-1995 varies from 2.4-11 per 100,000 live births. Diagnosis and reporting is presumed to vary greatly, with many physicians and labs not familiar with the disease and its diagnosis, and only the most severe cases tending to be fully diagnosed. The diagnosis of infant botulism is established by identification of C. botulinum organisms in the feces of an infant with clinical signs consistent with the paralyzing action of botulinum toxin. All cases of infant botulism have occurred in children less than 1 year of age, with 95% during the first 6 months of life. The illness occurs in all major racial and ethnic groups and equally in males and females. In general, the distribution of cases by toxin type parallels the distribution of toxin types in U.S. soils, with type A C. botulinum predominating west of the Rocky Mountains and type B in the rest of the country (west of the Rocky Mountains). Some assert that breast feeding increases the risk for infant botulism.

Honey is the one dietary reservoir of C. botulinum spores to date definitively linked to infant botulism. With honey not being nutritionally required, essentially all major pediatric, public health, and honey industry organizations in the U.S. recommend that honey not be fed to infants.

Medical: The recommended total dosage of BabyBIG is 1 mL/kg (50 mg/kg), given as a single intravenous infusion as soon as the clinical diagnosis of infant botulism is made. BabyBIG is administered by intravenous infusion at a recommended infusion rate of less than 1 mL/kg/hour (50 mg/kg/hr).

Botulinum immune globulin is the only therapeutic available for treatment of the cause of infant botulinum. Other treatments are supportive care and avoiding potentially-fatal complications. For example, antibiotics are generally not given, since these may cause lysis of the C. botulinum bacteria, resulting in rapid release of toxin. Recovery from infant botulism involves regeneration of the toxin-bound terminal unmyelinated nerve endings, requiring several weeks. Since botulinum toxin does not cross the blood-brain barrier, permanent neurological and cognitive damage do not occur.

Marketing: This product is not actively marketed and its distribution is tightly controlled by government authorities. The Average Wholesale Price (AWP) is not available (product not in 2007, 2005 or 2004 Red Book).

R&D: In Oct. 2003, Hematech, LLC (Sioux Falls, ND) received a $3.3. million (sub)contract from DynPort, now DVC LLC, the lead Department of Defense contractor for biodefense vaccine and related development and stockpiling, for development of human polyclonal antibodies against botulinum neurotoxins. Hematech uses its TransChromo system to produce human neutralizing antibodies in cows. The bovine TransChromo system is created by introducing the full, unrearranged sequences for both the human heavy and light chain antibody genes into cows, using a human artificial chromosome (HAC) vector, developed by Hematech’s collaborators at the Kirin Brewery Company. The HAC is inserted into bovine fetal fibroblast cells and cloned cattle are produced from the modified cells. Related research was published in the Sept. 2002 issue of Nature Biotechnology. In addition to this product likely being suitable for rapid, post-exposure treatment, it may also be administered before exposure to provide almost immediate protection against neurotoxins.

In Oct. 2004, Cangene Corp. reported that it planned to negotiate a sole-source agreement with the Centers for Disease Control and Prevention (CDC) to manufacture 200,000 doses of botulinum toxin immune globulin for the U.S. biodefense stockpile. Citing unusual and compelling urgency, the Department of Health and Human Services (DHHS) and CDC identified Cangene as the only prospective contractor possessing the needed experience, capability and capacity to fulfill its requirements. Cangene intends to develop and manufacture the product for use under an Investigational New Drug Application, and will later seek FDA approval.

In March 2005, Xoma Ltd. received a $15 million contract from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), to develop and manufacture three botulinum neurotoxin type A monoclonal antibodies for addition to the U.S. biodefense stockpile. SRI International (Menlo Park, CA) is a subcontractor and is developing potency assays to support antibody characterization.

In Sept. 2005, SRI received a $5.8 million grant from NIAID to develop human polyclonal antibodies in partnership with Therapeutic Human Polyclonals (THP).