Status: approved; marketed

Organizations involved:

Sanofi Pasteur Ltd. – Manuf.

Sanofi Pasteur Inc. – USA mark.

Sanofi Pasteur S.A. – R&D; Parent; Intl. mark.

Pasteur Institute – R&D; Tech.; Former

Aventis Pasteur Ltd. – Former

Aventis Pasteur Inc. – Former

Aventis Pasteur S.A. – Former

Cross ref: See the BCG Vaccine Products entry and the other BCG Live product entries.

Description: BCG Live (Intravesical) or TheraCys is a lyophilized (freeze-dried) suspension of a live attenuated Bacillus Calmette Guerin (BCG) strain of Mycobacterium bovis bac-terium. The vaccine is administered by intravesical instillation (poured into the bladder) for treatment of carcinoma-in-situ of the urinary bladder (superficial bladder tumors).

BCG Live is supplied in packages containing three vials, each containing 27 mg (dry weight) of BCG Live bacteria for suspension, equivalent to 3.4 +/-3 x 108 (0.4 to 6.4 x 108) colony forming units (CFU), with 5% w/v monosodium glu-tamate excipient, along with 3 vials of diluent (1 mL/vial), with no preservatives. The powder is reconstituted with 1 mL of supplied diluent, Phosphate Buffered Saline (PBS) - water with approximately 0.85% sodium chloride, 0.025% polysorbate 80, 0.06% w/v sodium dihydrogen phosphate, and 0.25% disodium hydrogen phosphate, with no preservatives. The vaccine is stored at 2-8˚C (refrigerated), with a shelf life of one year.

One dose consists of 3 pooled vials of reconstituted vaccine further diluted in about 50 mL of sterile saline for instillation into the urinary bladder using a urethral catheter. The dose to the patient after pooling the contents of three reconstituted vials is 81 mg (dry weight) of BCG, equivalent to 10.5 ±8.7 x 108 (1.8 to 19.2 x 108) CFU of live bacteria, TheraCys contains live, attenuated mycobacteria, and because of the potential risk for transmission, it is prepared, handled, and disposed of as a biohazard.

Nomenclature: BCG Live/Sanofi [BIO]; TheraCys [TR]; ImmuCyst [TR]; BCG Live [FDA]; Bacillus Calmette Guerin (BCG), live [SY]; Mycobacterium bovis (Bacillus of Cal-mette and Guerin strain), live [SY]; NDC 49281-880-01 [NDC]

Companies.: TheraCys is manufactured by Sanofi Pasteur Ltd., CBER/FDA est. no. 0073, formerly Aventis Pasteur Ltd. (and other company names; see the Companies Index entries) at facilities in Toronto, Canada. It is marketed in the U.S. by Sanofi Pasteur Inc., and is internationally by Sanofi Pasteur S.A. affiliates in over 40 countries.

Manufacture: manufacture of TheraCys involves culture (fermentation) of the bacterium using Sauton (potato and glycerin-based) medium, followed by separation/purification of bacterial cells from solution, lyophilization, and packaging. Production is initiated using BCG stored at below -20˚C. Primary growth is initiated with glycerinated-water-potato medi-um at 37˚C for 14 days. Surface growth is removed as a pelli-cle, transferred to containers of completely synthetic Sauton medium, and cultured for 7-8 days at 37˚C. Production flasks with Sauton medium are inoculated with pellicles from the secondary inoculum and incubated for 7-10 days. The bacilli are harvested, and excess moisture is removed. Packed BCG harvest is ground in 5% mono--sodium glutamate solution to disperse aggregated cells. This concentrate is diluted to 5% concentration with 5% monosodium gluta-mate. The bulk suspension is filled into final container vials and lyophilized.

The product is manufactured in compliance with “Additional Standards for Bacillus of Calmette and Guerin (BCG) Vaccine,” Title 21 CFR Part 620.40. Tests prior to release include: general safety, residual moisture, avirulence, sterility, intradermal tests in guinea pigs, and potential to induce delayed skin sensitivity to tuberculin.

FDA class: Biologic PLA

CBER class: Bacterial Antigens and Vaccines

Approvals: Date = 19900521; PLA (88-0621)

Date = 19991108; PLA supplement; Indication = for the prophylaxis of primary and recurrent Ta and/or T1 papillary tumors following transurethral resection (TURB)

Date = 20000224; approval revoked from Connaught Labs. Ltd. and granted (reissued) to new owner, Aventis Pasteur Ltd.

Indications: [full text of "Indications and Use” section from product insert/labeling]:

TheraCys is indicated for the treatment and prophylaxis of carcinoma in-situ of the urinary bladder of primary or recurrent stage Ta and/or T1 papillar tumors following transurethral resection (TUR). TheraCys is no recommended for state TaG1 papillary tumors, unless they are judged to be at high risk of tumor recurrence.

TheraCys is not indicated as an immunizing agent for the prevention of tuberculosis.

Status: In June 2012, an FDA inspection found mold in the Sanofi Toronto, Canada, facility where Theracys is manufactured. Manufacture was halted and was expected to come back online in late 2013.

No centralized EU approval granted; country-by-country in Europe.

Trials: Overall, in clinical trials, TheraCys treatment provided a complete response in 74% of bladder cancer patients, as determined by negative cytotoscopic exam and urine cytology, vs. 42% response in patients receiving chemotherapy with dox-o-rubicin. Among BCG- and doxorubicin-naive patients, response rates were 81% and 53%, respectively. Among fully treatment-naive (untreated) patients, response rates were 68% vs. 30%. Responding patients had a median of 48 months until treatment failure (disease progression, tumor recurrence, or death), compared with 5.9 months among doxorubicin-treated patients. No significant survival advantage was found between BCG and doxorubicin.

Market: The Sanofi Pasteur list price (Jan. 2006) is $153.20/package (vaccine plus diluent; same price in 2004) for 1-5 single dose packages and $120.20/package for 6-10 packages ($137.12 in 2004).

The 2007 Average Wholesale Price (AWP) is $183.84/vial, with a Direct Cost (Manufacturer’s discount price) of $153.20 (no change since 2004) (Red Book, 2007).

Pasteur Merieux Connaught (now Sanofi Pasteur) has reported that TheraCys “has been very successful.” This was the first product for Aventis in the cancer area (prior to merger with Sanofi).