TG4001/RG3484, partnered with Roche, is being developed to treat cervical diseases caused by the human papilloma virus.
TG4001/RG3484 product candidate is based on the MVA virus carrying and expressing mutation-inactivated human papilloma virus 16 (HPV16) E6 and E7 oncoproteins and human interleukin-2.
The pathogenesis of cervical intraepithelial neoplasia (CIN) follows a natural history characterized by HPV infection proceeding to CIN (in a fraction of patients) following a long latent period. If high-grade CIN (CIN2/3) lesions are not diagnosed and surgically excised, they can progress to invasive cervical cancer (ICC) in more than 10 per cent of cases. It is, therefore, considered to be a true pre-cancerous lesion. It is estimated that the number of newly diagnosed patients, in Europe and the United States, with CIN2 or CIN3 lesions to be around 900 000 women per year.
International guidelines recommend excisional procedures for the management of biopsy-confirmed CIN2/3 lesion. These surgical procedures are associated with obstetrical complications such as preterm delivery, low birth-weight, caesarean section, and premature rupture of membranes. Moreover, recurrence after excision may occur, rendering necessary alternative approaches.
Targeted immunotherapeutics are currently developed as alternatives to cervical loop excision in patients diagnosed with a CIN2/3 lesion, a population not eligible to prophylactic vaccines. Prophylactic vaccination is ineffective in patients already infected with HPV types 16, 18 or carrying CIN.
In phase II clinical trials, TG4001/RG3484 demonstrated safety and promising clinical response and efficacy in women with CIN2/3 lesion caused by HPV16. The results (press release, April 25, 2006) of a phase IIa trial conducted in France on 21 women patients with HPV16 CIN2/3 showed promise as 10 patients no longer had detectable levels of CIN2/3 lesion six months after vaccination. Furthermore, no serious side effects were observed. The sustainability of the response was assessed by an examination at month 12 of the patients who did not undergo surgical excision of CIN lesion at month six. No CIN2/3 relapse nor any HPV16 persistence or re-infection was observed in these women.
Phase IIa data on TG4001/RG3484 constituted the first proof-of concept of HPV16 targeted immunotherapy in CIN2/3 patients whilst also recording a good safety profile. In late 2009 Roche began a placebo controlled phase IIb trial on patients with HPV related CIN2/3 lesions. The trial is being conducted in clinical centers in Europe and the United States, and aims to recruit some 200 patients. The first patient was recruited in September 2009.
Corporate Partnership with ROCHE
Roche and Transgene announced on April 11, 2007 that they had entered into an exclusive worldwide collaboration agreement to develop and commercialize products from Transgene’s targeted immunotherapy program against human papilloma virus-mediated diseases. The agreement covers one of Transgene’s lead products, TG4001/RG3484 (MVA-HPV-IL2). Under the agreement, Roche will lead worldwide development and commercialization. Roche will fund all future costs associated with the development of TG4001/RG3484 and will lead the phase IIb and phase III studies.
Roche holds all manufacturing rights but has agreed to allocate, on commercial terms, exclusive responsibility to Transgene for the clinical-trial supply of TG4001/RG3484 and additional HPV products, which may be developed in the future. The agreement will be extended to include the commercial manufacture of clinical batches.
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