Therapy Analysis - Human papillomavirus
Today's treatments
Perhaps unsurprisingly, immunisation against high-risk strains of HPV has been the most successful therapeutic approach. Gardasil is a recombinant prophylactic vaccine, developed by CSL in collaboration with Merck & Co and the University of Queensland, Australia. It is a tetravalent vaccine, active against HPV strains 6, 11, 16 and 18. It is composed of genetically engineered virus-like particles containing HPV membrane proteins, but without viral genetic material. In a randomized, double-blind, placebo-controlled Phase III trial (FUTURE I) to evaluate the effect of Gardasil on CIN 1-3, vulvar and vaginal lesions, precancers and genital warts caused by HPV-6, 11, 18 or 18, the vaccine gave 100% protection from CIN 1-3, VIN 1-3, VaIn 1-3 and genital warts at 3-year follow-up. In a further Phase III trial (FUTURE II) in 12157 women, doses of the vaccine given at day 1, day 2 and 6 months gave 100% prevention of high-grade cervical precancers and cancers associated with HPV-16 and 18. It was well tolerated. First launched in 2006, it is widely launched as Gardasil and Silgard for the prevention of cervical, vulvar and vaginal cancer, genital warts and precancerous lesions. It is licensed to Merck & Co for all territories excluding Australia and New Zealand, where CSL retains rights.
Another forerunner in the HPV vaccine market is fellow Big Pharma giant GlaxoSmithKline, with its L1 virus-like particle (VLP) vaccine. Originally developed by MedImmune, the vaccine is a combination of MEDI-503 and MEDI-504, both produced in insect cells and directed against HPV-16 and -18, respectively, plus the MPL-containing adjuvant AS04. In a 4-year randomized, double-blind, parallel group Phase III trial (PATRICIA) in 18644 women aged 15-25 years, the vaccine gave 92.9% protection against HPV-16/18-associated precancers. It provided 93 and 80% protection against CIN2+ and CIN3+ lesions, respectively. Follow-up analysis showed antibody levels to be maintained for 7 years. It is launched in over 30 countries as Cervarix for the prevention of cervical cancer and precancerous lesions associated with HPV-16 and -18 in females aged 10-45 years, and approved in a further 99 countries, including the EU, Brazil, Mexico and Singapore. With CSL's Gardasil the only other marketed vaccine against HPV-16 and-18, Cervarix holds a significant share of the vaccine market for prevention of HPV.
In a move from prevention to treatment, a clinical candidate showing early promise is VGX Pharmaceuticals' VGX-3100, a DNA plasmid therapeutic vaccine which includes plasmids targeting the E6 and E7 proteins from HPV-16 and -18. It is currently in a non-randomized, open-label, dose-escalation Phase I trial in 18 females with CIN who have undergone surgery or ablative therapy to assess the safety and tolerability of intramuscular VGX-3100 at a dose of 0.6-6mg DNA per dose. Secondary endpoints include humoural and cellular immune responses. Interim results showed VGX-3100 to be safe and well tolerated, with significant immune responses observed. The vaccine is expected to enter a Phase II trial in 2010, and could offer a valuable therapeutic option for patients with CIN associated with HPV infection.
In a novel approach towards the treatment of HPV infection, PhotoCure is developing Cevira, a photodynamic therapy for the treatment of precancerous and cancerous cervical lesions. Cevira is in a proof-of-concept Phase I/II trial in 70 patients with low-grade CIN1 in Europe and the US to assess efficacy. It is in a further Phase I/II trial in 92 patients in Germany and Norway. Interim results showed regression of lesions in 73 and 38% of patients with moderate and severe CIN lesions, respectively, while preserving cervical tissues. PhotoCure has received a grant from the Research Council of Norway for further development, and Cervira is currently available for licensing worldwide. Pharmaprojects' data shows a large proportion of upcoming therapies to be at the preclinical stage. The Canada-based company, Akela Pharma, is developing two preclinical candidates for HPV-associated diseases. The first is a Coval heat shock protein (HSP) fusion vaccine containing HSP-6 and -11 antigens, for the treatment of genital warts and recurrent papillomatosis. The vaccine is in preclinical development, with an IND filing planned. The second compound is a topical poly-IC-polyarginine toll-like receptor 3 antagonist, for the treatment of genital warts and actinic keratosis. Formulation and toxicology studies are planned, and the compound is available for partnering worldwide.
Another promising compound is Kancer's oral formulation of interferon-alpha, under development for HPV infection and HPV-associated cervical cancer. Preliminary studies have been conducted, with formulation studies and large animal testing planned.
