Inovio Product Pipeline: VGX-3100: Therapeutic Vaccine for Cervical Dysplasia/Cancer
Product & Indication
VGX™-3100 is a proprietary, SynCon® therapeutic DNA vaccine candidate for the treatment of cervical intraepithelial neoplasias (CIN) caused by human papillomavirus (HPV) types 16 and 18. This vaccine includes plasmids targeting E6 and E7 proteins of HPV types 16 and 18. Intramuscular injection of the plasmid DNA vaccine is followed by electroporation using our CELLECTRA® delivering device.
Market Potential
Cervical cancer is caused by various types of human papillomavirus. Many people who have HPV may not show signs or symptoms. They can pass the virus to others without even knowing it. Approved prophylactic vaccines aimed at inducing natural immunity against HPV infection in non-infected individuals are effective at protecting against HPV infection. However, once a person has an established infection, these vaccines are ineffective for preventing development of cervical cancer. Furthermore, a large proportion of eligible young women do not receive these preventive vaccines due to socioeconomic reasons.
Cervical cancer is unique among all cancers in having an identifiable, slow-progressing precancerous stage. While 70% of HPV infections clear naturally, persistent infections may lead to benign atypical squamous cells of undetermined significance (ASCUS) and then further progress to the CIN stage.
With ASCUS and low-grade dysplasias, the initial treatment approach is typically just watch-and-wait to see if it regresses naturally or whether it is persistent. This may result in stress associated with contemplating possible progression to cancer. If a low-grade dysplasia persists or evolves into high-grade dysplasia, ablative or surgical procedures will be used to remove the precancerous lesions. These same procedures are used to remove cervical cancer. These procedures are unappealing due to their cost and morbidity (potential for disfigurement and possible negative impact on reproductive potential).
There is a great need for an effective therapeutic vaccine to treat cervical dysplasias and cancers caused by HPV.
Estimated impact of cervical cancer:
- Worldwide: 510,000 cases per year1, with 80% being in developing countries, and about 288,0002 deaths
- US: 20 million Americans are currently infected with HPV and another 6.2 million people become newly infected each year (CDC).
- About 1.4 million CIN 1 dysplasias, 35 - 50% caused by HPV types 6, 11, 16 and 18. Types 16 and 18 are responsible for about 70% of the 300,000 CIN 2/3 dysplasias3 and cases of cervical cancer.
- 11,270 new cases and 4,070 deaths from cervical cancer in the US in 2009.4
- Follow-up of abnormal Pap smears and management of cervical dysplasias cost $3.6M5 annual in the US.
- Approximately $1.7 billion spent in the United States each year to treat cervical cancers6.
Stage of Development
Phase I
Completed: dose escalation study achieved best-in-class immune responses. In that study, which treated subjects with a history of surgically treated CIN2 or 3, an assessment at month 4 indicated that 13 out of 18 vaccinated subjects (72%) developed significant T-cell responses, with positive responses ranging from under 100 to over 5000 SFU per million cells. In the third and highest dose group, 83% (5 of 6) had strong T-cell responses. In addition, 15 of 18 vaccinated subjects (83%) developed antibody responses to at least one antigen with most subjects developing responses to two or more antigens. No DNA vaccine has previously achieved this rate of response. The therapy was tolerable with no significant adverse events.
Inovio subsequently reported that VGX 3100 demonstrated nine-month durability of immune responses in 91% of evaluated patients (10 of 11), with strong and persistent memory T-cell responses.
In an extension of Phase I study, Inovio reported durability of T-cell immune responses of up to over two years (at the latest time measured) in 7 of 8 evaluated patients following a fourth vaccination of VGX-3100. In general, the durability of these T cell responses places Inovio's DNA vaccine technology on par with live virus vaccines, but without their various safety and other issues, and substantially exceeds current data from alternative non-replicating vaccine technologies. Furthermore, being able to use multiple vaccinations without safety concerns or unwanted immune responses is a notable advantage of Inovio's DNA vaccine technology.
Phase II
Purpose: Assess efficacy, immunogenicity and safety of a candidate cervical dysplasia DNA vaccine given as intramuscular injection followed by electroporation.
Study Type: Randomized, placebo-controlled, double-blind study
Study Design: Enroll and treat adult females with CIN 2/3 or CIN 3 and biopsy-proven HPV 16 or 18. Evaluate cervical tissue changes after three 6 mg doses of VGX-3100 are administered by injection in combination with Inovio’s CELLECTRA® electroporation delivery device. A total of 148 patients will be enrolled in 25 study centers in the US, Korea, South Africa, Australia, and Canada.
Primary endpoints: Assess regression of cervical lesions to CIN 1 or less and clearance of HPV 16 or 18.
The study will also assess humoral and cell mediated immune responses, tolerability and safety.
Study Start Date: March 2011
Status: Recruiting
For more information: www.clinicaltrials.gov Identifier: NCT01304524
Commercialization
Vaccine: licensed from The University of Pennsylvania.
Delivery technology: owned by Inovio.
Out-License Agreement: none.
Technical
Prophylactic vaccines already approved (Merck & GSK)
- Aimed at inducing protective immunity against HPV infection in naive individuals
- Generate serum-neutralizing antibodies
Therapeutic vaccines
- No therapeutic vaccine for HPV, cervical dysplasias, or cervical cancer approved to date
- Focused on women with CIN 2/3 and 3
- Aimed at eradicating cervical precancerous and/or cancer cells and replace surgical procedures for CIN
- Induction of strong cell-mediated response
- E6 and E7 proteins are expressed in most HPV-related precancerous and cancerous tumors
- Therapeutic vaccine directed at HPV types 16 and 18 could potentially treat about 70% of high-grade cervical dysplasias and cervical cancers
- Such a vaccine might also address other anogenital and head and neck cancers caused by HPV types 16 and 18 in both females and males
- Plasmid constructs for other HPV types can also be developed.
Therapeutic Cervical Cancer DNA Vaccine (VGX™-3100)
Prophylactic Tumor Challenge in Mice
1 Infectious Diseases of the Female Genital Tract, Fifth Edition. Richard L. Sweet, Ronald S. Gibbs. 2009
2 Infectious Diseases of the Female Genital Tract, Fifth Edition. Richard L. Sweet, Ronald S. Gibbs. 2009
3 Infectious Diseases of the Female Genital Tract, Fifth Edition. Richard L. Sweet, Ronald S. Gibbs. 2009
4 http://www.cancer.gov/cancertopics/types/cervical
5 Infectious Diseases of the Female Genital Tract, Fifth Edition, Richard L. Sweet, Ronald S. Gibbs. 2009
6 "Cancer Trends Progress Report" (http://progressreport.cancer.gov), in 2004 dollars, based on methods described in Medical Care 2002 Aug; 40 (8 Suppl): IV-104-17. Last updated September 2008.