HPV-Associated Diseases

INOVIO is focused on rapidly bringing to market precisely designed DNA medicines to potentially treat and prevent diseases associated with human papillomavirus (HPV). Specifically, INOVIO’s lead candidate VGX-3100, currently in Phase 3 trials for precancerous cervical dysplasia, demonstrated it eliminated high grade dysplasia in nearly 50% of women in a Phase 2b clinical trial; in 80% of those whose high grade dysplasia was eliminated, the HPV infection was also cleared by VGX-3100. High-risk HPV is responsible for 70% of cervical cancer, 91% of anal cancer, and 69% of vulvar cancer.1,2 Also in development are programs targeting HPV-related cancers and a rare HPV-related disease: recurrent respiratory papillomatosis (RRP).

Cervical Precancerous Dysplasia Facts

Cervical dysplasia, also known as high grade squamous intraepithelial lesion (HSIL), a precancerous condition caused by HPV types 16/18.1 The estimated annual incidence of cervical dysplasia caused by HPV 16 and/or HPV 18 is approximately 195,000 persons in the United States and 233,000 persons in Europe. Cervical dysplasia can only be treated by an invasive surgical procedure.2,3

Because surgery does not clear the underlying HPV infection, there is a 10-16% chance of high-grade pre-cancer lesion recurrence after surgery as a result of persistent HPV infection and/or incomplete removal of the lesion, with the persistent HPV infection being the better predictor of recurrence.2,3

Advances on the Horizon for Cervical Precancerous Dysplasia

Currently, there is no treatment option that addresses cervical dysplasia and the underlying HPV infection. INOVIO’s product candidate VGX-3100 is designed to significantly increase T cell immune responses against the E6 and E7 antigens of HPV types 16 and 18 that are present in both precancerous and cancerous cells transformed by these HPV types. E6 and E7 are oncogenes that play an integral role in transforming HPV-infected cells into precancerous and cancerous cells. The goal of the DNA medicine is to stimulate the body’s immune system to mount a killer T cell response strong enough to cause the killing of cells producing the E6/E7 protein. The potential of a DNA medicine would be to treat precancerous dysplasias caused by these HPV types.

Vulvar Precancerous Dysplasia Facts

Vulvar dysplasia, also known as high grade squamous intraepithelial lesion (HSIL), a precancerous condition caused by HPV types 16/18. If left untreated vulvar pre-cancers can progress to invasive cancer of the vulva.4 Approximately 27,000 cases of HPV-related vulvar pre-cancers occur in the U.S. each year, with a similar number of estimated cases in Europe each year. HPV 16 and/or HPV 18 are involved in about 80% of HPV-related vulvar precancers cases in the U.S. and Europe. Once vulvar precancers develop, spontaneous regression (i.e. natural resolution of the lesion) is rare and occurs in 1.5% to 5% of cases. An estimated 6,000 new cases of vulvar cancer occur in the U.S. each year5 with about 50% to 80% of those being HPV-associated.

Overall, less than 5% of women with vulvar dysplasia exhibit spontaneous resolution. Without adequate treatment vulvar dysplasia can progress to vulvar cancer which is projected to claim approximately 1,350 lives in the U.S. in 2020 alone.5

Advances on the Horizon for Vulvar Precancerous Dysplasia

INOVIO announced in late March 2020 positive interim results from an open label, Phase 2 trial that VGX-3100 reduced qualifying high-risk HPV 16/18-associated precancerous vulvar lesion area in 80% of patients (by 60% on average) and completely cured vulvar dysplasia with no virus detectable in 20% of patients.

Anal Precancerous Dysplasia Facts

Anal dysplasia, also known as high grade squamous intraepithelial lesion (HSIL), is a precancerous condition in the squamous cells lining the anus caused by HPV types 16/18. Anal dysplasia is an orphan disease that affects men and women in both immunocompetent and immunocompromised populations.6 Fewer than 1 in 5 people with HPV 16/18-associated precancerous dysplasia exhibit spontaneous resolution at one year. Without adequate treatment anal dysplasia could progress to anal cancer.6 HPV 16/18 cause more than 91% of all anal cancer,7 which is now considered one the most rapidly rising causes of cancer incidence and mortality.8 According to the American Cancer Society, anal cancer will claim the lives of more than 1,300 people in the U.S. and 8,590 news cases (5,900 in women and 2,690 in men) will be diagnosed in 20205 and according to a study published November 2019 in the Journal of the National Cancer Institute, from 2001 to 2015 the overall incidence of anal cancer increased by 2.7% per year and mortality jumped by 3.1% each year.8

Currently, the treatments for anal dysplasia are surgical excision, electro-cautery or laser therapy. Up to 50% of those treated with these invasive options experience disease recurrence within one year of treatment and nearly 70% experience recurrence within three years. Therefore, many patients with this condition need multiple invasive treatments.

Advances on the Horizon for Anal Precancerous Dysplasia

INOVIO announced in late March 2020 positive interim results from an open-label, Phase 2 study showing its lead DNA medicine candidate VGX-3100 to be safe and effective in treating men and women with anal dysplasia caused by high-risk HPV types 16/18.

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  1. NIH – MedlinePlus. Cervical dysplasia. Available at: medlineplus.gov. Accessed April 2, 2020.

  2. Xi LF, Kiviat NB, Wheeler CM, et al. Risk of cervical intraepithelial neoplasia grade 2 or 3 after loop electrosurgical excision procedure associated with human papillomavirus type 16 variants. J Infect Dis. 2007;195(9):1340-1344.

  3. Nobbenhuis MA, Meijer CJ, van den Brule AJ, et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer. 2001;84(6):796-801.

  4. NIH – MedlinePlus. Vulvar cancer. Available at: medlineplus.gov. Accessed April 2, 2020.

  5. American Cancer Society. 2020 Estimates. Available at: cancerstatisticscenter.cancer.org. Accessed April 2, 2020.

  6. Anal Cancer Foundation. Living with Anal Cancer / Anal Precancer. Available at: analcancerfoundation.org. Accessed April 2, 2020.

  7. Saraiya M, Unger ER, Thompson TD, Lynch CF, Hernandez BY, Lyu CW, Steinau M, Watson M, Wilkinson EJ, Hopenhayn C, Copeland G, Cozen W, Peters ES, Huang Y, Saber MS, Altekruse S, Goodman MT. HPV Typing of Cancers Workgroup. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst. 2015 Apr 29;107(6):djv086.

  8. Deshmukh AA, Suk R, Shiels MS, Sonawane K, Nyitray AG, Liu Y, Gaisa MM, Palefsky JM, Sigel K. Recent trends in squamous cell carcinoma of the anus incidence and mortality in the United States, 2001-2015. J Natl Cancer Inst. 2019 Nov 19. pii: djz219. doi: 10.1093/jnci/djz219.

Recurrent Respiratory Papillomatosis Facts

Recurrent respiratory papillomatosis (RRP) is a rare and potentially fatal disease in children, adolescents, and adults in which tumors called papilloma’s grow in the respiratory tract, requiring multiple, life-long surgeries. This disease is caused by the human papillomavirus (HPV) and while the tumors are typically benign, in very rare cases they can become cancerous.1,2

RRP is characterized by recurrent and often fast-growing tumors (papillomas) along the respiratory tract, most commonly in the larynx (voice box) and vocal cords. These tumors vary in size and over time may cause severe and potentially life-threatening airway obstructions.1,2

RRP is caused by HPV infection. There are more than 150 different genotypes of HPV, yet two specific genotypes – HPV 6 and HPV 11 – account for more than 90% of RRP cases.2 Although HPV is common, affecting nearly 80 million Americans,3 exposure to the disease does not necessarily mean that a person will develop RRP or other HPV-related diseases.There are approximately 15,000 active cases of RRP in the U.S., and approximately 3,000 new cases per year.

There is currently no cure for RRP and it is typically treated by frequent surgeries to remove the tumors, temporarily restoring the airway before renewed tumor growth. In the most extreme cases, a tracheostomy (surgical insertion of a tube into the windpipe) may be necessary.

Advancements on the Horizon for RRP

There is an urgent need for an effective and tolerable non-invasive RRP treatment that eliminates the need for recurrent invasive surgeries. A Phase 1/2 clinical trial will evaluate INOVIO’s DNA medicine INO-3107, a potential non-surgical RRP treatment targeting both HPV 6 and HPV 11 antigens.

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  1. NIH – National Institute on Deafness and Other Communication Disorders (NIDCD). Recurrent Respiratory Papillomatosis or Laryngeal Papillomatosis. Available at: nidcd.nih.gov. Accessed February 10, 2020.

  2. National Organization for Rare Disorders (NORD). Rare Disease Database – Recurrent Respiratory Papillomatosis. Available at: rarediseases.org. Accessed February 10, 2020.

  3. Centers for Disease Control and Prevention. Human Papillomavirus (HPV) – About HPV. Available at: cdc.gov. Accessed February 10, 2020.

HPV-Associated Cancer Facts

HPV-associated cancers include head and neck cancer including malignancies of the sinuses, nose, mouth, throat, pharynx, larynx, and saliva glands. The incidence of HPV-caused oropharyngeal squamous cell cancer (OPSCC) has increased significantly within the last 30 years in the U.S., including a 225% increase from 1988 to 2004, an average annual increase of 14%. Scientists have estimated that by 2030, OPSCC will constitute the majority of all head and neck cancers. About 70% of cancers of the oropharynx are now caused by HPV, with HPV-16 being the most prevalent genotype and causing about 86% of those HPV-caused cancers.1

Advancements on the Horizon for HPV-Associated Cancers

In June 2014, INOVIO initiated a Phase 1 clinical trial assessing the immunogenicity and safety of our product candidate MEDI0457 (consisting of a combination of VGX-3100 and our product candidate INO-9012) in head and neck cancer patients. INO-9012, a DNA-based IL-12 immune activator, was added to VGX-3100 for this cancer study because our prior HIV vaccine clinical study had indicated that the addition of IL-12 to our DNA medicine could enhance the activation of CD8+ T cells.

Increasing evidence suggests that response rates from checkpoint inhibitors can be enhanced when used in combination with cancer vaccines like MEDI0457 that generate tumor-specific T cells. Interim data from a MEDI0457 monotherapy study of head and neck cancer patients demonstrated that MEDI0457 generated robust HPV 16/18 specific CD8+ T cell responses in peripheral blood and increased CD8+ T cell infiltration in resected tumor tissue samples.

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  1. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32):4294–4301. doi:10.1200/JCO.2011.36.4596