Background

Human papillomavirus (HPV) is the most common sexually transmitted disease. At least 75 percent of sexually active people contract it at some point in their lives. At least 20 million people in the U.S. and 630,000,000 world wide are already infected with sexually transmitted HPV infections (*). Although HPV can remain latent or regress spontaneously in some people, it can also manifest itself physically as warts, dysplasias (the precursor to cancer) and cancers. More than 35 of the over 100 different types of HPV can be sexually transmitted and infect the genital area. Some types also infect head, neck and anal epithelial cells. Relatively benign types of HPV cause plantar and common warts.  

Warts, dysplasias (+) and cancers result from excessive cell growth. In HPV infections, uncontrolled cell growth can be caused by proteins expressed by HPV, such as E7, which interfere with normal cell functions that usually limit cell growth. HPV infects epithelial cells, which do not present antigens efficiently for detection by the immune system. The immune system does not always recognize or eradicate HPV-infected cells, which allows for warts, dysplasias and cancers to develop.

Serious HPV-related diseases include:

• Cervical Intraepithelial Neoplasia (CIN)
• Recurrent Respiratory Papillomatosis (RRP)
• Genital Warts
• Other

Cervical Intraepithelial Neoplasia (CIN)

CIN, also known as cervical dysplasia, is characterized by the presence in the cervix of abnormal cells that can precede and develop into cervical cancer. The primary cause of such abnormalities is infection with HPV types 16, 18, 31, 33 and 35. Experts recommend screening all sexually active women for HPV.

In the U.S., Pap screens are used to help detect HPV, and are estimated to cost up to US$6 billion per year. An estimated 1.2 million women each year are diagnosed with low grade cervical dysplasia in the U.S. Another estimated 200,000 to 300,000 women are diagnosed with high grade cervical dysplasia in the U.S. each year. There are no FDA-approved drug therapies for CIN.

Typically, high grade CIN is treated with a type of surgery called LEEP (Loop Electrosurgical Excision Procedure), estimated to cost from $400 to $1,450 per treatment in the US. The incidence of residual disease after LEEP varies from 20 percent to 30  percent. Potential complications include bleeding and the excessive removal of healthy tissue. LEEP is not recommended for lesions that are too deep to view with medical instruments. In those cases, widely used treatments include surgery, the cost of which varies depending upon the site of the lesion, or cold-knife cone biopsy, estimated to cost $3,700 per treatment in the US. These treatments are not always effective in removing all abnormal cells. The recurrence rates of CIN have been estimated at 19 percent of patients treated with cryotherapy and 13 percent of patients treated with laser surgery or LEEP. Market research indicates that physicians are eagerly looking for an alternative to LEEP, which does not treat the underlying HPV infection.

Recently, there has been much media attention paid to HPV as a result of the approval of the first preventative vaccine for the types of HPV that cause CIN. What this attention highlights, for those carefully watching the field, is that roughly 630 million people worldwide are already infected with HPV and many are in need of treatment rather than prevention.  None of the new vaccines treats this infected population, nor do any address the various HPV-related diseases that result.

Recurrent Respiratory Papillomatosis

RRP is usually caused by HPV types 6 and 11, types that also cause the better known condition of genital warts (see below). Rather than infecting genital tissue, the papillomas in RRP occur in the epithelial tissue located in the larynx and airways. Because of their location and size, these papillomas can interfere with breathing in pediatric patients and can occasionally be fatal. Death can occur from airway obstruction, cancerous transformation, the overwhelming spread of the disease or complications from surgical treatments. There are two groups of RRP patients. Juvenile-onset RRP can occur in children born to mothers infected with HPV. Adult-onset RRP may arise from birth or oral sexual activity.

Over 2,300 new cases of pediatric RRP and over 3,600 new cases of adult RRP were diagnosed in a 12-month period according to the most recent reported survey of U.S. otolaryngologists and bronchoesophagologists. The survey estimated that there were over 5,970 cases of active pediatric RRP for which surgery was required in the previous three years, and over 9,000 cases of active adult RRP in the U.S. Approximately 75 percent of diagnosed juvenile-onset cases become evident before the age of five.

No drugs are currently approved for the treatment of RRP in the U.S. Instead, patients are typically treated with surgery under general anesthesia using a microdebrider or a laser. Surgery is not a cure and recurrence is frequent. The average pediatric patient has approximately five surgeries per year, with some patients undergoing more than 20 procedures annually. Each surgery can cost thousands of dollars and result in complications, including the formation of scar tissue, decreased functioning of the larynx, hoarseness and reduced quality of life.

Genital Warts

Genital warts are soft, fleshy raised growths that can appear in internal and external genital areas. As in RRP, they are usually caused by HPV types 6 and 11. The incidence of genital warts is estimated at one million new cases in the U.S. each year. Despite a common misperception, genital warts can be spread even when condoms are used. Although warts are generally benign, they can cause psychological distress by making patients feel ashamed and less attractive thereby reducing quality of life.

There is no approved cure for genital warts; however, a variety of therapies are available. The choice of treatment depends on the extent and location of disease and the preferences of the physician and patient. External genital warts can be treated with topical medications. Published sustained clearance rate estimates for topical treatments are 60 percent; however, the duration of follow-up in most studies is very brief. Nventa believes that the rate of long term clearance is much lower with relatively high rates of recurrences.  When topical medications are not appropriate or effective, ablative therapies are typically used. These therapies, which require office visits, include the application of trichloroacetic acid, cryotherapy (freezing with liquid nitrogen), laser surgery, electrosurgery (burning) and, particularly for internal warts, surgical excision. Recurrence is common even after treatment.

HPV Infection in Immunocompromised Patients

Patients develop compromised immune systems for reasons including HIV infection, treatment with chemotherapy for cancer, and the use of immunosuppressants following an organ transplant.  HPV infection can cause a variety of clinical manifestations including genital warts, cervical dysplasia, cervical epithelial neoplasia (CIN), and invasive cervical carcinoma.  HIV-infected women have a higher risk of HPV infection that can lead to cervical abnormalities.  HPV infection is more persistent in HIV-infected women, and the viral types most commonly associated with malignant transformation (HPV 16 and 18) are more common in HIV-infected women, especially as the immunosupression progresses.
Cervical dysplasia or CIN are reported in HIV-infected women at rates of 15 percent to 40 percent.  Furthermore, there is a significant risk of short-term recurrence (40 to 60 percent) following standard therapies for pre-invasive diseases, such as cyotherapy, loop excision, laser therapy and cone biopsy.  Evidence suggests that HIV-infected women with atypical squamous cells (ASCUS) of undetermined significance on Pap smears will have a higher rate of progression to CIN.  Invasive cervical cancer in the HIV-infected women is characterized by high grade tumors, lymph nodes and other mestastatic involvement at the time of diagnosis.  The response to therapy is uniformly poor, and most women will die of their cancer as opposed to the HIV infection.  Invasive cervical carcinoma is now an AIDS-defining illness.

Head and Neck Cancer

Cancers of the oral cavity, pharynx and larynx constitute a serious and increasing public health problem worldwide. More than 55,000 Americans will develop cancer of the head and neck this year; nearly 13,000 of them will die from it.  Worldwide, there are an estimated 600,000 head and neck cancer cases reported in men and 270,000 cases reported in women annually.  In clinical studies, HPV DNA has been found in an average of 25-30 percent of head and neck tumors.   The specific percentages of cancers attributable to HPV can increase depending upon the location of the cancer. The majority of HPV-positive tumors contained the “high risk” HPV types 16 (70-90 percent) and 18 (5-34 percent, depending on location); Among head and neck sites, HPV was most often detected in tumors of the oropharynx (33-39 percent), followed by the oral cavity (22-25 percent) and larynx (22-26 percent).  These cancers are treated with surgery and with primary radiation therapy. 
Tumors of the pharyngeal wall are typically diagnosed in an advanced stage because of the silent location in which they develop.  Symptoms may include pain, bleeding, weight loss, and a neck mass. These lesions can spread.  Because most pharyngeal tumors extend past the midline, bilateral cervical metastases are common.

The Nventa Solution - HspE7

HspE7 is a novel therapeutic product candidate for the treatment of HPV-related diseases.

(+) Dysplasias refer to precancerous lesions. The dysplasias caused by HPV infection are graded into two main categories, Low Grade Squamous Intraepithelial Lesions ("LSIL") and High Grade Squamous Intraepithelial Lesions ("HSIL"), with HSIL being a later progression of the disease relative to LSIL.

(*) Sources: World Health Organization; National Institute of Health, Center for Disease Control; National Cancer Institute; National Institute of Allergy and Infectious Diseases.