Topical Interferon Alpha-2b

- Product Description
- Pharmacological Mechanism
- Medical / Market Need
- Low-Grade Cervical Lesions and Cervical Cancer
- Ano-Genital Warts

- Competitive Positioning
- Licensing
- Phase II Program
- Low-Grade Cervical Lesions
- Ano-Genital Warts Clinical Trial

Product Description

Our most advanced product in development is our Topical Interferon Alpha-2b. We are developing this product subject to a license option agreement with US-based Schering Corporation, a subsidiary of Merck & Co. Inc., as a treatment for for the treatment of certain skin/mucosal lesions caused by HPV infections.

Topical Interferon Alpha-2b incorporates Helix’s patented Biphasix™ drug delivery technology. It is a topical preparation that is intended to be easily self-applied to HPV-infected tissues, in order to deliver interferon alpha-2b into the skin and mucosal tissues.

Interferon-alpha therapy is often prescribed to patients by way of injection to augment their innate defense system capabilities by complementing the effect of interferon alpha-2b naturally produced by the body. Injectable preparations of the interferon alpha-2b drug compound have been on the market in North America and Europe since the mid 1980s, demonstrating a history of proven effectiveness against viral infection, including HPV.

Helix’s Topical Interferon Alpha-2b is intended to offer a superior means of delivering interferon-alpha therapeutically into diseased skin or mucosal tissues by leveraging the capabilities of the Biphasix™ drug delivery technology and eliminating the need to inject interferon-alpha by syringe.

Pharmacological Mechanism

Interferon alpha-2b is believed to function in an immunomodulatory fashion to promote an innate immune system response to viral pathogens by acting upon external cellular receptors and stimulating a host of intracellular and extracellular activities. Within the infected cell, interferon alpha-2b action is thought to stimulate the induction of enzymes such as 2'5' oligoadenylate synthetase and protein kinase R (PKR), which function to cause degradation of viral RNA and inhibit protein synthesis to antagonize viral propagation. Extracellularly, interferon alpha-2b is thought to also enhance the expression of human leukocyte antigens (HLAs) and other HPV-specific antigens on the cell surface, thereby promoting recognition of the infected cells by cytotoxic T cells, natural killer cells and other cells of the innate immune response.

Helix’s Topical Interferon Alpha-2b is intended to facilitate the transport of interferon alpha-2b across the surface of the skin/mucosa in order to permit access to the cells of the underlying basal epidermal layers where viral infection predominates. The exact mechanism by which Helix’s Biphasix™ technology accomplishes this is not fully characterized. However, it is theorized that the cream matrix, upon application to the skin/mucosal surface, temporarily improves the emolliency and fluidity of the skin, which is thought to permit free drug diffusion to the underlying viable epidermis. The viable epidermis is the location wherein HPV infection is known to induce hyperplasia of the intermediate viable epithelial layers. Improved fluidity of the stratum corneum in response to Topical Interferon Alpha-2b application is thought to be achieved by virtue of the constituency of the cream, which includes a combination of common emollients and surfactants, in addition to agents necessary to preserve the integrity of the cream and its drug payload.

Medical / Market Need

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Human Papilloma Virus (HPV) infections have reached epidemic proportions in the world. According to the American Social Health Association, the virus is the most common sexually transmitted disease known today, primarily affecting sexually active youth between the ages of 15 and 25, and it continues to spread at a rate of over 6 million new cases per year in the US alone.

HPV infection is known to cause hyperplasia of the intermediate viable epithelial layers of the skin. Unless resolved by the effects of the natural host immune system or otherwise by medical intervention, this rapid and unmediated cellular proliferation may proceed to cause any one of a range of cancerous conditions of the ano-genital tissues. Among these disease states, we are developing Topical Interferon Alpha-2b as a treatment for low-grade cervical lesions, which are a potentially pre-cancerous condition of the female cervix and considering it as a treatment for ano-genital warts, a generally benign lesion-bearing condition of the external ano-genital tissues.

Low-Grade Cervical Lesions and Cervical Cancer

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Potentially precancerous, low-grade cervical lesions detectable upon colposcopic directed biopsy are often referred to as cervical intraepithelial neoplasia grade 1 or 2 (CIN 1 or CIN 2) . There are approximately 1.3 million women diagnosed with CIN 1 or CIN 2 lesions each year in the U.S. alone, according to data from 2006 Consensus Guidelines in the American Journal of Obstetrics and Gynecology 2007; 340-345 and Kaiser Permanente Northwest Health Plan in the American Journal of Obstetrics and Gynecology (2004) 191, 105-13. Currently there are no pharmaceutical (non-surgical) treatments for women with CIN 1 or CIN 2 lesions. Available invasive/surgical techniques to treat CIN 1 or CIN 2 lesions are sometimes associated with serious unwanted side effects for patients including cervical complications with pregnancy and conception. For patients with CIN 1 or CIN 2 lesions, clinical management usually consists of protracted watchful waiting with frequent Pap smears, HPV testing, colposcopy and/or colposcopic directed biopsies, with invasive/surgical techniques to prevent the development of cervical cancer generally utilized only in the case of long-term persistence and/or progression after a period of many months. A diagnosis of CIN 1 or CIN 2 leads to frequent physician visits, procedures, and psychosocial stress for the patient. The goal of developing Topical Interferon Alpha-2b is to provide a safe and effective treatment for CIN 1 or CIN 2 at the time of diagnosis, as a proactive alternative to today’s often protracted observational management approach.

Ano-Genital Warts

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Another disease state induced by ano-genital HPV infection is a condition referred to as condylomata accuminata, or ano-genital warts. Ano-genital warts result from HPV infection of the external genitalia, and can manifest as outwardly visible growths of varying sizes and shapes in both men and women. Helix is considering Topical Interferon Alpha-2b for liberal application to the genitalia of patients with ano-genital warts as a means of delivering potent Interferon-alpha therapy intradermally across the entire surface of the external genitalia to combat the underlying viral infection.

The US Center for Disease Control (CDC) estimates that upwards of 750,000 people develop ano-genital warts each year in the US alone. However, in contrast to women in the Western world who are subject to routine gynecological examination, many HPV-infected men may go undiagnosed without proper medical assessment. Accordingly, in addition to the reported number of diagnosed cases of ano-genital warts each year, it is believed that there are a substantial number of infected men who have not sought medical assessment

Competitive Positioning

Existing therapies for cervical and external ano-genital human papilloma virus (HPV) infection are limited and, due to irritating, painful and destructive properties, they all share a common drawback: existing therapies only target visibly apparent HPV-induced lesions (e.g., visibly apparent ano-genital warts). This practice has limitations from a therapeutic perspective, because HPV infection is often characterized by sub-clinical viral presence that is not clinically palpable.

Helix’s Topical Interferon Alpha-2b, by comparison to today's therapies, is intended for liberal application to the surface of the skin or mucosa, due to its anticipated relatively non-irritating properties. Consequently, Helix’s Topical Interferon Alpha-2b is believed to achieve drug delivery across a broad tissue surface area in order to target the HPV infection widely and efficiently. Because of its anticipated effectiveness against both visibly-apparent and sub-clinical HPV infection, we expect Topical Interferon Alpha-2b to have significant and marketable advantages over today's available treatments.

Helix is not aware of any other interferon alpha-2b cream product under development today. Helix believes that its BiphasixTM formulation is specialized and unique among today’s dermal delivery vehicles in being able to offer a stable cream dosage form capable of delivering interferon alpha-2b into the skin and mucosal tissues.

The launch of HPV vaccines was an important step in the fight against HPV infections. Helix believes that the vaccines are complementary to Topical Interferon Alpha-2b. Companies such as Merck and Co. (“Merck”) and GlaxoSmithKline Inc. (“Glaxo”) have developed vaccines that are designed to protect against infection from several specific subtypes of HPV.

While such vaccines have the potential to be significant medical advancements, they are designed primarily to offer a means hopefully to prevent adolescent youths from becoming infected in the first place, rather than to treat patients once infection has occurred. As such they are intended to be essentially prophylactic in nature rather than therapeutic, Topical Interferon Alpha-2b is expected to offer a broadly applicable and efficacious therapeutic option to persons already infected or that contract virtually any of the wide variety of HPV subtypes linked to the development of cervical cancer and ano-genital warts.

Licensing

Helix has entered into an agreement with Schering Corporation, a subsidiary of Merck & Co., Inc., granting Schering the option to obtain an exclusive worldwide license to use Helix’s Biphasix™ technology in pharmaceutical products containing interferon alpha-2b. Schering's option may be exercised at any time up to a specific period following the successful completion of Phase III clinical trials. Included in the option agreement are terms for the grant of a license to Schering that provides for milestone payments and royalties on product sales.

Schering is a world leader in the production and sale of interferon alpha-2b therapeutics.

Phase II Program

Helix has conducted clinical studies of its Topical Interferon Alpha-2b for two possible therapeutic indications:

- Low-grade cervical lesions
- Ano-genital warts

Low-Grade Cervical Lesions

Helix has announced positive results from phase II clinical studies of Topical Interferon Alpha-2b in patients with low-grade cervical lesions.

On March 30, 2007, the Company announced positive results from a multi-center study in Germany was designed to assess the safety and effectiveness of Topical Interferon Alpha-2b treatment in patients with HPV-positive cervical LSIL. The primary study endpoint was cytological in nature, whereby subjects were being evaluated for evidence of resolution of their abnormal Papanicolaou (“Pap”) smear. Other study assessments included pre- and post- treatment histological examinations by way of colposcopy and qualitative assessment of HPV+ status using polymerase chain reaction testing. The study enrolled 20 patients and a group of 21 untreated women were separately studied as a control population with the expectation of giving a meaningful comparison for assessing the impact of treatment with Topical Interferon Alpha-2b, against today’s standard of care for newly diagnosed LSIL patients, which is no treatment. Nearly half (46.7%) of the women in the treated per-protocol population experienced resolution of their abnormal Pap smears, compared with only 15.8% of the per-protocol control subjects. Furthermore, the relative difference in the Pap-response rate improved substantially when only the more advanced PapIIID per-protocol women were analyzed. In this subset, none (0.0%) of the untreated control subjects experienced normalization of their Pap smear versus 42.9% of the treated patients. However, the Company subseuqently learned that an unconventional reporting practice was applied by the cytology laboratory involved in the study in interpreting the Pap smear results of the patients in this study. In light of this, the Company reassessed the Pap smear results according to standard reporting practices, which demonstrated an increased Pap-response rate in the women that participated in the study relative to that which was previously reported. Accordingly, 58.3% of the women in the treated per-protocol population actually experienced resolution of their abnormal Pap smears, compared with 36.8% of the per-protocol control subjects. Similarly, 57.1% of the PapIIID per-protocol subset of treated women experienced normalization of their Pap smear versus 28.5% of the untreated PapIIID per-protocol control subset. Beyond the Pap-response rate efficacy parameter, all other efficacy parameters evaluated showed the same tendency in favour of treatment. For example, 60% of the treated women experienced resolution of their associated abnormal cervical findings upon colposcopic diagnosis versus only 9.5% of the untreated women.

Following this study, Helix conducted a Phase II pharmacokinetic study in women with low-grade CIN 1 or CIN 2 cervical lesions on colposcopic directed biopsy. The clinical study employed an open-label, single-arm design and enrolled a total of 14 female patients. Eligible women were between 18 and 45 years of age, presented with mild to moderate CIN (CIN1 or CIN2 respectively) confirmed by biopsy/histology, had a cytological diagnosis of Pap IIID not older than 12 months and were human papillomavirus (HPV)-positive confirmed by the Hybrid Capture® 2 HPV-DNA test. The primary objective of the study was to determine the multiple-dose pharmacokinetic profile of Topical Interferon Alpha-2b following intravaginal application every other day of a total of 14 doses of the cream. Following the pharmacokinetic portion of the trial, assessment of the secondary efficacy and safety parameters continued until 35 doses of the cream were applied. As such, the clinical study was designed to also mimic the dosing regimen intended to be applied in Helix’s future contemplated U.S. Phase II/III and European Phase III pivotal efficacy trials for this indication. The clinical study was conducted under the direction of Prof. Dr. med. Achim Schneider M.P.H., a world expert in the field of cervical cancer and Director of the Department of Gynecology at the Charité University Hospital in Berlin, Germany.

On June 23, 2010, the Company announced that all 14 patients were found to have circulating interferon alpha-2b levels below the bioassay’s lower limit of detection (6.25 pg/mL) at all sampling time points. These findings were considered consistent with the primary purpose of the study: to confirm that Topical Interferon Alpha-2b causes no significant systemic interferon alpha-2b exposure in patients following cervical application using the dose and regimen in this study. On October 21, 2010, the Company further announced positive efficacy and safety findings from the study. Using colposcopic directed biopsy to determine the treatment’s effectiveness, 71.4% of the women in the study no longer had potentially pre-cancerous, low-grade lesions known as cervical intraepithelial neoplasia grade 1 or 2 (CIN 1 or CIN 2) following treatment. Colposcopic directed biopsy is generally considered the leading method for diagnosing potential cervical precancer today. In addition, Topical Interferon Alpha-2b demonstrated an excellent safety profile, with no significant local intolerance findings and no serious adverse events.

Ano-Genital Warts Clinical Trial

Helix has completed a second Phase II trial of Topical Interferon Alpha-2b for the treatment of ano-genital warts (condylomata accuminata) associated with HPV infection. The trial, which took place in Sweden and Germany, was designed to assess the efficacy and safety of Topical Interferon Alpha-2b compared with placebo using a double-blind, randomized design over an examination period of four months per patient. One hundred twenty patients were enrolled in the trial. Half received a placebo and half received Topical Interferon Alpha-2b. Only female subjects were enrolled in the trial to avoid inter-sex treatment variations at this stage.

The trials showed no statistically significant treatment effects between the treatment and the placebo groups. Topical Interferon Alpha-2b was very well tolerated with no serious adverse affects related to the treatment and any local skin reactions were mostly absent or mild in both groups, indicating the safety of Topical Interferon Alpha-2b. The Company will be considering the results of the AGW study in detail to determine its next steps forward for this indication, if applicable.

Topical Interferon Alpha-2b is a drug product candidate under investigation by Helix BioPharma Corp. Descriptions of the mechanism by which Topical Interferon Alpha-2b and the core Biphasix™ technology functions or will function are speculative and are based on scientific theories advanced by the Corporation. The Corporation is actively engaged in ongoing investigative research with Topical Interferon Alpha-2b , through which it will attempt to test its theories. The Corporation offers no guarantee that its theories will be proven, nor that Topical Interferon Alpha-2b will ultimately yield a medicinal therapeutic.