OMEGA DUROS® Device for Hepatitis C
Intarcia is developing interferon for delivery from the DUROS® device to improve the treatment of HCV by offering a more convenient and potentially safer and more efficacious therapy. The current standard of care for hepatitis C is a combination of pegylated alpha interferon and ribavirin. Standard therapy fails to induce sustained response in a majority of patients and the 48-week course of weekly injections required for most patients causes frequent and at times severe side effects. Such side effects may discourage patient compliance to therapy leading to dose reduction and at times treatment discontinuation.
DUROS delivery of interferon therapy provides a continuous and consistent dose of interferon for an extended duration via the implantable DUROS device without the need for frequent self-injection. Through this unique and proprietary delivery of interferon, Intarcia expects to improve efficacy by maintaining constant human exposure to a therapeutic level of interferon without peaks associated with severe side effects, and troughs associated with sub-therapeutic drug levels and viral breakthrough.
Intarcia has evaluated the class of type 1 interferons for compatibility with the DUROS device. Several of the assessed type 1 interferon candidates appear to present stability and chemical properties amenable to DUROS delivery. Intarcia acquired exclusive rights to one of these, omega interferon and has completed formulation development and preclinical testing of Omega DUROS interferon therapy. Omega interferon has been broadly studied by Intarcia as an injection therapy including phase 1 and 2 clinical studies involving over 200 HCV-infected individuals. These studies have demonstrated omega interferon’s potent anti-HCV activity and favorable safety profile.
Intarcia is currently conducting a 72-week phase 1b dose ranging clinical study of Omega DUROS interferon therapy (ITCA 638) under a US IND. The study is evaluating ITCA 638 in combination with ribavirin in 60 patients with genotype 1 HCV infection who had relapsed after achieving an end of treatment response following a 48-week course of pegylated alpha interferon plus ribavirin. Preliminary results from this study suggest a highly predictable PK/PD profile with steady state drug levels achieved within 24 hours of insertion of ITCA 638 and consistent delivery of desired interferon levels in the blood throughout the first 4 weeks of treatment. This is further supported by a rapid and profound decrease in HCV RNA within the first days of treatment.
The advantages of ITCA 638 over pegylated interferon can be summarized as follows:
- Ensures 100% patient compliance to therapy;
- Eliminates the need for frequent self-injections;
- Addresses common aversion to needles (especially among former drug abusers);
- Ameliorates “flu-like symptoms” associated with weekly peak concentrations;
- Reduces opportunity for viral breakthrough resulting from sub-therapeutic troughs; and
- Potential for improved clinical efficacy compared with pegylated interferon.
Based on these advantages and assuming positive continued clinical results, DUROS interferon therapy represents a compelling opportunity to improve treatment of chronic hepatitis C infection, both as an alternative to pegylated interferon for first-line therapy and as an opportunity to expand the treatable population, including patients who have failed prior pegylated interferon therapy and patients for whom injectable alpha interferon is not appropriate.
Chronic Hepatitis C Infection
The Centers for Disease Control estimate there are 3.2 million people in the United States infected with chronic HCV, and the World Health Organization recently increased its estimated global prevalence to over 170 million people. Since the early 1990s, incidence has been reduced in the developed world through screening of blood products. Still, approximately 26,000 new infections occur each year in the US. The current standard of care for HCV is a combination of weekly injections of pegylated alpha interferon and twice daily oral dosing of ribavirin. In clinical studies, sustained viral response (SVR) is achieved in approximately 50% of patients across all HCV genotypes. There remain many barriers to effective treatment, including:
- Genotype 1 virus, accounting for 70% of HCV in US and Europe, is less responsive to treatment (SVR: approximately 40% in clinical studies);
- Side effects cause frequent dose reduction and treatment discontinuation;
- Poor compliance may result in viral breakthrough and treatment failure; and
- Former I.V. drug abusers often can’t tolerate self injections.
Type 2 Diabetes Program
Among the many classes of effective treatments for type 2 diabetes, a new class called incretin mimetics represents some very important advantages. Incretin mimetics have the effect of lowering blood glucose and decreasing weight through multiple biological activities. The development of incretin mimetics offering these beneficial effects has been an important focus of research in the fields of type 2 diabetes and obesity. The first incretin mimetic was approved by the US FDA in 2005 and others are currently in clinical and preclinical development.
ITCA 650 (DUROS delivery of exenatide for type 2 diabetes)
Intarcia’s clinical stage type 2 diabetes candidate known as ITCA 650 involves the delivery of exenatide, an approved incretin mimetic, with the subcutaneous DUROS delivery device. Intarcia is developing ITCA 650 to provide type 2 diabetes patients with long-term steady state dosing of a incretin mimetic therapy. Exenatide and other incretin mimetics have demonstrated effective glycemic control and weight loss, as single agents and in combination with oral antidiabetic drugs. Like other incretin mimetics, exenatide is limited by pharmacokinetics that require twice-daily self injection and cause side effects such as nausea that often lead to poor compliance or premature discontinuation of treatment. ITCA 650 is designed to deliver a continuous and constant dose of exenatide over an extended period of time, thereby providing round-the-clock therapeutic benefits to the patient but minimizing peak drug level related side effects such as nausea. Due to the inherently short half-life of incretin mimetics, extended duration delivery options are an important consideration to facilitate patient compliance and convenience. However, some extended delivery options have compromised a healthcare provider’s ability to quickly withdraw therapy should an unscheduled cessation of treatment be required. DUROS delivery provides the longest duration of continuous treatment with the flexibility of near immediate reversibility.
ITCA 650 Program Status
Intarcia has developed ITCA 650 formulations that provide excellent stability of exenatide at human body temperature and consistent delivery from the DUROS device for 3, 6 or 12 months. An IND for ITCA 650 was filed with the US FDA in December 2008 and Intarcia initiated its first clinical trial of ITCA 650 in patients with type 2 diabetes in the first quarter of 2009. The ITCA 650 Phase 1b study is evaluating 4 different doses of exenatide over a treatment duration of 28-days delivered with a single insertion of a DUROS device. The goals of the ITCA 650 phase 1b study are to assess safety and establish an appropriate dose or doses for evaluation in a phase 2 study planned for the second half of 2009. The results of the ITCA 650 phase 1b study will be submitted for presentation at scientific conferences in 2009.
Type 2 Diabetes
Type 2 diabetes is the most common form of diabetes, accounting for more than 90% of all cases, affecting approximately 246 million adults worldwide and more than 23.6 million in the US alone. According to the American Diabetes Association, 1.6 million new cases of diabetes were diagnosed in people aged 20 years or older in the US in 2007. The treatment for type 2 diabetes can be divided into insulin and non-insulin segments. Patients can manage their type 2 diabetes for a time with careful adherence to a prescribed diet along with regular exercise. When diet and exercise alone can no longer provide adequate control of glucose levels, patients are usually treated with one or more oral antidiabetic drugs. Ultimately however, even combinations of these drugs fail to adequately control type 2 diabetes for most patients, at which point an insulin-based treatment regimen is prescribed. The Consensus Statement of the American Diabetes Association and the European Association for the Study of Diabetes recommends use of incretin mimetic therapy in combination with or to replace oral therapies in order to improve glycemic control or to avoid side effects common to other therapies.
Obesity Program
Research in the field of anti-obesity therapy has intensified significantly in response to a rapid increase in the overweight and obese population coupled with a greater understanding of the health risks posed by these conditions. But many pharmacologic approaches involving stimulant and appetite suppressants have proven unsuccessful in helping patients achieve sustainable reduction or control of their weight. Other drug classes working through the central nervous system have produced dangerous or unwanted side effects leading to product withdrawal in some cases. More recently, research has centered around understanding the role of natural human hormones in controlling appetite, food consumption and weight gain and the therapeutic potential of such hormones. Several natural human peptides produced in the digestive tract have been identified and tested as potential targets for development as therapeutic agents, in some cases producing favorable effects on weight loss in human studies. Developing natural human peptides or synthetic analogs as therapeutic agents is particularly challenging because such substances are often very short acting and require injection administration. These factors produce a treatment that would require patients to receive continuous infusion from an insulin-type pump or to self administer multiple injections every few hours throughout the day.
Intarcia is evaluating a series of human peptides for delivery with the DUROS technology as potential treatments for obesity. Based on the success Intarcia has achieved with human interferon and exenatide, we believe we can maintain stability and continuously deliver consistent levels of such peptides with the DUROS technology addressing some of the primary obstacles to developing safe and effective therapies in this class.
Obesity
The World Health Organization reports more than 1.6 billion people are classified as overweight and at least 400 million clinically obese. These conditions represent a major global health burden and pose significant additional chronic health risks including type 2 diabetes, cardiovascular disease, hypertension and stroke, and certain forms of cancer.
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