Bertilimumab in the Forefront
Immune Pharmaceuticals Inc. (IMNP:NASDAQ) is currently enrolling patients in two Phase 2 clinical trials with bertilimumab for the treatment of ulcerative colitis (UC) and bullous pemphigoid (BP). A third Phase 2 program in atopic dermatitis (AD) is planned for later in 2016.
Data from the Phase 2a program in BP is expected in late 2016. This open-label, proof-of-concept, single group study targets 10-15 adult patients with newly diagnosed, moderate to extensive BP (NCT0222146). Patient recruitment is occurring at two medical centers in Israel, with plans to open as many as six sites in the U.S. during Q2/16 or Q3/16. Additional sites in Europe are expected to come online shortly, which should greatly speed enrollment in the trial.
"If successful, Immune Pharmaceuticals Inc.'s expansion into oncology will provide diversification and potential upside to the core inflammatory and dermatology focus."
The scientific rationale for the use of bertilimumab in BP is extensive. Bertilimumab binds to eotaxin-1, a master regulator of the immune cellular network, by inducing key immune cytokine responses with very high affinity and specificity. A study published in the European Journal of Dermatology found an increased level of serum eotaxin-1 in BP patients compared to healthy controls. Eotaxin-1 has also been correlated with disease severity, with the highest levels of eotaxin-1 in patients suffering from the most severe disease, suggesting a correlation between the level of eotaxin-1 over-expression and disease severity.
Bullous pemphigoid is a chronic autoimmune skin disease in which blisters (bullae) form between the epidermis and dermis layers of the skin. There is no cure, and current treatment options primarily consist of anti-inflammatory agents like corticosteroids, tetracyclines and clobetasol. An estimated 65,000 patients in the U.S. and Europe have BP, and both agencies recognize the condition as an orphan disease. If the open-label Phase 2a study is successful, Immune Pharma will likely push forward into a Phase 2b clinical trial in 2017.
In November 2015, Immune Pharma announced enrollment of the first patient in the company's Phase 2 program in UC. The trial is double-blind and placebo-controlled, and will seek to randomize 42 adult patients with active moderate-to-severe UC at centers in Israel and Europe (NCT01671956).
As with BP, there is strong scientific evidence that bertilimumab will work in UC. One study found that significantly increased serum eotaxin-1 levels were observed in patients with both Crohn's disease and ulcerative colitis when compared with healthy controls. Moreover, patients with active disease showed significantly higher serum eotaxin-1 levels than patients with quiescent disease.
"Data from the Phase 2a program with bertilimumab in BP is expected in late 2016."
According to GlobalData, approximately 650,000 Americans have active UC, with another 765,000 afflicted in France, Germany, Italy, Spain, the UK, Canada and Japan. Worldwide sales of pharmaceutical products to treat irritable bowel diseases (IBDs) are expected to exceed $14 billion by 2019, with the UC market comprising approximately 35% of that total. If approved, bertilimumab would represent a new mechanism of action in the treatment of UC, and offer patients and physicians an alternative treatment option. Data from the ongoing Phase 2 study is expected in 2017.
Beyond Immune Pharma's belief that bertilimumab holds utility in BP, the underlying pathophysiology of atopic dermatitis (AD) leads management to believe the drug might have important utility in that indication as well. One paper investigated the level of circulating eotaxin in 78 children with skin allergy; the authors concluded that circulating levels of eotaxin increase in AD, and that this may represent a biomarker of lesional activity.
Recently, Regeneron Pharmaceuticals Inc. (REGN: NASDAQ) and Sanofi SA (SNY:NYSE) announced positive Phase 3 data for dupilumab in adults with atopic dermatitis. Dupilumab is a monoclonal antibody that targets the alpha subunit of the interleukin-4 receptor (IL-4Ra). If approved, dupilumab is expected to be the first system therapy in the treatment of AD. Immune believes that the recent success of dupilumab validates the opportunity for a systemic monoclonal antibody for the treatment of AD.
The Promise in Dermatology
Immune Pharma's focus on dermatology does not stop with bertilimumab. The company is eager to begin clinical studies with its topical nano-capsule formulation of cyclosporine A, Nanocyclo, for the treatment of atopic dermatitis and psoriasis in 2017.
Cyclosporine A (CysA) is a powerful polypeptide immunosuppressant drug that reversibly inhibits T-lymphocytes, most notably through targeting T-helper cells and, to a lesser extent, T-suppressor cells. CysA also inhibits lymphokine production and release, including release of interleukin-2 (IL-2) or T-cell growth factor. This mechanism of action has proven useful in the prevention of allogeneic organ transplantation rejection, with specific utility in skin, heart, kidney, liver and bone marrow transplantation. The drug has also been used to treat autoimmune diseases such as severe psoriasis, atopic dermatitis, rheumatoid arthritis, and to generate tear production in individuals with dry eyes.
"Bertilimumab would represent a new mechanism of action in the treatment of UC, and offer an alternative treatment option."
Neoral (oral cyclosporine; Novartis AG [NVS:NYSE]) is approved for the treatment of psoriasis. The label includes a bolded "black box" warning for nephrotoxicity and neurotoxicity issues, risk of serious infection, as well as a specific risk for the development of skin malignancies when used in combination with PUVA (psoralen and ultraviolet A radiation), radiation therapy or methotrexate. The concept of a topical formulation of CysA is quite simple—you get all the benefits of the powerful efficacy of the drug and avoid the primary systemic side effects. It is a commercially validated strategy that has been employed with many medications, including corticosteroids and nonsteroidal anti-inflammatory drugs.
It is worth noting that with bertilimumab and topical nano-CysA, Immune Pharma's goal is to become a major player in immuno-dermatology. Bertilimumab has potential in both bullous pemphigoid and severe atopic dermatitis, and will compete against dupilumab once approved. Nano-CysA could pick up market share in AD in the topical market, and will likely compete with Anacor Pharmaceuticals Inc.'s (ANAC:NASDAQ crisaborole (AN2728), which has successfully completed a Phase 3 trial in atopic dermatitis and is now under FDA review.
Aggressive Expansion in Immuno-Oncology
Immune Pharma has aggressively expanded its efforts in oncology with a two-fold strategy with its oncology pipeline. First, the company is developing a platform of next-generation nanoparticle cytotoxic agents and bispecific antibodies. Second, Immune Pharma is resurrecting legacy drug candidates via the company's acquisition of EpiCept in late 2013. If successful, Immune's expansion into oncology will provide diversification and potential upside to the core inflammatory and dermatology focus.
Immuno-oncology is a relatively new focus for Immune, so it is not surprising that the company has made a significant number of key hires over the past six months, including new executive vice president and head of oncology Dr. Miri Ben-Ami. Dr. Monica E. Luchi is the company's new chief medical officer, and Dr. Boris Shor is head of the company's research and development (R&D) laboratory at the Alexandria Center for Life Science in New York City.
In December 2015, Immune Pharma strengthened its efforts in bispecific antibodies with the licensing of technology and patents from Atlante Biotech SAS, a privately held European biotech company that was part of a European consortium working with Immune on its initial bispecific antibody prototype. In March 2016, the company announced the publication of preclinical data that demonstrates Immune Pharma has designed and validated a novel generic platform for the production of tetravalent IgG1-like chimeric bispecific antibodies. The company's goal for 2016 is to complete initial validation of several bispecific antibody candidates for further development based on internal R&D efforts, and to seek new intellectual property protection for these discoveries. For example, Immune has initiated several bispecific antibody discovery programs that target immune checkpoints, including PD-1, PD-L1 and Ox40.
"The company is eager to begin clinical studies with its topical nano-capsule formulation of cyclosporine A."
Immune Pharma's NanomAbs are next-generation nanoparticles that contain thousands of cytotoxic molecules conjugated to monoclonal antibodies that recognize specific targets (antigens) to enhance the nanoparticles' specificity, stability and therapeutic efficacy. The company has created a platform to provide a more efficient approach for tumor-specific delivery of cancer therapeutics and immunomodulatory agents. The platform allows for a variety of small molecules, peptides or proteins to be chosen based on sensitivity to cytotoxic agents, and then delivered in a nanoparticle formulation. Similarly, the highly targeted monoclonal antibody conjugated to the nanoparticle can be chosen based on tumor antigens. The company has prioritized development of several immune checkpoint inhibitor-targeted NanomAbs. This area has been gaining significant scientific validity over the past year. For 2016, the company's goals are the validation of manufacturing processes and the generation of preclinical proof-of-concept data.
Finally, Immune Pharma acquired Ceplene in 2013 with the takeover of EpiCept. Until recently, Ceplene sat on the back burner, but recent data has piqued the interest of management and now it seems there is a potential to monetize Ceplene through a partnership—or at the very least include the drug in the planned oncology subsidiary once formed. Ceplene has been granted orphan drug status for the treatment of acute myelogenous leukemia (AML) by the European Medicines Agency (EMA) and the FDA.
Newfound interest in Ceplene stems from recent breakthroughs in immuno-oncology that have significantly changed the potential treatment paradigm for AML. The future for a drug like Ceplene is likely in combination with newer advanced therapeutics, such as CAR T-cell therapies and checkpoint inhibitors. In this regard, the company is seeking a new patent for the combination of Ceplene and checkpoint inhibitors. For example, Immune recently performed a new, multivariable analysis of a Ceplene/IL-2 Phase 4 study (NCT01347996) in Sweden. The company believes it has identified new potential biomarkers that predict response to Ceplene + IL-2 in patients in complete remission and the post-consolidation phase of treatment. Immune Pharma will be presenting a poster of this data at the upcoming 2016 American Association of Cancer Research (AACR) annual conference. The company has also published an abstract highlighting these reported predictors of clinical outcome and identified certain biomarkers in patients with low-relapse-risk AML.
Immune Pharma has some important catalysts and key milestones upcoming in 2016, among them clinical results for the Phase 2 studies of bertilimumab in BP and UC; preclinical data and initiation of a Phase 2 study of bertilimumab in AD, submission of an investigational new drug application (IND) for Nanocyclo, potential partnership for Ceplene; and the release of preclinical results for other pipeline products. Results from the UC may slip into 2017, but I believe data from the BP trial is on track for the second half of the year. I view this as the single biggest driver of a potential turnaround at Immune for shareholders.
Jason Napodano of BioNap Consulting formerly worked for Zacks Investment Research as the company's senior biotechnology analyst. Prior to his tenure at Zacks, Napodano spent three years on the buyside with Eastover Capital in Charlotte, N.C., where he focused on large-cap equities and specialized in healthcare, energy and technology. Prior to joining Eastover, Napodano worked as a research scientist for TechLab Inc., a biotechnology company focused on developing diagnostic kits and vaccines for infectious diseases. He also spent a year working in a lab at the Fralin Biotechnology Center, and a year working for a cancer researcher in Virginia. Napodano has a bachelor's degree in biochemistry from Virginia Tech and a master's degree in business administration and finance, with a concentration in securities analysis, from Wake Forest University. Napodano is also a Chartered Financial Analyst (CFA).
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