Raanana, Israel based XTL Biopharmaceuticals Ltd. (XTL) has announced that following evaluation of market opportunity for its pipeline products its decision to focus efforts and expenditures exclusively on two core assets: hCDR1 for treatment of SLE/lupus and rHuEPO for “no-option” multiple myeloma patients. XTL, whose shares are traded on the NASDAQ and the Tel-Aviv Stock Exchange, and are included in the Tel-Aviv Biomed, Tel-Aviv MidCap, and Tel-Aviv Tech Index indices, specializes in acquisition, development and commercialization of pharmaceutical products for treating unmet clinical needs, also released its financial and operational results for the first quarter ended March 31, 2015.
XTL’s Chief Executive Officer Josh Levine comments: “Following our analysis of the market opportunity and commercial prospects for our leading clinical assets, we have decided to focus our resources and efforts exclusively behind the development of hCDR1 for the treatment of lupus and rHuEPO for “no-option” multiple myeloma patients and to withdraw from further progress on a combination therapy for schizophrenia in-licensed by the Company in 2011.”
XTLbio’s product pipeline is generated by systematically identifying, validating and in-licensing therapeutic candidates with advantages over current therapies for addressing unmet medical needs.
The debilitating disease Lupus (Systemic Lupus Erythematosus or SLE) is a severe systemic and chronic autoimmune disorder of unknown etiology in which various cell types and immunological pathways are dysregulated, allowing the immune system to go awry and dysfunctionally produce antibodies to cells within the body that attack and destroy healthy tissue causing irreversible damage. These autoantibodies cause inflammation, pain, widespread inflammation, and tissue damage. Lupus primarily affects women of childbearing age (ie: between 20 to 40), and women of color are two to three times more likely to develop Lupus than Caucasians. However, men, children, and teenagers and people of all races and ethnic groups can develop Lupus. Typically affecting many parts of the body, including the joints, kidneys, central nervous system, heart, hematological system and others, and can cause severe complications that necessitate aggressive therapies.
The Lupus Foundation of America says its research estimates that at least 1.5 million Americans have lupus, but that the actual number may be higher since there have been no large-scale studies to determine the actual number of people in the U.S. living with lupus. More than 16,000 new cases of lupus are reported annually across the country, representing a huge unmet medical need, with only one new treatment having been approved by the FDA in the past 50 years. A fourth quarter announcement by Eli Lilly that it has discontinued development of a Phase III asset in this space further emphasizes the unmet need and positions XTL to garner significant interest in its lupus asset from clinicians, lupus patients and partners which Mr. Levine says will no doubt lead to “game changing” opportunities for the company.
XTL’s drug candidate hCDR1 is a novel compound that works via a novel mechanism of action, for treatment of Lupus. The cause of the disorder is unknown, and treatment for SLE is reliant primarily on anti-malarial agents (mainly Hydroxychloroquine, HCQ), and general immune system-suppressing agents, such as corticosteroids, azathioprine, cyclosporine and and cytotoxic immunosuppressive agents cause many unwanted side effects. Corticosteroids, given orally or intravenously, have been proved effective for almost all lupus related manifestations, but their long-term adverse effects limit their usage. A recent study (Thamer M, Hernan MA, Zhang Y, Cotter D, Petri M. Prednisone, lupus activity, and permanent organ damage. J Rheumatol 2009;36:560e4) has demonstrated that a dose of prednizone as low as 6 mg per day increases corticosteroids-induced organ damage by 50 percent, rendering a steroid-sparing therapeutic approach mandatory.
It is therefore hoped that research into new therapeutic agents like XTL’s hCDR1 may lead to more focused treatments that would selectively block the abnormal immune response and cause fewer side effects. Based on recent better understanding of the pathogenesis of SLE, targeted biological therapies are under different stages of devel- opment. The latter include B-cell targeted treatments, agents directed against the B lymphocyte stimulator (BLyS), inhibitors of T cell activation as well as cytokine blocking means. Out of the latter, the sole product approved by the FDA for treatment of SLE in the last 50 years — Benlysta (belimumab) A drug that that targets BLyS — received FDA approval in 2011. However, notwithstanding that newly developed biological agents target cells and molecules that are involved in SLE pathogenesis of they are not lupus specific and may affect normal immune system function as well a result in various infections in some treated patients.
Attempts to develop therapeutic means that immunomodulate only SLE-associated autoimmune responses without affecting other immune system functions has led to synthesis of lupus specific tolerogenic peptides (such as hCDR1). These tolerogenic peptides have been studied for their mechanism of action and effects on SLE manifestations, and exhibit their effects on various cell types and immunological pathways that are involved in the pathogenesis of lupus. They suppress only SLE-related autoreactive responses without interfering with normal immune functions and the variants tested in SLE patients (P140 and hCDR1) have been reported to be safe and well tolerated. Thus, researchers maintain that tolerogenic peptides appear to be attractive candidates for specific treatment of lupus and suggest that further attempts towards their development are likely to be rewarding.
The design of the targeted Peptide hCDR1, which is poised to become a disease-specific treatment, was developed by Prof. Edna Mozes, a senior immunologist and chemist at the Department of Immunology, The Weizmann Institute of Science (Israel). hCDR1 ameliorates the SLE-related autoimmune process by specific upstream immunomodulation through the generation of regulatory T cells. The regulatory T cells then initiate a physiological cascade of events involving beneficial effects on auto reactive T and B cells, autoantibodies and various pathogenic cytokines and immunosuppressive molecules, which together resume immune balance.
In a study reported in the Proceedings of the National Academy of Sciences (April 29, 1997, Vol. 94), Prof. Mozes’s team synthesized two protein fragments that effectively immunized mice against lupus. The protein fragments were designed to mimic sections of the abnormal antibodies produced in lupus. Although their precise mechanism has not been fully clarified, studies indicate that they prevent the initiation of the autoimmune response. Where the disease already exists, preliminary results in mice suggest that the new compounds may also cure lupus and therefore serve as a basis for developing new treatments for humans.
In a related study, Prof. Mozes and her team provided a scientific basis for studies suggesting that the drug methotrexate – generally prescribed to treat rheumatoid arthritis and some cancers – also has a beneficial effect on lupus. Using mice with an experimental lupus-like disease, the scientists demonstrated that methotrexate, which is known for its anti-inflammatory effects, reduces production of inflammatory molecules characteristic of the disease. This finding was reported in the Journal of Rheumatology (June 1997, Vol. 24, No. 6).
In a 2014 study published in the Journal of Autoimmunity, entitled “Novel approaches to the development of targeted therapeutic agents for systemic lupus erythematosus” (Sthoeger Z, et al., Novel approaches to the development of targeted therapeutic agents for systemic lupus erythematosus, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.06.002), Prof. Edna Mozes and colleagues Zev Sthoeger and Amir Sharabi of the Department of Immunology at The Weizmann Institute of Science in Rehovot, Israel, and the Department of Internal Medicine B and Clinical Immunology of the Kaplan Medical Center also located in Rehovot, the scientists note that in addition to the non-antigen specific agents that may affect the normal immune system as well, SLE-specific therapeutic means are under development. These include synthetic peptides (e.g. pConsensus, nucleosomal peptides, P140 and hCDR1) that are sequences of conserved regions of molecules involved in the pathogenesis of lupus. The peptides are tolerogenic T-cell epitopes that immunomodulate only cell types and pathways that play a role in the pathogenesis of SLE without interfering with normal immune functions. Two of the peptides (P140 and hCDR1) have been tested in clinical trials and reported to be safe and well tolerated. Thus, synthetic peptides are attractive as a potential agent of specific treatment for lupus patients.
XTL notes that a large body of preclinical and clinical research has been performed on hCDR1, including on the mechanism of action on the clinical as well as the molecular levels. hCDR1’s beneficial effects in SLE were demonstrated in a number of animal models and species in more than 200 experiments. Similar effects were also demonstrated on human peripheral blood lymphocytes (PBL) ex-vivo and in-vitro. The results of these studies have been published in more than 40 peer reviewed papers.
For a specific SLE treatment Prof. Mozes says her team designed and synthesized the peptide hCDR1 based on the complementarity determining region (CDR) 1 of an anti-DNA autoantibody and tested its effects on several mice models for lupus:
• a) the spontaneous model of (NZBxNZW)F1 mice,
• b) induced experimental SLE in BALB/c mice, and
• c) a “humanized” model of severe combined immunodeficient (SCID) mice engrafted with PBL of SLE patients.
The researchers found that treatment with hCDR1 ameliorated the serological and clinical manifestation of the established lupus in these mouse models. Further, hCDR1 down-regulated disease manifestations associated with neurological lupus.
There have also been two placebo controlled Phase I trials and a placebo controlled Phase II trial (PRELUDE) conducted with hCDR1. The Phase I and Phase II studies consisted of over 400 patients, demonstrating that hCDR1 is well tolerated by patients and has a favorable safety profile. The PRELUDE trial did not achieve its primary efficacy endpoint based on the SLEDAI scale. However, the PRELUDE trial showed encouraging results in its secondary clinical endpoint, the BILAG index, and even the 0.5mg weekly dose showed a substantial effect. Multiple post-hoc analyses showed impressive results for this dose using the BILAG index, and those dosage schedules will be the focus of XTL’s clinical development plan moving forward. For more research results involving the BILAG Index, see: the study “The efficacy of repeated treatment with B-cell depletion therapy in systemic lupus erythematosus: an evaluation” (Rheumatology (2011) 50 (8): 1401-1408. doi: 10.1093/rheumatology/ker018).
The company notes that the FDA has directed that the primary endpoint in future trials for Lupus therapies, including those for hCDR1, should be based on either the BILAG index or the SLE Responder Index (SRI).
XTL First Quarter 2015 Financial Overview
XTL reported US$1.8 million in cash and cash equivalents as of March 31, 2015. The additional funds from the US$4 million fundraise in April 2015, will allow the Company to advance its hCDR1 program for the treatment of SLE and initiate a clinical trial on its rHuEPO for multiple myeloma asset.
The Company reported research and development expenses for the quarter ended March 31, 2015 of US$42,000 compared with US$47,000 in the first quarter of 2014. General and administrative expenses for the quarter ended March 31, 2015 remain under tight control with US$0.3 million in the first quarter compared with US$0.5 million for the same period in 2014.
XTL Biopharmaceuticals Ltd. reported an operating loss for the quarter ended March 31, 2015 of US$0.3 million compared to US$0.6 million for the same period last year. Finance expenses of US$0.2 million related to its investment in InterCure contributed to a net loss from continuing operations for the quarter ended March 31, 2015 of US$0.6 million, in line with results for the same period last year.
Mr. Levine comments that: “Our first quarter financial results are in line with our expectations and following the recent closing of a US$4 million registered direct offering with a US based healthcare dedicated investor and existing shareholders, we are ready to execute our strategic plan with the goal of bringing our programs to the clinic in the near future. We continue our discussions with the FDA regarding the regulatory pathway for both drugs and have made progress on the chemistry, manufacturing and control (CMC) activities for hCDR1 including the production of the drug substance. We look forward to the expected publication of the results of a Phase 2b trial on our lupus drug (PRELUDE trial) which shows favorable safety and efficacy data on over 300 patients and are pleased with the coverage initiated recently by a US research analyst confirming our belief that our assets provide significant upside as compared to our current valuation.”
XTL Biopharmaceuticals Ltd.
The Weizmann Institute of Science
Lupus Foundation of America
Journal of Autoimmunity
Journal of Rheumatology
Proceedings of the National Academy of Sciences
XTL Biopharmaceuticals Ltd.
The Weizmann Institute of Science