Lupus, a chronic debilitating inflammatory autoimmune disease, impacts 1.5 million people, mostly women, in the U.S. and 5 million worldwide. With a 10 year survival rate of 90%, patients suffer with a disease for which there is no effective treatment. Current drugs like immunosuppressants only provide palliative care by making symptoms easier to live with. These immunosuppressants often come with harmful side effects. Lupus impacts the entire body including skin, musculoskeletal, digestive, nervous and reproductive systems, as well as blood, lungs and heart.
Only one drug has been approved to treat lupus in the past 50 years. Benlysta received the FDA’s blessing in March 2011 and was subsequently acquired and is marketed by GlaxoSmithKline. Sales have been slower than expected due to limited efficacy, among other things. As other drugs for lupus gain FDA approval, the market for their sales is projected to reach $4 billion annually by 2022. Despite strong interest and efforts by big pharma to develop lupus drugs, an effective and safe therapy for this indication remains elusive.
Israel-based XTL Biopharmaceuticals is set to commence a Phase II study of its drug hCDR1 in the treatment of systemic lupus erythematosus (SLE), which accounts for 70% of lupus cases worldwide. If data show efficacy, it would position XTL and its drug very favorably in a market that is in dire need of a safe and effective treatment.
Q: Why has lupus been such a difficult disease for the medical community to understand and treat?
Levine: Lupus is more of a syndrome than a strictly defined disease with many different manifestations. It affects different people in vastly different ways. Furthermore, the course of lupus is characterized by flares and remissions, i.e. periods of intense disease manifestations are followed by periods of relatively few signs and symptoms. There are many categories of drugs physicians use to treat lupus, including corticosteroids, anti-malarials and B-cell inhibitors like Benlysta. Physicians do not like to prescribe steroids, especially long term, and other therapies have not proven to be sufficiently effective in treating the symptoms of this disease.
Q: Would you tell us how hCDR1 is different from FDA approved Benlysta and other drug candidates that are also B-cell inhibitors? How would hCDR1’s safety and efficacy profile offer benefits over B-cell inhibitors?
Levine: Due to the complexity of the disease (see question 1 above), many Key Opinion Leaders are excited about hCDR1’s unique Mechanism of Action, as it can be used as a stand-alone therapy or as part of a future combination therapy to combat the disease.
Belimumab, or Benlysta, is a B Lymphocyte Stimulator (BLyS)-specific inhibitor that blocks the binding of soluble BLyS, a B-cell survival factor, to its receptor on B-cells. By binding BLyS, Belimumab inhibits the survival of B-cells, including autoreactive B-cells, which are the basis of autoimmune disease.
hCDR1 is the acetate salt of a synthetic peptide composed of 19 amino acid residues. Unlike B-Cell inhibitors, hCDR1 has a unique Mechanism of Action that induces the generation of Regulatory T Cells, which, in turn, lead downstream to the lowering of the activated, autoreactive B-Cells. hCDR1 down-regulates the autoimmune responses elicited by the various autoreactive cell populations (e.g., T and B cells) and pathogenic autoantibodies, as well as up-regulates the expression of gene markers of immunosuppressive molecules, such as TGF-β and FoxP3.
In three clinical trials conducted to date involving >400 patients, hCDR1 has demonstrated a favorable safety profile, is well tolerated by patients, and has demonstrated efficacy in one and possibly more clinically meaningful endpoints. Results were published in Lupus Science & Medicine in August 2015.
Q: You have a Phase II trial coming up in the U.S. Can you tell us more about how the data compiled from the previous clinical studies and the use of BILAG as the primary measure of efficacy in the upcoming study significantly enhance the likelihood of a positive outcome?
Levine: As noted above, hCDR1 was studied in three clinical studies involving more than 400 patients including a Phase II study (the PRELUDE© study) which included more than 300 patients. In PRELUDE©, hCDR1 failed to meet the primary endpoint (SLEDAI) but the 0.5 mg dose showed a statistically significant effect (p=0.03) in the ITT (Intend to Treat) cohort against a pre-defined secondary endpoint – the BILAG index. Further, in a post-hoc analysis of patients on less than 20 mg daily dose of steroids, the 0.5 mg dose showed a highly statistically significant effect (p=0.007) against the pre-defined secondary BILAG endpoint. XTL recently approached the US FDA, which provided guidance supporting our plan to use the BILAG endpoint as the primary efficacy endpoint in our upcoming study (confirming the current FDA guidelines for lupus studies) and agreed with our proposed patient population. Therefore, we believe our proposed design of the upcoming study has an increased likelihood to succeed as the FDA’s guidance encourages the study to be substantially similar to the prior Phase II (PRELUDE©) trial which demonstrated safety and efficacy in the 0.5 mg dose using the BILAG index. We believe the FDA’s guidance validates the value and relevance of the safety and efficacy data from the previous trials performed on our drug. To further increase our likelihood of success, we plan on testing the 0.5 mg dose, that showed the best effect in PRELUDE©, as well another dose.
Q: hCDR1 has been tested in over 400 people, and in more than 200 animal experiments, with studies published in over 40 peer reviewed articles. What makes hCDR1 so compelling and such a well researched drug candidate?
Levine: I believe the answer begins with the disease itself. As noted above, SLE is a very difficult disease that affects millions of patients worldwide (primarily women of child-bearing years) and one in which there is an extremely high unmet medical need. There is currently no effective and safe treatment for the disease. In addition, hCDR1 has a unique mechanism of action (an immunomodulator as opposed to an inhibitor), which generates significant interest among researchers and clinicians. Further, as noted above, it can be used both as a stand-alone treatment as well as part of a combination therapy. It also has a clean safety profile on hundreds of patients including at doses far higher than what we intend to test in the upcoming study. Finally, from the PRELUDE© study, we have very encouraging efficacy data on the BILAG endpoint, which will be the primary efficacy endpoint in the upcoming study.
Q: If the Phase II study produces good efficacy and safety results, as expected, how do you see your development path moving forward? Would XTL seek a big-pharma partner or advance hCDR1 further along independently?
Levine: I believe that if we can achieve good efficacy/safety data in our upcoming study, hCDR1 will interest many Big-Pharma partners who are already active in the autoimmune space and who are looking for solutions for this very difficult disease. An example of such interest in the lupus space is GlaxoSmithKline’s purchase of Benlysta for $3 billion upon regulatory approval and ongoing studies in this space by Big Pharma. Having said that, the FDA also provided guidance to XTL concerning the number of patients required for its safety database to support an NDA filing for marketing approval Based on such guidance, it is possible that XTL could independently advance hCDR1 following a successful study. Much will depend on the results of the upcoming study, in which, we believe we have an increased likelihood to succeed, as noted above.
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