XTL Biopharmaceuticals (NASDAQ:XTLB) (TASE:XTL) is aiming to begin a Phase 2b clinical trial in the first half of 2015 with its hCDR1 peptide to treat patients with systemic lupus erythematosus (SLE).
"We are in the process of finalizing our trial design, approaching the FDA and hope to have feedback from the agency before the end of this year," CEO Josh Levine says in an interview with BioTuesdays.com.
"While nothing has been finalized yet, we will likely enroll approximately 250 patients at clinical sites in North and Latin America, Europe and Israel," he adds.
SLE is an autoimmune disease in which the body's immune system mistakenly attacks itself and, as a result, produces antibodies that damage healthy tissues. The cause of SLE is not known. According to the Lupus Foundation of America, it affects approximately 1.5 million people in the U.S. and five million worldwide, of which 90% are women, with the majority between the ages of 15 and 45.
Early on, patients typically endure skin rashes and arthritis-like symptoms. As the disease progresses, it can attack a wide variety of organs, including the kidneys, heart and lungs, the central nervous system (CNS), the blood and coagulation systems and the gastrointestinal system. The most common causes of death are renal failure, cardiovascular disease, CNS disorders and infections.
Mr. Levine points out that there are no completely effective treatments for lupus in the market and that there is a significant unmet medical need. GlaxoSmithKline's Benlysta is the only drug that has been approved for lupus in the past 50 years. It was cleared for sale in March 2011, but the launch has been slower than expected," he adds.
"Considering the large unmet need, the pipeline of new drugs in development for lupus is remarkably weak," Mr. Levine contends, adding that most are B-cell inhibitors like Benlysta.
XTL's hCDR1 has a different mechanism of action than Benlysta.
According to Mr. Levine, hCDR1 does not inhibit or destroy B-cells (as do most of the products in clinical development); rather, it modulates the auto-reactive T-cells that are upstream from the B-cells, thus down-regulating the SLE-related autoimmune process.
hCDR1 For the Treatment of Lupus: MOA
He says the compound is based on sequences of an antibody of lupus patients and seems to be disease-specific for lupus. The synthetic peptide was developed by Prof. Edna Mozes of the Weizmann Institute of Science in Israel, and there have been more than 40 peer-reviewed journal articles published on hCDR1.
The Weizmann Institute licensed the drug to Teva Pharmaceutical Industries, which conducted Phase 1a and 1b trials and the PRELUDE Phase 2 trial. The studies examined more than 400 patients, demonstrating that hCDR1 was well tolerated by patients and had a favorable safety profile.
The Phase 2 PRELUDE trial did not meet its primary endpoint, known as the systemic lupus erythematosus disease activity index (SLEDAI), which, at the time, was the gold standard in lupus testing. Benlysta also failed SLEDAI.
However, the drug achieved encouraging results in a secondary clinical endpoint, known as the British Isles lupus assessment group (BILAG) index. Mr. Levine recalls that a 0.5 mg weekly dose of the drug demonstrated a substantial effect, compared with the placebo arm.
Following the PRELUDE trial, in 2009, Teva returned hCDR1 to the Weizmann Institute's Yeda Research and Development Co.
As timing is everything, the FDA in 2010 published new guidelines stating that in future lupus trials, the BILAG index or another composite index called SLE Responder Index, or SRI, should be used as a primary endpoint. Benlysta's approval was based on the SRI endpoint.
XTL licensed hCDR1 from Yeda last January. According to Mr. Levine, the 0.5 mg dose of hCDR1 showed impressive results in its secondary endpoint, the BILAG index, on the "intended to treat" cohort. In addition, in multiple post-hoc analyses, there was an even more substantial effect in patients with reduced steroid use, as called for by the PRELUDE trial protocol, as well as a clear trend in other secondary endpoints.
"Had BILAG been the primary endpoint in Teva's PRELUDE trial, as called for by the updated FDA guidelines, the trial involving the 0.5 mg dose of the drug would have been successful," he contends.
"In our upcoming trial, we will not try to reinvent the wheel; all we have to do is replicate the Teva results in order to be successful. In addition, we intend to enforce a steroid sparing regimen that will afford us an even greater likelihood of success in our next trial."
XTL's proposed Phase 2b trial will have three arms. In addition to a placebo, it will dose patients with 0.5 mg and 0.25 mg weekly dose of hCDR1, enforce a defined regimen of steroids, with a trial duration of 52 weeks, and use a specialized contract research organization.
Mr. Levine expects the trial will cost between $12-million and $15-million and at this point, "we will look to raise the money and go it alone."
XTL's second program is recombinant human erythropoietin (rHuEPO) for the treatment of multiple myeloma ((MM)), an incurable malignant cancer of the blood. In the U.S., there are about 75,000 people living with MM, and 20,000 new cases are diagnosed annually, with 45,000 new cases diagnosed annually in the western world.
The disease is progressive with various complications, such as renal failure, bone pain and fractures, nervous system damage, anemia and infections, until death. Patients often stop treatment because of significant side effects and drug resistance
Current treatments include novel biological agents, such as lenalidomide and bortezomib, as well as other newly developed medications, with or without stem cell transplant. However, despite the progress in understanding the disease and the novel therapies, he says the disease is still incurable, and there is still an unmet need for a more effective and less toxic treatment, especially for patients that have failed all current treatments. The MM market is forecast to reach $5.3-billion in 2018.
Existing rHuEPO medicines include J&J's Procrit and Eprex, Roche's NeoRecormon and Amgen's Epogen and Aranesp. According to Mr. Levine, these treatments are used today primarily, if not exclusively, to treat anemia.
In the 1990s, Prof. Moshe Mittelman, who is now XTL's medical director, treated a number of advanced MM patients with rHuEPO for their anemia. Mr. Levine recalls that in the process, Prof. Mittelman noted that patients with advanced MM and with a life expectancy of approximately six months lived as long as eight years.
Further research by Prof. Mittelman and his team, in collaboration with other research teams, found that rHuEPO had an anti-myeloma effect by stimulating the immune system to induce disease regression and prolong survival of advanced MM patients. XTL has a use patent and orphan drug designation for the use of EPO in MM patients.
XTL plans to conduct a Phase 2 study to assess the safety and effect on survival of its rHuEPO in patients with advanced MM.
"Each of our two programs addresses areas of significant unmet medical needs, has compelling clinical data and should obtain significant clinical data in a reasonable amount of time," he adds. "XTL can manage the two proposed clinical trials simultaneously."
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