Zalicus (NASADQ:ZLCS) will have data in the second half of this year that will provide important insights into the potential of its lead drug candidate, Z160, to be a breakthrough new class of non-opioid analgesic for the treatment of both chronic and acute neuropathic pain.
“There hasn’t been a lot of innovation in the pain space in many years, and we are one of the few companies exploring multiple novel mechanisms to address pain,” Justin Renz, EVP and CFO, says in an interview with BioTuesdays.com. “We have an opportunity for a breakthrough pain medication.”
Mr. Renz explains that Z160 is an oral, state-dependent, N-type calcium channel blocker that is designed to target and modulate only those neurons transmitting pain signals—specifically neurons that are undergoing high frequency firing.
“Preclinical and clinical data to date with Z160 suggest that this state-dependent mechanism of action may avoid the severe psychiatric and neurological side effects of existing drugs and compares well with other drugs used to treat neuropathic pain in terms of efficacy,” he adds.
Specifically, he points out that in animal studies using the spinal nerve ligation model of neuropathic pain, Z160’s efficacy was on par with: ziconotide, which is sold as Prialt by Jazz Pharmaceuticals; gabapentin, which is sold as Neurontin by Pfizer; and morphine. The company also has established a significant safety database with over 200 people, with no notable dizziness, somnolence or neuropsychiatric side-effects, he adds.
Zalicus’ new formulation of Z160, dosed at 375 mg twice-daily, generated a sixfold improvement in bioavailability and positive pharmacokinetics in Phase 1 clinical testing, compared with an earlier formulation developed by Merck at 1,600 mg a day. Merck returned the original formulation to a predecessor of Zalicus in 2009 after a Phase 2 trial, even though the compound had no serious adverse events.
Last September, Zalicus initiated a Phase 2 proof-of-concept trial to evaluate the safety and efficacy of Z160 as a treatment in reducing chronic lower back pain, or lumbosacral radiculopathy (LSR). LSR is a common neuropathic pain condition resulting from the compression or irritation of the nerve roots exiting the lumbar region of the spine.
Approximately 70 LSR patients, at some 20 sites, will receive Z160 twice daily for six weeks, and 70 will receive placebo. The primary endpoint is the change in weekly mean pain score on an 11-point neurologic rating scale. Top-line data from the study is expected in the fourth quarter this year.
In January 2013, Zalicus began enrolling a separate Phase 2 proof-of-concept trial with subjects with postherpetic neuralgia (PHN), a chronic state of neuropathic pain resulting from an outbreak of the herpes zoster virus, which is otherwise known as shingles. Top-line data are due to be released in the fourth quarter this year.
The six-week, double-blind, placebo-controlled study is expected to enroll 140 subjects at over 40 sites in the U.S. The primary objective of the trial is to evaluate the efficacy of Z160, compared with placebo in reducing pain in subjects with PHN as measured by a change in an average weekly pain score.
“Postherpetic neuralgia is an important medical condition for evaluating the activity of Z160 for several important reasons,” Mr. Renz says. “It is a well-recognized standard for establishing clinical proof of concept in neuropathic pain, and, with a prevalence of less than 200,000 patients in the U.S., it has the potential for orphan drug status and could be a feasible first indication to pursue from a commercial perspective.”
“There is a significant unmet medical need for novel, targeted and more efficacious chronic neuropathic pain therapies, with improved safety and tolerability profiles, such as Z160,” he adds.
In a new research report, Zacks Investment analyst, Jason Napodano, writes that the two studies “have the potential to dramatically re-value Zalicus,” noting that LSR is an attractive market opportunity. The prevalence of the condition is high, affecting 3% to 5% of the global population, and to date, there are no drug treatments specifically approved to treat it.
He figures that in LSR alone, Z160 could have a peak sales potential of $500-million or more, with a $250-million opportunity in PHN. Larger indications, such as diabetic peripheral neuropathy and fibromyalgia, may offer significant upside potential, depending on the outcome of pivotal trials, he adds.
Mr. Renz says the mechanism of action for Z160 has been validated by Jazz’s Prialt, which has well- documented clinical efficacy and is the only non-opioid synthetic peptide approved for the management of severe chronic pain in patients who are intolerant of, or refractory to, other treatment options such as morphine.
The problem with Prialt, he notes, is that it must be given through injections directly into the spinal canal so it reaches the cerebrospinal fluid. The Prialt label also includes a “Black Box” warning that it may cause psychiatric and neurological impairment. Jazz sold only around $21-million of Prialt in 2012.
“If we can prove our oral, small molecule product can hit only those neurons transmitting pain signals, without the side-effects, we’d really have something; that’s what we believe we have with Z160,” Mr. Renz adds.
In addition to Z160, Zalicus is developing a T-type calcium channel blocker, Z944, for chronic or acute pain. It is also discovering Nav 1.7 channel blockers for chronic pain as part of a research collaboration with Hydra Biosciences to identify potential clinical candidates.
Mr. Renz says Z944 demonstrated efficacy in preclinical inflammatory pain models and successfully completed a Phase 1 single- and multiple-ascending dose trial in the U.K. at the end of 2012. “We also know that Z944 penetrates the brain, which is important for a potential pain drug.”
There are no approved T-type calcium channel blockers on the market, and Zacks’ Mr. Napodano describes Z944 as representing a “potentially new and revolutionary way to treat acute pain.”
The company is consulting key opinion leaders in the field for ideas about the best chance of success with the molecule, and it hopes to conduct a proof-of-concept clinical study later this year. “We’re being deliberate to find the right dosing and right indication for this potent molecule,” Mr. Renz says.