New Possibilities for Pain Treatment

7th Annual Pain Therapeutics Summit showcases therapies in development

by Megan Talkington on 20 Feb 2014

The annual Pain Therapeutics Summit, organized by Arrowhead Publishers and Conferences and chaired by William Schmidt, NorthStar Consulting, Davis, California, US, brings together investigators from industry and academia to discuss the progress of new pain therapies in preclinical and clinical development (see PRF related coverage of last year’s sessions here and here). For the most recent event, the organizers introduced a new format of two meetings, held September 25-26, 2013, in Boston, US, and November 7-8, 2013, in San Diego, US. The following report summarizes select presentations from the Boston meeting on novel pain targets and drug molecules.

Angiotensin II type 2 receptor antagonist gives first results

Inhibitors of the vasoconstrictive angiotensin II type 1 receptor (AT₁) are used widely to treat high blood pressure and heart failure. But researchers have also discovered that another member of the same receptor family, the AT₂ receptor, plays important roles in peripheral pain-sensing neurons (for recent results, see Anand et al., 2013). AT₂ is not involved in blood pressure regulation, and AT₂ receptor antagonists have been shown to be analgesic in a variety of rodent pain models, including a nerve injury model of neuropathic pain (Smith et al., 2013), a prostate cancer-induced bone pain model (Muralidharan et al., 2014), a model of antiretroviral drug-induced polyneuropathy (Smith et al., 2014), and an inflammatory pain model (Chakrabarty et al., 2013). Tom McCarthy of Spinifex Pharmaceuticals, Melbourne, Australia, presented results from a Phase 2 trial of the company’s AT₂ inhibitor, EMA401, in patients with post-herpetic neuralgia (PHN; Australian New Zealand Clinical Trials Registry). (Since the meeting, the trial results have been published; see Rice et al., 2014, and the accompanying review by Finnerup and Baastrup, 2014).

The study included 183 patients with PHN whose self-reported average pain intensity at baseline was 6.3 on a 0-10 scale. Patients were randomized to EMA401, taken orally twice a day for four weeks, or to placebo. In the treatment group, average pain scores dropped 2.3 points by the last week of treatment, compared to 1.6 points in the placebo group, for a statistically significant improvement over placebo of 0.69 points. Among patients receiving the drug, 34 percent showed at least 50 percent improvement in pain scores, compared to 19 percent of patients in the placebo group. Overall, McCarthy said that EMA401’s efficacy looked comparable to gabapentin, which is approved by the US Food and Drug Administration to treat PHN. And interestingly, benefit from EMA401 was similar regardless of whether patients were taking other pain medications during the trial. Adverse events were similar between drug and placebo groups and mostly mild; those that appeared more frequently in the drug group included headache and allergic dermatitis.

Spinifex is now testing EMA401 in a Phase 2 open-label study in patients with chemotherapy-induced painful neuropathy (Australian New Zealand Clinical Trials Registry) and is planning clinical trials in a range of chronic pain conditions, including diabetic neuropathy and pain due to osteoarthritis.

Glia-targeted therapy tested in dogs

In another talk, Linda Watkins, University of Colorado, Boulder, US, presented data on a glia-targeted therapy from Xalud Therapeutics, a company she founded and where she is currently chief scientific officer. The company, based in Boulder and San Francisco, US, is developing a non-viral interleukin-10 (IL-10) gene therapy.

Studies in animals have shown that in pathological pain states, activated glia in the spinal cord release proinflammatory products that drive pain and undercut opioid analgesia, and also create dependence and other undesirable effects (see PRF related news stories on morphine-induced neuroinflammation and hyperalgesia). IL-10, an endogenous anti-inflammatory cytokine, broadly counteracts those effects—it is “nature’s own negative feedback on neuroinflammation,” Watkins said. To boost IL-10 levels, Xalud developed XT-101, a non-viral gene delivery product in which IL-10-encoding plasmid DNA is packaged in biodegradable polymer microparticles. Watkins presented animal data showing that a single intrathecal injection of XT-101 reverses mechanical hypersensitivity for up to three months in rodent models of injury- and chemotherapy-induced nerve damage.

Watkins reported that the company has also tested XT-101 in pet dogs with naturally occurring painful conditions. In one dog with intractable neuropathic pain, she showed that a single intrathecal dose of XT-101 produced dramatic, progressive improvement in pain and disability (based on the treating veterinarian’s assessment) that continued for at least nine weeks. And injection of XT-101 directly into the osteoarthritic elbow joint of a dog resulted in a loss of pain and return to normal activity after three weeks, according to the owner’s assessment. To date, 12 dogs have been treated, and Watkins says “every single one” has shown improvement in their pain. “The dog data are so compelling,” she said. “It’s not just rats. It’s not just animal models. It’s real disease, spontaneous pain, quality of life.”

Now, Watkins hopes to replicate that improvement in people. She said Xalud is working toward beginning a Phase 1/2a ascending-dose trial of XT-101 in early 2015 in patients with radiculopathy or peripheral nerve injury-induced pain.

Building a gene delivery platform

Darren Wolfe of PeriphaGen, Pittsburgh, US, spoke about that company’s gene delivery technology for introducing therapeutic genes into peripheral neurons. PeriphaGen (formerly a subsidiary of Diamyd Medical) is developing an engineered herpes simplex virus type 1 (HSV1) for several different potential products, each of which expresses a natural pain-modulating or neurotrophic gene product.

The viral vectors are designed to be administered locally by intradermal injection. HSV1 naturally infects peripheral sensory neurons, and the vectors likewise enter those neurons at their peripheral termini. Experiments in animals show that the neurons transport the vectors back to the nerve body in the ganglia and express the gene there—and, in the case of secreted protein products, release the protein into the dorsal horn. Gene expression continues for weeks. (For a recent review from Wolfe and colleagues, see Goss et al., 2014.)

The first vector tested in people was PGN-202 (formerly called NP2), which expresses preproenkephalin (PENK), a precursor of the endogenous peptide ligands of the δ (delta) opioid receptor. In a previous Phase 1 open-label trial, patients with severe intractable pain from terminal cancer experienced profound pain relief, which lasted throughout the 28-day study for patients who received the highest dose (Fink et al., 2011; ClinicalTrials.gov). But, Wolfe said, a subsequent placebo-controlled Phase 2 study in 30 patients (ClinicalTrials.gov) failed to show statistically significant pain relief. He said PeriphaGen is interested in trying PGN-202 in other pain conditions. (For earlier coverage of preclinical and Phase 1 results presented by David Fink, University of Michigan, Ann Arbor, US, see PRF related news stories here and here.)

Wolfe also reported that two more vectors are moving toward clinical trials. PeriphaGen plans to test PGN-305, which expresses the GABA-producing enzyme glutamic acid decarboxylase (GAD), in patients with pain from diabetic neuropathy, and to test PGN-703, which expresses neurotrophin-3 (NT-3), as a prophylactic against chemotherapy-induced peripheral nerve damage. A vector expressing the endogenous opioid peptide endomorphin is also in preclinical development.

Targeting TRPV1

Selectively targeting primary afferent neurons was also the focus of a talk by Michael Iadarola, National Institutes of Health (NIH), Bethesda, Maryland, US. Iadarola and his team are working on agents that activate the transient receptor potential channel TRPV1. The channel is the target of multiple therapeutic strategies, including both agonists and antagonists (for a recent review, see Brederson et al., 2013). Paradoxically, while opening TRPV1 temporarily causes pain, keeping the channel open long enough can reduce pain. The prolonged activation of TRPV1 lets in a toxic flood of calcium ions that damage the axons of TRPV1-containing nociceptors or even kills the cells.

To wedge TRPV1 open, Iadarola is using resiniferatoxin (RTX), a highly selective, ultra-potent capsaicin analog and TRPV1 agonist from resin spurge plants. In previous studies in pet dogs with pain from bone cancer, intrathecal RTX produced dramatic improvement in comfort (Brown et al., 2005). The treatment has also been applied to arthritic pain in goats and nerve injury pain in horses. Iadarola and colleagues at the NIH are now performing an open-label Phase 1 trial (ClinicalTrials.gov) in people with pain from advanced cancer. The trial is ongoing, and it is too early to draw firm conclusions, but so far, Iadarola said, it appears that a single intrathecal injection of RTX can alleviate pain rapidly and greatly boost patients’ quality of life, allowing them to reduce or stop opioid use and become much more active. He said a future clinical trial will test intraganglionic injection for osteosarcoma pain.

In parallel, Iadarola is working on administering RTX at peripheral sites, to treat pain by targeting peripheral nerve terminals. In a proof-of-concept study in pet dogs, Iadarola reported that he and collaborator Dorothy Cimino Brown, University of Pennsylvania School of Veterinary Medicine, Philadelphia, US, found that peripheral treatment can have a strong and lasting effect. Iadarola showed a video of two dogs—one healthy and one with osteoarthritis treated with an RTX injection in the affected joint—and both were so active that the audience had a hard time telling the two apart. Iadarola said the treated dog is still pain free after a year and a half.

As an alternative to RTX, Iadarola and colleagues are pursuing positive allosteric modulators of TRPV1—compounds that do not open the channel by themselves but that help keep it open when it is already activated. Such drugs should selectively target neurons at sites of tissue damage or inflammation where TRPV1 is active. In a study published in 2012, Iadarola and colleagues injected the hind paws of rats with capsaicin to activate TRPV1 and found that co-injecting the allosteric modulator MRS1477 ablated nearby nerve terminals and reduced the animals’ thermal hypersensitivity near the injection site for several days. MRS1477 alone had no effect (Lebovitz et al., 2012). The results hint that MRS1477 could target nerve endings at sites of ongoing pain and selectively inactivate them, although the strategy has not yet been tested in a clinically relevant pain model. Iadarola and his colleagues at the National Center for Advancing Translational Sciences (NCATS) are also screening molecular libraries for additional allosteric modulators of TRPV1.

Trigeminal treatments

For the first time, the Pain Therapeutics Summit included talks on migraine, and Nadia Rupniak of CoLucid Pharmaceuticals kicked off with a presentation on lasmiditan, a 5HT1F subtype-selective serotonin receptor agonist being developed as an acute therapy for migraine. CoLucid, a virtual biotech based in Durham, North Carolina, US, acquired lasmiditan from Eli Lilly and so far has taken the compound through successful Phase 2 testing.

The current frontline treatments for migraine, triptans, activate members of the 5HT1 family of serotonin receptors, particularly vasoconstrictor 5HT1B receptors expressed in vascular smooth muscle. Lasmiditan selectively activates 5HT1F receptors, which are not widely expressed in blood vessels but are expressed on neurons in the trigeminal ganglia and brain.

That non-vascular mechanism of action may be important: Not only do triptans often provide inadequate pain relief, Rupniak said, but—because they constrict blood vessels—the drugs are contraindicated for the many patients who have cardiovascular or cerebrovascular conditions, and their use is further limited in patients with risk factors for undiagnosed cardiovascular disease. Animal studies indicate that lasmiditan does not cause vasoconstriction and instead acts on 5HT1F receptors on trigeminal neurons to inhibit nociceptive neurotransmission (Nelson et al., 2010).

Lasmiditan has shown significant migraine pain relief in two Phase 2 studies in migraine (Ferrari et al., 2010; Färkkilä et al., 2012; and see review by Charles, 2012). Rupniak also reported that the drug has been generally well tolerated in the Phase 1 and 2 program, in which over 700 patients have taken the drug. Side effects have been more pronounced at higher doses, with the most being CNS related, such as dizziness, with no evidence of cardiovascular adverse events. Now, she said, CoLucid is seeking to move the drug into Phase 3 studies.

David Yeomans, Stanford University School of Medicine, California, US, described work on nasal oxytocin as a new therapy for head pain conditions that involve the trigeminal nerves. A peptide hormone, oxytocin has been used therapeutically for 60 years, administered intravenously to induce labor or intranasally to promote lactation. Nasal oxytocin is no longer approved in most countries for lactation, Yeomans said, because of a lack of efficacy. But there is abundant evidence that oxytocin does relieve pain (for recent results in rodent models, see Juif et al., 2013, and de Araujo et al., 2014). And with its long history of widespread clinical use, Yeomans said, “It’s about as safe as you can get.” In 2007, Yeomans founded a company, Trigemina, to repurpose nasal oxytocin to treat chronic migraine, trigeminal neuralgia, and other forms of intractable chronic head pain.

The trigeminal neurons that signal pain in the face and head express oxytocin receptors, especially during painful inflammation. As a result, Yeomans reported, oxytocin has proven to be highly analgesic in rat models of head pain and inflammation. Nasal administration seems to be uniquely suited to deliver the peptide to the trigeminal system: Oxytocin sprayed into the nose gets picked up by the nerve terminals, transported back to the trigeminal ganglia, and then becomes distributed through the entire trigeminal system—“suggesting we have the potential to affect pain pretty much anywhere in the head,” Yeomans said.

Yeomans’ clinical colleagues have tested that theory by giving nasal oxytocin off-label to patients with a variety of intractable head pain conditions, and in 22 of 27 cases, he said, patients experienced complete or near complete relief.

Based on that anecdotal evidence, Trigemina initiated clinical trials with a nasal oxytocin formulation, TI-001. The first two trials, in episodic migraine, yielded results that were good but not dramatic, Yeomans said. But based on the evidence that oxytocin receptors are upregulated in inflammatory conditions, he and his colleagues looked at chronic migraine, which is thought to involve neurogenic inflammation. A controlled trial in 40 chronic migraineurs bore out that idea: By two hours after treatment, oxytocin showed a significant effect on pain compared to placebo. (Results from the trial were first presented at the June 2013 International Headache Congress.) Four hours after treatment, 27 percent of patients on oxytocin rated their pain at 0, compared to none of the patients on placebo. And a post-hoc analysis produced the interesting observation that the drug’s effects were stronger in patients who had not taken a non-steroidal anti-inflammatory drug (NSAID) within 24 hours—which echoed preclinical evidence that NSAIDs block oxytocin receptor expression. A larger Phase 2 trial for chronic migraine, in which patients receive TI-001 for eight weeks, is underway (ClinicalTrials.gov).

Yeomans is also keen to test nasal oxytocin in patients with trigeminal neuralgia, a condition notorious for its excruciating pain and lack of effective treatment. In a trigeminal root compression model in rats, TI-001 brought the animals’ mechanical sensitivity back almost to baseline, and Yeomans said that, in a small number of patients with trigeminal neuralgia who were treated with TI-001 in an open trial, all experienced pain relief.

Latching onto lipids

Roger Sabbadini, Lpath, San Diego, California, US, described a drug development effort focused not on proteins, but on the pain-promoting lipid lysophosphatidic acid (LPA). Lpath creates monoclonal antibodies that specifically and tightly latch onto and neutralize bioactive lipids. Lpath already has two antibodies targeting sphingosine-1-phosphate in Phase 2 clinical trials for cancer and macular degeneration. Sabbadini described their work on an anti-LPA antibody, Lpathomab, as a potential treatment for neuropathic pain.

LPA promotes neuronal damage and pain by acting via specific G protein­-coupled receptors in dorsal root ganglia (DRG) sensory neurons. In addition, a recent study showed that LPA may produce pain by directly activating TRPV1 (see PRF related news story). Given the multiple receptors through which LPA acts, Sabbadini said that targeting LPA itself, rather than its receptors, is the better strategy for stopping painful signaling.

Sabbadini reported unpublished data from collaborators showing activity of the antibody in several pain models in animals. In the partial sciatic nerve ligation model of neuropathic pain in mice, intrathecal injection of the antibody achieved days-long reduction of thermal and mechanical pain hypersensitivity. In streptozotocin (STZ)-induced diabetic neuropathy in rats, where LPA levels are increased in small-diameter DRG neurons, a single intravenous injection of the antibody ameliorated mechanical allodynia; chronic administration brought the animals’ sensitivity almost to normal, and allodynia returned when the treatment was stopped. The antibody also showed near complete, durable relief of mechanical allodynia in the Zucker diabetic fatty rat model of type 2 diabetes. And in the collagen antibody-induced arthritis (CAIA) model of rheumatoid arthritis, subcutaneous injection of Lpathomab relieved mechanical allodynia and reversed upregulation of pain-associated protein markers in the spinal dorsal horn.

Lpath is now manufacturing the antibody and beginning toxicity studies, Sabbadini said, in anticipation of clinical trials.

Finally, an old target made new

Not all talks covered such novel targets: Gavril Pasternak, Memorial Sloan-Kettering Cancer Center, New York, US, made the case for a still untapped potential in the opioid receptors. Each opioid receptor gene produces not one receptor, but a plethora of different splice variants that may have different downstream signaling properties. If pharmacologists could identify and target just those variants involved in modulating pain, they might effect analgesia without side effects. Pasternak focused on a set of μ (mu) opioid receptor (MOR) variants that lack the N-terminal transmembrane (TM) domain, producing receptors with only six (rather than the usual seven) TM segments. (For results on other splice variants from Pasternak and others, see PRF related news story.)

Pasternak’s lab has found, in experiments using knockout mice in which the different splice products are selectively deleted, that the MOR agonist IBNtxA (3-iodobenzoyl-6β-naltrexamide) acts on the six-transmembrane-domain (6TM) receptors. Morphine, on the other hand, acts only at the full-length receptor. Interestingly, IBNtxA is 10 times more potent than morphine, Pasternak said, and has performed well in animal models of neuropathic and inflammatory pain. Yet unlike morphine, IBNtxA does not cause respiratory depression in rodents, he said, and causes less constipation than morphine. Moreover, IBNtxA does not create physical dependence and is not rewarding in mice (Majumdar et al., 2011). “This is an interesting pharmacological profile,” he said. Encouragingly, he and his lab have found evidence that some opioid drugs that are used clinically and are well tolerated, such as buprenorphine, act on 6TM receptors—suggesting that targeting the truncated receptors might work in clinical practice.

How IBNtxA targets 6TM receptors remains unclear, but cell culture studies from Pasternak’s lab hint that the compound binds heterodimers of 6TM and full-length receptors. To dig further into the pharmacology, Pasternak said his lab is now synthesizing compounds with increased activity and selectivity for 6TM receptors.

As the meeting wound down, the participants were left with a number of new therapeutic possibilities to ponder. Which of the new drugs or mechanisms do you find interesting, or which have caveats that need to be addressed? Share your thoughts by commenting below.