Filling the Pain Drug Pipeline

The 6th Annual Pain Therapeutics Summit, held 3-4 October 2012 in San Jose, California, US, and organized by Arrowhead Publishers and Conferences, brought together approximately 100 researchers from industry and academia to hear reports from the leading edge of pain drug development. Part 1 of our meeting coverage reported on efforts aimed at improving analgesic clinical trials. This report covers new agents and molecular targets presented at the meeting.

Sixteen new analgesic products were approved by the US Food and Drug Administration (FDA) in 2011 and 2012, said William Schmidt, NorthStar Consulting, Davis, California, US, when he opened the Pain Therapeutics Summit on 3 October. Not one hits a new target or has a novel mechanism of action. Instead, the products are simply new formulations of existing drugs, or old drugs approved for new conditions.

But novel candidates are making their way through the drug development pipeline, Schmidt said, and over the course of the meeting, speakers presented data on a diverse range of compounds aimed at new molecular targets.

Talks about nerve growth factor (NGF)-targeted drugs garnered the most attention. Anti-NGF antibodies showed impressive pain relief in clinical trials, but the FDA ordered a halt to most testing in 2010 after reports of unexplained joint damage in people treated with the agents. In March 2012, an advisory panel to the FDA unanimously recommended resuming clinical development (see PRF related news story). No new trials have been announced yet, but given the FDA panel’s strong endorsement of the approach, attendees were anxious to hear the clinical results so far, discuss the safety concerns, and learn about progress toward new trials.

Mark Brown of Pfizer, New London, Connecticut, US, and David Upmalis, Janssen Research & Development, Raritan, New Jersey, US, recapped previously presented data from trials of their companies’ NGF antibodies (see PRF coverage of Brown’s presentation at the World Congress on Pain in August 2012). In the last session of the meeting, attendees got some news: Brown announced that the FDA had recently lifted the hold on trials of Pfizer’s antibody, tanezumab. In addition, Stephen Miller, Array BioPharma, Boulder, Colorado, US, presented work on a different class of drugs targeting NGF signaling: small-molecule inhibitors of the NGF receptor TrkA (also discussed in PRF coverage of the August meeting).

NGF therapeutics are the furthest advanced among new classes of analgesics, but other agents are showing promise in preclinical and early-phase clinical testing. Four speakers presented data on potential new pain treatments aimed at fresh targets in the spinal cord and periphery.

Closing a pain-producing channel in peripheral neurons

Magdalene Moran, Hydra Biosciences, Cambridge, Massachusetts, US, gave an update on CB-625, a small-molecule selective antagonist of the transient receptor potential channel A1 (TRPA1), which Hydra is developing with Cubist Pharmaceuticals, Lexington, Massachusetts. Moran reported that CB-625 was well tolerated in a recent Phase 1a safety trial in healthy subjects, and Hydra/Cubist now plans to test the drug in patients with acute and chronic pain.

TRPA1, a cation channel broadly expressed in peripheral pain-sensing neurons, has emerged as a promising target for acute and chronic pain because of its special role in inflammatory hypersensitivity (for a review, see Bautista et al., 2012). Environmental irritants and inflammatory mediators directly activate TRPA1 on nociceptors to produce pain. In addition, activation of TRPA1 regulates release of neuropeptides that promote further inflammation and lead to the thermal and mechanical hypersensitivity that comes with inflammatory pain. Because of its importance in inflammatory hypersensitivity, the hope is that TRPA1-targeted therapies will relieve pathological pain while preserving normal (protective) pain sensation.

Further justifying TRPA1 as a therapeutic target, genetic evidence directly links the channel to pain in people. A gain-of-function mutation in the TRPA1 gene causes a rare pain disorder, familial episodic pain syndrome (Kremeyer et al., 2010), and genetic variations in the gene have been associated with sensitivity to experimental cold pain in the general population (Kim et al., 2006).

Preclinical data suggest TRPA1 inhibitors could find broad applications in chronic pain. TRPA1 antagonists from Hydra/Cubist and other groups have been shown to be effective in animal models of inflammatory hypersensitivity, neuropathic pain after nerve injury, and painful diabetic neuropathy (for a review, see Moran et al., 2011). In addition, Moran presented unpublished data showing that a Hydra/Cubist TRPA1 antagonist alleviated cold and mechanical allodynia in a rat model of chemotherapy-induced neuropathy. That work was done in collaboration with Gary Bennett, McGill University, Montreal, Canada.

Moran also highlighted recent animal data suggesting that TRPA1 inhibition not only relieves pain, but also has the potential to affect underlying disease processes as well. In one study, researchers showed that a lead compound from Hydra blocked inflammatory edema induced by carrageenan injection in the hind paw of mice (Moilanen et al., 2012). Another group showed that a TRPA1 antagonist reduced nerve loss in the streptozotocin model of peripheral diabetic neuropathy (Koivisto et al., 2011).

Reporting on clinical work, Moran said that in the recent Phase 1a trial, Hydra/Cubist tested oral dosing of the TRPA1 inhibitor CB-625 in healthy men. The drug showed pharmacokinetics favorable to twice-a-day dosing, and no safety concerns. Encouragingly, CB-625 caused no loss of acute heat or cold sensation in the trial subjects.

Moran said the first trial of CB-625 for pain will probably be in acute pain, because of Cubist’s focus on acute care. Meanwhile, Moran said, Hydra/Cubist is seeking new partners to advance TRPA1 inhibitors for patients with chronic pain.

Hydra is not the only company with a TRPA1 inhibitor in the clinic. Recently, Glenmark Pharmaceuticals, Mumbai, India, registered a Phase 2 proof-of-concept trial (ClinicalTrials.gov) of its TRPA1 inhibitor in patients with painful diabetic neuropathy.

Targeting neuronal sensitization in post-surgical pain

Donald Manning, Adynxx, San Francisco, US, gave an update on AYX1, an oligonucleotide under development to prevent acute and persistent post-surgical pain by targeting neuronal sensitization in the spinal cord. Manning reported that in a recent safety trial, AYX1 was well tolerated, and the company is about to start a Phase 2 proof-of-concept trial for post-surgical pain.

When patients undergo surgery, the barrage of pain signals coming into the spinal cord leads to neuronal sensitization, in which neurons in the dorsal horn become hyper-responsive to sensory input, so that normally mild stimuli can produce excruciating pain. Manning said this hypersensitivity, which patients experience as pain during movement, can be a major impediment to post-surgical recovery and rehabilitation. And, in some cases, short-term hypersensitivity after surgery persists and turns into chronic pain.

Studies in animal models indicate that the zinc finger transcription factor EGR1 (early growth response protein 1, also called Zif268 or NGFI-A) directs the development of hypersensitivity. The protein is rapidly and transiently upregulated in the spinal cord after trauma and triggers changes in gene expression that lead to neuronal sensitization and persistent pain. In rats, knockdown of EGR1 in the spinal cord alleviates mechanical allodynia in a model of inflammatory pain (Rygh et al., 2006). Manning hypothesizes that, because EGR1 plays its part early after injury, treatment with an EGR1 inhibitor at the time of surgery might nip painful hypersensitivity in the bud.

To inhibit EGR1, Adynxx is using a synthetic, 23-base pair, double-stranded DNA molecule (AYX1) that mimics the EGR1 consensus binding sequence. This “transcription factor decoy” grabs EGR1, preventing it from binding genomic DNA and turning on target genes.

Manning reported that, in unpublished experiments in a variety of rodent models, a single pre-surgery treatment with AYX1 reduced both acute and chronic hypersensitivity and promoted recovery of normal function in the animals, measured up to the time when control animals recovered from surgery (28 days after surgery). Based on those data, he proposes that a one-time intrathecal injection of AYX1 in people before surgery will reduce pain and speed recovery. Importantly, Manning said blocking EGR1 does not stop acute pain in animal models of surgery and nerve injury, so patients will still need anesthetics during surgery and analgesics immediately after surgery.

In the recent Phase 1 safety study of intrathecal administration of AYX1 in healthy volunteers, there were no safety issues even at the highest dose, Manning said. One concern researchers had going into the trial was that AYX1 could have cognitive side effects, because EGR1 contributes not only to spinal synaptic plasticity, but also to hippocampal processes involved in memory. However, subjects showed no apparent changes on a test of cognitive function.

Manning said Adynxx will begin a Phase 2 proof-of-concept study in January 2013 (ClinicalTrials.gov), testing whether adding a single pre-surgery AYX1 treatment to the normal post-surgical analgesic regimen will affect pain after total knee replacement surgery. The trial will follow approximately 95 patients for 42 days, and its primary endpoint will be pain during movement. Subsequent trials will test the drug in other types of surgery such as thoracotomy, Manning said.

Selective agonists of adenosine receptors

Daniela Salvemini, Saint Louis University School of Medicine, US, presented recent preclinical studies from her laboratory on small-molecule agonists of the A3 adenosine receptor (A3AR). The compounds are already being tested in patients for liver cancer and other conditions, and Salvemini’s results suggest they might also help patients with chronic pain.

Researchers have long known that adenosine is antinociceptive, Salvemini said, but administering adenosine or adenosine receptor agonists systemically risks serious cardiovascular and other side effects because of the widespread expression and functions of adenosine receptors. To get around those problems, researchers are investigating ways to boost adenosine levels locally (see PRF related news story), or to selectively activate adenosine receptor subtypes. Salvemini said agonists of the A1 and A2 adenosine receptors are being developed to treat neuropathic pain—but systemic delivery still carries the risk of cardiovascular side effects because A1 and A2 receptors are expressed in heart and vascular smooth muscle cells. Instead, she is focusing on the A3 adenosine receptor, which is expressed broadly but at low levels, and is upregulated in immune cells, including glial cells, under inflammatory conditions.

In the 1990s, Kenneth Jacobson and colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, developed the A3AR-selective agonist IB-MECA (N6-(3-iodobenzyl)-adenosine-5’-N-methyluronamide) and a chlorinated analog, Cl-IBMECA. Those compounds have reached Phase 2 and 3 clinical trials for liver cancer and autoimmune inflammatory diseases including rheumatoid arthritis. Salvemini and colleagues are now collaborating with Jacobson’s laboratory to test IB-MECA and other A3AR agonists in animal models of pain.

In a paper published earlier this year (Chen et al., 2012), the researchers reported that IB-MECA was effective in two neuropathic pain models. In mice, intraperitoneal injection of IB-MECA rapidly reversed mechanical allodynia after chronic constriction injury of the sciatic nerve. IB-MECA had no effect in A3AR knockout mice or in the presence of an A3AR antagonist, demonstrating that IB-MECA relieved pain specifically through the A3 receptor, and not other receptor subtypes. In this model, IB-MECA was more potent than morphine, gabapentin, and amitriptyline, and also potentiated their analgesic effects.

In the same paper, the researchers reported that IB-MECA was also effective in rat models of chemotherapy-induced painful peripheral neuropathy. Daily systemic administration of the drug (during the four to six days of chemotherapy administration and until the time of pain onset at approximately 16 days) blocked development of mechanical allodynia and hyperalgesia induced by paclitaxel, oxaliplatin, or bortezomib. Salvemini showed additional, unpublished data indicating that giving IB-MECA after chemotherapy could reverse established chemotherapy-induced pain. She also said that giving IB-MECA just during the short period of chemotherapy was sufficient to prevent development of painful hypersensitivity—which Salvemini said she was pleased to see, because it means patients could potentially receive the drug along with chemotherapy.

Given the encouraging preclinical results, and the fact that A3AR agonists are already in Phase 2 and 3 trials for cancer and other conditions, Salvemini said the drugs are good candidates for trials in chronic pain.

In the question-and-answer period, conference chair William Schmidt raised the interesting prospect that ongoing clinical trials of A3AR agonists for cancer might yield clues about the drugs’ pain-relieving properties if the trials included some measures of neuropathic pain.

In further preclinical work, Salvemini is investigating exactly how the A3AR agonists work. Chemotherapeutic agents are thought to trigger painful peripheral neuropathy in at least two ways: by damaging mitochondria in peripheral sensory afferents, and by triggering neuroinflammation in the spinal cord. Salvemini presented unpublished data from her laboratory indicating that IB-MECA counteracts both effects. In peripheral afferents, the researchers found that the drug restored mitochondrial antioxidant enzyme activity and ATP production. In the spinal cord, IB-MECA blocked pro-inflammatory signaling and boosted levels of the anti-inflammatory cytokine interleukin-10 (IL10).

Gene therapy for cancer pain

Michael Graham, Benitec Biopharma, Sydney, Australia, spoke about a new gene therapy approach to combat central sensitization. His company is carrying out preclinical studies of lentivirus gene therapy vectors designed to achieve long-term gene silencing in the spinal cord, with the goal of treating intractable neuropathic pain in patients with terminal cancer.

Benitec is targeting the PRKCG gene, which encodes protein kinase C gamma (PKCγ), an enzyme that animal studies have shown is critical for the development of chronic inflammatory and neuropathic pain. For example, mice deficient for the gene display reduced pain from nerve injury while retaining normal acute pain sensation (Malmberg et al., 1997; Zhao et al., 2011), and researchers have also found that inhibiting spinal PKCγ reduces thermal hyperalgesia and mechanical allodynia in a mouse model of bone cancer pain (Xiaoping et al., 2010). The results in animal models have made PKCγ an attractive therapeutic target for neuropathic pain, but inhibitors that specifically target the gamma isoform, and avoid other PKCs, are lacking.

In a paper published last year, researchers in China tried a new tack for specifically blocking PKCγ: lentiviral-mediated RNA interference (Zou et al., 2011). In this method, lentiviral vectors deliver DNA sequences that, once inside of cells, are transcribed into short hairpin RNAs (shRNAs) that direct the cell to degrade PKCγ-encoding mRNAs. The researchers found that, in rats, injection of the PKCγ-targeting lentiviruses into the spinal cord reduced neuropathic pain from chronic constriction injury. Graham and his colleagues are aiming to use a similar strategy—which they call “ddRNAi” (DNA-directed RNAi)—in people.

To do that, Benitec developed lentiviral constructs that can silence both rat and human PKCγ, in hopes that they can take the same constructs through preclinical testing and clinical trials. Now, Graham said, David Yeomans and colleagues at Stanford University School of Medicine, California, US, are in the process of testing two of the vectors in the spared nerve injury model of neuropathic pain in rats.

In contrast to other gene therapy vectors, lentiviruses stably integrate into the host genome and confer permanent gene silencing. That could be a benefit: In the rat study, treatment with PKCγ-targeted lentiviral vectors relieved pain for at least six weeks (Zou et al., 2011). Likewise, Graham said he and his colleagues envision that a single treatment would provide patients with long-term relief. Some meeting attendees, however, expressed skittishness about gene therapy, and especially about an agent that would permanently alter the genome of spinal neurons.

In the question-and-answer period, Magdalene Moran compared the ddRNAi gene therapy strategy to intrathecal injection of resiniferatoxin, a strong agonist of TRPV1 that produces a toxic influx of calcium ions into nociceptive sensory neurons and thus selectively ablates those cells; the drug has shown weeks-long pain relief in animal models and is now being tested in patients with severe pain from advanced cancer (see PRF related news story). Resiniferatoxin, she said, has a long-lasting effect, but without the concerns of gene therapy.

Conference chair William Schmidt, too, expressed worry over gene therapy, but said that in patients with severe and treatment-resistant pain from advanced cancers, the need for new therapies is so pressing that Benitec’s approach may be worth a try. “There is relatively less concern about genomic alterations in patients who may have a short lifespan and are in intractable pain,” Schmidt told PRF.

At the close of the Pain Therapeutics Summit, attendees had a cache of early-phase drug candidates to consider—gene therapy vectors, one DNA drug, and two small molecules. Some expressed hope that, led by movement in the anti-NGF field, the analgesic pipeline may be flowing again at last.

Did you attend the Pain Therapeutics Summit, or have you been following any of these analgesic candidates? We invite you to share your thoughts by leaving a comment below.