Blocking pain – a long-term mission for pharma research

pharmafile | October 5, 2011 | Feature | Research and Development |  chronic pain, neuropathic pain, pain therapeutics 

Pain is a common, yet complex, clinical problem and one which remains an area of unmet need. There are however, a plethora of new targets – and clinicians and industry specialists discussed current challenges in the field at the recent Visiongain Annual Pain Management conference in London.

Researchers agree that while understanding of pain mechanisms has grown enormously in recent years – including the identification of potential drug targets – progress towards bringing new products to market has not matched this pace.

Dr Ramin Raouf is head of a pain research collaboration between King’s College London and Pfizer. Launched last year, it is an open innovation laboratory for pain research and brings together scientists from both sides to collaborate at the Wolfson Centre for Age-Related Diseases at the university’s Guy’s Campus in London.

Addressing the conference, Dr Raouf said there are four potential development strategies for pain therapeutics. Dosage forms or formulations of existing drugs can be improved. Existing medicines can be modified to improve efficacy or reduce side effects. New agents can be developed within an existing therapeutic class (Pfizer’s Lyrica [pregabalin], for neuropathic pain, which is similar to gabapentin, is a good example). And, finally, pharma can try to discover and develop innovative medicines based on new therapeutic targets – which is the interest of the Pfizer King’s lab under its open innovation scheme.

Chronic pain and fibromyalgia controversy

Chronic pain including neuropathic pain, fibromyalgia and osteoarthritis pain, represents a huge, but complicated, market opportunity for pharma. Anisur Rahman, professor of rheumatology, University College, London, spoke about approaches to the management of chronic musculoskeletal pain, which affects one in three in the Western world and elsewhere. “This is a huge burden on society and should be a priority for government,” he said.

Fibromyalgia, still a contentious diagnosis, accounts for many of these cases. Until relatively recently, fibromyalgia wasn’t a recognised condition, with some doctors believing it to be a merely a convenient catch-all for hard to diagnose pain.

However, it is now more widely recognised, and often labelled a syndrome. It is characterised by chronic widespread pain and tenderness at 11 out of 19 specific spots on the body. The existence of the latter allows for clear cut diagnosis and also inclusion of patients in clinical trials.

Drug companies are interested in the condition as it affects 2% of the population and is a long-term illness. Yet fibromyalgia is very hard to treat and in one study 85% of patients still had the condition after four years. Lyrica gained FDA approval as the first ever drug approved for the treatment of fibromyalgia in 2007.

This was swiftly followed by Lilly’s Cymbalta (duloxetine) a year later. Forest’s Savella (milnacipran) was then approved in the US in 2009.

Still no licensed fibro drug in Europe

Astonishingly, while all these drugs have been approved in the US, all have equally been refused marketing approval by Europe’s regulator the EMA. Pfizer filed the drug with the EMA in April 2009, but was twice rejected.

The following year, the EMA also rejected an application by Lilly and Boehringer Ingelheim for Cymbalta, saying efficacy data was insufficient and that it had not proven that benefits outweighed risks.

UCB became the latest company to be refused  approval for a fibromyalgia drug in March  2011, when its Xyrem (sodium oxybate) was rejected by the EMA. It should be noted that Jazz, which holds the US rights to the drug, has also had its marketing application rejected by the FDA.

EMA reservations about the drugs stem from the quality of trial data presented to them.

Professor Rahman says fibromyalgia trials have suffered from shortcomings such as follow up being too short and drop out rates due to side effects being too high. In future trials, ‘enriched enrolment’ may help to identify subsets of patients who are more likely to respond.

Neuropathic pain

Dr Michael Serpell, consultant and senior lecturer in anaesthesia, Greater Glasgow & Clyde NHS, spoke about the mechanisms of neuropathic pain with a focus upon painful diabetic neuropathy (PDN) which affects up to 25% of diabetes patients, and confer a 15% chance of amputation. The risk of PDN increases with age, duration of diabetes, and poor glycaemic control. Some pivotal pathways/targets underlie the pathogenesis of diabetic neuropathy, namely: aldol reductase, other oxidative pathways, C peptide replacement, nerve growth factor, cyclooxygenase, nuclear factor κβ.

Therapeutic goals in PDN include analgesia and improvements in physical activity, mood, sleep, side effects and concordance. “Over the last ten years there has been a lot more clarity on what drugs to use – mainly the three ‘anti’s (antidepressants, anticonvulsants, and antiarrhythmics),” Dr Serpell noted. Other drugs for PDN include capsaicin and opioids, while NICE recommends duloxetine as first line treatment.

Other new developments in this area include Grunenthal’s Versatis, a lidocaine hydrogel plaster which can be applied for 12-24 hours for post herpetic neuralgia, and Qutenza, a capsaicin patch which provides long-term relief in post-herpetic neuralgia.

In PDN, strict glycaemic control has been shown to reduce pain in the Diabetes Control & Complications Trial. It should be remembered that diabetes is a metabolic condition which means there are many different targets and mechanisms. This has led to the application of some new drugs such as the aldose reductase inhibitors (ARIs). The new ARIs have a lower toxicity profile and improved nerve penetration than older versions, examples including fidarestat, epalrestat, and ranirestat. “These are new and show promise,” said Dr Serpell. There is also benfotiamine, a lipid soluble thiamine derivative, which blocks three pathways involved in oxidative stress and has shown benefit in clinical trials. Meanwhile, α-lipoic acid is an antioxidant that reduces neurovascular hypoxia and also looks promising in trials.

Enzyme replacement could also play a role in the field. C peptide replacement is a promising new therapy which helps to regulate essential metabolic processes in type I diabetes and can prevent, and even reverse, axonal degeneration. There is also the possibility of neurotrophic replacement. US biotech company Cebix began phase Ib trials of its C peptide replacement therapy Ersatta in June this year.

Anti-NGF antibodies

A new class of biologic drugs could represent a major breakthrough in pain treatment – but their fate hangs in the balance following a halting of all trials in the area. Nerve growth factor (NGF) plays a key role in pain, sensitising nerve cells and triggering pain signals. New monoclonal antibodies that block NGF would be the first new class of pain treatment for decades, and there are numerous companies involved in the field. Pfizer is at the forefront with its candidate tanezumab (PF-4383119) in phase III trials, and pre-clinical studies suggested the molecule was equally or more effective than opiates or NSAIDs. Then in June 2010 some patients in the phase III osteoarthritis trial developed severe joint damage, sixteen of them requiring surgery to replace joints damaged by worsening osteoarthritis, and with evidence of bone necrosis. The FDA’s response was to suspend trials of Pfizer’s drug in June and July. When an additional case of joint failure emerged in another (unnamed) anti-NGF trial, the US regulator extended the trial suspension to all other ongoing anti-NGF trials. Other companies in the field include Sanofi and Regeneron (SAR164877, phase II) J&J and Amgen (Fulranumab, phase II), AstraZeneca (Medi-578) and Abbott (ABT-110).

Professor David Walsh, director of the Arthritis Research UK Pain Centre at the University of Nottingham said the class could be very significant. He noted in particular Johnson & Johnson’s trial of fulranumab in patients with moderate to severe OA. Like the other anti-NGF trials, it is ‘on hold’ at present, but he hoped trials could be resumed. ‘‘Clinical trials of blocking NGF in osteoarthritis are stunning. We have never seen anything like this since they invented joint replacement. Although there have been difficulties with side effects, this should still give hope.”

Professor Walsh discussed the pharmacological management of arthritis pain. He observed that a better understanding of the mechanisms and models of arthritis pain might lead to better treatments. For instance, osteoarthritis (OA) is a disease of the cartilage, but cartilage is not innervated so the source of the pain is not clear. Radiographs are only 50% efficient at predicting the presence or absence of pain. However, more modern imaging techniques have revealed structural associations of pain in osteoarthritis, including synovitis, osteochondrial vascularity, and bone marrow lesions. There is also evidence of inflammation in osteoarthritis, confirming that it is not just a degenerative condition. “The structure of the joint changes in ways likely to make the disease more painful,” explained Walsh. “It looks as if there is a widespread reduction in pain pressure thresholds in osteoarthritis compared to pain-free controls.”

No single animal model of OA actually mimics OA in patients, but a number have been developed that have helped show aberrant pain responses and how indomethacin or dexamethasone reduces joint swelling, macrophage infiltration, and pain behaviour. For instance, morphine and gabapentin reduce pain behaviour, and the bisphosphonate zoledronate inhibits osteochondral erosion and pain in animal models. 

New pain targets, trial designs

Ramin Raouf’s team is focused on researching ion channels as targets for pain. “We now know that multiple ion channels are involved in pain,” he said. “They are major players.” Pfizer’s pregabalin (Lyrica), which binds to a calcium channel is an existing example.

The Pfizer – King’s team is using advanced techniques to grow neurons in the lab, so that their action can be studied more closely.

The researchers have developed a microfluidic chamber (MFC) system consisting of 10 micrometer channels connecting two chambers which allows the isolation of the soma and axons of nociceptors and their better visualisation. “Axons can be independently excited in this model and the response in the soma recorded,” explained Raouf. 

The MFC has allowed axonal neurobiology studies which show that pain channels are present on the neurites of dorsal root ganglion neurons. Stimulation of axons and subsequent functional readout in the MFC represents an accurate in vitro model of nociceptor activation which is leading to a better understanding of pain mechanisms. They have also studied nociceptor innervation of skin, which is traditionally difficult to do, by co-culture of primary keratinocytes and DRG neurons.

Meanwhile, DRG and dorsal horn neurons have also been co-cultured in the MFC, which has led to the creation of a nociceptive circuit in vivo.

The ion channelopathy research is sure to lead to many new candidate drugs, but how these fare in clinical trials is uncertain. Pain, because of its complexity, is particularly difficult to treat in clinical trials. Dr Rolf Karlsten, medical science director, AstraZeneca, noted that many new analgesic drug candidates against new targets have failed to show efficacy. For instance, in the RELIEF study for diabetic neuropathy, 70% of those being treated in pain clinics received new treatments but only 15% got better and 8% actually got worse. There have been similar findings in post-herpetic neuropathy.

There are a number of reasons why studies with new analgesic drugs fail, some of which are to do with the trial design. Karlsten, who is working on an ‘ideal’ design for a phase IIa study in neuropathic pain, said it was particularly important to select trial participants with respect to the mode of action of the pain, rather than on disease entity.

He would also exclude patients with extreme pain, those receiving ongoing monetary compensation, with concomitant disease, a history of poor response and with long duration of pain. In short, trials should go for ‘enriched enrolment’ and be populated with patients most likely to show a response. Biomarker data would be helpful, but there are currently no validated biomarkers for pain response. The benefits of enhanced trial designs is that they are better at revealing the ‘efficacy signal’ of an analgesic drug and can help guide the selection of the target population for the next stage. 

“Pharmacological intervention is not the only approach to pain management. It needs to be combined with psychological approaches and physiotherapy,” Karlsten concluded.

Accessing the pain market

In 2009, Astellas signed a licensing agreement with NeurogesX to market Qutenza in Europe.

Qutenza is the first anaesthetic patch for post-herpetic neuralgia. The patch offers few systemic side effects, and gives up to three months of pain relief.

Dr Primrose Musingarimi, associate director in Health Economics and Outcomes Research, spoke about Astella’s experience in gaining market access. ‘‘We realise how important it is to understand pricing, reimbursement and the market access environment.” When it comes to cost-effectiveness analysis, much depends on whether the product is to be an add-on or a substitute for another drug. ‘‘There is not much information on what it costs to treat peripheral neuropathic pain,’’ Dr Musingarimi noted.

There is also little information on the prevalence of PNP. ‘‘This makes it challenging to apply for reimbursement if this pain condition is not even recognised as a problem. There is a need to understand the strengths and weaknesses of the product as perceived by payers and prescribers. It is really important to generate a roadmap to identify the health economics.” It may be necessary for a company to initiate observational studies to fill in the data gaps. Dr Musingarimi was optimistic on the product’s future:‘‘There is real excitement about Qutenza so we hope we will be able to overcome these barriers to market access in the next few years. ”

Beyond drugs

Drugs are not the only option for pain relief. Dr Sven Kili, global medical director of Genzyme’s Cell Therapy and Regenerative Medicine Group spoke about their hyaluronic acid products Celluvisc and Celluvisc-One.

Synovial fluid makes joints unique and it is hyaluronic acid which is responsible for the combination of elasticity and viscosity which is the hallmark of synovial fluid.

Viscosupplementation, by injections of Synvisc/Synvisc-One is a replacement for synovial fluid in osteoarthritis. It normalises the rheological environment of the joint, protects cells and tissues, restores synovial homeostasis, and is available for local application.

This results in decreased pain and increased mobility. Studies show that Synvisc gives long-lasting pain relief (up to 12 months) in knee OA and improves knee joint function.

The product can delay the need for total knee replacement by up to 3.8 years. Synvisc could also be used with earlier stage, younger, patients to help preserve the cartilage. Synvisc requires three injections, Synvisc-One just one injection. It is more difficult to inject than steroids, the traditional treatment for knee OA.

Originally Synvisc treatment was done by orthopaedic surgeons but is now being done by physiotherapists and GPs with a special interest in osteoarthritis.

‘‘It is all about educating people to do the injection properly and identifying the patient. Education for the patient is also very important,” concluded Dr Kili.