Pharmaceutical Industry Perspective and Developing Treatments for NP

1. Pharmaceutical Industry Perspective and Developing Treatments for NP John Messina, Pharm.D. Sr. Director Clinical Research Group Leader- Pain Management Cephalon, Inc

2. Areas requiring further discussion • Indications • EMEA vs FDA • Selection of painful conditions other than PHN or DPN • Two studies or One • Add on therapy • Appropriate duration of pivotal studies • Moving beyond pain intensity scales toward QOL and functioning benefits • Claims about efficacy for specific symptoms

3. US Pain associated with OA Mild to moderate pain Moderate to Severe Pain (opioids) Moderate to Severe Pain in opioid tolerant individuals Breakthrough cancer pain DPN PHN Fibromyalgia TGN EU Acute Mild to Moderate Acute Mod to Severe Chronic Mild to Mod Chronic Mod to Severe Cancer pain Breakthrough cancer pain Peripheral neuropathic (specific and broad) Central neuropathic Neuropathic pain Pain Indications

4. Examples of Medications Approved for Neuropathic Pain

5. Peripheral neuropathic pain • Acute/ chronic inflammatory demyelinating polyradiculoneuropathy • Alcoholic polyneuropathy • Chemotherapy-induced polyneuropathy • Complex regional pain syndrome • Entrapment neuropathies (eg, carpal tunnel syndrome) • Iatrogenic neuralgias (postthoracotomy pain) • Idiopathic sensory neuropathy • Nerve compression or infiltration by tumor • Nutritional deficiency–related europathies • HIV • Painful diabetic neuropathy • Phantom limb pain • Postherpetic neuralgia • Postradiation plexopathy • Radiculopathy • Toxic exposure–related neuropathies • Tic douloureux (trigeminal neuralgia) • Posttraumatic neuralgias Dworkin et al 2003

6. Central neuropathic pain • Compressive myelopathy from spinal stenosis • HIV myelopathy • Multiple sclerosis–related pain • Parkinson disease–related pain • Postischemic myelopathy • Postradiation myelopathy • Poststroke pain • Posttraumatic spinal cord injury pain • Syringomyelia Dworkin et al 2003

7. NP Conditions Where Antiepileptic medications with PHN and/or DPN indications are Prescribed Source: Verispan (PDDA)

8. Regulatory Guidance • FDA • No guidelines available • Sponsor meetings and review of recent approvals needed to determine path • Only have indications for specific NP conditions • EMEA • Provide guidance for indications of PN, CN, and for Broad NP • Require 2 studies in specific condition and 1 in another condition for broadening to claim • Feedback from member states indicates reluctance for this

9. Patient Selection • Methods for selecting patients with DPN and PHN have become well accepted • Outside US Central pain conditions have been accepted for indications • US Fibromyalgia indication has been given but no FDA published criteria • Is this a NP condition? • How do we move beyond this?

10. Indications with Mixed Pathophysiology ie Back pain • Previous presentation has defined the epidemiology of Nerve compressions/ nerve entrapments • Far more prevalent/ treated than PHN/DPN • Neuropathic Low Back Pains are the most common diagnosis and treated conditions • Patients with back pain commonly have pain consistent with neuropathic diagnosis • No criteria available for any sub-category of back pain from any regulatory authority despite large number of patients treated

11. Indications with Mixed Pathophysiology ie Back pain (cont.) • Unclear what would be required for achieving an indication for this use • Clinical symptoms • Clinical signs • Radiologic/ EMG evidence when diagnosing? • Pre-surgery vs post-surgical conditions • Should sponsors lump all nerve compressions in one trial? • Will authorities require a positive trial in each nerve compression? • Above would be prohibitive

12. Add-on Therapy • No one therapy has been proven to be overwhelmingly effective for treatment of NP • Response seen in 40-60% of patients • Even responders still have 70-50% of baseline pain still present • Increasing number of approved medications with different MOA • Nearly all potential clinical trial patients will be using one or more of these medications • What is the path forward for an add-on therapy indication • Will two arm studies suffice? • Is it mandatory to do a 3 arm study?

13. Trial Methodologies • Required duration of trials • PHN 8-12 weeks • DPN 12 weeks after determining dose • Fibro 12 weeks and 6 months • Why is 12-weeks on maintenance dose mandatory? • Claims of onset and assessment of effect over time • Primary outcome is always pain measure but requiring additional secondary's to be positive ie PGIC • Handling missing data • LOCF vs. BOCF • Mixed linear models should make BOCF redundant • Relapse Prevention Trials: • Will this be a requirement for all new drugs?

14. Outcome Measures • IMMPACT Group has identified key domains for chronic pain trials • Pain Intensity • Physical Functioning • Emotional Functioning • Patient Global Rating • Symptoms and Adverse Events • Patient Disposition

15. IMMPACT Recommended Outcome Measures

16. Dworkin 2008

17. Moving beyond analgesia • More and more demands being made to prove “benefits” of long-term analgesic therapy • If patient simply hurts less but has not impact on other domains risk benefit ratio becomes less positive (eg opioids) • What is the path forward for obtaining claims for these domains? • Patient selection (do we enrich?) • How long do we have to treat? • Is benefit in pain required within the trial/patient? • Proving Benefits in pain characteristics • Allodynia, hyperalgesia, dysthesia • Specific symptoms- burning, shooting, etc…