DARA Bio ($DARA) - KRN5500 article from the Journal of Pain and Symptom Management International

Vol. - No. - - 2011 Journal of Pain and Symptom Management 1Original ArticleA Spicamycin Derivative (KRN5500) ProvidesNeuropathic Pain Relief in Patients WithAdvanced Cancer: A Placebo-Controlled,Proof-of-Concept TrialSharon M. Weinstein, MD, Amy P. Abernethy, MD, Susan E. Spruill, PStat, MS,Isadore M. Pike, MD, Andrea True Kelly, PhD, and Linda G. Jett, MSNPain Medicine and Palliative Care Program (S.M.W.), The Huntsman Cancer Institute, andDepartment of Anesthesiology (S.M.W.), University of Utah, Salt Lake City, Utah; Duke Cancer CareResearch Program (A.P.A.), Duke Cancer Institute, Durham, North Carolina; Applied Statistics &Consulting (S.E.S.), Spruce Pine, North Carolina; Izzy Pike MD Consulting (I.M.P.), Fairhope,Alabama; ATK Clinical Consulting (A.T.K.), Charleston, South Carolina; and DARA BioSciences(L.G.J.), Raleigh, North Carolina, USAAbstract Context. Neuropathic pain in patients with cancer can be difficult to treateffectively. Objectives. The purpose of the study was to determine safety and efficacy ofKRN5500, a novel, spicamycin-derived, nonopioid analgesic agent, in patients withadvanced cancer and neuropathic pain of any etiology. Methods. The study was a Phase 2a, multicenter, double-blind, placebo-controlled, dose escalation clinical trial. Patients with refractory neuropathic painand advanced cancer were randomly assigned 2:1 to receive a maximum of eightsingle escalating doses of KRN5500 or placebo, ranging from 0.6 to 2.2 mg/m2.The primary objective was safety and tolerability. The secondary objective wasefficacy, measured by change in average pain intensity on a 0e10 numeric ratingscale administered one week after the patient’s final dose. Results. Nineteen patients received treatment (KRN5500 n ¼ 12; placebon ¼ 7). The most frequently reported adverse events were gastrointestinalsymptoms, which were more frequent and severe with KRN5500 than placebo; two(17%) KRN5500 patients discontinued the study because of nausea and vomiting.At study end point, KRN5500 exhibited a significant median decrease in painintensity from baseline of 24% compared with 0% for placebo (P ¼ 0.03). Themedian for largest weekly reduction in target pain intensity was 29.5% forKRN5500 and 0% for placebo patients (P ¼ 0.02). Conclusion. This proof-of-concept study for KRN5500 in patients with advancedcancer and any type of neuropathic pain found gastrointestinal adverse events tobe the predominant safety concern. The results also provided the first indicationAddress correspondence to: Linda G. Jett, MSN, DARA Accepted for publication: May 5, 2011.BioSciences, 8601 Six Forks Road, Suite 160, Raleigh,NC 27615, USA. E-mail: ljett@darabio.comÓ 2011 U.S. Cancer Pain Relief Committee 0885-3924/$ - see front matterPublished by Elsevier Inc. All rights reserved. doi:10.1016/j.jpainsymman.2011.05.003

2 Weinstein et al. Vol. - No. - - 2011of clinical and statistical efficacy in reducing pain intensity. J Pain SymptomManage 2011;-:-e-. Ó 2011 U.S. Cancer Pain Relief Committee. Published by ElsevierInc. All rights reserved.Key WordsNeuropathic pain, cancer, KRN5500, spicamycin, allodyniaIntroduction nonopioid analgesics and adjuvant therapy consisting of anticonvulsants, antidepressants, Neuropathic pain is characterized by an ab- and corticosteroids was successful for bothnormal hypersensitivity to innocuous and nox- types of pain, although the lack of controlledious stimuli and can persist long after the treatment and comparison arms makes the re-tissue damage and inflammation that induced sults difficult to generalize.10,11the pain have resolved. The International Asso- KRN5500, a novel spicamycin derivative pro-ciation for the Study of Pain defines neuro- duced by Streptomyces alanosinicus, was discov-pathic pain as ‘‘pain initiated or caused by ered in an effort to identify new agents thata primary lesion or dysfunction in the nervous induced differentiation of myeloid leukemiasystem’’1 and more recently, as ‘‘pain arising as cells. KRN5500 failed to establish significanta direct consequence of a lesion or disease therapeutic efficacy as a potential antineo-affecting the somatosensory system’’ in an plastic agent in Phase 1 trials conductedattempt to more effectively distinguish neuro- under a cancer Investigational New Drugpathic pain from nociceptive (e.g., inflamma- application.12e14 However, clinical observa-tory pain) and musculoskeletal or other types tions of a patient who experienced remissionof pain that arise indirectly in the course of neu- of severe neuropathic pain while receivingrologic disorders.2 KRN5500 for metastatic cancer sparked inter- Eleven million patients worldwide are af- est in this drug as a possible neuropathicflicted by neuropathic pain.3 The etiology of pain treatment. For more than two decades,neuropathic pain includes diverse conditions, the patient, who was enrolled in a KRN5500such as diabetic neuropathy, postherpetic neu- cancer trial, had been treated for peripheralralgia, trauma, HIV/AIDS, and cancer-related neuropathy and severe pain secondary to im-neuropathy secondary to tumors, surgery, ra- munoglobulin A monoclonal gammopathydiotherapy, and chemotherapy, as well as toxic and Raynaud’s disease. Surprisingly, althougheffects from a number of medications.4 More no pain response was anticipated, the patient’sthan one pathophysiologic mechanism may neuropathic pain improved from the time ofunderlie neuropathic pain symptoms in cancer his first infusion with KRN5500. His progresspatients, making this population more difficult was well documented and later published asto treat effectively.5,6 In addition, some experts a case history. He remained free of this long-in the field consider neuropathic pain more standing and severe neuropathic pain untilresistant than nociceptive or inflammatory his death from cancer two months after stop-pain to standard analgesic treatments.7,8 A ping study treatment, although over the samelarge prospective epidemiological study found period of time, there was no apparent effectthat the proportion of neuropathic pain con- on the patient’s upper quadrant pain, whichtributing to cancer pain was 33%, with opioid was associated with liver metastases. The ab-therapy effective in providing 50% relief for dominal pain continued to worsen duringthe neuropathic pain.9 Another large prospec- the last months of his life, thus providing antive study surveyed routine clinical practice, initial indication that KRN5500 may not bebased on the 1986 version of the World Health effective for nociceptive pain.15Organization cancer pain guideline, in a large This serendipitous finding led to nonclinicalpopulation of advanced cancer patients with in vivo studies evaluating response to KRN5500neuropathic or mixed (neuropathic and noci- in rodent pain models. In three standard ratceptive) pain. A combination of opioid and

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 3models of nerve injury-induced neuropathic curative therapeutic option. There was no re-pain, single doses of KRN5500 reversed pain striction on therapies that might contributehypersensitivity within two hours, with effects to patients’ comfort or quality of life. Palliativelasting up to six weeks. KRN5500 had no ef- (noncurative) chemotherapy was allowed iffects in uninjured rats or in a rat model of compatible with study drug in terms of dosingacute inflammatory pain, suggesting specificity schedule and stable adverse event (AE) profile.for pain that is neuropathic in nature and sup- Although the patient population comprisedporting earlier clinical observations of neuro- patients with advanced cancer, refractory neu-pathic but not nociceptive pain relief.16e18 ropathic pain of any etiology was acceptable KRN5500 inhibits acetylcholinesterase and for study entry. Refractory was defined as fail-fatty acid amide hydrolase enzymes, both tar- ure to achieve adequate pain relief from atgets that can modulate aspects of neuropathic least two commonly used treatments for neuro-pain. KRN5500 lacks activity at 87 other evalu- pathic pain. The target neuropathic pain forated G protein-coupled receptor, ion channel, the study had to be characterized by at leastand enzyme targets. The prolonged duration two of the following symptoms: burning pain,of action seen in the rat pain model studies shooting/lancinating pain episodes, dysesthe-does not correlate with plasma pharmacokinet- sias, or allodynia at an overall pain score ofics (terminal half-life ¼ 0.6e1.5 hours), sug- $4 on a 0e10 numeric rating scale (NRS), de-gesting that KRN5500 might have disease spite any pain therapies patients were receivingmodifying activity through synergistic interac- at the time. Patients were allowed to continuetions between the two identified mechanisms their usual pain treatments, including nonste-or through an as yet unidentified mechanism. roidal anti-inflammatory, antidepressant, anti- convulsant, and opioid medications if the treatments were thought to be contributing to partial pain relief for the target neuropathicMethods pain or other pain conditions. Because eachPatients patient was likely to have more than one type This Phase 2a study was a multicenter, and location of pain, the neuropathic paindouble-blind, randomized, placebo-controlled that was considered the primary complaintdose escalation trial designed to evaluate the was identified as the target neuropathic painsafety and efficacy of KRN5500 in patients for clinical assessments and patient self-with advanced cancer and neuropathic pain evaluation; study staff recorded the targetedof any etiology (Fig. 1). Advanced cancer was pain area in each diary NRS page as reinforce-defined as cancer in which there was no ment for patients in rating their daily ‘‘target’’ Fig. 1. Schematic of dose escalation and treatment decisions.

4 Weinstein et al. Vol. - No. - - 2011pain. Eligibility was restricted to patients with Clinical personnel, monitors, patients, andno radiation therapy to the target pain site the sponsor remained blinded throughoutwithin four weeks of screening and no major the study to treatment received.surgery within two weeks. Patients were re-quired to be at least five half-lives posttreat- Treatment Schedulement with any other investigational drugs. A maximum of eight single escalating dosesEligibility was not restricted by type of cancer ranging from 0.6 to 2.2 mg/m2 were adminis-or projected life expectancy. tered during weekly visits as an intravenous (IV) infusion completed in one hour or less,Study Design with a maximum of 5 mg established for any The primary objective of this trial was to eval- single dose. KRN5500 (6-[4-Deoxy-4-[(2E,4E)-uate the safety and tolerability of KRN5500 tetradecadienoylglycyl]amino-L-glycero-ß-L-manfor neuropathic pain in patients with advanced nohepto-pyranosyl]amino-9H-purine) was for-cancer. Secondary objectives were to assess the mulated in a mixture of dehydrated alcohol;analgesic activity and the dose-response rela- propylene glycol, NF; polysorbate 80, NF;tionship of KRN5500. All investigative sites, N,N-dimethylacetamide (DMAC), monoetha-the protocol, and study materials were ap- nolamine, NF; and normal saline and was ad-proved by the investigator’s local or a central- ministered intravenously. Placebo was normalized Institutional Review Board. The study saline, indistinguishable visually from thewas independently monitored by i3Research, KRN5500 IV solution. Blinding was furthera contract research organization, and conduct- enhanced by covering IV bags with an opaqueed in accordance with Good Clinical Practice material.guidelines. Safety was assessed on an ongoing Patients were evaluated over a 14-week pe-basis through monthly review of all available riod, inclusive of follow-up. At each clinic visit,data by a safety committee comprising the the investigator evaluated whether to redosestudy oncology adviser and medical monitor. the patient with the same dose, a lower dose, Patients were randomly assigned to receive the next higher dose, or no dose, based on as-up to eight doses of test article (KRN5500) sessments of tolerability, efficacy, and the pa-or placebo over a 10-week treatment period tient’s desire for treatment. During eachfrom December 2006 to March 2009. The ran- clinic visit, diary 0e10 NRS pain scores were av-domization schedule, generated by a third- eraged for the six days after the previous dose,party statistician, assigned 24 patients to one and the percent change from the previousof two treatment groups in a 2:1 ratio week’s average was calculated. This informa-(KRN5500:placebo) using a block size of three tion was used clinically to determine the ap-over all sites in an effort to obtain sufficient propriate dose for that visit. For dosingdata from at least 18 patients. The study was purposes, response to study drug was definednot powered for prospective efficacy out- as at least a 20% decrease in target pain inten-comes; rather, information regarding esti- sity from the previous week’s average NRSmates of efficacy was to be used to make an scores. Before dosing, patients were asked,informed decision regarding further develop- ‘‘Is your target pain still significant enough toment. As such, no formal sample size calcula- you that you’d like further treatment?’’ Fig. 1tions were carried out for this study. The presents a schematic of dose escalationsample size of 18 was considered typical for guidelines.similar proof-of-concept/feasibility studies.19 During the course of treatment, if unaccept-Patients were assigned to treatment in sequen- able treatment emergent AEs (TEAEs) oc-tial order based on the randomization scheme curred, the patient could receive the nextusing an automated web-based central ran- lower dose. If unacceptable TEAEs occurreddomization process accessed by site study per- at the minimum dose (0.6 mg/m2), the pa-sonnel on obtaining signed informed consent tient was discontinued from the trial. Labora-and verifying all eligibility criteria. Random- tory values and patient-reported AEs wereized patients who discontinued study participa- considered when evaluating tolerability andtion before being dosed were replaced with additional dosing. The patient’s overall physi-new patients assigned to the same treatment. cal condition related to the patient’s cancer

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 5also was a factor in dosing. There were occa- from 0 to 10, where 0 represented ‘‘no pain’’sions when dosing was withheld because of and 10 represented the ‘‘worst possible pain,’’the need for respite from therapy or to accom- collected by a clinician at each weekly clinicmodate increased treatment for underlying visit. Secondary efficacy measurements in-conditions. Patients were encouraged to com- cluded NRS scores recorded by patients eachplete at least four treatment visits to allow for evening in a diary. The mean change in scoresthe possibility of full dose escalation but were for the six days after each dose was used forinstructed that they were not expected to par- dosing decisions and secondary end pointticipate beyond that if they did not perceive analyses. Other secondary efficacy assessmentsany benefit from study participation. included examinations and questionnaires for measuring dimensions of neuropathic painSafety, Tolerability, and Pain Response and quality of life. These included the Neuro- Evaluation of safety and tolerability of pathic Pain Questionnaire (NPQ), Brief PainKRN5500 was the primary objective of this Inventory-Short Form (BPI-SF), allodyniastudy. To assess safety and tolerability, AEs, physical examination, Karnofsky Performanceclinical laboratory assessments, vital signs, Status (KPS), and the 12-item Short Formand electrocardiogram data were collected at Health Survey (SF-12v2Ò).21e24 Patients alsoeach visit. TEAEs were defined as AEs with on- recorded all pain medication use in a diary.set after the date and time of the first treat- Results were summarized by treatmentment, or, if the event was present before group. Statistical tests, when performed, weretreatment, worsening after study intervention. two sided, nonparametric tests (WilcoxonTEAEs were assessed for intensity (mild, mod- Rank Sum Test), conducted at the a ¼ 0.05 sig-erate, or severe) and relatedness to treatment nificance level. Data summaries and analysesby the investigator. Levels of intensity were de- of results were generated using SASÒ versionfined as: milddthe symptom was barely notice- 8 or later (SAS Institute, Cary, NC). No interimable to the patient, did not influence analyses were performed. All statistical analysesperformance or functioning, and generally were prospectively planned and documenteddid not require prescription drug treatment; in an analysis plan before unblinding the data.moderatedthe symptom was of sufficient sever-ity to make the patient uncomfortable, perfor-mance of daily activities was influenced, andprescription of other treatment for the symp- Resultstom may have been needed; severedthe symp- Demographic and Baseline Characteristicstom caused severe discomfort, sometimes of Nineteen male and female patients, agedsuch severity that the patient could not con- 18 years or older with advanced cancer and re-tinue in the study, and prescription or other fractory neuropathic pain of any etiology, weretreatment for the symptom was likely neces- enrolled at nine centers across the continentalsary. Serious adverse events (SAEs) were de- U.S. and Puerto Rico. Because of a randomiza-fined per U.S. Food and Drug Administration tion error at one site, a patient who was toguidelines as any AE meeting one or more of receive KRN5500 was given placebo, resultingthe following criteria: 1) was fatal or life- in 12 patients receiving KRN5500 and seventhreatening; 2) was permanently disabling; patients receiving placebo. Data presented3) resulted in unplanned or prolongation of are based on treatment received (Fig. 2).hospitalization; 4) resulted in persistent or Chemotherapy-induced peripheral neuropa-significant disability/incapacity; 5) resulted thy was the most frequently recorded etiologyin birth defect/congenital anomaly; or 6) re- for patients’ neuropathic pain, followed byquired medical intervention to prevent any of complex regional pain syndrome-Type II andthese outcomes.20 surgery-related neuropathic pain. Investigators The secondary objective of this study was frequently documented more than one etiol-evaluation of efficacy. The efficacy end point ogy. Patients most often identified lower limbs,measurement was the average target pain in- followed by upper limbs, back, and face as thetensity score over the previous 24 hours as site of the target neuropathic pain for the pur-measured by an 11-point NRS score, ranging pose of assessing NRS scores, allodynia

6 Weinstein et al. Vol. - No. - - 2011 Assessed for eligibility (n=25) Excluded (n=6) ♦ Not meeting inclusion criteria (n=5) ♦ Declined to participate (n=0) ♦ Other reasons Schedule conflict (n=1) Randomized (n=19) Allocated to KRN5500 (n=13) Allocated to placebo (n=6) ♦ Received KRN5500 (n=12) ♦ Received placebo (n=7) ♦ Did not receive KRN5500 (patient received ♦ Did not receive allocated intervention (n=0) placebo in error) (n=1) Lost to follow-up (n=0) Lost to follow-up (n=0) Discontinued KRN5500 (n=9) Discontinued placebo (n=5) ♦ Adverse event (n=3) ♦ Adverse event (n=1) ♦ Withdrawal of consent (n=3) ♦ Protocol violation (n=1) ♦ Progression of disease (cancer) (n=2) ♦ Withdrawal of consent (n=3) ♦ Bed-rest ordered by oncologist (n=1) KRN5500 patients analyzed (n=12) Placebo patients analyzed (n=7) Excluded from analysis (n=1) Excluded from analysis (n=0) ♦ Intention to treat (n=13) ♦ Intention to treat (n=6) ♦ Modified efficacy (n=12) ♦ Modified efficacy (n=7) Fig. 2. CONSORT diagram of patient disposition in the study.examination scores, and all other assessments. study (10 treatment weeks), the protocol andThe same target neuropathic pain location, informed consent form specified that patientsspecified at the initiation of the trial, was to were not expected to remain in the study be-be consistently assessed for efficacy measure- yond its perceived benefit to them. Of the 14ments throughout the study. Baseline patient patients who discontinued before receivingdemographics and neuropathic pain charac- their eighth possible dose, nine (75%) wereteristics are summarized in Table 1. treated with KRN550 and five (71%) were treated with placebo.Safety and TolerabilityExposure to Study Drug. Table 2 provides data Adverse Events. A summary of TEAEs is pre-on exposure to study drug and reasons for dis- sented in Table 3. All patients (100%) whocontinuation. The median duration of expo- received KRN5500 had at least one TEAE, com-sure was 40 days for the KRN5500 treatment pared with 86% who received placebo. Eventsgroup compared with 29 days for the placebo of greater severity were more frequent in thetreatment group. On average, KRN5500 pa- KRN5500 group compared with placebo,tients took 5.3 doses whereas placebo patients and more patients treated with KRN5500 dis-took 4.4 doses. The highest dose of KRN5500 continued study participation because ofreceived was 2.2 mg/m2. Seven (58%) patients TEAEs (25%) compared with those treatedtreated with KRN5500 were exposed to at least with placebo (14%). The most frequently re-one dose at this level, and four (57%) placebo ported TEAEs were gastrointestinal (GI) in na-patients were escalated to at least one dose of ture (primarily nausea and vomiting), whichnormal saline at this level. occurred more often and with greater severity Given the serious nature of patients’ ill- in the KRN5500 group than in the placebonesses and the relatively long length of the group. GI events in the KRN5500 treatment

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 7 Table 1 Table 2 Baseline Patient Demographics and Exposure to Study Drug and Discontinuation Characteristics KRN5500 Placebo KRN5500 Placebo Metric (n ¼ 12) (n ¼ 7) (n ¼ 12) (n ¼ 7) Median number of 5.5 (3, 8) 4.0 (2, 8)Variable Mean (SD) Mean (SD) doses (range) Median days of 40 (14, 71) 29 (9, 64)Age (years) 61 (12.0) 63 (13.4) exposure (range)aBody surface area (m2) 1.9 (0.21) 1.7 (0.35) Median dose densities 1.27 (0.7, 1.5) 1.20 (0.6, 1.5) (mg/m2/week)bNRS 7.4 (1.62) 6.4 (1.90) (range) Number (%) of patients n (%) n (%) by dose levelc 0.6 mg/m2 12 (100) 7 (100)Gender 1.2 mg/m2 12 (100) 6 (86) Male 6 (50) 4 (57) 1.8 mg/m2 10 (83) 6 (86)Race 2.2 mg/m2 7 (58) 4 (57) Caucasian 9 (75) 5 (71) Patients completed $4 10 (83) 6 (86) Black 1 (8) 1 (14) dosing visits Other 2 (17) 1 (14) Patients completed all 3 (25) 2 (29) a dosing visitsEtiology of neuropathic pain Patients withdrawn 9 (75) 5 (71) Chemotherapy induced 10 (83) 7 (100) Reason for early Complex regional pain 4 (33) 0 withdrawal syndrome-Type II AEd 3 (25) 1 (14) Complex regional pain 1 (8) 0 Protocol violation 0 1 (14) syndrome-Type I Lost to follow-up 0 0 Postherpetic 1 (8) 0 Withdrawal of 3 (25) 3 (43) Cancer related 1 (8) 0 consente Radiation induced 1 (8) 0 Death 0 0 Diabetic 1 (8) 0 Otherf 3 (25) 0 Surgery related 1 (8) 1 (14) Carpal tunnel syndrome 1 (8) 0 AE ¼ adverse event. a Duration of exposure ¼ date of last dose À date of first dose þ 1 in bTarget neuropathic pain the specified interval. b Lower extremity 7 (58) 5 (71) Dose density is calculated as average weekly dose, including rest Upper extremity 3 (25) 1 (14) weeks. c Trunk 1 (8) 1 (14) The number of unique patients receiving each dose level. The percentage is calculated using the number of patients in each treat- Face 1 (8) 0 ment group as the denominator. dSD ¼ standard deviation; NRS ¼ numeric rating scale. One KRN5500 SAE (seizures) and two KRN5500 AEs of nausea/a Most patients had more than one etiology recorded. vomiting led to withdrawal; one placebo SAE (stroke) led tob Target neuropathic pain identified as specific body area for all as- withdrawal. esessments; recorded on the NPQ and diary NRS forms for patients No explanations were collected for ‘‘Withdrawal of Consent.’’ It isto refer to. possible that some patients withdrew consent because of lack of benefit (absence of pain relief). f Reasons for ‘‘Other’’ included: two KRN5500 for progression of disease; one KRN5500 attending oncologist recommended bed rest.group were considered related to study drugand required treatment with antiemetic medi- study drug; and 3) hospitalization 18 days aftercations. After the first study dose, antiemetics the last dose of study drug for convulsions andcould be provided prophylactically if clinically secondary memory loss (caused by the devel-indicated. Two patients receiving KRN5500 opment of a new brain metastasis in a patientwithdrew from the study because of GI with head and neck cancer). All events weresymptoms. followed until resolution. One patient receiv- A greater percentage of patients in the ing placebo experienced a stroke after the sec-KRN5500 group (25%) experienced an SAE ond dose of placebo, which led to disabilitycompared with those in the placebo group and discontinuation from the study. This SAE(14%). All SAEs in the KRN5500 group oc- was considered not related to treatment andcurred during the posttreatment follow-up pe- remained unresolved at the end of theriod and were not considered related to study follow-up period.drug. The following SAEs occurred in theKRN5500 group: 1) hospitalization for conges-tive heart failure and pneumonia 24 days after Other Safety Assessments. No significant labora-the last dose of study drug; 2) hospitalization tory abnormalities related to study drug werefor dehydration 29 days after the last dose of observed in either treatment group. As a whole,

8 Weinstein et al. Vol. - No. - - 2011 Table 3 NRS data plotted to show baseline, weekly, and TEAEs and Organ System Most Affected end point scores and depicts positive or nega- KRN5500 Placebo tive final outcome. (n ¼ 12) (n ¼ 7) The median greatest weekly reduction (i.e.,TEAEs n (%) n (%) best response) in target pain intensity wasPatients with any TEAE 12 (100) 6 (86) 29.5% for KRN5500 patients, whereas the me-Patients with any TEAE by gender dian in placebo patients was 0% (P ¼ 0.02) Male 6 (100) 3 (75) (Fig. 4). Clinic NRS data also were evaluated Female 6 (100) 3 (100) for clinically meaningful levels of pain reduc-Patients with an SAEa 3 (25) 1 (14) tion achieved during the study (Table 5).Patients with an AE leading to 3 (25) 1 (14) withdrawalb There was little difference between treatmentPatients with an AE outcome of 0 0 groups for patients that achieved $50% pain death reduction; 25% of KRN5500 vs. 14% of pla-By organ system most affectedc cebo patients achieved this level. However, GI disorders 11 (92) 4 (57) Mild 4 (33) 2 (29) 50% of KRN5500 vs. 14% of placebo patients Moderate 3 (25) 2 (29) achieved $30% pain reduction. In addition, Severe 4 (33) 0 83% of KRN5500 patients reached $20% Related 11 (92) 1 (14) Nervous system disorders 6 (50) 2 (29) pain reduction compared with 29% of placebo Infections and infestations 3 (25) 0 patients who reached this level. Metabolism and nutrition 3 (25) 0 Daily patient diary NRS ratings were highly disorders Musculoskeletal and connective 3 (25) 2 (29) correlated with in-clinic ratings (r ¼ 0.87; tissue disorders P ¼ 0.007); however, there was no statistical dif- Psychiatric disorders 3 (25) 0 ference between groups, with the KRN5500 Skin and subcutaneous tissue 3 (25) 4 (57) disorders group providing a median decrease from base- General disorders and 2 (17) 0 line of 16% compared with 0% for placebo administration site conditions (P ¼ 0.07) (Fig. 5). Investigator allodynia test-TEAE ¼ treatment emergent adverse event; SAE ¼ serious adverse ing yielded a 33% median decrease in painevent; AE ¼ adverse event; GI ¼ gastrointestinal.a All SAEs were assessed as not related to study drug. for both mechanical and cold stimuli in theb One KRN5500 SAE (seizures) and two KRN5500 AEs of nausea/ KRN5500 group compared with 0% and 8%vomiting led to withdrawal; one placebo SAE (stroke) led towithdrawal. decrease, respectively, in the placebo group.c Events experienced by two or more patients in either treatment There was no median change (0%) in KPSgroup. scores for either treatment group (Table 5).no clinically relevant changes in vital signs or Additional Questionnaires and Assessmentsnegative changes in physical examinations In general, when a difference between treat-were observed in either treatment group. Elec- ment groups was observed in patient self-ratedtrocardiogram changes were within acceptable written questionnaires and assessments, thelimits for all parameters. results were mixed (Table 6). In the NPQ, placebo patients had more reduced scores for individual symptoms (seven of 10) thanEfficacy Assessments KRN5500 patients (two of 10). However, theAnalgesic Activity of KRN5500. Patients receiv- difference in symptom improvement betweening KRN5500 exhibited a statistically significant the two groups was generally <12%, exceptmedian decrease in average pain intensity of for Pain because of weather change, which pro-24% based on baseline in-clinic NRS scores, vided the difference in favor of placebo withwhereas the median change in patients receiv- 21% improvement compared with 3% foring placebo was zero (P ¼ 0.03). There was no KRN5500 and Freezing pain, which showedclear linear relationship between reduction in a larger decrease in the KRN5500 group atpain intensity and increasing dose for either 33% compared with 0% in the placebo group.group (Table 4). The median for absolute unit The BPI-SF also showed very little differencedecrease on the 11-point NRS scale was two between treatment groups, with the only nota-units for KRN5500 and zero for placebo ble difference in favor of placebo for Pain relief(Table 5). Fig. 3 provides individual patient in last 24 hours showing 32% improvement

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 9 Table 4 Median Change From Baseline NRS in Target Pain Intensity and Median Best Response Across Dosesa KRN5500 (mg/m2) Placebo (mg/m2)Dose 0.6 1.2 1.8 2.2 Allb (range) 0.6 1.2 1.8 2.2 Allb (range)n 1 2 3 6 12 1 0 2 4 7Endpointc change (%) À25 À14 À30 À6 L24 (L100, 0) À20 d 0 0 0 (L20, 25) one week after final dose KRN5500 (mg/m2) Placebo (mg/m2)Dose No dosed 0.6 1.2 1.8 2.2 Anye (range) No dosed 0.6 1.2 1.8 2.2 Anye (range)n 3 4 1 2 2 12 2 3 1 0 1 7Bestf response (%) one À29 À24 À13 À32 À92 L29 (L100, 0) 13 0.0 À60 d À13 0.0 (L60, 25) week after any doseNRS ¼ numeric rating scale.a Based on in-clinic NRS results.b Includes all final doses for endpoint analysis.c P ¼ 0.03, obtained from a Wilcoxon rank sum test.d Some patients achieved their best responses after the rest week, when no dose was given.e Denotes best response at any dose.f P ¼ 0.02, obtained from a Wilcoxon rank sum test.compared with 6% in the KRN5500 group. as fibrosis or myelopathy post-radiotherapy,The SF-12 quality-of-life instrument showed chemotherapy, surgery, or combinationsno difference between treatment groups, nor thereof.25 Treatment of neuropathic pain indid two self-rated allodynia questions for cancer patients is even more complicatedtouch- and cold-induced pain. given that epidemiological research is severely lacking.26 Additionally, most agents devel- oped for neuropathic pain have been studiedDiscussion and Conclusions in noncancer patients, such as those with Diagnosis and treatment of neuropathic postherpetic neuralgia or diabetic peripheralpain in cancer patients remains challenging. neuropathy. Successful results in those set-There are often multiple pathophysiologic tings may not always apply to the complex pa-pain etiologies present in a single patient tient with advanced cancer and neuropathic(neuropathic pain and nociceptive or inflam- pain.27matory pain), often with multiple origins. For This Phase 2a randomized and controlledexample, neuropathic pain can be the result trial using NRS scores as a measure of efficacyof nerve lesions caused by direct tumor inva- provides the first demonstration of safety andsion or result from secondary causes, such efficacy for KRN5500 in a small cohort of Table 5 Changes From Baseline by Treatment Group for NRS Absolute Units, Standard Percentage Reductions, Allodynia Examinations, and Performance StatusMeasure KRN5500 (n ¼ 12) Placebo (n ¼ 7)Actual NRS unit change from baseline, median (range) À2 (À7, 0) 0 (À1, 1)Clinic NRS: standard percentage reductions Number (%) of patients who achieved $50% reduction 3 (25) 1 (14) Number (%) of patients who achieved $30% reduction 6 (50) 1 (14) Number (%) of patients who achieved $20% reduction 10 (83) 2 (29)Allodynia physical examination, median (range) Dynamic (mechanical)dtouch-induced pain À33 (À100, 0) 0 (À100, 300) Thermaldcold-induced pain À33 (À100, 0) À8 (À100, 100)KPS, median (range) 0 (À10, 30) 0 (À10, 0)NRS ¼ numeric rating scale; KPS ¼ Karnofsky Performance Status.

10 Weinstein et al. Vol. - No. - - 2011 Baseline Endpoint Weekly Visits Pain Improved Pain Worsened 10 9 8 7 Clinic NRS 6 5 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 |-------------------------KRN5500--------------------------| |-----------PLACEBO---------------| PatientsFig. 3. Absolute change in NRS scores for each patient by treatment group. (Total number of NRS weekly scoresper patient [up to 11] cannot be ascertained in this figure as duplicate scores are not depicted, with the exceptionthat a score [only 1] that overlays baseline and/or end point is visible.)patients with treatment-resistant neuropathic significant GI symptoms emerging as the pre-pain (of any etiology) and advanced cancer. dominant and only safety concern at doseThe KRN5500 safety profile showed clinically levels that notably reduced pain intensity.Fig. 4. Maximum reduction in neuropathic pain score by patient ordered from greatest to least within treatmentgroup. (P ¼ 0.02 obtained from a Wilcoxon rank sum test.)

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 11 Table 6 10 Median Percent Change From Baseline in Patient-Rated Questionnaires One Week After Final Dose 8 KRN5500 Placebo (n ¼ 12) (n ¼ 7)Clinic NRS 6 Patient self-rated assessmentsa % change (range) % change (range) 4 r = 0.87 NPQ Burning pain À15 (À100, 0.0) À7 (À100, 67) 2 Sensitive to À8 (À100, 100) À17 (À100, 0) touch Shooting pain 0 (À100, 200) À11 (À100, 20) 0 Numbness À5 (À100, 50) À7 (À40, 11) 0 2 4 6 8 10 Electric pain À14 (À100, 0) 20 (À100, 20) Diary NRS Tingling pain À14 (À100, 300) À23 (À100, 0) Squeezing pain 0 (À100, 300) 0 (À100, 20)Fig. 5. Correlation of weekly diary and clinic NRS Freezing pain À33 (À100, 0) 0 (À21, 0)scores for all subjects. (Diary scores are plotted as Pain because À6 (À100, 700) À16 (À100, 100) of touchthe mean of the first six daily NRS scores after Pain because À3 (À100, 900) À21 (À100, 0)each weekly visit.) of weather changes BPI-SF Pain at its worst 0 (À100, 33) 0 (À25, 25) Study safety data demonstrate that drug- in last 24 hours Pain at its least À16 (À100, 20) 0 (À40, 300)related GI symptoms of nausea, vomiting, in last 24 hoursand less frequently, diarrhea were a distressing, Pain on the 0 (À100, 100) 0 (À40, 13)though temporary, adverse effect of KRN5500. average Pain right now 0 (À100, 67) 0 (À43, 50)Although these symptoms occurred in the pla- Pain relief in À6 (À50, 250) À33 (À100, 0)cebo group as well, the frequency, severity, and last 24 hoursrelatedness to study drug indicate that this may Mean of pain 2 (À100, 29) 0 (À29, 12) severitybe a clinically significant problem associated Mean of pain À10 (À100, 131) 2 (À23, 51)with the use of KRN5500. No other safety con- interferencecerns were identified. SF-12Ò Certain excipients, namely DMAC and mono- Physical 0 (À2, 10) À1 (À3, 2)ethanolamine, part of the Phase 1 anticancer component summaryformulation that also was administered in this Mental 3 (À10, 11) 2 (À20, 8)study, are known to cause nausea and vomit- componenting;28,29 in addition, patients receiving placebo summarywere given normal saline without any of the for- Self-rated allodyniamulation excipients used with KRN5500. Thus, questionnaireit is not possible at the present time to deter- Touch-induced À30 (À100, 60) À17 (À100, 33)mine whether the GI effects are a result of the pain Cold-induced À32 (À100, 29) À31 (À100, 0)active pharmaceutical ingredient, formulation painexcipients, or a combination thereof. In an ef- NPQ ¼ Neuropathic Pain Questionnaire; BPI-SF ¼ Brief Painfort to better understand and decrease these Inventory-Short Form; SF-12Ò ¼ Short Form Health Survey. aside effects, reformulation efforts are underway For all assessments, decreases in scores indicate improvements, except for SF-12, where higher scores indicate better healthto replace emetogenic components with ingre- status.dients that are Generally Recognized as Safe(GRAS). KRN5500 yielded a significant median de-crease in pain intensity from baseline when correlated with clinic NRS scores, and clinicalcompared with placebo. Efficacy was further testing of allodynia yielded a substantial me-supported by the significant difference in dian pain decrease for both mechanical andthe median best (largest) pain reduction per cold stimuli in the KRN5500 group and nonepatient. Diary NRS scores were highly in the placebo group.

12 Weinstein et al. Vol. - No. - - 2011 Study results also provided clinically mean- led to fatigue and confusion in scoring. It alsoingful decreases in absolute pain units on is possible that several versions of the samea standard clinical 0e10-point pain intensity question served to divide the level of pain intorating scale, with 10 of 12 KRN5500 patients smaller components, in much the same wayachieving a two-point reduction compared that the NPQ divides pain into symptomwith one of seven placebo patients (Fig. 3). components.Six of 12 KRN5500 patients achieved $30% A major limitation of the study was its smallreduction in pain, whereas one of seven pla- sample size, making the study vulnerable tocebo patients achieved this level. In similar variable outcomes. In particular, because pa-studies, meeting a standard cutoff of 30% tients were allowed to escalate to an effectivefor pain reduction or an absolute reduction dose, the number of patients in any particularof two units on a standard 0e10-point pain dose level was too small to reliably estimateintensity rating scale is considered clinically a dose-response relationship. Although it issignificant.30 possible that positive results in this study repre- Except for the diary NRS scores, none of the sent a Type I error (false positive outcome),32data collected entirely by patient self-rated in- there is strong evidence supporting the posi-struments showed a trend for efficacy in either tive analgesic outcome, including both clini-group. Results from the NPQ and BPI-SF were cally and statistically significant results, as wellvaried and did not provide clinically significant as nonsignificant but positive trends.differences in individual symptoms or overall It is notable that, except for diary NRS scores,levels of pain or relief. Small differences and each of the positive efficacy results is based onmedian scores with wide ranges make the data ascertained by clinician interview (askingresults difficult to interpret. Aside from the the patient to rate their pain) or clinician exam-small sample size, the authors have no clear ination with an interview component, such asexplanation for these inconsistencies other the allodynia examination, which combinedthan the possibility that some tools were mechanical and cold stimulation with verbalmore sensitive than others in detecting treat- collection of NRS pain scores before and afterment differences in this particular group of the stimulation. The diary NRS question wassubjects. written with exactly the same wording as the ver- The NPQ divides the overall target pain bally administered clinic NRS question, whichlevel into 12 components (symptoms). With likely contributed to its positive correlationthe exception of burning pain, changes from to primary efficacy end point results. None ofbaseline on individual questions varied greatly the other data collected through patient-from week to week, suggesting that the recorded outcomes provided meaningfulcomponent questions were not a sensitive trends in either direction.measure of treatment differences in this study. Patients did choose a ‘‘target neuropathicBecause the pattern of symptoms is different pain’’ site for focused assessment throughoutfor each patient, it may not be reasonable to the study, and although there may be variabilityexpect component scores to show the same in the degree to which patients and clinicianspattern or degree of change as the overall were able to separate one site and kind ofpain rating. The NPQ is designed as a diagnos- pain from another, tests, such as the allodyniatic tool for confirming neuropathic pain and physical examination could only have pro-has not been validated as an instrument for duced results by strictly focusing on the targetmeasuring efficacy through changes in symp- area. The fact that pain was significantly re-tom scores.31 duced is in itself a positive finding, even if it rep- The BPI-SF asks patients to rate pain in four resents a more nonspecific site or overall paindifferent ways on the same 11-point NRS scale, relief in some patients. Careful selection of di-as follows: ‘‘worst pain in the last 24 hours,’’ agnostic and neurological tests, more thorough‘‘least pain in the last 24 hours,’’ ‘‘pain on the av- training for patients, and appropriate patient-erage,’’ and ‘‘pain you have right now.’’ None of rated questionnaires will be important forthese is exactly the same wording used for the future studies.clinic/diary NRS assessment. It is possible that Large placebo effect in pain trials often con-asking so many versions of the same question tributes to difficulty in establishing significant

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 13differences between treatments.33 Placebo re- results or a positive trend not considered ro-sponse, although present, was low in this study. bust enough. Given the burden of suffering as-The reasons for this are not known, but the sociated with severe pain, resultant greatfact that patients were more or less near clinical need for new pain therapies, and thethe end of life, and were willing to enter into overwhelming odds against bringing new ther-a placebo-controlled trial, may be an indica- apeutics to proof of concept, we believe that ittion that pain was sufficiently severe to make is important to move forward with cautious op-any sustained placebo response unlikely. timism to design a Phase 2b study. Future stud-Though baseline pain levels were not unusu- ies of KRN5500 with modified formulationally high, it is possible that baseline and contin- excipients may shed additional light onued pain levels represented subjectively higher whether this investigational drug holds prom-discomfort than would be the case in patients ise as a tool for oncologists and pain specialistswho have not endured as much physical and working with cancer patients or for those whoemotional stress. may have recovered from cancer only to find High study withdrawal rate is another factor their quality of life seriously impaired by con-that has repeatedly contributed to failure in tinued neuropathic pain.oncology symptom control studies.34 Because In conclusion, KRN5500 demonstratedthis study was considered lengthy for patients safety at dose levels providing first therapeuticwith advanced cancer and a serious pain condi- evidence for treatment-resistant neuropathiction, an unusual approach was used to proac- pain in patients with advanced cancer, al-tively address an anticipated high withdrawal though causing transient GI side effectsrate. In this study, over and above the usual that were generally manageable. Despite thestatement that participation is voluntary and relatively small sample size, statistically signifi-patients can withdraw at any time, patients cant and clinically meaningful improvementswere explicitly told that they were not ex- in pain were observed in patients treatedpected to continue participation if the study with KRN5500 when compared with placebo.was not beneficial or if other more pressing With continued formulation development,needs presented. Patients were asked to com- better selection of diagnostic and efficacy as-mit to at least four treatment visits if possible, sessment tools, and larger well-controlled tri-to allow for the possibility of escalation to the als, KRN5500 may hold promise as a safe andhighest dose to assess for efficacy if it would oc- effective treatment, especially for patientscur. This may have contributed to subjects re- with severe disabling neuropathic pain.maining on study at least long enough toreach an efficacious dose or to determinethat the study drug was not providing analgesia(no response). Most patients stayed in the Disclosures and Acknowledgmentsstudy for the minimum period requested. This study was funded by the sponsor,The analysis plan called for data collected DARA Therapeutics, a subsidiary of DARA Bio-one week after the last dose, no matter when Sciences (DARA). DARA personnel participatedit occurred, to serve as the efficacy end point, with industry advisers, investigators, and consul-which resulted in no missing end points and tants in designing the study. i3Research, a con-no data carried forward to fill in missing tract research organization under contract withassessments. the sponsor, conducted the study, including Given the difficulty in reproducing positive site monitoring, data management, and statisti-outcomes in postmarketing and comparator cal analysis.trials of analgesic medications (e.g., gabapen- Of the authors, Sharon M. Weinstein was antin), it is possible that pain studies may be par- investigator; Amy P. Abernethy was an investiga-ticularly susceptible to a Type II error (false tor and has been a DARA consultant as well;negative outcome) related to some of the is- Isadore M. Pike (oncologist), Susan E. Spruillsues discussed above. As a result, potentially (statistician), and Andrea True Kelly (clinicalbeneficial therapeutics may be abandoned adviser/medical writer) are DARA consultants.too early in development because of negative Linda G. Jett is an employee of DARA.

14 Weinstein et al. Vol. - No. - - 2011 The authors thank the patients, study coor- intravenous infusion for five consecutive days to pa-dinators, and enrolling investigators: Ghassan tients with refractory solid tumors. Clin Cancer ResAl-Jazayrly, Enser Cole, Thomas Cosgriff, Tanya 2003;9:5178e5186.Dorff, Louis Rivera-Colon, Jack Saux, Leonard 14. Yamamoto N, Tamura T, Kamiya Y, et al. Phase 1Sender, and Jose Stable. and pharmacokinetic study of KRN5500, a spicamycin derivative, for patients with advanced solid tumors. Jpn J Clin Oncol 2003;33:302e308. 15. Borsook D, Edward A. Antineuropathic effectsReferences of the antibiotic derivative Spicamycin, KRN5500. 1. Merskey H, Bogduk N. Classification of chronic Pain Med 2004;5:104e108.pain. Seattle, WA: IASP Press, 1994. 16. Abdi S, Vilassova N, Decosterd I, Feroz N, 2. Treede R-D, Jensen TS, Campbell JN, et al. Neu- Borsook D. The effects of KRN5500, a spicamycinropathic pain: redefinition and a grading system for derivative, on neuropathic and nociceptive painclinical and research purposes. Neurology 2008;70: models in rats. Anesth Analg 2000;91:955e999.1630e1635. 17. DiLorenzo L, Kobierski L, Moore KA, 3. Olsen S. Providing an enhanced perspective on Borsook D. A water soluble synthetic Spicamycin de-neuropathic pain. Consulting and marketing report. rivative (San-Gly) decreases mechanical allodynia inSan Mateo, CA: WWMR, Inc., 2002. Available from a rodent model of neuropathic pain. Neurosci Letthttp://www.highbeam.com/publications/pr-newswire- 2002;330:37e40.p3672/aug-27-2002/2. Accessed September 28, 2011. 18. Kobierski L, Abdi S, DiLorenzo L, Feroz N, 4. Pappagallo M, ed. The neurological basis of Borsook D. A single intravenous injection ofpain. New York: McGraw-Hill, Co., 2005. KRN5500 (antibiotic spicamycin) produces long- term decreases in multiple sensory hypersensitivities 5. Baliki MN, Gehe PY, Apkarain AV, Chialvo DR. in neuropathic pain. Anesth Analg 2003;97:174e182.Beyond feeling: chronic pain hurts the brain, dis-rupting the default mode network dynamics. 19. Skare K, Sietsema W. From serendipity to sci-J Neurosci 2008;28:1398e1403. ence. Good Clin Pract J 2005;12:1e4. 6. Kuchinad A, Schweinhardt P, Wood P, Chizh BA, 20. U.S. Food and Drug Administration. Code ofBushnell MC. Accelerated brain gray-matter loss in Federal Regulations Title 21. IND safety reports.fibromyalgia patients: premature aging of the brain? 21CFR312.32.J Neurosci 2007;27:4004e4007. 21. Krause S, Backonja M. Development of a neuro- 7. Arner S, Arner B. Differential effect of epidural pathic pain questionnaire. Clin J Pain 2003;19:306e314.morphine in the treatment of cancer-related pain. 22. Cleeland C, Ryan K. Pain assessment: global useActa Anaesthesiol Scand 1985;29:32e36. of the Brief Pain Inventory. Ann Acad Med 1994;23: 8. Cherny NI, Thaler HT, Friedlander-Klar H, et al. 129e138.Opioid responsiveness of cancer pain syndromes 23. Karnofsky D, Abelman W, Craver L, Burchenal J.caused by neuropathic or nociceptive mechanisms: The use of nitrogen mustards in the palliative treat-a combined analysis of controlled single-dose stud- ment of carcinoma. Cancer 1948;1:634e656.ies. Neurology 1994;44:857e861. 24. Ware J, Kosinski M, Tuner-Bowker DM, 9. Garcia de Paredes G, del Moral Gonzalez F, Gandek B. Version 2 of the SF-12 health survey.Martinez del Prado M, et al. First evidence of onco- Boston, MA: Quality Metric, Inc., 2002.logic neuropathic pain prevalence after screening8615 cancer patients. Results of the On study. Ann 25. Hausheer F, Foley K. Cancer neuropathic pain:Oncol 2011;22:924e930. overview of current status and future objectives. Oncologist 2010;15(Suppl 2):1e2.10. Grond S, Radbruch L, Neuser T, et al. Assess-ment and treatment of neuropathic cancer pain fol- 26. Lema M, Foley K, Hausheer F. Types and epide-lowing WHO guidelines. Pain 1999;79:15e20. miology of cancer-related neuropathic pain: the in- tersection of cancer pain and neuropathic pain.11. World Health Organization. Cancer pain relief. Oncologist 2010;15(Suppl 2):3e8.Geneva, Switzerland: World Health Organization,1986. 27. Cleeland C, Farrar J, Hausheer F. Assessment of cancer-related neuropathy and neuropathic pain.12. Gadgeel SM, Bionpally RR, Heilbrun LK, et al. Oncologist 2010;15(Suppl 2):13e18.A phase 1 clinical trial of spicamycin derivativeKRN5500 (NSC 650426) using a phase 1 accelerated 28. Material Safety Data Sheets for monoethanol-titration ‘‘2B’’ design. Invest New Drugs 2003;21: amine. Available from http://www.sciencelab.com/63e74. msds.php?msdsId¼9922885. Accessed September 11, 2011.13. Supko J, Eder J, Ryan D, et al. Phase 1 clinicaltrial and pharmacokinetic study of the spicamycin 29. Material Safety Data Sheets for N, N-dimethyla-analog KRN5500 administered as a 1-hour cetamide. Available from http://www.caledonlabs.

Vol. - No. - - 2011 KRN5500 and Neuropathic Pain 15com/upload/msds/3900-1e.pdf. Accessed September pharmacotherapy: a blueprint for ACTION. Pain11, 2011. 2011;152:S107eS115.30. Younger J, McCue R, Mackey S. Pain outcomes: 33. Dworkin R, Katz J, Gitlin M. Placebo response ina brief review of instruments and techniques. Curr clinical trials of depression and its implications forPain Headache Rep 2009;13:39e43. research on chronic neuropathic pain. Neurology31. Backonja M, Glanzman R. Gabapentin dosing 2005;65(Suppl 4):S7eS19.for neuropathic pain: evidence from randomized, 34. Rao R, Flynn P, Sloan J, et al. Efﬁcacy of lamotri-placebo-controlled clinical trials. Clin Ther 2003; gine in the management of chemotherapy-induced25:81e104. peripheral neuropathy: a phase 3 randomized,32. Dworkin R, Turk D, Katz N, et al. Evidence- double-blind, placebo-controlled trial, no1c3. Can-based clinical trial design for chronic pain cer 2008;112:2801e2808.

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DARA Bio ($DARA) - KRN5500 article from the Journal of Pain and Symptom Management International Document Transcript

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