Gary Romano

Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial

Objective: To assess efficacy and safety of fulranumab, a fully human monoclonal antibody against nerve growth factor, in patients with diabetic peripheral neuropathic pain (DPNP). Methods: In this phase II, double-blind, placebo-controlled trial, patients with moderate to severe DPNP were randomized to treatments with fulranumab (1, 3, or 10 mg) or placebo administered subcutaneously every 4 weeks. Results: Because of early study termination (clinical hold) by the US Food and Drug Administration, 77 (intent-to-treat) of the planned 200 patients were enrolled. The primary endpoint, the mean reduction of average daily pain at week 12 compared with baseline, showed a positive dose-response relationship (p = 0.014, 1-sided); the pair-wise comparison between the 10-mg group and placebo was significant (unadjusted p = 0.040, 2-sided). An exploratory responder analysis revealed that a greater proportion of patients in the 10-mg group reported ≥30% reduction in the average DPNP intensity compared with placebo at week 12 (p = 0.006). Although not statistically significant, several secondary endpoints showed directionally similar results to the primary efficacy dose-response relationship. During the combined efficacy and safety extension phases, the top 3 treatment-emergent adverse events in the combined fulranumab group were arthralgia (11%), edema peripheral (11%), and diarrhea (9%). No cases of joint replacement or death were reported. Conclusion: Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated. Classification of evidence: This study provides Class I evidence that in patients with DPNP, fulranumab 10 mg reduces pain by 1.2 points on an 11-point scale compared with placebo.

SCN9A Variants May be Implicated in Neuropathic Pain Associated With Diabetic Peripheral Neuropathy and Pain Severity.

Objectives:Previous studies have established the role of SCN9A in various pain conditions, including idiopathic small fiber neuropathy. In the present study, we interrogate the relationship between common and rare variants in SCN9A gene and chronic neuropathic pain associated with diabetic peripheral neuropathy. Design:Using a cohort of 938 patients of European ancestry with chronic neuropathic pain associated with diabetic peripheral neuropathy enrolled in 6 clinical studies and 2 controls (POPRES, n=2624 and Coriell, n=1029), we examined the relationship between SCN9A variants and neuropathic pain in a case-control study using a 2-stage design. The exonic regions of SCN9A were sequenced in a subset of 244 patients with neuropathic pain, and the variants discovered were compared with POPRES control (stage 1). The top associated variants were followed up by genotyping in the entire case collection and Coriell controls restricting the analysis to the matching patients from the United States and Canada only (stage 2). Results:Seven variants were found to be associated with neuropathic pain at the sequencing stage. Four variants (Asp1908Gly, Val991Leu/Met932Leu, and an intronic variant rs74449889) were confirmed by genotyping to occur at a higher frequency in cases than controls (odds ratios ∼2.1 to 2.6, P=0.05 to 0.009). Val991Leu/Met932Leu was also associated with the severity of pain as measured by pain score Numeric Rating Scale (NRS-11, P=0.047). Val991Leu/Met932Leu variants were in complete linkage disequilibrium and previously shown to cause hyperexcitability in dorsal root ganglia neurons. Conclusions:The association of SCN9A variants with neuropathic pain and pain severity suggests a role of SCN9A in the disease etiology of neuropathic pain.

Impact of cerebrospinal fluid matrix on the detection of Alzheimer's disease with Aβ42 and influence of disease on the total‐Aβ42/Aβ40 ratio

The 42‐amino acid fragment of amyloid β (Aβ1‐42) in cerebrospinal fluid has continued to be important for detecting cerebral β‐amyloidosis in Alzheimers disease (AD). However, there are impediments to our ability to fully understand this measurement, including matrix interference and changes linked to apolipoprotein E (APOE) ε4 genotype. This study investigated matrix interference as a contributing factor for detecting AD in APOE ε4‐negative patients by comparing total extractable Aβ1‐42 to free Aβ1‐42. It also examined the ratio of total Aβ1‐42 to Aβ1‐40, since changes relative to other Aβ peptides may provide a measurement of cerebral β‐amyloidosis that is neutral to changes in APP metabolism. Total Aβ1‐42 lost the diagnostic power for detecting AD, confirming a role for matrix in the diagnostic. However, when total Aβ1‐42/Aβ1‐40 was examined, the separation between groups was reestablished. This result was confirmed in a second sample set of unknown APOE status. These results confirmed that matrix interference in some cerebrospinal fluid samples appears to contribute to identifying AD patients and this can be compensated by using a total extracted Aβ1‐42/Aβ1‐40 ratio when matrix interference is small. It may be preferable to employ a total Aβ1‐42/Aβ1‐40 measurement, since this could minimize variability because of matrix and compensate for across patient differences.

Novel Statistically-Derived Composite Measures for Assessing the Efficacy of Disease-Modifying Therapies in Prodromal Alzheimer’s Disease Trials: An AIBL Study

BACKGROUND There is a growing consensus that disease-modifying therapies must be given at the prodromal or preclinical stages of Alzheimers disease (AD) to be effective. A major unmet need is to develop and validate sensitive measures to track disease progression in these populations. OBJECTIVE To generate novel statistically-derived composites from standard scores, which have increased sensitivity in the assessment of change from baseline in prodromal AD. METHODS An empirically based method was employed to generate domain specific, global, and cognitive-functional novel composites. The novel composites were compared and contrasted with each other, as well as standard scores for their ability to track change from baseline. The longitudinal characteristics and power to detect decline of the measures were evaluated. Data from participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study characterized as mild cognitively impaired with high neocortical amyloid-β burden were utilized for the study. RESULTS The best performing standard scores were CDR Sum-of-Boxes and MMSE. The statistically-derived novel composites performed better than the standard scores from which they were derived. The domain-specific composites generally did not perform as well as the global composites or the cognitive-functional composites. CONCLUSION A systematic method was employed to generate novel statistically-derived composite measures from standard scores. Composites comprised of measures including function and multiple cognitive domains appeared to best capture change from baseline. These composites may be useful to assess progression or lack thereof in prodromal AD. However, the results should be replicated and validated using an independent clinical sample before implementation in a clinical trial.

TRPV1 antagonist JNJ-39439335 (mavatrep) demonstrates proof of pharmacology in healthy men: a first-in-human, double-blind, placebo-controlled, randomized, sequential group study

Abstract This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ-39439335 on capsaicin-induced flare and sensory testing on naïve and UVB-sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30–86 hours). Renal clearance of JNJ-39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development.

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease : Perspectives from the Research Roundtable

The Alzheimers Associations Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimers Association Research Framework for Alzheimers disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimers Association Research Framework. This review will summarize the “A, T, N System” (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.

Fulranumab in Patients with Pain Associated with Postherpetic Neuralgia and Postraumatic Neuropathy: Efficacy, Safety and Tolerability Results from a Randomized, Double-blind, Placebo-controlled, Phase-2 Study.

Objective: Fulranumab is an antibody that specifically neutralizes the biological activity of human nerve growth factor. This multicenter, phase-2, randomized, double-blind (DB), placebo-controlled study evaluated the analgesic efficacy and safety of fulranumab in postherpetic neuralgia (PHN) and posttraumatic neuropathy (PTN) patients. Methods: Patients (18 to 80 y) with inadequately controlled moderate-to-severe pain received study medication (subcutaneous injection) every 4 weeks. PHN patients were randomized (3:2:2:3) to receive either placebo or one of 3 doses of fulranumab: 1 mg (1 mgQ4 wk), 3 mg (3 mgQ4 wk), or 10 mg (10 mgQ4 wk). PTN patients were randomized (1:1) to receive either placebo or fulranumab 10 mgQ4 wk. Results: The US Food and Drug Administration placed a clinical hold (December 23, 2010) on all trials of antinerve growth factor drugs, including fulranumab, due to identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only 49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the DB efficacy evaluation. There was no significant difference (P>0.05, fulranumab vs. placebo) for change in 7-day average of daily pain intensity scores from DB baseline to end of 12-week DB efficacy phase in PHN or PTN patients (primary endpoint). No significant difference was found with fulranumab versus placebo (P>0.05) in other efficacy measures in either PHN or PTN patients. The most common treatment-emergent adverse events (>10% incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and headache, whereas in PHN patients it was arthralgia. Discussion: Fulranumab did not demonstrate efficacy in either PHN or PTN patients, but was generally well-tolerated in this small underpowered and abbreviated study.

A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis

Abstract Background/Aims Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep. Methods In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50 mg mavatrep, 500 mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed. Results Of 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p = 0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p = 0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p = 0.049] and 7 [p = 0.041], stiffness on day 7 [p = 0.075]), and function on day 7 [p = 0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred. Conclusion Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep’s safety profile was consistent with its mechanism of action as a TRPV1 antagonist. Implications Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception. Trial Registration 2009-010961-21 (EudraCT Number).

Analgesic efficacy of fulranumab in patients with painful diabetic peripheral neuropathy in a randomized, placebo-controlled, double-blind study

OBJECTIVE: To evaluate analgesic efficacy of fulranumab, a human recombinant investigational anti-nerve growth factor (NGF) monoclonal antibody, in patients with painful diabetic peripheral neuropathy (DPN). BACKGROUND: NGF antibodies offer a potential treatment option in DPN. DESIGN/METHODS: Multicenter, phase 2, placebo-controlled study (initiated Oct. 2009) with a 12-week double-blind (DB) efficacy-, 40-week DB safety extension-, and 52-week open-label safety extension phase. Patients with moderate to severe pain, stratified by concomitant treatment for neuropathic pain (yes/no), were randomized (3:2:2:3) to receive either placebo or fulranumab (1 mg-, 3 mg-, or 10 mg fulranumab; every 4 weeks [Q4wk] subcutaneously). RESULTS: Due to US FDA clinical hold, only 77 of planned 200 patients were enrolled: 62 (81%) patients (55.8% men; 81.8% white; mean [SD] age 58.7 [9.48] years) completed the DB efficacy phase. Change in 7-day average of daily pain intensity score from baseline to end of 12 week DB efficacy phase (primary endpoint) showed a positive dose response (p=0.014, one-sided). At DB efficacy endpoint, the pair-wise comparison between 10 mgQ4wk dose to placebo was significant (nominal p=0.04, two-sided). Least square (LS) means differences (95% CI) in change from baseline in average pain intensity scores vs placebo were: fulranumab 1mgQ4wk, 0.1 (-1.26; 1.36); 3mgQ4wk, -0.6 (-1.98; 0.74); and 10 mgQ4wk, -1.2 (-2.44; -0.06). 30% responder rates (≥30% improvement in average pain intensity score) at DB efficacy endpoint were: placebo, 21%; 1mgQ4wk, 44%; 3mgQ4wk, 43%; and 10 mgQ4wk, 61%. Multiple secondary efficacy endpoints showed dose-related improvement trends. Most common (≥5 patients) adverse events for total fulranumab-treated patients (n=53) vs placebo (n=24) were: peripheral oedema (11% vs 0%), arthralgia (11% vs 13%), and diarrhoea (9% vs 8%). No cases of joint replacement or deaths were reported during the study. CONCLUSIONS: Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated in this study. Supported by: Janssen Research & Development, LLC (previously known as Johnson & Johnson Pharmaceutical Research & Development, L.L.C), New Jersey, USA. Disclosure: Dr. Wang has received personal compensation for activities with Janssen Pharmaceutical as an employee. Dr. Wang has received (royalty or license fee or contractual rights) payments from Netrin3. Dr. Romano has received personal compensation for activities with Janssen Research & Development as an employee. Dr. Romano holds stock in Janssen Research & Development. Dr. Frustaci has received personal compensation for activities with Johnson & Johnson as an employee. Dr. Frustaci holds stock and/or stock options in Johnson & Johnson. Dr. Sanga has received personal compensation for activities with Janssen Research & Development as an employee. Dr. Ness has received personal compensation for activities with Janssen Research and Development LLC as an employee. Dr. Ness holds stock and/or stock options in Janssen Research and Development LLC. Dr. Russell has received personal compensation for activities with Janssen Pharmaceuticals as an employee. Dr. Russell holds stock and/or stock options in Janssen Pharmaceuticals. Dr. Fedgchin has received personal compensation for activities with Janssen Research & Development as an employee. Dr. Kelly has received personal compensatino for activities with Janssen Research and Development LLC as an employee. Dr. Kelly holds stock and/or stock options in Johnson & Johnson. Dr. Thipphawong has received personal compensation for activities with Janssen Pharmaceuticals as an employee. Dr. Thipphawong holds stock and/or stock options in Janssen Pharmaceuticals.

A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep)

Abstract Background and aims: This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2). Methods: Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2–50 mg; part 2: 10–50 mg): n=6; placebo: n=2] and follow-up (total study duration ~10 weeks). Results: Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%). Conclusions: JNJ-39439335 (doses 2–50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain. Implications: Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.