Duncansville, PA, United States
Duncansville, PA, United States

Time filter

Source Type

News Article | April 17, 2017
Site: www.biosciencetechnology.com

Tummy tucks really hurt. Doctors carve from hip to hip, slicing off skin, tightening muscles, tugging at innards. Patients often need strong painkillers for days or even weeks, but Mary Hernandez went home on just over-the-counter ibuprofen. The reason may be the yellowish goo smeared on her 18-inch wound as she lay on the operating table. The Houston woman was helping test a novel medicine aimed at avoiding opioids, potent pain relievers fueling an epidemic of overuse and addiction. Vicodin, OxyContin and similar drugs are widely used for bad backs, severe arthritis, damaged nerves and other woes. They work powerfully in brain areas that control pleasure and pain, but the body adapts to them quickly, so people need higher and higher doses to get relief. This growing dependence on opioids has mushroomed into a national health crisis, ripping apart communities and straining police and health departments. Every day, an overdose of prescription opioids or heroin kills 91 people, and legions more are brought back from the brink of death. With some 2 million Americans hooked on these pills, evidence is growing that they're not as good a choice for treating chronic pain as once thought. Drug companies are working on alternatives, but have had little success. Twenty or so years ago, they invested heavily and "failed miserably," said Dr. Nora Volkow, director of the National Institute on Drug Abuse. Pain is a pain to research. Some people bear more than others, and success can't be measured as objectively as it can be with medicines that shrink a tumor or clear an infection. Some new pain drugs that worked well were doomed by side effects - Vioxx, for instance, helped arthritis but hurt hearts. -"Bespoke" drugs, as Volkow calls them. These target specific pathways and types of pain rather than acting broadly in the brain. One is Enbrel, which treats a key feature of rheumatoid arthritis and, in the process, eases pain. -Drugs to prevent the need for opioids. One that Hernandez was helping test numbs a wound for a few days and curbs inflammation. If people don't have big pain after surgery, their nerves don't go on high alert and there's less chance of developing chronic pain that might require opioids. -Funky new sources for medicines. In testing: Drugs from silk, hot chili peppers and the venom of snakes, snails and other critters. -Novel uses for existing drugs. Some seizure and depression medicines, for example, can help some types of pain. The biggest need, however, is for completely new medicines that can be used by lots of people for lots of problems. These also pose the most risk - for companies and patients alike. In the early 2000s, a small biotech company had a big idea: blocking nerve growth factor, a protein made in response to pain. The company's drug, now called tanezumab (tah-NAZE-uh-mab), works on outlying nerves, helping to keep pain signals from muscles, skin and organs from reaching the spinal cord and brain - good for treating arthritis and bad backs. Pfizer Inc. bought the firm in 2006 and expanded testing. But in 2010, some people on tanezumab and similar drugs being tested by rivals needed joint replacements. Besides dulling pain, nerve growth factor may affect joint repair and regeneration, so a possible safety issue needed full investigation in a medicine that would be the first of its type ever sold, said one independent expert, Dr. Jianguo Cheng, a Cleveland Clinic pain specialist and science chief for the American Academy of Pain Medicine. Regulators put some of the studies on hold. Suddenly, some people who had been doing well on tanezumab lost access to it. Phyllis Leis in Waterfall, a small town in south-central Pennsylvania, was one. "I was so angry," she said. "That was like a miracle drug. It really was. Unless you have arthritis in your knees and have trouble walking, you'll never understand how much relief and what a godsend it was." Her doctor, Alan Kivitz of Altoona Center for Clinical Research, has helped run hundreds of pain studies and consults for Pfizer and many other companies. "You rarely get people to feel that good" as many of them did on the nerve growth factor drugs, he said. A drug with that much early promise is unusual, said Ken Verburg, who has led Pfizer's pain research for several decades. "When you do see one, you fight hard to try to bring one to the market," he said. An independent review ultimately tied just a few serious joint problems to tanezumab and the suspension on testing was lifted in August 2012. But a new issue - nervous system effects in some animal studies - prompted a second hold later that year, and that wasn't lifted until 2015. Now Eli Lilly & Co. has joined Pfizer in testing tanezumab in late-stage studies with 7,000 patients. Results are expected late next year - about 17 years after the drug's conception.


Burmester G.-R.,Charité - Medical University of Berlin | Kivitz A.J.,Altoona Center for Clinical Research | Kupper H.,AbbVie Deutschland GmbH and Co. KG | Arulmani U.,Abbvie Inc. | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2015

Objective: CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA). Methods: Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance. Results: Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose. Conclusions: Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent. © 2015, BMJ Publishing Group. All rights reserved.


Laine L.,University of Southern California | Kivitz A.J.,Altoona Center for Clinical Research | Bello A.E.,University of Illinois at Chicago | Grahn A.Y.,Horizon Pharma | And 2 more authors.
American Journal of Gastroenterology | Year: 2012

Objectives: We performed two 24-week double-blind trials (REDUCE-1 and-2 (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies)) to assess whether double-dose famotidine given in a single-tablet combination with ibuprofen (HZT-501) significantly reduces gastric and duodenal ulcers as compared with ibuprofen. Methods: Patients (40-80 years) requiring daily non-steroidal anti-inflammatory drugs (NSAIDs) for 6 months with no prior ulcer complications, negative H. pylori stool test, and baseline endoscopy showing no ulcers and 5 erosions were randomly assigned in a 2:1 ratio to HZT-501 or identical-appearing ibuprofen 800 mg tablets thrice daily. Study endoscopies were done at 8, 16, and 24 weeks. After unblinding and initial analyses, 12 patients were found to be misclassified as having gastric ulcers based on the adjudication of endoscopy reports, and analyses were re-run. Results: In REDUCE-1, the primary end point analysis of gastric ulcers at 24 weeks with HZT-501 vs. ibuprofen was 12.7% vs. 22.9% (P=0.0044) in the post-adjudication analysis. In REDUCE-2, the primary end point analysis of upper gastrointestinal (GI) ulcers was 13.0% vs. 20.5% (P=0.0587) in the post-adjudication analysis. Prespecified pooled analyses showed significantly fewer gastric (12.5% vs. 20.7%) and duodenal ulcers (1.1% vs. 5.1%) with HZT-501 vs. ibuprofen. Proportional hazards analysis of multiple potential risk factors showed the risk ratio of upper GI ulcers with HZT-501 vs. ibuprofen was 0.46, 95% confidence interval was 0.34-0.61. Conclusions: Combined results of the REDUCE studies indicate that double-dose famotidine plus ibuprofen, given as a combination tablet, decreases endoscopic upper GI ulcers as compared with ibuprofen alone. © 2012 by the American College of Gastroenterology.


Brown M.T.,Pfizer | Murphy F.T.,Altoona Center for Clinical Research | Murphy F.T.,University of Pennsylvania | Radin D.M.,Stamford Therapeutics Consortium | And 3 more authors.
Journal of Pain | Year: 2012

The objective of this study was to compare the analgesic efficacy of tanezumab versus placebo in patients with osteoarthritis (OA) of the knee. This was a 32-week, randomized, double-blind, placebo-controlled phase III trial (NCT00733902). The patient criteria included diagnosis of OA; Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively; Patient's Global Assessment of Osteoarthritis (PGA) ≥3; and failure of nonopiate pain medications or candidacy for invasive interventions. Patients received 3 intravenous doses of tanezumab (2.5, 5, or 10 mg) or placebo. The co-primary efficacy end points were changes in WOMAC subscales and PGA at week 16. Adverse events were monitored throughout. Overall, 690 patients (61% female) were randomized and treated. Those treated with tanezumab showed significant improvement in the 3 co-primary end points (P ≤.015 for all). The incidence of adverse events was 55 to 60% for tanezumab-treated patients versus 48% for placebo-treated patients. Joint replacement was reported in 4 patients, 1 in each treatment group; a total of 5 joints were replaced (1 index knee and 4 hips). The tanezumab OA clinical program is currently on clinical hold due to potential adverse reactions leading to joint replacement. Perspective: This is the first phase III randomized, controlled trial to demonstrate that nerve growth factor blockade by tanezumab has superior analgesic efficacy in OA of the knee compared with placebo. Tanezumab was well tolerated, and reports of worsening OA and/or joint replacement were evenly distributed across the treatment groups. © 2012 by the American Pain Society.


Fleischmann R.M.,University of Texas Southwestern Medical Center | Damjanov N.S.,University of Belgrade | Kivitz A.J.,Altoona Center for Clinical Research | Legedza A.,Vertex Pharmaceuticals | And 2 more authors.
Arthritis and Rheumatology | Year: 2015

Objective. To assess the efficacy and safety of oral decernotinib (VX-509; Vertex Pharmaceuticals) monotherapy in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study of patients with rheumatoid arthritis (RA). Methods. Two hundred four adults with active RA who had been unsuccessfully treated with ≥1 disease-modifying antirheumatic drug were administered placebo tablets or decernotinib twice a day at dosages of 25 mg, 50 mg, 100 mg, or 150 mg. Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and mean change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Results. At week 12, the ACR20 response rates were 39.0%, 61.0%, 65.0%, and 65.9% in the 25-mg, 50-mg, 100-mg, and 150-mg groups, respectively, and were significantly higher in the 50-mg group (P = 0.007) and the 100-mg and 150-mg groups (P = 0.002) as compared to the response rates in the placebo group (29.3%). The mean change from baseline in DAS28-CRP was greater in the 50-mg, 100-mg, and 150-mg groups as compared to the placebo group (P < 0.001). Decernotinib treatment resulted in higher ACR50 and ACR70 response rates, more patients with DAS28-CRP scores <2.6, and improvements in the Health Assessment Questionnaire disability index as compared to placebo. The most common adverse events in any decernotinib group were nausea (6.1%), headache (4.3%), an increase in levels of alanine aminotransferase (4.3%), and hypercholesterolemia (3.7%). In the groups receiving decernotinib, there was an increased risk of infections and increased liver transaminase levels. Conclusion. Decernotinib was efficacious in improving clinical signs and symptoms of RA at week 12 at dosages of 50-150 mg twice a day. Infections and increases in liver transaminase and lipid levels were noted as potential safety signals. Copyright © 2015 by the American College of Rheumatology.


Brown M.T.,Pfizer | Murphy F.T.,Altoona Center for Clinical Research | Murphy F.T.,University of Pennsylvania | Radin D.M.,Stamford Therapeutics Consortium | And 3 more authors.
Arthritis and Rheumatism | Year: 2013

Objective To compare the efficacy of tanezumab versus placebo for reducing pain and improving physical function in patients with osteoarthritis (OA) of the hip. Methods This was a 32-week, randomized, double-blind, placebo-controlled, phase III trial. Patients with baseline Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively, and patient's global assessment of OA as "fair," "poor," or "very poor" were treated at baseline and weeks 8 and 16. Coprimary efficacy end points were change from baseline to week 16 in WOMAC Pain and Physical Function subscales and patient's global assessment, analyzed using analysis of covariance. Adverse events (AEs) were monitored throughout. Results Patients (n = 621) were randomized 1:1:1:1 to treatment with intravenous tanezumab 2.5 mg, 5 mg, or 10 mg or placebo. Each tanezumab group showed significant improvement for the 3 coprimary end points versus placebo (P ≤ 0.001 for all). AE incidence ranged from 55% to 58% across tanezumab groups versus 44% for placebo. Safety findings were similar to those previously reported. The tanezumab OA clinical program was temporarily placed on hold because of AEs leading to joint replacement. Total joint replacements were reported in 8 patients: 1 in the 10 mg, 2 in the 5 mg, 2 in the 2.5 mg, and 3 in the placebo group. A total of 9 joints were replaced (8 hips [7 index joints] and 1 shoulder). Conclusion Our findings indicate that tanezumab provides superior pain relief and improvement in physical function and patient's global assessment versus placebo in patients with painful hip OA, and is generally well tolerated. Copyright © 2013 by the American College of Rheumatology.


Schmitt C.,Hoffmann-La Roche | Kuhn B.,Hoffmann-La Roche | Zhang X.,Hoffmann-La Roche | Kivitz A.J.,Altoona Center for Clinical Research | Grange S.,Hoffmann-La Roche
Clinical Pharmacology and Therapeutics | Year: 2011

In rheumatoid arthritis (RA), interleukin-6 (IL-6) concentration is elevated, which may cause reduced cytochrome P450 (CYP) activity and increased exposure (peak plasma concentration and area under the plasma concentration-vs.-time curve (AUC)) to certain drugs. Tocilizumab may reverse IL-6-induced suppression of CYP3A4 activity. In this study, exposure to simvastatin was significantly reduced at 1 and 5 weeks after tocilizumab infusion in 12 patients with RA. The mean effect ratio for simvastatin AUC last was 43% (90% confidence interval (CI), 34-55%) at 1 week after tocilizumab infusion (day 15) and 61% (90% CI, 47-78%) at 5 weeks after tocilizumab infusion, as compared with baseline (day 1); both ratios were significantly lower than the bioequivalence boundary (80-125%). Mean plasma C-reactive protein (CRP) levels normalized within 1 week after tocilizumab was initiated; the time course of tocilizumab's CRP-reducing effect paralleled that of simvastatin pharmacokinetics. The study findings suggest that caution should be exercised when starting tocilizumab in RA patients who are taking simvastatin. © 2011 american Society for Clinical Pharmacology and Therapeutics.


Burmester G.-R.,Charité - Medical University of Berlin | Kivitz A.J.,Altoona Center for Clinical Research | Kupper H.,AbbVie Deutschland GmbH & Co KG | Arulmani U.,Abbvie Inc. | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when increasing MTX dose in patients with early rheumatoid arthritis (RA). Methods: Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance. Results: Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose. Conclusions: Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.


Tiseo P.J.,Regeneron Pharmaceuticals Inc. | Kivitz A.J.,Altoona Center for Clinical Research | Ervin J.E.,Center for Pharmaceutical Research | Ren H.,Regeneron Pharmaceuticals Inc. | Mellis S.J.,Regeneron Pharmaceuticals Inc.
Pain | Year: 2014

The safety, tolerability, and efficacy of fasinumab (REGN475), a fully human monoclonal antibody against nerve growth factor, was evaluated for the treatment of pain in patients with osteoarthritis (OA) of the knee. This was a 24-week, double-blind, placebo-controlled, parallel-group, repeat-dose, exploratory study. Eligible patients 40 to 75 years of age with a diagnosis of OA of the knee and moderate to severe pain were randomized 1:1:1:1 to intravenous fasinumab 0.03, 0.1, or 0.3 mg/kg or placebo and received study drug on day 1 and day 57. Pain intensity was recorded daily using the numeric rating scale. Safety and tolerability, assessed by the incidence of treatment-emergent adverse events (TEAEs), was the primary study endpoint. Secondary study endpoints included the change from baseline in daily walking knee pain and the assessment of pain, function, and stiffness using the Western Ontario and McMaster Osteoarthritis (WOMAC) index. Baseline characteristics were similar among treatment groups (N = 217). After 24 weeks, the incidence of TEAEs ranged from 66.1% to 75.0% in the fasinumab groups vs 63.6% for placebo. The most common TEAEs included arthralgia, hyperesthesia, myalgia, peripheral edema, and joint swelling. Discontinuation for TEAEs occurred in 5.6% of fasinumab patients and 3.7% of placebo patients. All 3 doses of fasinumab were associated with significant (P <.05) improvements compared with placebo in walking knee pain and WOMAC total and subscale scores. Fasinumab was generally well tolerated, and was associated with a significant reduction in walking knee pain and an improvement in function for up to 8 weeks. © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. ©2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Dervieux T.,Exagen Diagnostics | Weinblatt M.E.,Harvard University | Kivitz A.,Altoona Center for Clinical Research | Kremer J.M.,Center for Rheumatology
Annals of the Rheumatic Diseases | Year: 2013

Objective: The combination of methotrexate (MTX) with infliximab can modify infliximab pharmacokinetics and lower the incidence of antibodies against infliximab (ATIs). We hypothesised that the pharmacokinetic interaction between MTX and infliximab is related to activation of MTX to immunosuppressive MTX polyglutamates (MTXPGs). Methods: Adult patients with rheumatoid arthritis receiving weekly MTX with infliximab for more than 3 months were enrolled in a cross-sectional study. Blood was collected at trough before the infusion of infliximab. Red blood cell (RBC) MTXPGs were measured using liquid chromatography, and circulating levels of infliximab were measured using a cell-based assay. ATIs were measured using enzyme immunoassays. Statistical analyses consisted of multiple regression and Wilcoxon tests. Results: In the 61 patients enrolled in the study, ATIs were detected in 11 (18%). Regression analyses revealed that lower infliximab levels (median 3.3 μg/ml) were associated with the presence of ATIs and lower RBC MTXPG levels (median 28 nmol/l) (p<0.05). Logistic regression revealed that RBC MTXPG levels above 25 nmol/l were associated with a 4.7-fold lower likelihood of having ATIs (OR=4.7; 95% CI 1.1 to 20.8; p=0.02). None of the 12 patients with RBC MTXPG levels above 50 nmol/l tested positive for ATIs. Conclusions: These hypothesis-generating data indicate that MTXPGs are associated with infliximab pharmacokinetics and ATI formation.

Loading Altoona Center for Clinical Research collaborators
Loading Altoona Center for Clinical Research collaborators