Clinical Trials Web

Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis

2008-08-24T15:08:00.000-07:00

Juvenile rheumatoid arthritis is the most common rheumatic disease of childhood and is an important cause of disability among children.1 Weekly methotrexate (oral or parenteral), at dosages of up to 15 mg per square meter of body-surface area per week for parenteral administration, has been established as an effective therapy in polyarticular juvenile rheumatoid arthritis.2,3 During the past decade, the use of tumor necrosis factor (TNF) antagonists in adult rheumatoid arthritis has shifted the paradigm of care.4,5,6 More recently, TNF blockade has been shown to be an efficacious treatment option for polyarticular juvenile rheumatoid arthritis.7 Adalimumab (Humira, Abbott Laboratories) is a fully human, IgG1, monoclonal anti-TNF antibody. In patients with adult rheumatoid arthritis, adalimumab, with or without concomitant methotrexate, reduces the signs and symptoms of disease, improves the quality of life and physical functioning, and inhibits radiographic progression.5,8,9,10 Sustained efficacy has been demonstrated during long-term administration.11 We conducted this study to evaluate the efficacy and safety of adalimumab in children with polyarticular-course juvenile rheumatoid arthritis.

Discussion

Adalimumab, administered with or without methotrexate, improved signs and symptoms of disease in children with juvenile rheumatoid arthritis. Disease flares were significantly less frequent among children receiving adalimumab than among those receiving placebo. Disease flare was defined conservatively in this study, with a relatively small degree of worsening exceeding the threshold for a flare. Therefore, many patients met the criteria for a disease flare while showing substantial improvement as compared with baseline disease activity. The ACR Pedi scores at week 48, which defined all patients who had disease flares as having no response, were significantly greater for patients treated with adalimumab than for those receiving placebo, both among patients receiving methotrexate and among all patients regardless of whether they received methotrexate, but not among patients not receiving methotrexate. Of patients treated with adalimumab, 30% not receiving methotrexate and 42% receiving methotrexate had an ACR Pedi 90 response, a measure that we believe has not previously been included in an efficacy trial of juvenile rheumatoid arthritis (Table 3). During 2 further years of adalimumab treatment in the open-label extension phase, ACR Pedi responses were sustained, including achievement of ACR Pedi 100 responses by 40% of the patients.

The study was not statistically powered to detect differences between patients receiving and those not receiving methotrexate; however, the proportions of patients with ACR Pedi 30, 50, 70, or 90 responses were somewhat higher among those receiving adalimumab in combination with methotrexate than among those receiving adalimumab without methotrexate. Although these results are consistent with findings of studies in adult patients with rheumatoid arthritis,8,14 any differences between patients in the two strata (those receiving and those not receiving methotrexate) are difficult to interpret, because the patients underwent randomization within each stratum but not across strata. Eleven of 86 patients not receiving methotrexate withdrew from the study before undergoing randomization, because of lack of efficacy of adalimumab.

A small percentage of patients withdrew because of adverse events. The most frequently reported adverse events were infections and injection-site reactions. Serious adverse events considered possibly drug-related by the investigator occurred in 14 patients, 7 of whom had serious infections. No deaths, opportunistic infections, malignant conditions, demyelinating diseases, or lupuslike reactions occurred in this study. The size of the study population and the length of the study were not sufficient to determine the risks of rare adverse events.

Approximately 16% of the patients had at least one positive test for anti-adalimumab antibody during the study. This percentage is greater than the 5% observed during clinical trials of adult patients with rheumatoid arthritis.14 There were no increases in discontinuations of the study drug or adverse events associated with the presence of anti-adalimumab antibody. Positive anti-adalimumab antibody tests were less frequent among patients receiving concomitant methotrexate than among those receiving adalimumab monotherapy, a finding consistent with the findings of trials in adult patients with rheumatoid arthritis.

Conducting placebo-controlled trials in pediatric populations requires special consideration of the ethical issues associated with denying active treatment during a double-blind phase. At the time the adalimumab trial was designed, two other trials of TNF antagonists in pediatric patients were ongoing. Our trial of adalimumab was designed after considering both parallel and randomized approaches to withdrawal, in consultation with the Food and Drug Administration (FDA). The FDA and the study designers agreed that the blinded, randomized medication-withdrawal design provided acceptable scientific rigor while minimizing exposure to placebo in this population of children with severe, active juvenile rheumatoid arthritis and that the primary end point should be a comparison, in the no-methotrexate stratum, between the percentages of patients with disease flares in the group receiving adalimumab and the group receiving placebo during the double-blind phase.

Although the double-blind phase, and thus the primary end-point analysis, was conducted in patients who had a response, the open-label lead-in approach is generalizable to clinical practice, given that treatment decisions are made in an open-label setting after a reasonable trial with a new active treatment. If a patient does not have a response to an active treatment after a period of time (16 weeks or so, as in the current trial), a physician will probably consider other treatment options. For patients who do have a response, treatment will be continued.

Adalimumab, alone or in combination with methotrexate, appears to be an efficacious option for the treatment of children with polyarticular juvenile rheumatoid arthritis. Responses were sustained through 2 years of continued treatment.

Supported by a research grant from Abbott Laboratories.

Toclizumab For Rheumatoid Arthritis - Video

2008-05-06T01:59:00.000-07:00

Toclizumab is a humanized anti-interleukin 6 receptor agent that blocks the action of the inflammatory cytokine. The drug is in phase III trials worldwide, and is licensed in Japan as an orphan drug for treatment of Castleman's disease.

In a phase II European trial of toclizumab, 61% of patients had an ACR20 response, 43% had an ACR50 response, and 16% had an ACR70 response at a dose of 8 mg/kg.

Rheumatoid Arthritis - MorphoSys Announces Completion Of First Dosing In Phase 1 Trial For MOR103 Program

2008-05-03T08:52:00.000-07:00

MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX) announced the completion of a first dosing regimen in a phase 1 clinical study on healthy volunteers of the HuCAL-derived antibody MOR103 with no adverse events reported. Six healthy volunteers in the first dosing group have been enrolled and received MOR103 injections, three volunteers received placebo.

The safety review of the medical data from the lowest dosing group concluded that it was safe to proceed to the second dosing group. The randomized, double-blind, placebo-controlled, single-ascending dose trial will be conducted in approx. 50 healthy volunteers and is being conducted in a Clinical Pharmacology Unit (CPU) in Utrecht, the Netherlands. The trial is scheduled to be finalized in 2008 and final reporting is expected in Q1 2009.

The company's lead development program MOR103 is a fully human HuCAL antibody directed against GM-CSF (granulocyte macrophage-colony stimulating factor), being developed in the area of inflammatory diseases, such as rheumatoid arthritis, where current treatment options are inadequate. Due to its diverse functions in the immune system, GM-CSF can be considered a target for a broad spectrum of anti-inflammatory therapies. MorphoSys had submitted the clinical trial application in December 2007 and received the approval by the Dutch authorities six weeks later. The study will evaluate the safety and tolerability as well as pharmacokinetics of escalating doses of MOR103.

"We are very pleased to see our first proprietary drug candidate progress according to plan," commented Dr. Marlies Sproll, Chief Scientific Officer of MorphoSys AG. "Antibodies that neutralize GM-CSF could represent a new generation of medicines that reduce inflammation with greater beneficial effects."

Pine Bark Naturally Reduces Osteoarthritis, Lowers Joint Pain, Improves Physical Function

2008-04-20T08:38:00.000-07:00

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More than 20 million Americans suffer from osteoarthritis, with half a million Americans having a total joint replacement each year. A new study to be published in the April 2008 edition (Volume 22, issue No 4) of the journal of Phytotherapy Research shows Pycnogenol (pic-noj-en-all), an antioxidant plant extract from the bark of the French maritime pine tree, was shown to reduce all osteoarthritis symptoms by 56 percent. The study revealed a particularly high efficacy of Pycnogenol for lowering joint pain by 55 percent. Moreover, patients required dramatically less standard pain medication (-58 percent), which greatly improved the gastrointestinal complications resulting from the pain medication by 63 percent.

"Pycnogenol seemed a natural fit for this study," said Dr. Gianni Belcaro, a lead researcher of the study. "There are a few main components contributing to the clinical picture of treatment management in osteoarthritis: inflammation causing a progression in the disease, alteration of fatigue resistance and muscular performance - reversing and blocking the vascular problems associated to altered mobility. Theoretically, a treatment with a compound specifically active on all those aspects could be highly effective, which is why we chose Pycnogenol."

The randomized, double-blind, placebo-controlled study, held at Italy's Chieti-Pescara University, sampled 156 patients with osteoarthritis of the knee (OA). Patients were administered 100 mg Pycnogenol or placebo, daily for three months. Symptoms were evaluated by WOMAC index scores and mobility by recording their walking performance on a treadmill. Patients were permitted to continue taking their choice of pain medication provided they recorded every tablet in a diary for later evaluation.

To describe and rate osteoarthritis symptoms (joint pain, stiffness and physical function), WOMAC questionnaires were evaluated by the investigator and patient at the start and after three months of treatment. Patients were trained on a treadmill test and performance evaluation was recorded on total distance that could be covered without pain. Measuring foot volume by the water-displacement method was used to evaluate ankle/foot edema in a randomly selected subgroup of subjects within the two treatment groups.

After three months, scores for pain dropped significantly for the Pycnogenol treatment group and no significant effects were recorded for the placebo group. Scores for stiffness were reduced by 53 percent. The scores for physical function were reduced by 57 percent in the Pycnogenol group and improvement under placebo was not significant. The global WOMAC score decreased following Pycnogenol treatment and very little in the placebo group, from 56 percent vs. 9.6 percent for Pycnogenol and placebo, respectively. Overall well-being of patients (emotional function) was significantly enhanced with the Pycnogenol group, by 64 percent and 15 percent for the placebo group.

Results of exercise tests on the treadmill demonstrated an increased performance after three months of Pycnogenol treatment. At the start of the study, patients could only walk a mean of 74 yards without feeling pain and after three months, they could walk 216 yards, compared to the placebo group that noted 71 yards at the beginning of the study and 96 yards at the end.

In addition to the osteoarthritis results, 76 percent of the patients in the Pycnogenol group and 79 percent in the placebo group showed visible ankle and foot edema at inclusion of the study. After the three months, edema decreased in 79 percent of the Pycnogenol patients and only one percent in placebo-treated patients.

Patients were allowed to use their regular dosage of NSAIDS. Usage dropped by 58 percent during treatment with Pycnogenol and one percent with the placebo. Evaluation of data demonstrated a decrease of gastrointestinal complications of 64 percent in the Pycnogenol group versus three percent in placebo.

"The results of this study are significant as they clearly demonstrate the clinical action of Pycnogenol on OA and management of symptoms. The use of Pycnogenol many reduce costs and side effects of anti-inflammatory agents and offer a natural alternative solution to people suffering from OA" said Dr. Belcaro.

A previous study on osteoarthritis which was carried out at the University of Arizona Tucson (published in Nutrition Research) had discovered that Pycnogenol was effective for improving pain and joint function. After three months in the Pycnogenol group, there was a reduction of 43 percent in pain, 35 percent in stiffness, 52 percent in physical function subscales, respectively. The placebo group showed no significant scores throughout the entire study. Dr. Belcaro confirms this earlier study with a much larger number of patients and with a more detailed investigation procedure.

The benefits of Pycnogenol for arthritic joints are suggested to result predominantly from the anti-inflammatory potency of Pycnogenol which was demonstrated in a series of clinical investigations in the past. There are more breakthrough studies on Pycnogenol and osteoarthritis expected to be published next year allowing for development of innovative, natural formulas for joint health. Additionally, Horphag Research, the exclusive worldwide distributor of Pycnogenol has filed for several patents for Pycnogenol's application for COX-1, COX-2 and treating osteoarthritis.

"The new research in the field of osteoarthritis has been a paradigm shift for Pycnogenol. We were able to demonstrate Pycnogenol's impact on all inflammatory parameters and have succeeded in providing strong clinical evidence of Pycnogenol efficacy in this field. It is obvious that Pycnogenol will have to be considered as an innovative ingredient of choice for the joint health market," said Victor Ferrari, CEO of Horphag Research, the exclusive worldwide supplier of Pycnogenol.

ACTEMRA Rheumatoid Arthritis Study

2008-03-21T05:40:00.000-07:00

Patients with rheumatoid arthritis treated with Roche's ACTEMRA(TM) (tocilizumab) experienced significant and rapid reduction in the signs and symptoms of their disease, according to a study published in this week's issue of The Lancet. Results from the OPTION (TOcilizumab Pivotal Trial in Methotrexate Inadequate respONders) trial -- a Phase III international study -- demonstrated that RA patients achieved greater improvement of symptoms and a higher quality-of-life with ACTEMRA, an interleukin-6 (IL-6) receptor inhibitor, in combination with methotrexate, compared with methotrexate plus placebo.

"Results of this pivotal study convincingly demonstrate that tocilizumab can effectively and rapidly diminish the painful and debilitating effects of rheumatoid arthritis," said Josef Smolen, M.D., lead investigator of the OPTION trial and Professor of Medicine at the Department of Internal Medicine at the Medical University of Vienna, Austria. "These trial findings are significant because we know that many rheumatoid arthritis patients continue to experience symptoms of joint pain, stiffness, physical disability and fatigue, despite treatment with existing therapies."

About OPTION Study

In the OPTION trial, a three-arm, double-blind, controlled Phase III study, 623 patients were randomized to receive ACTEMRA intravenously (either 4mg/kg or 8mg/kg) every four weeks plus methotrexate weekly or placebo infusions plus methotrexate weekly. The study was conducted in 73 trial sites in 17 countries outside the United States.

At 24 weeks, 58.5% of ACTEMRA patients (8mg/kg) achieved a 20% reduction in RA symptoms (ACR20)(1), compared with 26.5% of patients in placebo plus methotrexate patients. In the study, 43.9% of patients treated with ACTEMRA (8mg/kg) plus methotrexate achieved at least a 50% (ACR50) reduction in symptoms compared to 10.8% of patients receiving placebo and methotrexate; ACR70 was achieved in 22% of the treatment group versus 2% in the control group. A rapid decrease in disease activity (DAS28)(2) was seen as early as two weeks in a greater proportion of patients treated with ACTEMRA plus methotrexate, with 27.5% achieving DAS28 less than or equal to 2.6 by 24 weeks.

Additionally, results showed that 80% of patients in the ACTEMRA (8mg/kg) plus methotrexate group responded with moderate to good improvements in RA symptoms, according to the EULAR response criteria(3), compared with 35% for those treated with placebo and methotrexate at 24 weeks. ACTEMRA was generally well tolerated; the most common adverse events reported more frequently in the ACTEMRA arms of the OPTION trial were upper respiratory tract infection, nasopharyngitis and headache.

The OPTION trial also assessed physical function and quality-of-life at baseline and every four weeks thereafter. Patients receiving ACTEMRA achieved significantly greater improvement in areas of fatigue and mental function at 24 weeks, and achieved normal levels of hemoglobin and C-reactive protein (CRP), a marker of inflammation due to RA, compared with patients receiving placebo plus methotrexate.

"We are very encouraged by the findings of the study as they further establish the role of ACTEMRA and its unique blockade of IL-6 receptors as a potential new biologic treatment option for patients with RA," said Lars Birgerson, M.D., Ph.D, Vice President, Global Head Medical Affairs, Roche.

About ACTEMRA(TM) (tocilizumab)

ACTEMRA is the first humanized interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody. Studies suggest that reducing the activity of IL-6, one of several key cytokines involved in the inflammatory process, may reduce inflammation of the joints and relieve certain systemic effects of RA. The extensive clinical development program conducted by Roche includes five clinical studies and has enrolled more than 4,000 patients in 40 countries, including the United States. Three of these studies are completed and have reported meeting their primary endpoints. Another Phase III trial evaluating ACTEMRA in RA is an ongoing two-year study and is expected to report one-year data evaluating the effect of ACTEMRA on the inhibition of structural joint damage later this year. ACTEMRA is awaiting approval in the United States and Europe.

ACTEMRA is part of a co-development agreement with Chugai, a Japanese company. In June 2005, ACTEMRA was launched by Chugai in Japan as a therapy for Castleman's disease; in April 2006, additional indications for rheumatoid arthritis and systemic-onset juvenile idiopathic arthritis were also filed in Japan and are currently under review.

The serious adverse events reported in ACTEMRA clinical trials were serious infections and hypersensitivity reactions including anaphylaxis. The most common adverse events reported in clinical studies were upper respiratory tract infection, nasopharyngitis, headache and hypertension. Increases in liver function tests (ALT and AST) were seen in some patients; these increases were generally mild and reversible, with no hepatic injuries or any observed impact on liver function.

Phase 3 Trials Results For Puricase(R) (pegloticase)

2008-03-03T11:41:00.000-08:00

Savient Pharmaceuticals, Inc. (NASDAQ: SVNT) announced further information related to infusion reactions and deaths for their Phase 3 clinical trials for Puricase(R) (pegloticase) being developed for treatment failure gout patients.

Severe and Serious Infusion Reactions

Our preliminary analysis indicated that 19 patients or 11% of pegloticase treated patients experienced an infusion reaction termed "serious" or "severe." Based on further information that has become available, we have determined that the number of patients who experienced a "severe" or "serious" infusion reaction is 18, a reduction of 1 due to a patient whose adverse event occurred after departing the clinical site post-infusion.

We also recently reported that 7 patients experienced a "severe" infusion reaction. Of the 18 patients who experienced a "serious" or "severe" infusion reaction, 5 had a "serious" infusion reaction that was also characterized as "severe" in an overlapping manner, whereas 7 patients had a "severe" infusion reaction that did not also carry the designation of "serious." Of the remaining 6 patients who had a "serious" infusion reaction, one was also reported as "mild" and five were reported also as "moderate."

Further Information Regarding Number of Patients Deaths

Of the 212 patients in the Intent-To-Treat (ITT) population, 158 patients completed all visits. These 158 patients are included in the ITT analysis, including 3 patients who were assigned to pegloticase treatment who died during the trial; not drug related. One patient who was randomized to the placebo group died before the first placebo dose administration and is not included in the ITT population. Two patients who completed the study, but died after completion, are also included in the ITT analysis. We recently learned that one of these two patients was assigned to a pegloticase treatment arm and the other was assigned to the placebo. This last patient's death occurred 4 months after placebo administration.

It should be pointed out that the company does not seek out post-study follow-up information on patients who dropped out of the trial, or did not enroll in the Open Label Extension. However, if a patient's death is reported to the company after the patient has had a final visit (either a drop out or a completed patient), then this death will be included in accounting of patient dispositions in our regulatory submissions and reports. We are releasing this information at this time because we understand that a number of our stockholders and members of the analyst community are interested in better understanding these issues. However, we do not undertake any commitment to continue to disclose information of this sort.

The company is scheduled to release financial results for the fourth quarter and year-end 2007 following the close of the market on Tuesday, March 11, 2008 and will host an investment community conference call beginning at 10:00 a.m. Eastern Time on March 12, 2008.

About Puricase® (pegloticase)

Puricase is a pegylated recombinant mammalian urate oxidase in development to control hyperuricemia and its clinical consequences in patients for whom conventional therapy is contraindicated or has been ineffective. The two Phase 3 pivotal trials assessed the safety and efficacy of a six-month course of pegloticase therapy in patients with treatment-failure gout under the auspices of a Special Protocol Assessment from the U.S. Food and Drug Administration. Savient has licensed worldwide rights to the technology related to Puricase from Duke University and Mountain View Pharmaceuticals, Inc. Puricase is a registered trademark of Mountain View Pharmaceuticals, Inc.

About The Treatment-Failure Gout Population

Approximately three to five-million Americans suffer from gout, many of whom experience only limited success in the long term management of their painful symptoms. Within this group, we estimate that allopurinol, the mainstay of therapy for control of uric acid, is contraindicated or has failed to achieve therapeutic success at appropriate dosages in approximately 25,000 to 100,000 patients, meaning that today tens of thousands of gout patients have no effective treatment option. It is for these treatment-failure patients that pegloticase potentially offers a unique benefit and for which the product has been granted Orphan drug designation.

About Savient Pharmaceuticals, Inc.

Savient Pharmaceuticals is a biopharmaceutical company engaged in developing and distributing pharmaceutical products that target unmet medical needs in both niche and broader markets. The company's product development candidate, Puricase (pegloticase) for treatment-failure gout, has reported positive Phase 1, 2 and 3 clinical data. Patient dosing in the Phase 3 clinical studies began in June 2006; patient enrollment was completed in March 2007; and the Phase 3 clinical studies were completed in October 2007. Pegloticase became the official generic name for Puricase assigned by the USAN Council replacing the previously used name of PEG-uricase. Savient's experienced management team is committed to advancing its pipeline and expanding its product portfolio by in-licensing late-stage compounds and exploring co-promotion and co-development opportunities that fit the Company's expertise in specialty pharmaceuticals and biopharmaceuticals with an initial focus in rheumatology. Savient also manufactures and supplies Oxandrin® (oxandrolone tablets, USP) CIII in the U.S. Further information on Savient can be accessed by visiting: http://www.savient.com.