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Diabetic Neuropathy

May 28, 2012

Janssen Pharmaceuticals issued results from a phase III study of Nucynta ER (extended release) for the treatment of pain in diabetic peripheral neuropathy (DPN). This randomized-withdrawal, placebo-controlled study enrolled 459 adult patients who had moderate to severe, chronic painful DPN for six months or more and a history of analgesic use for painful DPN for three months or more. The trial was split into three phases: a three-week titration period during which the individually optimized Nucynta ER dose (100-250mg two times per day) was determined for each patient; a 12-week, double-blind maintenance phase, during which patients with a one-point or greater reduction in pain intensity from beginning to end of titration were randomized either to continue taking Nucynta ER (at their optimal dose) or to receive placebo; and a follow-up period with a clinic visit at four days and a telephone interview at 10-14 days after discontinuation of study drug. The study met its primary endpoint of a mean change in average pain intensity from baseline, which was reduced from 7.3 to 3.6 on the NRS 11-point scale. Adverse events experienced by patients included nausea, dizziness, constipation and somnolence. Janssen is currently waiting for the FDA to review Nucynta ERs Supplemental New Drug Application.

July 26, 2010

Arcion Therapeutics released positive results from a phase IIb trial of ARC-4558 (0.1% clonidine gel) for the treatment of painful diabetic neuropathy. This double-blind, randomized, placebo-controlled clinical trial enrolled 180 adult subjects with diabetic neuropathy. The subjects applied ARC-4558 0.1% gel or placebo to the affected area three times a day (3.9 mg per day) for a 12-week treatment period, and continued stable doses of their existing pain medications. The primary endpoint was the change in pain at week 12 compared to baseline, measured by the numerical pain rating scale (NPRS). ARC-4558 was significantly more effective in reducing pain than placebo (p<0.05). The significance of the response increased with higher levels of nociceptors in the subject's skin (p<.005). ARC-4558 was well tolerated and there were no serious or severe adverse events attributable to the treatment.

May 25, 2009

Arcion Therapeutics released positive results from a phase II trial of ARC-4558 for the treatment of painful diabetic neuropathy. This double-blind, placebo-controlled trial enrolled 166 subjects with chronic, bilateral, lower extremity, painful diabetic neuropathy. The subjects were randomized to receive 0.1% or 0.2% topical ARC-4558 gel or placebo gel, and remained on their existing pain management treatments. The gel was applied to both feet twice daily for the first two weeks and three times a day for six weeks. The subjects receiving 0.1% ARC-4558 gel reported significantly greater reductions in pain when compared to placebo (p≡0.015) and this improvement was demonstrated in the first week of the study (p≡0.003). Subjects in the 0.2% group did not differ from those in the placebo group, though a trend was observed (p≡0.054). Responder analysis revealed that 47.2% of patients across both treatment groups combined had 30% or more pain relief compared to 29.3% in the placebo group (p≡0.031). A phase IIb trial is currently underway.

September 22, 2008

Sangamo Biosciences reported positive interim results from a phase II trial of SB-509 for the treatment of moderate-to-severe diabetic neuropathy. This single-blind, multi-center study enrolled 45 subjects with diabetic peripheral neuropathy and between one and six nerves in the lower limb that were blocked, or could not have nerve conduction velocity (NCV) measured. The subjects were randomized to receive two treatments in both legs of either placebo or SB-509 (60 mg total dose, 30 mg per leg), one at Day 0 and one at Day 90. At 180 days post-treatment, recovery of NCV was observed in 75% of the SB-509-treated subjects compared to 25% of the placebo-treated group. SB-509 was well tolerated and no drug-related severe adverse events were observed. This study has been expanded to include a third treatment cohort with a higher dose of SB-509.

May 12, 2008

Schwarz Pharma released positive results from a phase III trial of lacosamide for the treatment of diabetic neuropathic pain. This placebo-controlled, withdrawal study was a sub-trial of an open- label, follow-on to a phase III, double-blind trial. Subjects had been followed for a mean of twenty months before entering the sub-trial. Prior to any lacosamide treatment, subjects had an average daily pain score of 6.5. After more than a year of open-label treatment, the mean pain score was 2.5, the baseline score of the withdrawal sub-trial. A total of 106 subjects treated with lacosamide (100-400 mg/day) participated in the withdrawal study. In a blinded fashion, lacosamide was withdrawn (less than or equal to twenty-eight days) and reintroduced. The primary endpoint was the change in average daily pain score from baseline to the last seven days of each period, using the 11-point Likert pain scale. The difference in average daily pain scores was statistically significant in favor of lacosamide over placebo (p= 0.007). Average daily pain scores increased during placebo treatment and improved to values similar to sub-trial baseline (2.5 on the pain scale) when lacosamide was reintroduced. A key secondary endpoint, worsening of pain when lacosamide was withdrawn, was also reached. The intra-individual change in average daily pain score from open-label lacosamide treatment at baseline to the end of the placebo period was statistically significant (p<0.001). More subjects receiving placebo (39%) versus lacosamide (29%) experienced sustained worsening of pain during the withdrawal periods. Treatment was safe and well tolerated. An MAA and NDA are currently under review by the EMEA and FDA, respectively.

March 17, 2008

Keryx released negative top-line results from a phase III trial of Sulonex for the treatment of diabetic nephropathy. This randomized, double-blind, placebo-controlled study enrolled one thousand subjects with type 2 diabetes and persistent microalbuminuria, in Europe, the US and Asia Pacific countries. The subjects were randomized to receive 200 mg KRX-101 or placebo daily, both in addition to maintained maximum tolerated dosing with background ACEi or ARB therapy. The primary endpoint, which was to increase the proportion of subjects achieving therapeutic success at six months compared to placebo, was not reached. Therapeutic success was defined as conversion from microalbuminuria to normoalbuminuria, as measured by albumin/creatinine ratio (ACR), with at least a 25% reduction in ACR relative to baseline ACR, or a 50% reduction in ACR relative to baseline ACR. There was little difference in the mean changes in ACR over time between the Sulonex and placebo arms. Based on the results, Keryx plans to discontinue the development of Sulonex and re-focus on other products in their development pipeline.

February 18, 2008

Epicept released positive preliminary results from a phase II trial of NP-1 for the treatment of diabetic peripheral neuropathy (DPN). This double blind, placebo-controlled study, dubbed Neuracept, enrolled two hundred and fifteen subjects. The primary endpoint, the difference in changes in pain intensity between NP-1 and placebo over a four week trial duration, was reached (p=0.0715). Secondary endpoints were reached as well. Sixty percent of subjects in the NP-1 treatment arm achieved a reduction of pain scores of at least 30% compared with 48% of subjects in the placebo arm (p=0.076). In addition, 33% of subjects in the NP-1 treatment arm achieved a reduction in pain scores of at least 50% compared with 21% of subjects in the placebo arm (p=0.078). Based on the results, Epicept plans to move forward with phase III trials of NP-1 for this indication.

April 23, 2007

Avanir announced positive results from a phase III trial of Zenvia (dextromethorphan hydrobromide/quinidine sulfate, "DMQ") for the treatment of diabetic neuropathic pain. This randomized, double-blind, placebo-controlled, parallel assignment study enrolled 379 subjects in the US and Israel. Subjects were placed into one of three treatment arms: 45 mg dextromethorphan /30 mg quinidine (DMQ 45) BID dose, 30 mg dextromethorphan / 30 mg quinidine BID dose (DMQ 30) and placebo. The primary endpoint was the score on the Pain Rating Scale based on daily journal entries. In both Zenvia treatment groups the pain ratings were lower than placebo (p less than 0.0001). Statistical significance in pain score reductions was reached with both treatment groups when compared to placebo. In the DMQ 45 group average reductions in pain score were significantly greater than placebo at days 30, 60, and 90 (p less than 0.0001 at each time point). In the DMQ 30 group statistical significance was also reached at days 30 and 60 (p less than 0.0001) and day 90 (p=0.007). The average pain relief reductions as measured on the Pain Relief Rating Scale were greater for the DMQ 45 patient group (p=0.0002) and for the DMQ 30 patient group (p=0.0083), compared with placebo. Reductions on the Pain Intensity Rating Scale reached statistical significance in the DMQ 45 group when compared to placebo (p=0.029). In addition, on the secondary endpoint of Peripheral Neuropathy Quality of Life Scale Composite score, the DMQ 45 and DMQ 30 subjects showed a greater improvement than placebo subjects (p=0.05 and p=0.08, respectively). Based on the results Avanir plans to meet with the FDA to determine the next steps toward acquiring approval for Zenvia.

Epix reported positive results from a phase Ib trial of PRX-07034 for the treatment of obesity and cognitive impairment associated conditions. This randomized, double-blind, placebo-controlled, multiple ascending dose trial enrolled 33 obese subjects who received PRX-07034 orally once-daily for 28 days. Treatment was well tolerated at doses up to 600 mg once per day. No dose limiting toxicity was identified and no serious adverse events were reported. Pharmacokinetic data was predictable, with dose proportional increases in exposures, and a half-life supporting once-daily administration. Overall results on cognitive function showed a dose-dependent trend for improvement and a dose-dependent effect was statistically significant (p=0.014 vs. placebo) at the 600 mg dose. Based on the results the company plans to move forward the development of this therapy.

January 8, 2007

Depomed released positive results from a phase II trial of Gabapentin GR for the treatment of diabetic peripheral neuropathy (DPN). This multicenter, double-blind, placebo-controlled trial enrolled 147 subjects who were randomized into one of three treatment groups: 3000 mg Gabapentin GR dosed once or twice daily or placebo, for four weeks. Treatment was well tolerated, with no serious adverse events reported. Significant improvements in the pain score, based on the Likert pain scale, were reached in the once daily Gabapentin GR arm, with a mean change from baseline to study end of -2.45 compared to -1.26 for placebo (p= 0.002). The number of responders, defined as patients with at least a 50 percent reduction in pain at endpoint compared to baseline, reached statistical significance as well. The proportion of responders was 35% for once daily Gabapentin GR (p= 0.001), 26% for twice daily Gabapentin GR (p= 0.015) and 8% for placebo. Based on the results, Depomed plans to move development of Gabapentin forward.

June 19, 2006

Isis Pharmaceuticals issued positive result of a phase II trial of ISIS 113715, for the treatment of type 2 diabetes. This 2-stage, randomized, double-blind, placebo-controlled study enrolled patients in 2 stages. In the first stage, 66 patients received escalating weekly doses of 100 mg, 200 mg, 400 mg or 600 mg or placebo for 6 weeks. In the second stage, 22 subjects received treatment with 200 mg of the drug or placebo for 3 months. Results from the first stage yielded no serious adverse events, no incidence of hypoglycemia, weight gain, or metabolic acidosis, and a dose dependent reduction in fasting blood glucose (-21mg/dl, p=0.05) and LDL cholesterol levels (-17 mg/dl, p=0.02) at the highest dose level. Results from the second stage that all subjects receiving the weekly 200 mg dose for 3 months experienced improvements in several measures of glucose control and cardiovascular health from baseline compared to placebo, including self monitored fasting blood glucose (-23 mg/dl vs. -5 mg/dl; p=0.03), fasting serum glucose (-24 mg/dl vs. +5 mg/dl; p=0.002), total cholesterol (-16 mg/dl vs. +20 mg/dl; p=0.002), and LDL cholesterol (-13 mg/dl, vs. +11 mg/dl; p=0.03). A non-significant improvement was noted in HbA1c levels (-1.10% vs. -0.86%; p>0.05).

Novocell has issued preliminary results of a phase I/II trial of their encapsulated human islet allografts, for the treatment of Type I diabetes. Data collected to date from the first two subjects receiving the transplants yielded preliminary evidence that the transplanted cells were functional, and there was no indication of autoimmune reactions or allograft rejection to date. Subjects received only transient low dose cyclosporine (50-100 ng/ml 12hr trough), and did not require long term immunosuppression regimens. This open-label proof-of-concept study is ongoing in San Antonio, Texas, under the direction of Dr. Sherwyn Schwartz and Dr. Paraic Mulgrew.

Sangamo BioSciences issued positive pooled results of a phase Ia and phase Ib trial of SB-509, for the treatment of diabetic neuropathy. Trial data indicated that single administrations of the drug were well tolerated, with no serious adverse events reported at doses predicted to be clinically relevant. The most common overall adverse events were injection site reactions. Preliminary anecdotal data were positive, and included reports of clinical improvement: all subjects receiving the drug in both trials showed a positive trend towards improvements in total neuropathy score (TNS; a composite score including neurologic exam, QST, electrophysiologic studies and neurologic symptoms), while the subjects receiving placebo showed TNS deterioration. The phase Ia dose-escalation study enrolled 12 subjects with mild to moderate disease, who received a single injection of one of 4 dose levels of the drug (1 mg, 5 mg, 15 mg and 30 mg) in one legs, with placebo administration in the other leg, with observational follow-up at 1, 2, 3 and 6 months post-treatment. In a phase Ib extension of this study, 11 subjects had been enrolled to date who received single injections of one of two doses of the drug (15 mg, n=3; or 30 mg, n=4) or placebo (n=4) in both legs. Based on these results, 18 additional patients were to receive treatment with either the highest dose regimen (30 mg per leg) of SB-509 or placebo in the phase Ib trial, with a phase II study slated to begin in the second half of 2006.

March 8, 2004

Quigley Corporation reported positive results from a French clinical trial investigating QR-333, a topical treatment for diabetic peripheral neuropathy. Results showed that the active group greatly outperformed the placebo group in thirteen out of fourteen Quality of Life parameters. The randomized, double-blind, placebo-controlled study enrolled 30 subjects. Efficacy was determined using a Quality of Life questionnaire completed at baseline, two and four weeks of treatment, and two weeks post treatment. Results were reported at the Diabetes 2004 Conference in Nice, France. The conference was sponsored by the Association for French Language Studies of Diabetes and Metabolic Illnesses (ALFEDIAM).

June 16, 2003

MetaPhore Pharmaceuticals reported positive results from a phase IIa trial investigating M40403, a superoxide dismutase mimic for the treatment of dental pain. Results showed that after administration of M40403 (20 mg), statistically significant pain relief was achieved compared with placebo treatment. Data also confirmed that M40403 had positive safety profile with no serious adverse events reported. The randomized, double blind, placebo-controlled, parallel group study enrolled 250 subjects with moderate to severe pain following dental extractions. An intravenous bolus dose of 30 mg ketorolac was used as a positive control. The trial compared three doses of M40403 (5, 10, and 20 mg) by intravenous infusion. Earlier data showed evidence of synergistic pain relief, the apparent ability to reverse or prevent tolerance to the analgesic effects of opioids, and lack of sedating side effects.

March 24, 2003

Endo Pharmaceuticals reported positive results from a series of phase IV trials investigating Lidoderm (lidocaine patch 5%) for the treatment of pain. The first study a randomized, open-label, multicenter, two-week pilot study designed to assess the impact of Lidoderm in subjects with postherpetic neuralgia (PHN), diabetic neuropathy (DN), or low back pain. Results showed that addition of Lidoderm reduced most pain interference in the PHN group and all interference in the DN and back pain groups. In the second study, an open-label, two-week pilot study of low back pain, subjects were treated with the patch for two weeks. Results showed that Lidoderm produced significant improvements in pain intensity in all groups and the treatment was well tolerated. Positive results were also reported in trials for the treatment of osteoarthritis knee pain and diabetic neuropathy.