ISELIN, NJ--(Marketwire - Nov 12, 2012) - Pharmos Corporation (
Background/Purpose: The investigational new drug levotofisopam is the S-enantiomer of racemic tofisopam, a 2, 3-benzodiazepine derivative approved in over 20 countries outside the US for treatment of anxiety and autonomic instability. Two Phase 1 trials of levotofisopam in healthy volunteers demonstrated acceptable safety and unexpected reductions in serum urate (SUA). This finding raised the possibility that levotofisopam may be an effective urate-lowering therapy (ULT) in patients with gout. The objectives of this proof of concept (POC) study were to evaluate the safety and tolerability of levotofisopam and its effect on SUA in patients with hyperuricemia and gout.
Methods: This was an open-label, inpatient study of levotofisopam 50 mg TID administered for 7 days to men and women with hyperuricemia and gout. Patients were required to have had 1+ gout flare in the previous 6 months, 1+ chronically swollen joint due to gout, or 1+ tophus; and screening SUA ≥8.0 mg/dL and ≤12 mg/dL after stopping ULT for ≥10 days. Key exclusions were estimated GFR <60 mL/min/1.73 m2 and 24-hour urine uric acid excretion >1000 mg. Patients were admitted for 3 days prior to dosing and received levotofisopam 50 mg as a single dose on Day 1, 50 mg TID on Days 2-6, and 50 mg as single dose on Day 7. The primary efficacy variable was % reduction in SUA from baseline to Day 7. Secondary variables included absolute reduction in SUA, proportion of subjects with SUA <6 mg/dL on Day 7, change in fractional excretion of urate, and 24-hour urinary urate on Day 6. Adverse events (AEs) were assessed during the screening, treatment, and follow-up periods.
Results: Twenty patients were to be enrolled, but after 13 subjects were dosed, the primary objective of confirming urate-lowering potential in gout patients was achieved and the study was stopped. Baseline characteristics: mean age 47.7 years (range 39-64); 11M/2F; mean BMI 28.5 kg/m2 (range 21-33). Baseline mean SUA was 8.0 mg/dL (range 7.0-9.7). At Day 7, the mean percent reduction in SUA was 48.8% (range 31.1%-64.6%). Mean absolute reduction in SUA was 3.9 mg/dL (range 2.3-5.3), and mean treated SUA was 4.1 mg/dL (range 2.9-5.8). All 13 patients achieved a therapeutic SUA of <6.0 mg/dL. Substantial reduction in SUA was observed, to <5 mg/dL in 10/13 and <4 mg/dL in 7/13 patients. Significant increases in fractional excretion of urate and 24-hour urine urate excretion were observed. There were no serious or severe AEs or premature discontinuations due to AEs. Three patients experienced gout flare. Other AEs were musculoskeletal pain/stiffness (7), headache (6), and dizziness, diarrhea, dyspepsia, toothache, rash, and ECG lead dermatitis (2 each). No clinically meaningful changes were observed in other safety assessments.
Conclusion: Monotherapy with levotofisopam led to clinically meaningful reduction of SUA in patients with hyperuricemia and gout. Treatment was generally well tolerated with 23% of the patients experiencing gout flare. Increased fractional excretion of uric acid suggests that levotofisopam reduces SUA primarily through uricosuric activity. These results support further studies to investigate the potential role of levotofisopam for in the treatment of hyperuricemia in gout.
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Statements made in this press release related to the business outlook and future financial performance of Pharmos, to the prospective market penetration of its drug products, to the development and commercialization of its pipeline products and to its expectations in connection with any future event, condition, performance or other matter, are forward-looking and are made pursuant to the safe harbor provisions of the Securities Litigation Reform Act of 1995. Such statements involve risks and uncertainties that may cause results to differ materially from those set forth in these statements. Additional economic, competitive, governmental, technological, marketing and other factors identified in Pharmos' filings with the Securities and Exchange Commission could affect such results.