Bristow M.R.,Aurora University |
Bristow M.R.,Duke University |
Bristow M.R.,ARCA biopharma
Pharmacology and Therapeutics
Pharmacogenetic drug development represents an ideal approach to enhance a drug's response rate in a disease indication cohort, thereby increasing the therapeutic index. The most straightforward way to develop a pharmacogenetically targeted drug is to identify a functionally important genetic variant in the drug's target(s), or in a target modifier. There are two general ways to detect such genetic variation, the candidate gene variant hypothesis testing approach, and genome wide scanning "hypothesis free" methods. In order to impact drug development either approach needs to be implemented early in the drug development process, with the candidate strategy having the advantage that it can be introduced earlier, during preclinical development. Contrary to conventional wisdom, a pharmacogenetic approach does not increase the overall efficiency of drug development, because the required additional genetic and biologic function discovery work will be layered onto standard regulatory steps. However, identification of a hyper-responsive subpopulation by a genetic biomarker does increase the chance of success in Phase 3, which may lower the cost of pivotal trials. Perhaps most importantly from a commercial standpoint, pharmacogenetics use patents, typically submitted relatively late in the development process, can greatly extend a drug's exclusivity period. This will recoup the extra cost inherent to pharmacogenetic drug development, and increase the product's return on investment by providing a longer period for branded exclusivity. Most importantly, pharmacogenetic targeting will result in a therapeutic agent with a greater therapeutic index and a better pharmacoeconomic profile than would be possible with pan-genetic, entire cohort positioning. © 2012 Elsevier Inc. Source
Han S.M.,University of Southern California |
Weaver F.A.,University of Southern California |
Comerota A.J.,Toledo Vascular Institute |
Perler B.A.,Johns Hopkins Medical Center |
Joing M.,ARCA biopharma
Journal of Vascular Surgery
Purpose: To investigate the safety and effectiveness of a novel thrombolytic, alfimeprase, in catheter-directed thrombolysis (CDT) of acute peripheral arterial occlusions (PAO). Methods: Between April 2005 and March 2007, patients with acute PAO (Rutherford class I or IIa) of a lower extremity and onset of symptoms within 14 days prior to randomization were included. Studies HA004 and HA007 enrolled respectively 300 and 102 patients. Both studies HA004 and HA007 were placebo-controlled. HA004 had two placebo arms, intrathrombus and perithrombus, while HA007 had intrathrombus placebo arm. HA004 was partially double-blind (perithrombus group was not blinded) and HA007 was double-blind. Patients were randomized to intrathrombus alfimeprase (0.3 mg/kg), intrathrombus (IT) placebo, or perithrombus (PT) placebo (HA004 only) in two divided weight-based infusions 2 hours apart. Depending on arteriographic results after treatment, patients received no further intervention or underwent endovascular therapy or open vascular surgery. The primary endpoint of both studies was efficacy of alfimeprase compared with placebo as measured by avoidance of an open vascular surgery procedure at 30 days. Results: The avoidance of open vascular surgery at 30 days was seen in 52 (34.9%), 42 (37.2%), and 7 patients (18.4%) with alfimeprase, IT placebo, and PT placebo in HA004 and 15 (29.4%) and 9 patients (17.6%) with alfimeprase and IT placebo in HA007; differences between alfimeprase and IT placebo were not statistically significant. Results were similar for secondary endpoints, including arterial flow restoration in 4 hours, 30-day ankle-brachial index, index limb pain severity, and hospital stay duration. The overall rate of adverse events was higher with alfimeprase than placebo. Hemorrhagic and peripheral embolic event rates with alfimeprase were 23% (34 patients) and 10.1% (15 patients) in HA004 and 9.4% (5 patients) and 9.8% (5 patients) in HA007; rates with IT placebo were 11% (12 patients, P = .107) and 5% (5 patients, P = .148) in HA004 and 10% (5 patients, P = .982) and 0% in HA007 (P = .07). No deaths were related to study drug administration. Conclusions: CDT for acute PAO with alfimeprase was as safe as placebo. However, alfimeprase was no more effective than placebo in increasing 30-day surgery-free survival. The surprising effectiveness of placebo alone demonstrates that the inclusion of a placebo arm is essential to the design of future lytic trials. © 2010 Society for Vascular Surgery. Source
ARCA biopharma | Date: 2015-01-06
Disclosed is bucindolol substantially free of its R-stereoisomer. Also disclosed are pharmaceutical compositions that include bucindolol substantially free of its R-stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also disclosed are methods of treating a patient that involve administering to the patient a therapeutically effective amount of a composition of the present invention.
ARCA biopharma | Date: 2014-04-17
Anti-LRP6 antibodies and antigen-binding fragments thereof, as well as pharmaceutical compositions comprising such antibodies and antigen-binding fragments are described. These anti-LRP6 antibodies can be used to enhance Wnt activity and/or antagonize Dkk1 activity. Also described are methods of therapy using such antibodies and antigen-binding regions to bind modulate Wnt/LRP6 signaling to promote tissue homeostasis, regeneration and repair in diseases such as, but not limited to, bone disorders, such as osteoporosis, rheumatoid arthritis, and osteolytic lesions caused by osteoarthritis and multiple myeloma, gastrointestinal disease and wound healing.
ARCA biopharma | Date: 2010-12-07
Anti-NTB-A antibodies and antigen-binding fragments thereof, as well as pharmaceutical compositions comprising such antibodies and antigen-binding fragments are described. Also described are methods of using such antibodies and antigen-binding regions to bind NTB-A and treat diseases, such as hematologic malignancies, which are characterized by expression of NIB-A.