CombinatoRx Incorporated

Cambridge, MA, United States

CombinatoRx Incorporated

Cambridge, MA, United States
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Haugen I.K.,Diakonhjemmet Hospital | Slatkowsky-Christensen B.,Diakonhjemmet Hospital | Lessem J.,CombinatoRx Inc. | Kvien T.K.,Diakonhjemmet Hospital | Kvien T.K.,University of Oslo
Annals of the Rheumatic Diseases | Year: 2010

Objective: To evaluate the responsiveness of joint counts, patient-reported measures and proposed composite scores in hand osteoarthritis (HOA). Methods: Data were used from a previously reported study in which 83 patients with HOA were randomly assigned to CRx-102 or placebo. CRx-102 consists of prednisolone (3 mg/day) and dipyridamole (400 mg/day), and was shown to be superior to placebo. Assessments were performed at baseline and after 7, 14, 28 and 42 days, and included the Australian/Canadian osteoarthritis hand index (AUSCAN), visual analogue pain subscale (VAS) pain and patient global, and counts of distal interphalangeal (DIP), proximal interphalangeal (PIP), metacarpophalangeal and carpometacarpal (CMC) joints (tenderness, soft tissue swelling, bony enlargement, limited motion). Various combinations of patient-reported outcomes and joint counts were computed as composite scores (similar to clinical disease activity index) and tested for responsiveness. For each measure, mean change from baseline to day 42, treatment effect, standardised response mean (SRM) and relative efficiency compared with AUSCAN pain were calculated. Results: The SRM were largest for VAS patient global (0.92), VAS pain (0.77) and AUSCAN pain (0.68), whereas the responsiveness of tender (0.46) and swollen joint counts (0.51) (18 joint assessment of DIP, PIP, CMC) was similar to AUSCAN stiffness (0.53) and physical function (0.37). Composite scores showed similar responsiveness as patient-reported pain and global. Conclusion: Patient-reported pain and patient global assessment were the most responsive outcomes, whereas joint counts had similar responsiveness to patient-reported stiffness and physical function. Composite scores were as responsive as VAS pain, and these results encourage further elaboration and validation of composite scores in HOA in larger studies.


Owens C.M.,CombinatoRx Incorporated | Mawhinney C.,CombinatoRx Incorporated | Grenier J.M.,CombinatoRx Incorporated | Altmeyer R.,CombinatoRx | And 5 more authors.
Molecular Systems Biology | Year: 2010

The search for effective Hepatitis C antiviral therapies has recently focused on host sterol metabolism and protein prenylation pathways that indirectly affect viral replication. However, inhibition of the sterol pathway with statin drugs has not yielded consistent results in patients. Here, we present a combination chemical genetic study to explore how the sterol and protein prenylation pathways work together to affect hepatitis C viral replication in a replicon assay. In addition to finding novel targets affecting viral replication, our data suggest that the viral replication is strongly affected by sterol pathway regulation. There is a marked transition from antagonistic to synergistic antiviral effects as the combination targets shift downstream along the sterol pathway. We also show how pathway regulation frustrates potential hepatitis C therapies based on the sterol pathway, and reveal novel synergies that selectively inhibit hepatitis C replication over host toxicity. In particular, combinations targeting the downstream sterol pathway enzymes produced robust and selective synergistic inhibition of hepatitis C replication. Our findings show how combination chemical genetics can reveal critical pathway connections relevant to viral replication, and can identify potential treatments with an increased therapeutic window. © 2010 EMBO and Macmillan Publishers Limited.


Rickles R.J.,CombinatoRx Inc. | Pierce L.T.,CombinatoRx Inc. | Giordano III T.P.,CombinatoRx Inc. | Tam W.F.,CombinatoRx Inc. | And 6 more authors.
Blood | Year: 2010

Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substantial activity in a panel of MM and diffuse large B-cell lymphoma (DLBCL) cell lines and tumor cells from MM patients. We have used selective adenosine receptor agonists, antagonists, and PDE inhibitors as well as small interfering RNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. The adenosine A2A receptor and PDE2, 3, 4, and 7 are important for activity. Drug combinations induce cyclic AMP (cAMP) accumulation and up-regulate PDE4B.We also observe rigorous mathematical synergy in 3-way combinations containing A2A agonists, PDE inhibitors, and Dex at multiple concentrations and ratios. Taken together, these data suggest that A2A agonist/PDE inhibitor combinations may be attractive as an adjunctive to clinical glucocorticoid containing regiments for patients with MM or DLBCL and confer benefit in both glucocorticoid-sensitive and -resistant populations. © 2010 by The American Society of Hematology.


Patel K.,Duke Clinical Research Unit | Lim S.G.,National University Hospital Singapore | Cheng C.W.,Singapore General Hospital | Lawitz E.,Alamo Medical Research | And 5 more authors.
Antiviral Therapy | Year: 2011

Background: 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors inhibit HCV replication in vitro. The combination of sertraline and simvastatin has synergistic antiviral activity in vitro, but there are no prior in vivo studies. Our aims were to prospectively assess the antiviral efficacy and safety of this drug combination in chronic hepatitis C (CHC) patients. Methods: A total of 15 CHC adults (including 1 control subject) that were treatment-naive or prior partial responders/relapsers to standard-of-care therapy were enrolled at four centres (2 in Singapore and 2 in the US). Patients received simvastatin 40 mg once daily and sertraline 50 mg once daily for 7 days, and then 80 mg once daily and 100 mg once daily, respectively, for another 21 days with a 14-day follow-up. Results: Of the 15 CHC patients, 13 completed the study. Subjects were mostly Caucasian (8/15), mean age 49.1 ±9 years and the genotype distribution was 1=10, 2=2 and 3=3. No subject discontinued dosing due to adverse events. Mean HCV RNA change from baseline was from -0.005 to -0.236 log 10 IU/ml across study intervals. Three subjects had transient >1 log 10 HCV RNA declines. No subject achieved >2 log 10 HCV RNA decline. Conclusions: The combination of sertraline and simvastatin is well-tolerated over the short-term, but has no significant antiviral or anti-inflammatory response in CHC patients. This may reflect in vivo differences in synergy between statin and/or selective serotonin reuptake inhibitors and incomplete inhibition of membrane protein prenylation with statin therapy. ©2011 International Medical Press.


The invention features methods, compositions and kits comprising a corticosteroid and a non-steroidal immunophilin-dependent immunosuppressant for treating an ophthalmic disorder in a patient, wherein at least one of said corticosteroid and said non-steroidal immunophilin-dependent immunosuppressant is present at a low concentration, in particular wherein said corticosteroid is prednisolone acetate and said non-steroidal immunophilin-dependent immunosuppressant is cyclosporine A.


Trademark
Zalicus and CombinatoRx Inc. | Date: 2011-11-01

Pharmaceuticals, namely, combination therapeutic compositions for the treatment of immunological diseases.


Z

Trademark
Zalicus and CombinatoRx Incorporated | Date: 2010-07-30

Pharmaceutical preparations for the treatment or prevention of immuno-inflammatory disease, pain, proliferative disease, or infectious disease; diagnostic preparations for medical purposes. Medical apparatus, namely, drug delivery devices and systems; apparatus for clinical diagnosis. Pharmaceutical research and development. Medical Services.


Trademark
Zalicus and CombinatoRx Incorporated | Date: 2010-06-04

Pharmaceutical preparations for the treatment, prevention, or diagnosis of proliferative disease or infectious disease. Medical apparatus, namely, drug delivery devices and systems. Medical Services.


Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substantial activity in a panel of MM and diffuse large B-cell lymphoma (DLBCL) cell lines and tumor cells from MM patients. We have used selective adenosine receptor agonists, antagonists, and PDE inhibitors as well as small interfering RNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. The adenosine A2A receptor and PDE2, 3, 4, and 7 are important for activity. Drug combinations induce cyclic AMP (cAMP) accumulation and up-regulate PDE4B. We also observe rigorous mathematical synergy in 3-way combinations containing A2A agonists, PDE inhibitors, and Dex at multiple concentrations and ratios. Taken together, these data suggest that A2A agonist/PDE inhibitor combinations may be attractive as an adjunctive to clinical glucocorticoid containing regiments for patients with MM or DLBCL and confer benefit in both glucocorticoid-sensitive and -resistant populations.


PubMed | CombinatoRx Incorporated
Type: | Journal: Molecular systems biology | Year: 2010

The search for effective Hepatitis C antiviral therapies has recently focused on host sterol metabolism and protein prenylation pathways that indirectly affect viral replication. However, inhibition of the sterol pathway with statin drugs has not yielded consistent results in patients. Here, we present a combination chemical genetic study to explore how the sterol and protein prenylation pathways work together to affect hepatitis C viral replication in a replicon assay. In addition to finding novel targets affecting viral replication, our data suggest that the viral replication is strongly affected by sterol pathway regulation. There is a marked transition from antagonistic to synergistic antiviral effects as the combination targets shift downstream along the sterol pathway. We also show how pathway regulation frustrates potential hepatitis C therapies based on the sterol pathway, and reveal novel synergies that selectively inhibit hepatitis C replication over host toxicity. In particular, combinations targeting the downstream sterol pathway enzymes produced robust and selective synergistic inhibition of hepatitis C replication. Our findings show how combination chemical genetics can reveal critical pathway connections relevant to viral replication, and can identify potential treatments with an increased therapeutic window.

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