After getting mixed results in a Phase II trial of CRx-150 in rheumatoid arthritis, CombinatoRx Inc. decided to discontinue development of the product and reallocate its funding to CRx-102, which is poised to begin two Phase IIb arthritis studies later this year.

"Getting straight to the point, CRx-150 does not meet our target product profile," CombinatoRx President and CEO Alexis Borisy said during a conference call. "CRx-150's activity is clearly not competitive in the current or future RA marketplace. We also believe we have a much stronger RA candidate with CRx-102," he added.

The decision didn't get much of a reaction from investors: shares of Cambridge, Mass.-based CombinatoRx (NASDAQ:CRXX) shares remain unchanged, closing at $6.10 on Wednesday and Thursday. But at least one analyst was pleased. On the conference call, Edward Tenthoff of Piper Jaffray and Co. applauded the company for its "ability to make these decisions and kill programs that aren't making your high criteria."

The Phase II trial compared the combination of CRx-150 and a disease-modifying anti-rheumatic drug (DMARD) to placebo plus DMARD in 64 RA patients. Patients receiving CRx-150 did not achieve reduced C-reactive protein (CRP) levels, the primary endpoint in the trial. However, the data weren't all bad. The CRx-150 group scored -0.51 on the DAS28 composite measure of disease activity, significantly better than the -0.05 in the control group (p=0.05). CRx-150 treatment also improved pain as measured on a visual analogue scale, with a median change of -11.5 mm in the CRx-150 group versus -2.0 mm in the control group (p=0.04).

Despite encouraging secondary endpoint data, CombinatoRx pulled the plug on CRx-150, a combination of the antidepressant amoxapine and the cardiovascular drug dipyridamole. CRx-150 had previously failed to reduce CRP in a Phase II chronic inflammatory periodontitis trial, and Lazard Capital Markets analyst Matthew Osborne said in a report that the drug's failure "to make the cut in RA" was not unexpected.

This is not the first time CombinatoRx has had trouble with combinations using amoxapine. Last year, the amoxapine-prednisolone combination drug CRx-119 also failed to reduce CRP in a chronic periodontitis Phase II trial and was subsequently discontinued. (See BioWorld Today, April 11, 2006.)

"As an oral, systemic agent, I think we are done with amoxapine," Borisy said. He added that antidepressants such as nortriptyline may have a better risk/benefit ratio.

Yet the CRx-150 data will not go to waste. Borisy said knowledge about the drug's effect on pain will be incorporated into the CRx-170 program. The same goes for knowledge gained from CRx-139, a paroxetine-prednisolone combination that was placed on hold after it failed a Phase II rheumatoid arthritis trial. CRx-170, a combination of nortriptyline and prednisolone, is slated to move into Phase II for pain later this year.

Moving forward in the arthritis space is CRx-102, a combination of dipyridamole and prednisolone. The drug met its primary endpoints in Phase II studies in RA and osteoarthtirits and is slated to begin Phase IIb studies in both indications by mid-year. (See BioWorld Today, Jan. 31, 2006.)

CombinatoRx also plans to begin Phase II trials this year with CRx-191 (nortriptyline-mometasone) in psoriasis, CRx-197 (nortriptyline-loratadine) in atopic dermatitis, and CRx-401 (bezafibrate-diflunisal) in type 2 diabetes. Data from two ongoing Phase II psoriasis trials with CRx-191 are expected later this year. Also in the clinic is CRx-026, a combination of the sedative chlorpromazine and the antibiotic pentamidine for cancer.

Although CombinatoRx has a healthy pipeline, analysts on the conference call noted that the company's development of combination products that act synergistically to target new indications has been peppered with both success and failure. Borisy explained that by designing more rigorous clinical trials and applying "greater rigor and experience" to the selection of product candidates from its platform, CombinatoRx plans to ensure the future holds more of the former than the latter.