New drug combination shows promise as effective, safe treatment for rheumatoid arthritis

A new drug combination for rheumatoid arthritis treats the disease just as well as other intensive treatment strategies but with less medication and fewer side effects at a significantly lower cost. Doctoral researcher Diederik De Cock (KU Leuven) describes the strategy in a new study published in Annals of Rheumatic Diseases.

Rheumatoid arthritis (RA) is a chronic auto-immune disease that causes pain and stiffness in the joints, fatigue, bone damage and, eventually, loss of mobility. RA afflicts around 1% of people in the western world; in Belgium, 80,000 to 100,000 people currently live with the disease.

Because there is no known cure for RA, physicians focus treatment on suppressing disease activity. Therapies have improved in recent years, and clinical studies show that intensive treatment of early RA can prevent joint damage and improve patients' quality of life.

In the two-year study, called 'CareRA' (Care in early RA), researchers and clinicians in the rheumatology unit at University Hospitals Leuven examined various therapies for early RA. Their goal: to find the optimal combination and dosage of three commonly prescribed antirheumatic drugs (methotrexate, sulfasalazine and leflunomide) in combination with glucocorticoids (a class of steroid hormones).

The researchers divided 290 early RA patients into three treatment groups. Each group received a different combination therapy: 'COBRA Classic' (methotrexate, sulfasalazine and a high first dose of glucocorticoids), 'COBRA Slim' (methotrexate and a moderate dose of glucocorticoids) or 'COBRA Avant-Garde' (methotrexate, leflunomide and a moderate dose of glucocorticoids).

New drug combination shows promise as effective, safe treatment for rheumatoid arthritis

RA Study Misses Primary Endpoint (CH-4051)...

In continuation of my update on CH-4051

Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) announced that a preliminary analysis of its dose-ranging exploratory Phase II trial of CH-4051, a non-metabolized antifolate, in patients with rheumatoid arthritis (RA) who experience an inadequate response to methotrexate (MTX) treatment indicates that CH-4051 did not demonstrate superior efficacy to methotrexate in the dose range evaluated.

"Results of this study provide evidence of the clinical activity of CH-4051, in a dose dependent manner, across multiple RA assessment criteria," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "However, the outcome of the trial was confounded by the unexpectedly robust response reported by patients treated with methotrexate. While we believe that higher doses of CH-4051 could provide enhanced therapeutic benefit in RA and that CH-4051 could be developed for other anti-inflammatory and autoimmune indications, we believe our current resources would be better allocated toward the planned completion of our Northera™ (droxidopa) development program in neurogenic orthostatic hypotension. Consequently, we have no immediate plans to continue development of CH-4051."

FDA approves Chelsea Therapeutics' Phase II protocol for CH-4051 antifolate in rheumatoid arthritis

Chelsea Therapeutics International, Ltd. announced the  confirmation by the U.S. FDA,  that its proposed Phase II protocol for CH-4051  in rheumatoid arthritis has been approved by the agency. Chelsea plans to initiate patient screening next month and initiating treatment in October.

This multi-national, double-blind, randomized Phase II trial of CH-4051, an orally available metabolically stable antifolate, is intended to evaluate the safety and efficacy of CH-4051 in a 250-patient head-to-head study against methotrexate (MTX). Patients with rheumatoid arthritis who are experiencing an inadequate response to MTX treatment will be randomized to receive daily oral doses of 0.3 mg, 1.0 mg, 3.0 mg or 3.0 mg plus folate of CH-4051 or 20 mg weekly dose of MTX plus folate supplement for 12 weeks following a two-week MTX-washout. The primary efficacy analysis will be conducted using the hybrid American College of Rheumatology, or ACR, score (hACR), which allows for a more comprehensive assessment of treatment benefit across all seven symptomatic and functional components of the standard ACR 20/50/70 evaluations historically used in RA trials.

"Although MTX is considered the standard of care in RA, both as a monotherapy and in combination with other RA treatments, the dosing and maximal therapeutic benefit of MTX is limited by well-documented tolerability issues, long-term safety concerns and variable bioavailability," commented Dr. Simon Pedder, president and CEO of Chelsea Therapeutics. "Given that CH-4051 is metabolically stable and that all of our preclinical and clinical work suggests enhanced absorption, dramatically increased potency and improved tolerability over MTX, we believe CH-4051 will be safe and highly efficacious in a historically treatment-resistant patient population."

Chelsea intends to conduct an un-blinded interim efficacy analysis after approximately 50% of patients in the two lower CH-4051 dose groups complete treatment and expect to report results from this analysis in the third quarter of 2011. Full study results, inclusive of all dose groups, are expected in mid-2012.

As previously reported, results from Chelsea's Phase I single and multiple ascending dose studies demonstrated that CH-4051 was well tolerated at doses up to and including 7.5mg, a dose range likely to be effective for multiple autoimmune disorders. The 5mg dose was as well tolerated as placebo. No serious adverse events occurred during the study and pharmacokinetic data indicated dose proportionate increases in plasma levels of CH-4051. Furthermore, it was revealed that plasma concentrations in the study were comparable to those seen in animal pharmacology studies in which CH-4051 demonstrated superior suppression of RA than both the maximally tolerated dose of methotrexate and equivalent doses of CH-1504 (see structure)....

Ref : http://www.irconnect.com/chtp/pages/news_releases.html?d=200159

Methotrexate & Ocrelizumab combination a new hope for RA patients....

In recent days, I have seen many researchers are trying the combination of existing drugs in combination with a monoclonal antibodies for many diseases like cancer, rheumatoid arthritis and are successful too. As synthetic chemist I was interested in knowing about these monoclonal antibodies and found some interesting info, which I am sharing herewith...

About monoclonal antibodies :

monoclonal antibodies (mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell. Given almost any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non-proprietary drug name ends in -mab.

The invention is generally accredited to Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975; who shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells. In 1988 Greg Winter (Nat Rev Cancer 2001;1:118-129) and his team pioneered the techniques to humanize monoclonal antibodies, removing the reactions that many monoclonal antibodies caused in some patients. Interestingly, many monoclinical antibodies have been tried for rheumatoid arthritis, chrohn's disease and as anticancer agents.

Many monoclonal antibodies like infliximab, etanercept and adalimumab were tried for the rheumatoid arthritis now its interseting to note that Genentech and Biogen Idec reported positive outcome from ocrelizumab ( humanized anti-CD20) -MTX (Methotrexate - see the structure : this drug is a part of DMARD treatment meant for RA patients) combination study in RA. The results are significant because they are the first data from a large Phase III trial to show that a humanized antibody targeted at B-cells improves the signs and symptoms of rheumatoid arthritis. Hope patients suffering from RA and those are not responding will breathe a sigh of relief in the days to come...

Ref : http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=12487