A Phase II trial of CH-4051, a product in development for rheumatoid arthritis (RA) from Chelsea Therapeutics Inc., failed to meet its primary endpoint of superiority over methotrexate.

The news sent Chelsea's stock (NADAQ:CHTP) falling 61 cents, or 31.3 percent, to close at $1.34 Thursday.

CEO Simon Pedder blamed the failure on an "unexpectedly robust" response to methotrexate, and he maintained that the drug had potential in RA and other inflammatory and autoimmune disease. Nonetheless, Chelsea will discontinue development of CH-4051 to focus on Northera (droxidopa).

CH-4051 is an antifolate engineered to be an analogue of methotrexate. Methotrexate bears a high rate of side effects, including gastrointestinal disturbances, renal toxicity and hepatic toxicity due to its conversion to toxic metabolites. CH-4051 is metabolically inert, and preclinical data suggested that it inhibits enzymes required for cell proliferation, including dihydrofolate reductase.

The Phase II trial compared CH-4051 to methotrexate in 244 patients with RA who had not done well on methotrexate previously. Patients received 0.3-mg, 1-mg or 3-mg doses of CH-4051 daily, 3 mg of CH-4051 with folate or 20 mg methotrexate weekly with a folate supplement for 12 weeks following a two-week methotrexate washout. Efficacy was assessed by the hybrid American College of Rheumatology (hACR) score followed by 20 percent improvement in ACR criteria (ACR 20).

After 12 weeks, the methotrexate group showed greater improvement in mean hACR and ACR 20, with a 56 percent response rate. Response rates for patients receiving CH-4051 were 41.7 percent at 0.3 mg, 45.8 percent at 1 mg, 34.7 percent at 3 mg and 45.8 percent at 3 mg with folate.

The drug was found safe and well tolerated, and there were no dose-limiting toxicities.

Chelsea reported that there was "evidence of clinical activity of CH-4051, in a dose-dependent manner, across multiple RA assessment criteria," but that is difficult to see from the data reported. Deutsche Bank analyst Robyn Karnauskas wrote, "Notably, there was not a clear dose response with CH-4051."

According to Karnauskas, the Street does not assign any value to CH-4051; Northera, for neurogenic orthostatic hypotension (NOH), will continue to be a value driver for Chelsea going forward.

Chelsea is regrouping from an unexpected disappointment in March when the FDA issued a complete response letter (CRL) for Northera even though the agency's Cardiovascular and Renal Drugs Advisory Committee had given it a positive recommendation. (See BioWorld Today, March 30, 2012.)

The CRL requested data from an additional positive trial before it would consider approving Northera in NOH patients with primary autonomic failure due to conditions such as Parkinson's disease, multiple system atrophy and pure autonomic failure, dopamine beta hydroxylase deficience and nondiabetic autonomic neuropathy. (See BioWorld Today, Feb. 14, 2012.)

That subject came up in the Feb. 23 advisory panel meeting, as well, with the vote splitting 7 to 4 in favor of approval. (See BioWorld Today, Feb. 24, 2012.)

The active ingredient in Northera, droxidopa, has been marketed for more than 20 years in Japan for NOH, a disorder characterized by sudden drops in blood pressure upon standing. It can lead to falls and serious injuries, and the only currently approved drug for it is ProAmatine (midodrine, Shire plc), although Florinef (fludrocortisone) is sometimes used off-label.

Following the CRL, a class-action lawsuit was filed against the company, alleging material misstatements and omissions concerning the safety and efficacy of Northera.

Upon completion of its end-of-review meeting with the FDA, Chelsea said it will revise its plan and submit a modified proposal to the FDA calling for a change in the endpoint of one of its studies, Study 306B, to another orthostatic hypotension symptom assessment item (dizziness) at two weeks post-titration and will increase the number of patients enrolled from 160 to 200.