Methotrexate (MTX) Polyglutamates Test | Early RA Prediction Algorithm

Methotrexate (MTX) Polyglutamates Test – Helping physicians to optimize dosage and efficacy of MTX once therapy has been initiated in patients with rheumatoid arthritis (RA) by determining the level of MTX polyglutamates, the active metabolite of MTX

The MTX Polyglutamates Test, which we anticipate launching in late 2008, allows physicians to more rapidly titrate MTX to an appropriate therapeutic dose, and to determine whether MTX will be effective for patients based on their MTX metabolism. There is great clinical and economic benefit in optimizing MTX therapy before considering alternate or additive treatments, such as biologic therapies.

The MTX Polyglutamates Test is a useful tool for assessing patients with RA who are partial or non-responders after being treated with MTX for more than three months. Since dose is not well correlated with therapeutic response to MTX, and up to 40% of patients do not fully respond to MTX, measurement of MTX polyglutamates can help physicians to determine whether their patients should be switched to another disease-modifying anti-rheumatic drug (DMARD) or whether the MTX dose can be successfully increased to achieve a therapeutic level.

Background on Methotrexate- A Cornerstone Therapy for Rheumatoid Arthritis

Even with the expanding use of new biologic therapies, MTX continues to be the first line DMARD of choice among U.S. rheumatologists.  MTX is available at a relatively low cost, and is generally the antimetabolite therapy of choice in combination with biologic agents for treatment of RA. MTX can help limit the formation of auto-antibodies to biologic agents, thereby decreasing the incidence of injection site reactions and loss of response. In fact, the product labels for infliximab and rituximab specify combined use with MTX, and product labels for adalimumab, etanercept and abatacept indicate that those products may be used either alone or in combination with MTX. Physician experts anticipate that MTX will remain the cornerstone of RA treatment for the foreseeable future.

MTX is a prodrug requiring activation to MTX polyglutamates in order to exert anti-inflammatory and immunomodulatory effects in RA. While MTX can be very effective in treating some patients with RA, only about 60% of patients on MTX monotherapy achieve an ACR20 response, and only about 35% achieve an ACR50 response. There is significant inter-patient variability in the pharmacokinetics of MTX. On average, up to 75% of MTX is excreted unchanged in the urine within 48 hours, and about 10% of patients excrete 99% of a given dose. Further, about 30% of patients experience acute toxicities to MTX, including nausea, headache, fatigue, stomatitis and rash. , The discontinuation rates of MTX in RA have been found to be 21% to 40% at 5 years and up to 70% at 10 years. The causes of MTX discontinuation are toxicity in 56% of cases and lack of efficacy in 33% of cases.6,

Recent evidence suggests that MTX dosing is often suboptimal in patients with RA. Most physicians tend to ‘start low and go slow’, titrating the dosing of MTX upward in an attempt to balance issues of potential toxicity against efficacy. As a result, some patients never achieve a therapeutically effective dose based on their individual metabolism.

Given that MTX therapy is relatively inexpensive (at an average wholesale price of about $900 per year for generic MTX), there is enormous benefit in optimizing MTX therapy to improve efficacy before adding or switching to biologics, which typically cost over $15,000 per year.

Clinical Validation

The MTX Polyglutamates Test was developed and validated in collaboration with leading RA clinical researchers in the United States, in three independent studies enrolling a total of 348 patients with RA.3, , Key study findings include:

• Patients with MTX polyglutamate levels above 60 nmol/L afterthree months of MTX therapy were 13-fold more likely to have agood response to MTX than those with levels below 60 nmol/L.

• Patients with MTX polyglutamate levels below 20 nmol/L after three months of MTX therapy were 8-fold more likely to have a poor response to methotrexate than those with levels above 20 nmol/L.

Process for Testing

The MTX Polyglutamates Test will be performed in our CLIA certified laboratory. MTX polyglutamate levels are measured in erythrocytes from a whole blood sample using a proprietary HPLC-fluorometry method. Results are sent to the physician electronically or by fax, at the physician’s preference.

Intellectual Property

Cypress Bioscience holds a worldwide, exclusive license to the MTX Polyglutamates Test, which includes one issued US patent that provides protection through March 2023, two published US patent applications, and a number of additional US and foreign patent applications.