CH-1504 might be more effective, less toxic than MTX

[Guest guest]



CH-1504 might be more effective, less toxic than MTX



October 24, 2005



Janis



Charlotte, NC and Mobile, AL - The new antifolate CH-1504 (Chelsea

Therapeutics, Charlotte, NC), formerly known as MobileTrex or M-

Trex,does not give rise to the polyglutamated and hydroxylated

metabolites associated with methotrexate (MTX) toxicity and might be

the first " nontoxic " antifolate suitable for treatment of rheumatoid

arthritis (RA).



" It is our belief that most of the side effects are caused not by the

parent compound but by its metabolites. "



CH-1504 recently completed a phase 1 (single escalating doses) trial,

and data from a small open-label comparison with methotrexate are

scheduled to be presented at the upcoming American College of

Rheumatology 2005 meeting [1]. Both studies were described by Chelsea

president Dr Simon Pedder in an October 20 presentation at the BIO

InvestorForum 2005 conference in San Francisco [2].

" It is our belief that most of the side effects are caused not by the

parent compound but by its metabolites, " Pedder said. CH-1504 is

metabolically inert and so does not produce the kinds of metabolites

associated with methotrexate toxicity.

CH-1504 tested head to head with MTX in pilot study in RA

The single-center, open-label, nonrandomized pilot study was

conducted at Cayetano Heredia University Hospital in Lima, Peru, from

December 2002 to July 2003. Twenty patients were treated either with

methotrexate 10 mg/week or with CH-1504 7 mg/day for six months. All

patients had RA according to American College of Rheumatology (ACR)

criteria, but the 10 patients treated with CH-1504 had a longer

disease duration (16.7 vs 7.3 years). Four of the 10 patients had

failed prior methotrexate therapy. All patients were on stable doses

of NSAIDs and oral corticosteroids at doses not greater than 10 mg of

prednisone per day.

Efficacy measures included ACR20 and ACR50 and changes in laboratory

markers of inflammation such as erythrocyte sedimentation rate (ESR)

and C-reactive protein (CRP). Safety measures included adverse

reactions, complete blood-cell count with differential and platelet

count, creatinine, and liver enzymes.

Pedder said there were no laboratory abnormalities reported with

CH-1504. He reported that there was a general elevation of liver

enzymes beginning after week 4 in the methotrexate group, while the

CH-1504 group had normal liver enzyme levels throughout the six-month

study. Neither group had significant changes in creatinine values.

About 20% of CH-1504 patients (vs none of the MTX patients) reported

somnolence, but Pedder said that this was not a serious problem. " Dr

[Oswaldo] Castaneda said that he just treated this with caffeine. It

did not affect the patients' activities of daily living, " he said.

Pedder also said that the CH-1504 patients had " complete absence of

the gastrointestinal side effects associated with MTX. " They also had

fewer infections. At the end of week 24, nine of the 10 CH-1504

patients were ACR20 responders vs four of 10 MTX patients. Four

CH-1504 patients were ACR50 responders vs only one MTX patient. Six

of the MTX patients were ACR nonresponders, vs only one CH-1504

patient. However, Pedder also noted that the MTX patients were

treated with 10 mg/week, while RA patients in the US are often

treated with 20 mg/week.

Adverse effects in pilot study of CH-1504 vs methotrexate in RA patients

Adverse effect

CH-1504 (n=10) (%)

Methotrexate (n=10) (%)

Dizziness

10

10

Somnolence

20

0

Nausea/vomiting

0

20

Dyspepsia

0

20

Abdominal pain

0

10

Diarrhea

0

20

Acne

10

0

Alopecia

10

10

Infections

10 (UTI)

30

*Source: Pedder S. 2005 BioInvestor Forum; October 20, 2005; San

Francisco, CA.

The pilot study also suggested that CH-1504 may have an earlier onset

of action than MTX. Pedder said that by week 4, six of 10 CH-1504

patients had already reached ACR20 response criteria, vs only one of

10 MTX patients. " A major problem with MTX is that patients often get

little benefit until they have taken the compound for eight to 10

weeks but are at risk of side effects, " he said.

Swollen joint counts were significantly lower by week 12 with CH-1504

vs MTX (p=0.05), and this difference was sustained to week 24.

Painful joint counts showed a similar trend.

ESR levels dropped by week 8 of CH-1504 and remained significantly

lower than with MTX at week 24 (p=0.05). CRP levels changed more

slowly but the curves appeared to be diverging beginning at about

week 16 and continuing through week 24.

CH-1504 is now in a phase 1b multiple-dose, dose-escalation trial in

normal volunteers in the UK. Pedder predicted that the company

expects to file Investigational New Drug (IND) submissions with the

US FDA later this year to begin phase 2 trials in RA and in psoriasis

in early 2006.

" Everything we do at this point seems to confirm the hypothetical

benefits of this molecule, " Chelsea Therapeutics vice president for

drug development Dr Art Hewitt told rheumawire.

Cost, of course, will remain an issue. Pedder said that Chelsea plans

to charge about $3000/year for CH-104, about three times the cost per

year for methotrexate.

How CH-1504 works

CH-1504 inventor Dr Madhavan G Nair (University of South Alabama,

Mobile), who has been studying antifolate drugs for 25 years,

discovered both the polyglutamation and the hydroxylation steps in

methotrexate metabolism.

Polyglutamation involves attachment of chains of glutamate molecules

to the glutamate side chain of MTX. Glutamate is ubiquitous in cells,

and Peddersaid that chains of glutamates bind appear to trap MTX

within cells. " We think this stimulates a lot of the toxicity

associated with methotrexate, " Pedder said.

Hydroxylation converts active MTX to the inactive 7-hydroxy

metabolite. This compound competes with active MTX for entry into the

target tissue, further reducing MTX efficacy. The 7-hydroxy MTX can

also be polyglutamated, and these compounds contribute to liver and

kidney toxicity, Nair said.



CH-1504 has a quinazoline in place of methotrexate's pteridine ring

and methylglutamate instead of glutamate. [Click on the image for a

larger view.]

To download table and figure as slides, click on slide logo below.

Nair tells rheumawire that he set out to build a better MTX by

attacking both of these problem areas. He attached a methylene group

onto the terminal glutamate, which stopped polyglutamation and

greatly sped CH-1504's entry into and exit from cells.

Next, Nair replaced methotrexate's pteridine ring with quinazoline,

which prevented hydroxylation of the molecule.

The result, which Nair patented, is one of a series of " metabolically

inert anti-inflammatory and antitumor antifolates " [3].

" The result remains active at lower doses and should cause less

toxicity, " Nair said.



Castaneda O, Nair G. An open-label, non-randomized, pilot clinical

trial of a novel, metabolically stable antifolate, Ch-1504, in the

treatment of advanced rheumatoid arthritis. American College of

Rheumatology meeting; November 12-17, 2005; San Diego, CA. Abstract

1502. Pedder S. CH-1504 presentation. BIO InvestorForum 2005, October

20, 2005; San Francisco, CA. Available at: . US patent 5912251.