ACR: Second JAK Inhibitor Shows Potential in RA

[Guest guest]

ACR: Second JAK Inhibitor Shows Potential in RA

http://www.medpagetoday.com/MeetingCoverage/ACR/23308

Published: November 11, 2010

Action Points

*Note that this study was published as an abstract and presented at a

conference. These data and conclusions should be considered to be

preliminary until published in a peer-reviewed journal.

*Note that in this manufacturer-supported study of 125 rheumatoid arthritis

patients, the novel agent INCB028050 produced at least 20% reductions in

symptom scores in up to 70% of patients after 24 weeks.

ATLANTA -- The emergence of the JAK kinase as the new hot target in

rheumatoid arthritis was further cemented here with positive phase II data

on an oral drug that may compete with tasocitinib, the field's current

leader.

Called INCB028050, the agent produced ACR20 responses (at least 20%

reductions in symptom scores) in up to 70% of patients after 24 weeks, and

ACR70 responses in nearly 30% of patients, reported Greenwald, MD, of

Desert Medical in Palm Desert, Calif.

Depending on the dosage, swollen joint counts declined by 60% to 70%, and

from 30% to 48% of patients achieved remission by week 24, as defined by a

DAS28-CRP score of 2.6 or less, Greenwald told attendees here at the

American College of Rheumatology's annual meeting.

As with tasocitinib, which had phase III results reported earlier in the

meeting, INCB28050 treatment led to increases in both HDL and LDL

cholesterol of up to 25%, depending on the dosage.

Otherwise, there were few issues of concern regarding safety, Greenwald

indicated. Infection rates in the 125-patient trial were low and not

markedly higher in the active-drug groups relative to placebo, and there was

no apparent impairment of renal or liver function.

One patient among 94 taking INCB28050 showed a large increase in alanine

aminotransferase levels, she said.

Hemoglobin values declined in a dose-dependent fashion, with patients at the

highest dosage level showing a mean decline of about 7% from baseline after

24 weeks.

On the other hand, there appeared to be no consistent impairment of

neutrophil counts.

Greenwald concluded that the efficacy and safety were good enough to warrant

a larger phase IIb trial, which is now enrolling with a target of 270

patients.

JAK has attracted increasing attention as a drug target in rheumatoid

arthritis because it's central to the inflammatory response -- mediating the

release of tumor necrosis factor and other cytokines -- and because, as a

kinase enzyme, it should be amenable to blockade by an oral, small-molecule

drug.

Tasocitinib, formerly known as CP-690,550, was first out of the gate, with

the first phase II efficacy data reported at the 2009 ACR meeting.

INCB28050 differs from tasocitinib in two potentially important respects.

One is that there are three JAK isoforms and the two agents inhibit them to

different degrees: tasocitinib primarily inhibits JAK1 and JAK3, whereas

INCB28050 selectively targets JAK1 and JAK2. Greenwald said the different

profile may make INCB28050 more effective at suppressing inflammatory

activity.

The other significant difference -- perhaps more important for clinicians --

is that tasocitinib is administered twice daily, but INCB28050 appears to be

suitable for once-daily dosing.

In the study of INCB28050 Greenwald reported here, patients were randomized

to three dosage levels of the drug -- 4, 7, or 10 mg/day -- or to placebo.

After 12 weeks, the placebo group was rerandomized to one of the two higher

doses of the drug for an additional 12 weeks, while those originally taking

INCB28050 remained on their assigned doses.

At baseline, mean tender and swollen joint counts were about 15 and 12,

respectively. Most patients were taking methotrexate and about 40% were on

corticosteroids, which they were allowed to continue during the study.

Approximately 30% of patients had previously been treated with biologic

drugs, with roughly half of these classed as " biologic failures. "

The primary outcome was the percentage of patients showing ACR20 responses

at 12 weeks in a modified intent-to-treat analysis.

It was met easily, Greenwald reported. ACR20 responses were achieved by 67%

of the 4- and 7-mg groups and by 72% of those in the 10-mg group, compared

with 32% of the placebo group (P<0.05).

Week 12 ACR50 responses were achieved by 30% to 35% of patients in all

active-drug groups versus 12% of the placebo group. ACR70 responses were

seen at week 12 in about 10% to 15% of patients taking INCB28050 and 3% of

the placebo group.

None of those differences were statistically significant, presumably because

there were only about 30 patients in each treatment arm. " We didn't have

enough numbers, " she said.

For the patients initially assigned to the active drug, an additional 12

weeks of treatment led to small to moderate increases in the ACR20 and ACR50

response rates. But the ACR70 response rate more than doubled for patients

in the 7- and 10-mg groups.

Greenwald said the outcomes at week 24 for the original placebo-group

patients, at which point they had received INCB28050 for 12 weeks, were

similar to those seen in the active-drug groups after their first 12 weeks

of treatment.

One peculiar effect that Greenwald was at a loss to explain was a large

increase in platelet counts with the drug, particularly during the first 12

weeks of treatment. Counts had risen by 17% to 35% from baseline at week 12,

though by week 24 the change had fallen back to 11% to 22% relative to

baseline.

She said the reasons for the spike were unclear and further research was

needed to understand it, as well as to determine whether it poses a clinical

problem.

Greenwald made a particular point of highlighting the DAS28-CRP remission

rates, which were extraordinarily high for rheumatoid arthritis drugs in

monotherapy.

For example, the phase III tasocitinib data showed remission rates according

to a slightly different criterion, the DAS28-4/ESR score, of 12% to 22%

depending on dosage.

Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center

in Dallas, who presented the tasocitinib data here, criticized the emphasis

on the DAS28-CRP remission data in Greenwald's presentation.

" I would say that's not validated, and those are not the right numbers, " he

declared during the question-and-answer period following the presentation.

He contended that only the ACR20 responses should have been cited as showing

a clear advantage for the INCB28050 relative to placebo.

The study was supported by Incyte and Eli Lilly. Greenwald reported no

disclosures other than the research funding for this study. All co-authors

were employees of Incyte or Eli Lilly. Fleischmann reported consulting fees

from Pfizer.

Primary source: American College of Rheumatology

Source reference: Greenwald M, et al " A randomized dose-ranging,

placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor

in subjects with active rheumatoid arthritis " ACR 2010; Abstract 2172.