Kantarjian

[Guest guest]

Hi Gang,

R here, with info from Hagop Kantarjian on the AMN107 experience with

CML and Ph+ ALL, from a talk on Sunday, December 11.

Starting with IM’s basic chemical structure, Novartis “rationally

designed†AMN107 to address various ways that bcr-abl has learned to become

resistant to IM. They succeeded in that AMN107 binds 20-50x more tightly to

bcr-abl than IM does, and overcomes all the resistance mutations except the one

big bugaboo, T315I.

The Phase I AMN trial included CML patients in chronic phase who are IM

resistant, patients in advanced or chronic phase, or patients who have relapsed

on or are refractory to IM. The purpose of the trial (as in all Phase I trials)

is to determine the safety, activity, pharmacokinetic profile AMN107.

The trial involved 119 patients over one year in 3 sites. The approach was to

escalate drug dose continuously until toxicity was observed. AMN was given as a

single dose at first, but investigators found that at above 400mg, blood levels

were saturated (suggesting that the gut can’t take up more than 400mg at a

time), so when they went above 400mg, AMN was given at a twice daily dose.

Reported side effects were similar to those from IM, but fewer and less

frequent. We are cautioned, however, that with most drugs, side effect profiles

tend to increase over time. The most frequent side effects were skin rashes and

neutropenia (low white count).

Here are some (but not all, because I couldn’t type fast enough, and you

weren’t allowed to photograph the Powerpoints) of the results from the trial

are as follows. Keep in mind that these patients had all flunked IM therapy:

• 35 % of CML patients reached CCR by 6 months.

• A couple of patients with PH+ ALL did very well, but I didn’t catch the

baseline number. It was something like 25% who responded, I think.

• Patients got a better response with bid dosing

• Durable responses were seen in patients in accelerated and chronic phase,

but not in blast phase.

• Patients in CP experienced an average 2 log reduction in qPCR (13

patients). Patients in AP saw a 1 log reduction, and patients in BP saw no

reduction at all.

• 43% of the patients in the trial had BCR-ABL mutations, but except for

patients with T315I, these folks responded the same as folks with no mutations.

• Myelosuppression was the main factor limiting AMN dosage.

• Based on Phase I results, the plan is to use 400mg bid (twice a day) for

phase II studies.

Cheerio,

R