Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : ARIAD Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: jq1234si who wrote (2935)

11/4/2013 7:30:43 AM

From: GregorioAllegri

Read Replies (2) | Respond to of 4474

OK. So I looked at the ihub values board and I looked for the FDA review on-line (but didn't find it) and still have questions.

First, assigning motives to anyone is a hazardous occupation, whether it be the FDA, Ariad, the docs or another message board poster, so apologies in advance if I do not precisely capture your intent.

It appears that you are saying:
a) the FDA does its own analysis, partly separate from the docs on the trials, using, among other things the actually blood pressure readings off the charts. Because of this their results may differ from what is presented at scientific meetings.
b) because ponatinib is an inhibitor of VEGFR2, they specifically looked for cardiovascular effects because they had seen them with other drugs that inhibit VEGF or VEGFR.

Did they have a method for retrospectively looking at anything other than hypertension?
Can you really reconcile these two statements as merely difference in methodology?

From Ariad's web-site, a press release dated June 2, 2013 that described a presentation at ASCO on the phase 1 trial:
"The most common non-hematologic treatment-related adverse events among all patients in this trial included rash (42%), arthralgia (20%), increased lipase (20%), fatigue (20%) and dry skin (19%), with the majority of these being grades 1 or 2 in severity. The most common hematologic treatment-related adverse events included thrombocytopenia (34%), neutropenia (14%) and anemia (12%), with thrombocytopenia and neutropenia being primarily grades 3 or 4 in severity."

Contrasted with:

"...approximately 48 percent of patients in the Phase 1 clinical trial (median treatment duration 2.7 years) have experienced serious adverse vascular events, including fatal and life-threatening heart attack, stroke, loss of blood flow to the extremities resulting in tissue death, and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow..." (FDA)

A little different? (just a rhetorical question)

Question 1: Does the 48% include hypertension?

Incidentally, here is a chart for hypertension by age (from the CDC).

AgeMen (%)Women (%)20-3435-4445-5455-6465-7475 and olderAll

11.1	6.8
25.1	19.0
37.1	35.2
54.0	53.3
64.0	69.3
66.7	78.5
34.1	32.7

The mean age in PACE was, as I recall about 60 years old...

Question 2: What other data could they glean off the patient charts and various tests that differed from the trial docs' data (other than hypertension)?

Final thoughts from the phase 1:

"The median follow-up for CP patients still on study is now more than three years (36.5 months)" (no median duration to MCyR of CML found.) Given this, even with a slow degradation of the vascular system, it seems to me harsh to remove this life saving drug. Hopefully the FDA is going to quickly find a way to restrict it. A certain percentage of patients who have complete molecular responses may actually be cured and able to go off drug (based on the STIM trial with Gleevec.) Given the high inhibition of VEGFR2 the only way to reverse the cardio symptoms is likely to be a long drug holiday (the 2 weeks done with sunitinib is not long enough.) To control both CML and the majority of the cardio effects before they become irreversible in the majority of patients will require monitoring both all the same time, and I am thinking that at $110,000/year, it should be part of the treatment. If the FDA expects Ariad to identify a safe dose, I am not sure that will ever happen. This is hardly the only VEGF/VEGFR inhibitor on the market. It is merely the only one that actually puts patients in complete remission that have no other options and thus live long enough to fully express the cardio effects. In other words, the agency's concern is a direct consequence of (a) the efficacy of the drug and (b) the fact that there are safer alternatives for CML without the T315I mutation. It logically follows that the European label (must fail the second line drugs or have the T315I mutation) is the correct label and waiting to find a safe dose is a fool's errand given the inhibition of the T315I mutant and VEGFR2 occur at the same concentration.

ga