Replies to post #166833 on Biotech Values

[jq1234]

1) a class effect
2) a function of the very sick 3/4th line patients in the PACE trial with pre-existing CV conditions
3) specific to Iclusig

I think sometimes during the shouting between bulls and bears passing by each other, people ignore subtle points between class effect vs specific to Iclusig. Let's take a closer look:

From Iclusig label:

Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3.

From Tasigna label:

Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: BCR-ABL (20-60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125-250 nM) and DDR1 (3.7 nM).

From Sprycel label:

Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRß.

From Gleevec label:

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-KIT, and inhibits PDGF- and SCF-mediated cellular events.

While these 4 drugs are considered the same class of BCR-ABL, there are major differences highlighted in red: Iclusig is also potent inhibitors of VEGFR2 (1.5nm), FGFR1 (2.2 nm). As I mentioned earlier this year, FDA medical reviewers made clear they believed serious arterial thrombosis were due to VEGFR class of drugs, not BCR-ABL class of drugs:

7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class

The pharmacology-toxicology review noted a broad spectrum of kinase inhibition for ponatinib, which includes inhibition of the VEGFR-family of kinases. The safety profile for ponatinib is notable for similar features to kinase inhibitors active against the VEGFR-kinases. These similar features include arterial thromboembolic events, hypertension, gastrointestinal perforation, and compromised wound healing. The
following listing includes FDA-approved drugs and biologics with anti-VEGF activity:

Sorafenib
Sunitinib
Pazopanib
Axitinib
Regorafenib (Stivarga)
Bevacizumab (Avastin)
ziv-Aflibercept (Zaltrap)

The reviewers certainly could be wrong in their assessment. However, the notable differences in inhibition of VEGFR and FGFR by Ponatinib that are absent from the other drugs in the class are certainly worthy of observation whether AE profiles are different from other drugs in BCR-ABL class of drugs IMO.