Replies to post #126423 on Biotech Values

[JJM760]

Nevertheless, I've mentioned on the ARIA board before that I am nervous about its approval chances. I'm not excited about ridaforolimus' commercial potential for sarcoma either. Ponatinib is undoubtedly ARIA's crown jewel. For me, any success with ridaforolimus would be a bonus.

Agreed and I think Berger would agree otherwise I sincerely doubt he would have sold Rida to Mrk. :-)

I was at a conference in NYC where Berger was asked about the chances of Rida approval. He responded that because Rida met its endpoints (of its designed trial) and also the obvious lack of current options for Sarcoma patients, he felt strongly that it would be approved. Now whether that is a CEO talking his book or not I guess remains to be seen. Mrk seems to agree and for what it's worth, so do I.

We will know fairly soon if the FDA and the EMA agree. Fingers crossed.

[biomaven0]

I am nervous about its approval chances

The bull case is that they have an SPA and easily met the criteria in that SPA. Further, the median PFS improvement clearly understates the actual benefit given the median happened to be on a scallop on the K-M curves where the two curves were relatively close - the improvement is quite a bit better at say both 45% and 55%. Furthermore there is really nothing available for sarcoma and there is a reasonable chance that the drug will end up being used successfully in combination therapy (both with existing drugs and with others in development).

The bear case is that the FDA can tear up an SPA if they want, and the OS curves aren't that great. Further there is no quality of life data (for reasons I don't understand). And there seems to be no identifiable subgroup where it works great. So an AC could balk.

In terms of commercial success, I really think this partly depends on whether they can find some way to break the AKT/mTOR inhibition feedback loop. If so, this could still be a big drug.

Merck seems to be proceeding with studies - for example there was this new trial posted last week (along with a PK study in Chinese patients in China and a monotherapy pediatric trial).

Study of Dalotuzumab Alone and With Ridaforolimus in Pediatric Participants With Advanced Solid Tumors (MK-8669-062)
This study is not yet open for participant recruitment.
Verified on September 2011 by Merck

First Received on September 7, 2011. No Changes Posted

Dalotuzamab is an antibody against IGFR1. Here is the rationale:

The PI3-K/AKT/mTOR pathway as a target for breast cancer therapy.
Print this page

Sub-category:
Receptor-Targeted Antibodies
Category:
Developmental Therapeutics - Experimental Therapeutics
Meeting:
2007 ASCO Annual Meeting
Session Type and Session Title:
Clinical Science Symposium, mTOR Inhibitors: Ready for Prime Time?
General Poster Session, CDA/YIA Grant Recipients' Scientific Session
Abstract No:
3511
Citation:
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3511
Author(s):
S. Di Cosimo, M. Scaltriti, D. Val, F. Rojo, M. Guzman, J. Jimenez, J. Seoane, J. Arribas, J. Baselga
Abstract Disclosures

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^) here and in the printed Proceedings.


Abstract:

Background: The PI3K/Akt/mTOR pathway is found dysregulated in multiple tumours, including breast cancer (BC). RAD001 is a recently developed drug which blocks mTOR. To study this compound's anti-tumour effect and interactions with the aforementioned pathway, we set up a translational research program which integrates basic and clinical research data. Methods: The preclinal studies performed in BC cell lines and xenografts included the use of proliferation assays, western blot (WB), small interfering RNA and immunohistochemistry (IHC) analysis. The clinical studies consisted in a phase I study with escalating doses and collection of tumour biospies at different time points Results: Our first achievement was validating the antibodies used in WB and IHC and directed towards different components of the PI3K/Akt/mTOR pathway. We first reported that sensitivity to RAD001 correlated to basal levels of p-Akt. We then observed that RAD001 inhibits mTOR downstream, pS6 and eIF4G, but increases the levels of p-Akt, both in vitro and in patients'tumour biopsies. We demonstrated that knock down of the pS6 kinase mimics the effect of RAD001. Indeed, by combining the PI3K inhibitors and the genomic approch of p85 dominant negative vector, we demonstrated that RAD001 induced p-Akt is through PI3K. Besides the p-Akt induction we also found a RAD001 induction of IRS-1, the pivot mediator of the Insulin like Growth factor-1 Receptor (IGF-1R). We reported that RAD001 resulted in a prolonged activation of IRS-1 and in a sustained association with the p85 subunit of PI3K. Thus RAD001 disrupts an inhibitory mechanism impinging on the PI3K signalling, resulting in sustained activation of the IGF-1R pathway. Accordingly we demonstrated that combination of RAD001 with coumpounds directed against the IGF-1R, i.e. both IGF-1R tyrosine kinase inhibitors and monoclonal antibodies, prevented RAD001 induced p-Akt and resulted in a supradditive growth inhibitory effects both in vitro and in MCF-7 human BC derived xenografts.We are now conducting a phase I study with a monoclonal antibody directed at the IGF-1R that blocks IGF-1R signalling. Conclusions: Dual inhibition of mTOR and IGF-1R completely blocks the PI3K/Akt/mTOR pathway and provide a mechanistic-based combined approach. Clinical studies in BC patients are being planned.