Ariad Pharmaceuticals Inc fka ARIA

[BTH]

Many subsets of sarcoma? Why do an "all comers" trial??

These are all the different "sub-sets" of sarcoma (bone and soft-tissue)..... see my discussion below:

1. Chondrosarcoma
2. Ewing's
3. Osteosarcoma
4. Hemangioendothelioma
5. Gastrointestinal stromal tumor


Soft tissue sarcomas:

6. Alveolar soft part sarcoma
7. Angiosarcoma
8. Cystosarcoma Phyllodes
9. Dermatofibrosarcoma
10. Desmoid Tumor
11. Desmoplastic small round cell tumor
12. Extraskeletal chondrosarcoma
13. Extraskeletal osteosarcoma
14. Fibrosarcoma
15. Hemangiopericytoma
16. Hemangiosarcoma
17. Kaposi's sarcoma
18. Leiomyosarcoma
19. Liposarcoma
20. Lymphangiosarcoma
21. Lymphosarcoma
22. Malignant fibrous histiocytoma
23. Neurofibrosarcoma
24. Rhabdomyosarcoma
25. Synovial sarcoma


25 different types of sarcoma. Granted, there are some "exclusions" of the 25 that are not allowed in the SUCCEED trial. However, you get the pictures that "Sarcoma" is just not "one disease". If you ask any oncologist out there, they will tell you that each one is different. Take this quote from ESMO from a renowned oncologist specializing in sarcomas:

Paolo Casali is a Board Member of ESMO, Medical Oncologist at the National Cancer Institute in Milan, and an international expert on sarcomas. He remembers the time when soft tissue sarcomas were treated in exactly the same way, lumped together as one rarish disease. After (failed) surgery, either doxorubicin, or ifosfamide and mesna, or all three were given, irrespective of histotype. One size fitted all. This Special Symposium on sarcomas blows that strategy out the water. Not only are the new targeted drugs dependant on histological subtype (imatinib and GIST led the way), but it seems that on closer scrutiny some of the old fashioned cytotoxic drugs are better in some sarcomas than others. When asked why gemcitabine is active in leiomyosarcomas and angiosarcomas, Paolo admits that the molecular basis "remains a mystery"! Taxanes and dacarbazine are also more useful in angiosarcomas than other subtypes. A recent addition to the cytotoxic armamentarium is trabectidin which acts like a cytotoxic in shrinking leiomyosarcomas and some liposarcomas, but resembles a targeted agent in displaying excellent activity in those myxoid liposarcomas which have a specific translocation. This symposium will go into detail on why sorafenib and sunitinib have specific activity for instance in solitary fibroid sarcomas, anti- Insulin Growth Factor receptor drugs target Ewing's sarcoma and anti-mTor drugs may be useful in lymphangiosarcoma. Never has the histopathologist been more important in the cancer management of patients than with these rare tumors, and never has it been so critical that they are always referred to a specialist cancer center. The take-home message is that "One drug does not fit all!"."

The bolded words should ring home quite a bit. First of all, he is telling you loud and clear that "ONE DRUG DOES NOT FIT ALL". NOW, if there was a drug out there (namely Ridaforolimus) that was an "all comer" "one drug fits all" do you really think this renowned specialist in sarcoma wouldn't have mentioned it? Instead, he point blank loudly proclaims, that there are different drugs with different types of sarcomas and each subtype will likely act differently depending on what drug the patient is on. Further, he assesses that "anti-Mtor drugs MIGHT be useful in lymphangiosarcoma." Again, not all sarcomas, but this specialist mentions one single small soft-tissue subset of sarcoma.

Furthermore, and this from ESMO, written by more sarcoma specialists:

Adult Sarcoma Medical Treatment Unit, Istituto Nazionale Tumori, Milan/ITALY 1

Anecdotal patients with the rare malignant PEComas were then shown to respond to sirolimus. and temsirolimus as well. This proves that suppression of mTOR signalling can be therapeutic in a subset of soft tissue sarcomas (STS), marked by loss of the TSC1/TSC2 complex (leading to activation of mTOR). Aside from this speci?c histology, anecdotal responses have been reported in other STS, but clinically validated biological predictive factors are lacking. Everolimus and ridaforolimus have been tried in Phase 2 studies in sarcomas, with hints of activity. Thus, a Phase 3 trial on ridaforolimus as maintenance therapy after best response to standard chemotherapy is ongoing. The main limitation of unselective trials is that small differences might be due to big differences con?ned to selected sarcoma histological types, or tumors marked by speci?c molecular alterations. Another possibility is an unspeci?c mechanism of action, namely an antiangiogenic effect. The therapeutic window of mTOR inhibitors may be such as to require dose adjustments based on pharmacokinetics (PK). Unfortunately, PK-based drug
development is challenging, but the risk is to overlook antitumor activity because of problems with dosing. Currently, the mTOR cascade can be hit at various levels, with different PI3K/AKT inhibitors being under development. Some are able to exert concomitant inhibition of different targets within the mTOR pathway. Clinical studies are ongoing, or due to start, on these drugs even in STS. Mutations, ampli?cation, and overexpression of PI3K, as well as inactivation of PTEN, have been seen in STS. Thus, speci?c anti-tumor activity could be expected in STS displaying such alterations. However, these are differently represented across histological types in the STS family. Thus, one should always pay attention to the combination of the molecular and the histological phenotype. Clearly, this makes new drug development in STS a challenging enterprise. For this reason, new study methodologies are required both for early Phase 2 and Phase 3 trials in STS, marked by their rarity overall as well as their histological partitioning in 50-plus histological types. mTOR inhibitors can be combined with cytotoxics or other molecularly targeted agents. Clinical studies are underway on both approaches. A well known mechanism of resistance to mTOR inhibition is Akt feedback activation. This may be blocked by inhibitors of IGF-R, providing a rationale to the combination of the two classes of agents. Another potential use of mTOR inhibitors is in combination with radiation therapy, through their radiosensitizing effects.

Another Abstract:

STS with a complex genomic pro?le represent more than 50% of all STS and are composed of leimyosarcomas, myxo?brosarcomas, pleomorphic rhabdomyosarcomas and LPS, and poorly differentiated sarcomas. Leiomyosarcomas have a particularly poor prognosis but may be more sensitive to trabectidin and gemcitabine. Moreover, a loss of PTEN activity leading to an AKT-mTOR pathway activation has been shown in a subset of leiomyosarcomas and poorly differentiated sarcomas with the possibility of target therapy. Other molecular alterations have been suggested as possible therapeutic targets, such as MET overexpression in clear cell sarcoma, synovial sarcoma, alveolar soft part sarcoma, PNET and epithelioid sarcoma. The reviewed data suggest that there may be histological subtype speci?city in drug sensitivity and propose several possible molecular targets. This calls for a change in STS clinical trial design towards histological and/or molecular subtype-speci?c studies.

http://annonc.oxfordjournals.org/content/21/suppl_8/viii35.full.pdf

Further:

From the Japanese Study with data released last week (that MRK and ARIA never PR'd):

Osteosarcoma: 3.7 weeks of PFS
Osteosarcoma: 4.0 weeks of PFS
Liposarcoma: 16.1 weeks of PFS
Leiomyosarcoma: 16.3 weeks of PFS
Liposarcoma: 17. weeks of PFS

Hmmmm. Osteosarcoma (bone sarcoma) has only ONE month of PFS. While, the other soft-tissue subsets have nearly FOUR months of PFS.

So, what happens to the overall numbers in the SUCCEED trial when you throw in a larger weight to Osteosarcoma? And, is it good that one subset performed SO poorly in this study, while the other subsets tripled the PFS?? Again. Different sub-sets, different responses....yet, Ariad chose to thrown them ALL in ONE BIG BASKET.

Granted, they did it three years ago, and probably wish they hadn't.



Oh and, BTW, the abstracts and information above were from renowned specialists in the world of oncology-sarcoma, who do this for a living. The publications were from last week, all new data as of 2010 - yes, 2-3 years AFTER Ariad started the Phase 3 data. So, ...things change, and, IMO, the more data that has come in since the SUCCEED trial has started, the less favorable it makes for a highly-positive outcome for this trial, IMO. Yes, the data is from oncologists- not "someone put on a message board to spread fear and doubt" as some foolish people would say.

And before you say, "Why wouldn't invest money in something if they thought it would fail." Well, tell that to the CEO of Merck who spent MILLIONS developing drugs such as Rolofylline, Vicriviroc, MK-677, MK-3207 all of which were big-time failures in their indications. Phase 3 drug development is always a gamble. Merck likely knows that using this drug in combination with their other drugs has a much higher level of success.

For LAX:

I like your responses, and you seem like one of the knowledgable ones here. You asked, why I am invested if I think it might fail? Well, I have answered it several times before, but I will one more time. Why: '534. If they didn't have '534, I would have a very very very small gambling position here. Trust me, I wish Dendreon had a Phase 2 drug BEHIND Provenge before Provenge results were out...I would have LOADED the boat, instead of taking a decently sized gamble on Provenge. '534 is a PUT on this company...if SUCCEED fails, IMO. I am willing to gamble that Ariad gets incredibly lucky with Rida in the SUCCEED trial because I do believe the upside is unlimited (bc of 534) while the downside is going to be painful, all will not be lost. And, obviously, I hope I am entirely wrong and ariad knocks the cover off the ball in succeed, but since the trial didn't stop at the interim its highly unlikely