Biotech Values

[ThomasS]

ARRY: Further color on ARRY 886 (AZN's 6244 molecule) and probability of success by AZN. AZN is presenting data this week at ASCO showing that the drug was comparable, though non-superior, to SoC in various settings. Obviously, AZN smartly chose to advance the drug in combination, since their attempt at a lead-off home run in a monotherapy setting did not achieve statistical superiority. (I once stated that the AZN trials were designed for failure and another poster mocked the remark, not understanding why I said it... AZN attempted to position 886 to win outright as a monotherapy; now they know to go back and use it in combo. They tried the swing-for-the-fences route.)
From the ARRY website:

AZD6244 (ARRY-886) is an anti-cancer drug in Phase 2 development in a wide range of tumors. It is a small molecule inhibitor that targets a key position in the Ras/Raf/MEK/ERK signaling pathway. This pathway is implicated in the development and progression of cancers. AZD6244 is a novel, orally active, potent, selective, non-ATP-competitive inhibitor of MEK 1 / 2 that has the potential to treat a range of malignant diseases. Oral administration of AZD6244 has demonstrated tumor suppressive or regressive activity in multiple preclinical models of human cancer, including melanoma, pancreatic, colon, lung and breast cancer models. We believe our MEK inhibitor’s advantage over current therapies include the ability to target certain cancers with over-activation of MEK or activating pathway mutations, improved efficacy linked to novel mechanism and, because it is an oral agent, ease of use. In 2003, AZD6244 was out-licensed to AstraZeneca for further study.
About MEK Inhibition
MEK is a critical enzyme at the intersection of several biological pathways, which regulates cell proliferation and survival as part of the Ras/Raf/MEK/ERK pathway. This pathway is often permanently switched on in human cancers, including lung, pancreatic, colon, melanoma and thyroid cancer, by activating mutations in BRaf or Ras and, consequently, is implicated in the aberrant proliferation and survival of cancer cells. MEK is a target for therapeutic intervention as it is downstream of the Ras and Raf and is the only activator of ERK.

Phase 1 Clinical Trial
We initiated Phase 1 clinical testing of AZD6244 in June 2004. The trial was designed to evaluate tolerability and pharmacokinetics of AZD6244 following oral administration to patients with advanced cancer. In addition, the trial examined patients for indications of therapeutic activity as well as pharmacodynamic and tumor biomarkers. As reported in November 2006 at the 18th EORTC-NCI-AACR conference, AZD6244 showed promising results in solid tumors in this Phase 1 trial. AZD6244 was well tolerated (100 mg twice daily) with the best clinical response being prolonged stable disease in a number of heavily pre-treated cancer patients. AZD inhibited the MEK pathway in tumor tissue at the dose that was later selected for the Phase 2 study (100 mg twice daily).

Phase 2 Clinical Trials
In June 2006, AstraZeneca initiated a Phase 2 study for AZD6244 in malignant melanoma in a randomized Phase 2 study, enrolling 180 patients at 40 centers worldwide, comparing AZD6244 to temozolomide (Temodar®) in the treatment of stage III / IV melanoma patients. In December 2007, top-line results were announced from this study as well as two other studies.


Melanoma: AZD6244 demonstrated single agent anti-tumor activity with no significant difference in efficacy to temozolomide. However, AZD6244 did not demonstrate superiority for the primary endpoint of progression free survival versus temozolomide in the overall population;
2nd and 3rd line advanced non-small cell lung cancer: AZD6244 was compared to pemetrexed (Alimta®) and demonstrated single agent anti-tumor activity and no significant difference in efficacy to pemetrexed. However, AZD6244 did not demonstrate superiority for the primary endpoint of delaying disease progression versus the comparator;
3rd line advanced colorectal cancer: AZD6244 was compared to capecitabine (Xeloda®), and did not demonstrate superiority for the primary endpoint of delaying disease progression versus the comparator.
AZD6244 continues to be studied in a randomized Phase 2 trial comparing AZD6244 with capecitabine in patients with advanced or metastatic pancreatic cancer who have failed 1st line gemcitabine (Gemzar®) therapy. Also, AZD6244 is being studied in six signal searching single agent trials conducted by the National Cancer Institute, including ovarian, biliary, liver, thyroid and head and neck cancers, and acute myeloid leukemia.

Future Milestones
AstraZeneca is completing data analysis of the Phase 2 melanoma, NSCLC and colorectal trials and plans to present the data mid-2008. They also will complete signal searching single agent studies in collaboration with the National Cancer Institute in six tumor types and complete a dose escalation trial with a solid dosing form of AZD6244. Additional randomized Phase 2 trials of AZD6244 will begin during the second half of 2008, testing AZD6244 in combination with a cytotoxic chemotherapeutic agent; one trial in melanoma patients and the other in non small cell lung cancer patients. These plans are based upon AZD6244’s previous activity as a single agent in monotherapy Phase 2 trials and on data from multiple preclinical studies.

The following slide can be viewed on ARRY's website in it's original (readable/zoomable format). It clearly "predicts" a successful outcome for further combination trials:

4/15/08 AACR: http://www.arraybiopharma.com/_documents/Publication/PubAttachment276.pdf





CONCLUSIONS
• AZD6244 exhibits significant monotherapy
activity in a range of human tumor xenograft
models. This is associated with a strong
inhibition of the primary biomarker p-ERK in
tumor tissue.
• In AZD6244 chronically treated samples levels
of the pro-apoptotic protein BIM were seen to
increase. This is consistent with the observation
that BIM is regulated by the ERK1/2 pathway.4
• AZD6244 in concurrent combination with a variety
of SoCs (docetaxel, temozolomide, irinotecan or
gemcitabine) or an EGFR kinase inhibitor (e.g.
gefitinib) exerted beneficial antitumor effects
when compared with single-agent dosing regimes.
• Our sequencing studies demonstrated that
the administration of docetaxel followed
by AZD6244 resulted in a greater efficacy,
compared to AZD6244 dosed first followed by
docetaxel.
• All drug combinations were well tolerated
as judged by clinical observations and body
weights of the animals.
• The results presented here support the rationale
for potential further clinical studies using
AZD6244 in combination with either SoCs or
novel agents.