Replies to post #147323 on Biotech Values

[NP1986]

I very much take your point on the balance issue (it is a fairly small trial), but I nevertheless think the OS results will drive the stock. Maybe they shouldn't, but they will.

I wouldn't be surprised if the share price continues to increase due to over-exuberance. I just hope the longs realize that the phase II results themselves are unlikely to lead to approval, despite what some of the PPHM execs have suggested. They will probably need a phase III trial to confirm the OS results, and I doubt they have enough cash for that.

[jq1234]

Yeah, it is rare to have ORR as primary endpoint in randomized trial, which is why it is very odd they did that especially considering the touted MOA of the drug.

There is other way to make money too :-)

Yes, crossover can give misleading OS if study drug doesn't work by preventing placebo arm getting more effective subsequent treatments while study drug arm got better subsequent treatments. This is why people shouldn't look past weak PFS primary endpoint data to OS secondary endpoint data in crossover trial. This just shows people shouldn't look top line number alone from small randomized oncology trial. It is the detail that predict drug effectiveness, and whether it could be replicated in larger trial.

[ariadndndough]

biomaven after reading the article agian

http://www.frontiersin.org/Cancer_Molecular_Targets_and_Therapeutics/10.3389/fonc.2012.00017/full

and then the future part. its hard not to get excited about the data coming out in sept 30 on ariad 113 drug. it seems to fit nicely. we shall see.


Future Perspectives
Crizotinib recently received accelerated approval from the FDA, coming hot on the heels of the B-raf inhibitor vemurafenib (Zelboraf®, approved August 17, 2011 for melanoma patients with the B-raf V600E mutation). Significantly, both agents were approved not for a broad indication, but for a molecularly defined subset of patients and both were approved with a companion diagnostic test. Unlike vemurafenib, crizotinib is an “off-the shelf” inhibitor in the sense that it was already in clinical development when the molecular setting for which it was eventually approved was discovered. This certainly gave the compound a strong competitive advantage over those originating within ALK-focused programs, but what contributed vitally to its successful registration was the efficiency with which ALK-positive NSCLC patients, which represent only circa 5% of the indication, were detected and selected for treatment within the expansion arm of the first Phase I/II studies. Such logistic efficiency, organization, and vision on the part of Pfizer and collaborators is praiseworthy and indeed registration and marketing of the drug were made possible by the parallel availability of a companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc.) which was approved alongside crizotinib for detection of patients eligible for treatment with the drug (FDA News, August 26, 2011).

Data available to date and comparison with other kinase inhibitors approved for NSCLC, such as gefitinib and erlotinib, indicate that in most cases, treatment of ALK-driven tumors with crizotinib will not be curative, but that relapse will occur with at least two types of mechanism, differing on the basis of whether or not tumors retain ALK-dependency. In the case of ALK-dependent relapse, current evidence indicates that acquired resistance to crizotinib will certainly occur through secondary ALK mutations, resulting in variants which are intrinsically less sensitive to the drug, but it has also been suggested that crizotinib may possess other weaknesses, such as inability of the drug to act effectively in pharmacological “sanctuary” sites, for example beyond the blood–brain barrier (Camidge, 2011). This is an important consideration for a disease in which circa 40–50% of cases experience brain metastases (Eichler et al., 2011). For ALK-dependent progressive disease, several second-generation compounds, originating from ALK-focused programs, are currently undergoing, or will soon enter clinical testing and it is likely that efficacious new agents will emerge amongst these within the next couple of years.

With regards to ALK-independent acquired resistance to crizotinib, it is not yet clear how frequently this will occur and which signaling pathways will be involved. However, we expect that approaches such as “deep” DNA sequencing of relapsed lesions (e.g., Ross and Cronin, 2010) and genome-wide functional genetic studies (e.g., Ashworth and Bernards, 2010) will define major resistance mechanisms, some of which, such as EGF receptor activation, may be suitable for targeting in combination with ALK inhibition.

From a Pharmaceutical point of view, it is clear that ALK was relatively neglected as a target for drug discovery until the emergence of its role in NSCLC. Despite the great interest this finding has since generated, ALK targeting nonetheless remains a relatively niche area for drug discovery, given that only ca. 5% of NSCLC patients harbor the rearrangement and that the other ALK-driven malignancies known to date are very rare tumor types. Several factors therefore came into play in the relatively rapid clinical development of crizotinib and appearance on the scene of second-generation ALK inhibitors. Firstly, the great deal of emphasis that both large pharmas and small biotechs have placed on developing kinase programs in the last two decades means that kinases are amongst the best characterized enzyme classes from the pharmacological point of view, with inhibitors now available, on the benchtop at least, for hundreds of kinases (e.g., Posy et al., 2011). The ever-increasing understanding of “chemical space” for targeting this class of enzyme means that today, identification of kinase inhibitors is a relatively rapid and low-cost process compared to other classes of drug target.

Another important factor that was key for the successful clinical development of crizotinib is the rapid definition of the molecular characteristics of patients likely to benefit from therapy and the application of a reliable diagnostic method for upfront identification of these patients during clinical trials. The Phase I/II responses observed in patients with rearranged ALK allowed crizotinib to be reviewed under the FDA’s accelerated approval program, which permits conditional approval of a drug for a serious disease based on reasonable likelihood of clinical benefit. In the field of cancer, in which patients with the specific genetic context required for drug activity may be relatively rare within a given tumor type, this type of provision considerably facilitates clinical development of targeted agents in the very well defined molecular contexts for which they were designed. It is probable that development of next generation compounds targeting secondary mutations of ALK will follow a similar strategy

AP26113 (Ariad Pharmaceuticals) is a potent and orally available inhibitor of ALK whose chemical structure has not been disclosed. Biochemical characterization shows that in addition to ALK, the compound cross-reacts with a number of other kinases (>45 inhibited with IC50 < 200 nM), among which EGFR is inhibited with an IC50 of 129 nM. Considering that EGFR is a well validated target per se in NSCLC and that in at least one case, resistance to crizotinib was associated with EGFR activation, this cross-reactivity was considered an opportunity by the company and the compound is in clinical testing as a dual ALK/EGFR inhibitor. Additionally, AP26113 was evaluated on the crizotinib resistant gatekeeper mutant L1196M both in vitro and in vivo and appeared to be able to overcome resistance to crizotinib. Ki determination demonstrated a very similar biochemical potency on wild-type ALK and the L1196M ALK mutant (0.09 and 0.08 nM respectively), with both cellular and in vivo data (using engineered Ba/F3 cells) indicating that growth of ALK–L1196M mutant driven-cells is inhibited at similar, albeit slightly higher, doses which inhibit cells harboring wild-type ALK (Katayama et al., 2011). AP26113 was also described to be active on a series of in vitro induced crizotinib resistant mutations, which however have not been observed to date in clinical cases of acquired crizotinib resistance (Zhang et al., 2010).

Clinical development of this drug has initiated recently (September 2011), with a Two-Stage development strategy (ClinicalTrials.gov Identifier: NCT01449461). The initial dose escalation will be conducted in patients with advanced cancers, particularly NSCLC. The expanded cohort of patients treated at the RP2D will include four genetically defined patient populations: including: patients with ALK-positive NSCLC who have not previously received an ALK inhibitor, patients with ALK-positive NSCLC who are resistant to at least one ALK inhibitor, patients with EGFR positive NSCLC who are resistant to at least one prior EGFR inhibitor and patients with other cancers expressing ALK.