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I just realized that my post #msg-82505647 implied that Ariad's Iclusig's MMR was achieved in just 12-months. Just to be clear, the MMR data I referenced was based on 24 and 30 months for tasigna and iclusig, respectively. Unfortunately, I was unable to find an apples-apples comparison (e.g same line of therapy/same time period). However, just to put Iclusig's 51% MMR in 3/4 line in context, in a front-line setting, gleevec has a 3-year MMR of around 53%.
Well, good luck trying to buy it at $30 five years from now. :)
fwiw, Citi reiterated their $31 price target yesterday (the bolding is my own). The report is appropriately entitled “Seeing The Forest” –Efficacy Provides Most Differentiation
Conclusion - We recognize the “black box” warning for Iclusig (ponatinib) is a negative surprise to the Street. However, as the drug was approved based on a single arm trial the FDA is likely compelled to outline all the prominent toxicities despite if there is evidence they were related to the Iclusig or not. We do not expect these warnings to dramatically impact uptake of ponatinib, as physicians treating these patients are likely broadly familiar with the adverse effects caused by this disease and prior treatment, and will be able to assess these warnings with what they would normally expect. We view the weakness in ARIA as overdone and would be buyers of the stock.
Efficacy Is the Clear Differentiator. Ultimately, we believe the tolerability for Iclusig, Sprycel, and Tasigna will likely be viewed by physicians as unique but generally equivalent, with each agent having their drawbacks. Efficacy on the other hand is a clear differentiator for Iclusig and we believe will not be ignored.
Granting of a Broad Drug Label Signals FDA’s View of Risk/Reward. The FDA granted Iclusig a broader label of “patients that have failed any prior TKI therapy” than those patients enrolled in the approval PACE trial. We note that this nearly doubles the available patients who could receive Iclusig, and all towards patients who are generally healthier than those treated in PACE. We think the willingness of the agency to broaden use of Iclusig to healthier patients than those exposed to the drug to date puts these warnings included in the label in perspective.
The key take-away for me is that Ponatinib got approved, 3-months early, with a broad, second-line label. As far as the label warning goes, have you seen Tasigna's black box label?
WARNING: QT PROLONGATION AND SUDDEN DEATHS
"Sudden deaths have been reported in patients receiving nilotinib"
By the way, NVS reported tasigna revenue of $231 million in their most recent quarter; the drug will easily exceed $1 billion in sales next year.
Yesterdays 20% drop was an over-reaction driven largely by the markets perception that Iclusig is going to meet resistance (no pun intended) in a 2nd-line setting. Given the 12-month follow-up data released last week at ASH, I think this risk is largely without merit. In a 3/4 line CP setting Iclusig achieved a 51% MMR compared with Tasigna's 28% MMR in 2nd-line. For Iclusig, the MMR was reached in just 5.6 months(the median duration of response has not been reached). Compared with tasigna, iclusig generates a faster, deeper molecular response in 3/4 line as tasigna does in 2nd. It's not even close.
As far as peak sales go, most analysts are well north of $1 billion:
Cowen thinks "it could have over $1B in revenue at peak."
Maxim projects "global peak sales of ponatinib stay at around $1.3B."
Mike King recently wrote that "even under what we believe are conservative assumptions, we forecast ponatinib sales at $1.9 billion worldwide in FY2018."
Oppenheimer is also forecasting "peak sales of $1.9 billion ($700 million front-line/ $1.2 billion refractory)
>>"What would be a reasonable multiple on that figure, perhaps 5x sales?<<
Sure, 5x is reasonable (although I backed out a 6X multiple from Merrill's report). Assuming $1 billion in revenue, ARIA is worth $5 billion on Iclusig alone. With 168mm shares outstanding, that's right around a $30 price target or 60% upside from Friday's close. Plus you get a free ride on the ALK inhibitor, AP26113 which, btw, Merrill is already valuing at $11 a share.
Being non-ATP competitive, I'm hoping tivantinibs' more specific targeting will result in fewer side effects thus making it a good candidate for potential combination in indications where MET over-expression is a possible predictive biomarker. While it was a small study (n=20) the sorafenib combination trial in HCC indicates this approach may meet with success. In front-line HCC, sorafenib has historically achieved around a 2-3% response rate, however, in the tivantinib+sorafenib trial the ORR improved to 10% (even though 40% of pts failed a prior VEGF inhibitor (6 sorafenib; 1 sunitinib; 1 sorafenib plus sunitinib)). The DCR also improved to 70% in the combo trial as compared to the 43% achieved by sorafenib alone in the SHARP trial.
fwiw, I don't view XL184 as necessarily competitive with tivantinb as a stand-alone agent...the question is how it'll stack up vs a VEGF+Tivantinb combination therapy in various settings.
With Servier picking up the tab, basically XOMA has a free shot on goal in both the ACS and diabetes indications. If either one of them pans out, the company has the ability to reacquire the US/Japan rights. Nice deal.
Yes, it's a mess lol. JQ, do you know off-hand how they tested for MET in the KRAS trial?
I hope you don't mind if i chime-in. With tivantinib's recent failure, MetMab certainly has the lead to market in Met+ NSCLC, however, I do think it's worth noting that MetMab's P2 results were not statsig for either PFS or OS. Clearly there are different mechanisms of action between tivantinib and MetMab. For example, ARQL enrolled non-squamous nsclc hoping it would capture a high percentage of MET+ pts however in the MetMab trial the hazard ratio for PFS in this same patient population was only .98 The same is true for the mutant KRAS cohort where MetMab basically showed no improvement over placebo (HR=1.04) while Tivantinib had an HR=0.18. http://cancergrace.org/lung/files/2010/08/schiller-arq-197efficacy-by-subgroups.jpg
If MetMab's P3 demonstrates a meaningful OS, I seriously doubt whether ARQL or its partners would pursue the indication further, however, given that MetMabs P2 results were inconclusive, I'm not ready to write the NSCLC indication off entirely especially if the KRAS mutant trial results expected 1H2013 turn out to be particularly compelling.
So be it. I'll be joining the long-line of folks who rarely post here anymore.
fwiw, here are the upcoming catalysts that are on my radar:
1) Ponatinib early approval-dec/jan (positive impact on revenue/cashflow)
2) Broad 2nd-line label(positive impact on revenue/competitive position)
3) Successful US ponatinib launch = upside surprise on sales/sales/sales
4) AP113 P1 read-out (ASCO?)
5) EMA approval and launch
6) AP113 registration trial (2nd-line ALK+ NSCLC)
7) EPIC Trial initial read-out
8) GIST or other pona registration trial
Of these, #3 is the most important in terms of pps (fwiw, a new compound won't even move the needle)
Nice find but this board apparently prefers to discuss taxes, buyout rumours, geopolitics etc
CLVS I've also been following development of CO-1686. There is a real need for an effective T790 inhibitor.
Abstract
Even though lung cancer patients harboring a mutation in the epidermal growth factor receptor (EGFR) gene exhibit an initial dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance is almost inevitable after a progression-free period of approximately 10 months. A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs. Nevertheless, several lines of evidence indicate that the T790M mutation confers growth advantage to cancer cells, and it was shown that mice expressing tetracycline-inducible EGFR transgenes harboring the T790M mutation develop lung tumors. Thus, T790M mutation seems to play a double role in the survival of lung cancer cells. Several second-generation EGFR-TKIs are currently being developed to overcome the acquired resistance caused by the T790M mutation. MET (met proto-oncogene) amplification or activation of IGF1R are reported as alternative mechanisms for acquired resistance to EGFR-TKIs. Clarification of the pathways leading to acquired resistance is essential to maximize the efficacy of EGFR-TKI therapy for patients with lung cancer.
http://journals.lww.com/jto/Fulltext/2009/01000/EGFR_T790M_Mutation__A_Double_Role_in_Lung_Cancer.1.aspx
I'm still betting on Ariad's AP26113 but Clovis' pre-clinical data looks promising http://www.celgene.com/pdfs/2011_1116_EORTC_Clovis-Avila.pdf
ARIA is at an inflection point. It's no longer a small bio being driven primarily by clinical trial results. The company now sports a healthy $3.5 billion market cap. The only catalyst the market is focused on now is ponatinib's launch. Earlier approval = sooner sales. Broader label = greater sales. Once the company demonstrates ponatinibs ability to take market share from gleevec/tasigna/sprycel, it'll be reflected in the share price. Until then, we'll trade with the general market.
CPRX CPP-109 Phase 2b trial did not meet the primary endpoint
Catalyst Pharmaceutical Partners Announces Top-Line Results of CPP-109 Phase II(b) Trial for Cocaine Addiction
CORAL GABLES, Fla., Nov. 8, 2012 (GLOBE NEWSWIRE) -- Catalyst Pharmaceutical Partners, Inc. (Nasdaq:CPRX) today announced top-line results from its U.S. Phase II(b) clinical trial evaluating the use of CPP-109 (vigabatrin) to treat cocaine addiction. The data from the trial showed that CPP-109 did not meet the primary endpoint -- that a significantly larger proportion of CPP-109-treated subjects than placebo-treated subjects were cocaine-free during the last two weeks of the treatment period (Weeks 8 and 9). The data also showed that the two key secondary endpoints, a significantly larger increase in cocaine negative urines and a significant decrease in the weekly fraction of use days in medication-treated subjects during weeks 3-9, also were not met. The clinical trial did not reveal any unexpected "serious" adverse events.
Catalyst expects the remaining protocol-specified analyses for other secondary and exploratory clinical endpoints and safety data to be completed during the first half of next year, after all the follow-up clinical data have been received to be able to fully unblind the trial data.
Patrick J. McEnany, Catalyst's Chairman and Chief Executive Officer, commented, "We are obviously very disappointed with the top-line results from our Phase II(b) cocaine trial, particularly given the changes that were incorporated into the protocol for this trial to ensure maximum medication compliance from a more motivated patient population. Once we have the full data set, we will meet with our collaborator on the Phase II(b) trial, the National Institute of Drug Abuse (NIDA), to determine next steps, if any, in the clinical development program for CPP-109 for cocaine addiction."
Mr. McEnany continued, "In the near term, we intend to focus all of our efforts on the development of our two other product candidates: FirdapseTM for the treatment of Lambert-Eaton Myasthenic Syndrome (LEMS) and CPP-115 for the treatment of infantile spasms. Both of these product candidates have received orphan drug designation and are intended to treat a rare neurological disorder. We will also monitor the results of the ongoing investigator-sponsored study evaluating the use of CPP-109 for the treatment of Tourette's Disorder to determine whether we should pursue future studies of CPP-109 with respect to that orphan indication."
http://ir.catalystpharma.com/releasedetail.cfm?ReleaseID=719702
That sound you hear is me slapping myself in the forehead, lol. Thanks for the explanation
With regard to ARQL, the question I'm grappling with is why was there such a big difference in OS between the placebo arm in the brivanib BRISK trial and the ARQ197 2nd-line HCC trial? Both trials enrolled pts who had progressed on, or were intolerant to, sorafenib but had good liver function (Child-Pugh A) yet the OS in the tivantinib control arm was only 3.8 months as compared to 8.2 months in the brivanib trial. Caveats about direct comparisons between trials aside, the 7.2 month OS tivantinib achieved in the 2nd-line, high MET population isn't nearly as compelling when one considers that even with an OS of 9.4 months brivatinib ultimately failed to meet its primary endpoint. Any help understanding this issue would be greatly appreciated.
only the physical trading floor is closed
http://www.nyx.com/sandy
Warning: hypothetical "black swan" event may occur at any time.
Although I'm sure NVS will spend a small fortune trying to position Tasigna as a "cure", the reality is the drug is ineffective against the most common mutation. Who are you going to believe the pharma rep or key opinion leaders like Cortez, Druker, and Shaw?
With nearly 1000 oncology drugs in the pipeline, I agree that very few will ultimately emerge as winners but I don't think that necessarily makes investing in oncology focused biotechs a suckers bet. The majority of the biotech's I invest in are pre-revenue so I'm primarily focused on identifying situations where the value of the pipeline isn't reflected in the current share price irregardless of the commercial outcome (which could be 5 or 10 years down the road).
Of course, this makes the handful of companies, like ARIA, who are able to develop and commercialize multiple potential best-in-class oncology compounds all the more valuable.
Yes, KOL's like Dr Cortez are beginning to make the case that using ponatinib in a front-line setting may prevent mutations from developing in the first place. He mentions this possibility in an interview he gave at ASCO (starts around the 9:30 mark) https://accesscmldrugs.wordpress.com/2012/10/14/dr-jorge-cortes-explains-latest-on-existing-and-emerging-treatments/
Thanks for the exchange...being able to test ones's assumptions is one the great things about this board.
btw, just to thoroughly confuse the matter, Ariad recently made the case that T315I was not a predictor for response. Surprisingly, the high response rate in T315I isn't specific to the mutation but is more a function of getting on the drug sooner(perhaps due to earlier testing). If that's indeed the case, it could have an interesting implication for the front-line EPIC trial which by definition enrolls patients who have a shorter time since diagnosis.
Aren't overlapping patients??? Sure that's possible but I think it is far more likely that the TKI failures are from the T315I mutation against which imatinib, nilotinib, and dasatinib are ineffective. The reason I suspect this is that Teva ran a T315I trial and got a 23% response rate (along with some nasty side effects).
Look, I got your point I just don't think it's very convincing.
In the PACE trial, 93% of the pts had failed at least two tki's; 53% had failed three or more. In the Synribo trial, 47% of CP patients and had failed 3 tki's. It's pretty clear the ITT population in both trials were pts who had failed multiple tki's.
ps nice catch on the median duration...the response data was from April 2012.
None that I've seen published...but given the comparison i made earlier, I think it would be a stretch to think this drug is going to have much success in patients resistant to ponatinib.
That doesn't invalidate the comparison I made, Dew.
I believe the market is going to stratify along two-lines with the majority of patients WW continuing to start on gleevec, or its generic equiavalent, and (based on the new NCCN guidelines in CML) move to ponatinib in 2nd-line. Furthermore, I believe this can be accomplished without running a large multi-arm sprycel/tasigna head-to-head trial.
The key to ponatinib's near-term value will be in obtaining approval with a broad 2nd-line label. The PACE trial enrolled pts with the T315I mutation or who had failed 2 prior tki's. For the most part, the analyst models I've seen assume that ponatinib will only get 2nd-line T315I pts and 3rd line sprycel/tasigna failures. If granted, the broader "one or more prior TKIs" label would significantly expand ponatinib's commercial opportunity.
ARIA has gone up....a lot. So, it doesn't surprise me that a few folks here think it's overvalued. I disagree but that's what makes a market.
Three years ago, when the stock was trading at $2.62, I made the following post on this board:
"I was valuing AP534 primarily as a 2/3 line treatment option focused primarily on pts with the T315I mutation. I now believe we are looking at much greater upside with a clear path to regulatory approval for not only pts with mutations but also those who have failed at least 2 other TKI's. As was pointed out in today's presentation, pts are now typically on gleevec for 12 to 18 months before moving to 2nd line treatment options. Over time this time-frame will become compressed and with better testing pts will move to the AP534 option much faster. This, in combination with an increasing patient population in maintenance mode, leads me to conclude that I may have been underestimating AP534's potential."
Today the FDA accepted ponatinib's (AP534) NDA and granted accelerated approval. I believe it will receive a broad 2nd-line label before its March 27, 2013 PDUFA date. fwiw, I don't think ponatinib, let alone 113, is "baked" into the current $22 price. Today, even the much respected Rachel McMinn has a $30 price target on the stock :)
Today would be a good day for the ponatinib NDA to be accepted for accelerated approval, lol.
As the article points out, mutation of c-kit is the crucial step in the development of GIST. While gleevec is getting good initial response rates, the durability of the response is only about 24 months. Given that ponatinib is potentially a far more potent inhibitor of mutated KIT than existing TKI's (see AACR 2012 Abstract), I suspect GIST represents a potentially significant incremental revenue opportunity for the company.
It sounds to me like Berger is just managing expectations in order to ensure a successful launch. Check out slide 106. 300 patients are already diagnosed with the T315I mutation and are expected to switch therapies. How many of these will move to ponatinib? My guess is all of them.
Additionally, if they just get 10% of the remaining 2200 projected resistant and intolerant patients eligible in the US in 2013, they'll hit their numbers. To put this in context, currently "other" is getting 10% in 2/3 line. So, the bar is pretty low, lol.
Also, EU approval is anticipated mid-2013. Considering that 11% of the 3800 EU patients resistant to current therapies likely have the T315I mutation, I would assume a quick uptake in this patient population but as far as i can tell no revenue is factored into the $50mm number.
Detection of BCR-ABL mutations negatively affects response to Sprycel
Impact of BCR-ABL mutations on response to dasatinib after imatinib failure in elderly patients with chronic-phase chronic myeloid leukemia.
Abstract 2012 Oct 10. [Epub ahead of print]
To assess the impact of BCR-ABL kinase domain mutations on dasatinib response in elderly chronic myeloid leukemia (CML) patients, we analyzed the outcome of 76 individuals aged >60 affected by imatinib-resistant chronic-phase CML. We found that 36 cases (47 %) displayed mutations before dasatinib. Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. Our data suggest that, in elderly patients, detection of BCR-ABL mutations negatively affects response to dasatinib.http://www.ncbi.nlm.nih.gov/pubmed/23053188