Just to clarify, OGXI licensed ISIS' second-generation antisense technology for custirsen but that was after OGXI's co-founder Dr. Martin Gleave decided that clusterin would be a good target for a cancer drug. Or maybe that just makes things muddier, as far as the F-R rule is concerned.
EXEL's market cap still around $800mm according to Yahoo, mostly, I believe, on expectations for this indication, though I don't follow EXEL that closely. OGXI's $185mm market cap, along with expectations for OGX-427 in Borealis-1 later this year, may serve as a buffer if SYNERGY fails, at least if there is a non-statistically-significant trend towards efficacy. But who knows.
The Independent Data Monitoring Committee recommended that the trial continue to the final analysis. EXEL announced this after the close yesterday, probably to allow a little time for the market to process the news and calm down before reacting. Obviously it hasn't worked.
Equally obviously, there was no leak of this data. Not that you would expect there to be, since it's a double-blind trial.
Yes, but I wasn't particularly troubled by it because he didn't seem to be citing it to show that the control group in SYNERGY was likely to have survived only 20 months and therefore the trial could be successful even if the treatment group survived only 24-25 months. Rather, he was just saying that since survival for prostate patients once they experience metastasis and undergo chemo hasn't increased beyond 20 months in recent years, the market opportunity for an agent that can enhance the effect of chemo and increase survival for those patients is still substantial.
Well, Dr. Kuvasz, the main thing I got out of today's CC is that they are probably going to wait until after your return before they announce the SYNERGY results. At least that's how I interpret their insistence they'll announce "by mid-year." I doubt they'll take until the actual mid-year of June 30-July 1 but it doesn't look like it will be in March. So you can be relatively carefree as you're petting those lions, if that's possible.
The other thing I noted was that Cormack said there are 3 possible outcomes for SYNERGY: success, failure, and achieving a result that misses the required p-value but is "still signficant." I'm not sure what that means exactly -- that they achieve p=less than .05 but not as low as some unspecified p-value below .05 that's required per the SPA? or that they achieve a "trend" in favor of the custirsen group but p is more than .05 (I thought that would not be technically "significant")? In any case, he said that in that scenario if the AFFINITY trial is successful they'd present it as "confirmatory" of SYNERGY and file for approval in both first and second line. I think if that's the outcome, the stock wouldn't necessarily get hammered, especially since they gave the impression that wouldn't do a financing until after they get the results from Borealis-1 in H2 of 2014. At least that's how I interpret their repeated declarations that they have enough cash to last until after the results from both SYNERGY and Borealis-1. I'm still holding onto my put options though.
I have no idea whether there's a leak of positive data or not but I do find the contrast between the current stock activity and the activity leading up to the miss on the interim analysis that was announced on November 19 to be striking. Despite passing two futility analyses OGXI traded down most of last year, especially in October and early November, and closed at 7.48 on November 18, close to a multi-year low. I suspected at the time that whoever was selling must have had inside info since if SYNERGY had succeeded at the interim and the trial had been halted early the stock presumably would have rocketed, perhaps even more than if it succeeds on the final analysis. If there was a leak then maybe there's also one now. But it's just as possible that I'm wrong on both counts.
If nothing else this runup suggests, as I've said before, that there's no leak of negative data, and for now I'm happy with that.
If SYNERGY succeeds, it would mean (a) Teva would pay OGXI a substantial milestone payment and later royalties, which would reduce and possibly even eliminate the need for more dilutive financings, (b) expectations for success in the other P3 trials of 011, AFFINITY (second-line prostate) and ENSPIRIT (lung cancer), which are wholly funded by Teva, would increase substantially, (c) Teva would probably initiate trials of 011 in other indications, and (d) expectations of success for 427 in Borealis-1 and the other 6 ongoing randomized P2 trials would also be raised. The market may take awhile to digest all of that but once it does I don't see why a $1 billion market cap is unreasonable. The size of the market for just the prostate indication for 011 probably isn't comparable to the size of the market for an oral standalone drug like Xtandi but then MDVN's market is over $5 billion.
Haven't checked but I think today was the best day since they announced the data was locked, which seemed to stop the runup we were having just before that. I'm okay with either a leak of positive news or no leak at all, just as long as there isn't a leak of negative news. If this can be sustained for a few days it would seem to reduce the chance of that.
Meanwhile, TEVA has been having a nice run the last few weeks. I don't own any and don't know if they've got something else going on but if not maybe it's a good sign.
Earnings call for OGXI on Tuesday. Sometimes the stock runs up ahead of those and then sells off but everyone knows there won't be any news on SYNERGY yet so that's probably not it.
One more thought: unlike SNUS, OGXI has been trading in a narrow range (11.50-12) since announcing that data was locked. If that continues through announcement of the results (not saying it will), then I would interpret that as meaning either (a) the outcome is unknown, either because there's been no leak or because the result is too close to call, or (b) there's an expectation SYNERGY will fail but sufficient expectation of positive results in Borealis-1, for which data is expected a few months later, or in other P2 trials of 427 or the other P3 trials of custirsen (AFFINITY and ENSPIRIT) to justify the current market cap of around $170mm. That cap seems too low to reflect an expectation of SYNERGY success.
Borealis-1 is double-blinded so I wouldn't think there could be any leak there but the previously-reported results for 427 could justify some optimism. Scott Cormack said at Leerink last week that Borealis-1 would report before either the PACIFIC or SPRUCE trials of 427. SPRUCE is double-blinded but PACIFIC is open label so there could be a leak there but it's still recruiting so it seems unlikely.
If the price trend continues and it in fact reflects a belief that SYNERGY will fail but the pipeline justifies the current market cap then if SYNERGY does fail there may not be a big selloff. Not that I'm predicting that.
Since we're now 3 months or less from SYNERGY results, I was wondering what experiences posters have had with whether the stock price action ahead of a "binary"-type P3 result foreshadowed the outcome.
The P3 experience I remember most vividly, because it's the one where I had the most invested, involved SNUS, the company which "reverse merged" into OGXI in mid-2008. The Yahoo tab for "historical prices" for OGXI actually lists prices for SNUS prior to mid-2008. SNUS announced the failure of the P3 for its lead product on September 24, 2007. The stock, which had closed at $4.35 the previous session, opened at 68 cents. The steepness of the plunge was due in large part to the fact that SNUS had no pipeline to speak of behind its lead product. (They did have $30mm in cash, which OGXI, which was then a private company that had a pipeline but no cash, needed -- hence the reverse merger.)
If you look at the historical price chart you find that SNUS closed at $6.13 on June 5. It then drifted down to the low 5s in July, then into the high 3s around August 15 -- about 5 weeks before the data announcement -- before recovering slightly.
The SNUS P3 trial was open-label, as SYNERGY is, so I've always interpreted the price action as a sign of a leak. I suppose it could have just been people exiting because they were unsure of the outcome and didn't want to be holding, or there could be other explanations. Most analysts were predicting success because the trial seemed to have a low bar and the P2 results, though non-randomized, were promising.
So I'm curious what others' experiences have been, at least with open label trials . It doesn't look like we'll be meeting the Feuerstein-Ratain Rule standard, which I believe is a market cap of at least $300mm ahead of data. That would be $20 a share. But the rule seems premised in part on the idea that there are leaks, so it would seem to me that a favorable price direction may be more important than the market cap
Thanks Summer, you seem to have an encyclopedic knowledge of clinical trials to go with your mastery of statistics.
I feel somewhat reassured that the miss on the interim, while disappointing, is not necessarily a harbinger of doom as I was afraid it might be. Based on what you and some others have posted in the last few days, the treatment group in SYNERGY may not achieve a median OS of 30.2m and the blended median may not be 27.8m, but it's also possible the controls won't achieve a median OS of 25.4m. And in any case, the trial doesn't need to achieve p less than 0.0001 or a difference in the medians of 4.8m, since you estimated earlier today that around 3m might suffice. So on the whole I feel a little better. I hope you're a bit more optimistic than you seemed to be a couple of days ago as well.
Summer, this is probably an unfair question but when has that ever stopped me. Is it possible to calculate what the difference would have had to be to succeed at the interim? I know they haven't disclosed what the required p-value was but maybe you can pick one that you think was likely. Obviously I'm hoping that the difference would have had to be a lot more than 3m which would give us some breathing room with respect to the final.
I just looked it up: Xtandi was approved in the EU in June 2013, well after enrollment in SYNERGY had been completed although many of the later enrollees were still alive and potential candidates for treatment. Still, I don't think it would have been a huge factor even discounting for the apparent likelihood that patients who already received Zytiga wouldn't have benefited much from Xtandi.
I don't know enough to know whether the following is relevant but am presenting it for those who do to let us know. When OGXI first announced tentative results for the P2 prostate trial for 011 on December 3, 2008, it said the following in the PR: "The median survival was 27.5 months for the patients in the OGX-011 arm and 16.9 months for those in the control arm. Results currently indicate that patients in the OGX-011 arm have a death rate approximately 40% lower than patients in the control arm. The current results are based on study data with a median follow-up of approximately 30 months for both arms. Additional survival updates are needed before a mature median survival for the OGX-011 arm can be reported. Based on the current results, OncoGenex has calculated that the final median survival for patients in the OGX-011 arm can not be lower than 22.7 months." By ASCO in May 2009 the final data we are familiar with were reported as 23.8 months median for the 011 arm, with the 16.9 months median for the controls remaining unchanged.
Clearly, a lot of the patients in the 011 group died in the few months between the 2 PRs, though the final 6.9 month difference in the medians was still impressive. (We know SYNERGY won't achieve that or the trial would have been stopped at the interim.) Does this tell us anything about why the required number of deaths in SYNERGY was reached sooner than expected? (I don't know if it does.)
One point Scott Cormack made in his opening remarks at Leerink this morning that was new to me was that recent studies have shown that if you follow Zytiga with Xtandi or vice versa there's "cross-reactivity and resistance" so that the treatment period for the second drug is "very short." He said this was much discussed at ASCO GU.
As I vaguely recall, Xtandi wasn't approved ex-US until fairly late in SYNERGY (I once looked it up but am too lazy to do it again now) so given the large number of ex-US trial sites I'm not sure it would be that much of a factor in any event. But Cormack's comment would seem to make it more likely that the combined effect of Zytiga and Xtandi in SYNERGY should probably not be much more than 4 months. If so, then median survival for the control group of 24 months or less doesn't seem unreasonable. (If you add 4 months to the 16.9 months of the P2 trial you'd get less than 21 months but posters more knowledgeable than I seem to think the 16.9 months result was an outlier and 20 months or so for the controls in pre-Zytiga trials was more common.)
BTW, for those who unlike me understand Kaplan-Meier curves there's one for the SATURN results in the poster on the website under Investors/Scientific Publications.
As I've suggested before, I think if SYNERGY fails but there is a trend towards efficacy it wouldn't mean the end of 011. Both the AFFINITY and ENSPIRIT (lung cancer) trials are second-line so patients would receive few if any other therapies after being treated with 011 and therefore the confounding variables we are likely to see in SYNERGY would be largely absent. That should make for a cleaner result and may improve the odds of success.
If SYNERGY fails OGXI would need to raise cash but it would probably wait for the results of the Borealis-1 trial of 427 in bladder that are due in the second half of this year. (Perhaps Scott Cormack will provide an update on the timing in the Leerink call this morning.) If the results there are good then that will help the stock price if they do a financing or alternatively it would give them the leverage to negotiate a partnership deal for 427 which would obviously also bring in cash. Borealis-1 is a double-blind study so presumably no one knows at this time how it's going. There's also a good chance that they'll have interim results on the PACIFIC trial of 427 with Zytiga sometime this year, which could potentially also give the pps a boost.
Thanks Summer. If I understand you correctly, the most likely outcomes for SYNERGY would be either success (achieving statistical significance) or a trend towards statistical significance but failure to achieve it. Less likely, given that (based mostly on the P2 results and the recent SATURN results) custirsen appears to be an active agent, would be a complete failure where there wasn't even a trend in favor of the treatment group (although there's always the possibility of a statistical fluke producing that result even if custirsen is active). If we end up with a failure with a favorable trend and AFFINITY succeeds there may be a chance for approval. So if SYNERGY fails the existence of a favorable trend would be important, at least as far as AFFINITY (and maybe ENSPIRIT) are concerned.
Well, Summer did post something about how the deaths would occur in an asymptotic rather than linear fashion, which I think is consistent with dilivent's "rash of deaths" theory. It would probably be best to let Summer speak for herself though, especially since I don't really remember what an asymptote is.
But as long as we're asking her questions, I have one. If custirsen should fail to achieve statistical significance in SYNERGY, is the FDA likely to require a lower p-value than .05 in the AFFINITY trial? Since AFFINITY involves second-line patients and SYNERGY first-line patients, I'm not sure why the results in one should affect the requirements in another but maybe they would. OGXI has said the FDA has agreed that success in SYNERGY would suffice for approval (because the results in the P2 trial would count as the second trial it usually requires) but it's never said that about AFFINITY. Would it matter whether SYNERGY showed a trend in custirsen's favor?
"We are encouraged about the docetaxel results and their potential impact on market opportunity for custirsen, and we look forward to the Phase 3 SYNERGY results by mid-2014."
This study should put to rest any concerns that the market for chemo in prostate cancer is disappearing and it suggests that its use may increase. It's possible that the announcement of these results in early December has helped to propel OGXI's pps since then.
The question as always comes down to whether SYNERGY will show that custirsen in fact enhances the effectiveness of docetaxel. But let's say it fails to show a statistically significant effect but does show a "trend" towards significance, i.e., the treatment group does better than the controls but not by enough to achieve significance. In that scenario, might Teva still be interested in funding a trial of custirsen + (docetaxel + hormone therapy)? I would think it's possible, though they'd probably wait for the results of the AFFINITY trial in second-line patients before deciding. In the meantime, unfortunately, OGXI would run out of funds and would have to do a financing. That could be extremely dilutive although if the Borealis-1 P2 trial of 427 in bladder reports strong results in H2 of 2014 that could support the pps enough to reduce the dilution.
Here's what Scott Cormack had to say about this study in his "CEO Journal" on the OGXI website:
"On Dec. 5, 2013, the NCI announced the results of an NIH-funded study that showed improved survival outcomes in men with metastatic prostate cancer who received chemotherapy when starting hormone therapy. The study (E3805) enrolled 790 men who received either the hormone therapy known as androgen deprivation therapy (ADT) alone or ADT in combination with the chemotherapy drug docetaxel.
"Docetaxel is a proven therapy that has historically been used to treat patients that have progressed following ADT. The results of this study suggest that using docetaxel earlier in the treatment of castrate-resistant prostate cancer (CRPC) dramatically improves survival. Not only did the addition of docetaxel to hormone therapy improve patient survival, but it also benefited patients with advanced disease, including bone or organ involvement.
"After speaking with key opinion leaders and study investigators about these results, we share in their excitement as it could usher in another practice-changer for the prostate cancer landscape and give patients and clinicians more treatment options. As Christopher Sweeney, lead investigator at the Dana Farber Cancer Institute in Boston stated in the announcement, “The results of this study are practice-changing” and that “the findings of this study are important both for improving the clinical care we deliver now and in designing new clinical trials as we strive to further improve the lives of men with metastatic prostate cancer.”
"Our candidate, custirsen, is currently being evaluated in our Phase 3 SYNERGY trial in combination with docetaxel for patients with metastatic CRPC. The goal of custirsen is to improve upon the proven and these results further validate that docetaxel and chemotherapy can play an important role in the treatment of CRPC. [CONTINUED]