Yahoo would not allow me to post links (thanks a million!). There is some evidence that cabo is used off label. It is said to work really well for bone pain. Go to healingWell website and search cometriq and you can read the discussions.
Similar comments from CEOs of Vical, Oncogenex and others before crashing.
Feel your pain. I still remember that OGXI spinned its failed phase 2 (OGX-011, failed its primary end point PFS) into a success and even got some money from TEVA. Of course, Phase 3 just failed. A failed trial is a failed trial. What happened to ZINC cysteine and Alzheimer's and other junk? Same-O same-O.
Compare to the P2 trial in ovarian trial, the HR (0.75) is really disappointing. The HRs in PFS for cancer drugs are generally much better than 0.7 (Zytiga, Xtandi or any other recently approved oncology drugs). Hope the HR in OS could reach 0.75 or better (P2 ovarian HR about 1.0).
It sounds like the management is tempering expectations. The CEO stated numerous times in the last 6 months of 2013 that the expected medians to be 21 and 27 (to 28) months. However, in the last couple of presentations as well as today, he insisted on the median should be less than 20 months (control) no matter what. Is there some trepidation of the results by the company? Any thoughts, Dr. K, Mr_s and Summer?
I am trying to get some info from patient experience forums, nothing come up with ogx-011 or Custirsen. For xtandi or zytiga, there were plenty of info from patients participated in the clinical trials before their approval. I had similar experience with vical's cancer vaccine in comparison with other drugs, such as anti-PD1s. Any one has better info?
About 2.5 months earlier. From various company presentations, I got the impression that the earliest time would be end of April. I was quite encouraged as the KM curve for CRPC is relatively linear and every month counts. My conservative assumption was that the median for the control is 25 months and the treatment arm of 29 months (for a blended of 27). Therefore it needs at least additional 3 months from end of 2013 (original projection of blended 24 to 25 months from Oncogenex) to reach the target of 27+ months. Due to the heterogeneous responses to docetaxol combo therapies from patients, statistic significance is quite difficult to reach without relatively large median survival differences (4+ months).
No. I am adding 3 to months to the median of the control arm of other failed trials whose patients did not benefit from Zytiga. The 17 months median survival in the P2 trial (control arm) is just an outlier.
That's the estimate from Oncogenex. The company stated many times during its investor conferences as well earning calls that the estimated impact of the new drugs to be 4 months longer in the median survival.
The event reached much earlier than I expected from my model (the CEO also projected near the end of first or early second quarter). It looks like the event rate was very close to the company's original projection (24 to 25 months median). All large trials started after 2006 without much benefit of zytiga xtandi (combination with docetaxel, such as Aflibercept, Dasatinid, bevacizumad and others) produced median between 21 to 22.5 months (control arm). Zytiga and Xtandi should add 3 to 4 months to the media which approaches 25 to 26 months. From the company's projection, the overall median for SYNERGY patient is most likely between 24 to 26 months. The chance of statistical significance now is exceedingly low
What happened to Zinc and Alzheimer's disease? As long as there's hype, suck investors in. In a few years, change name again and hopefully create more hype .........
I think ECYT has a potent drug discovery platform and should have decent shot at the conditional EY approval soon. However, the relentless selling by the insiders (everyone with options). It seems that those guys excise their options as soon as allowed and sell the shares the next day. The CEO said that ECYT communicates with EU constantly. I guess they knew something we don't.
Men with hormone-sensitive, metastatic prostate cancer who received docetaxel chemotherapy at the start of standard androgen deprivation therapy (ADT) lived longer than patients who received ADT alone.
• The projected 3-year overall survival data were
o 69.0 percent for men randomized to ADT + docetaxel-based chemotherapy
o 52.5 percent for men randomized to receive ADT alone
• The projected 3-year overall survival data for the men with a high extent of metastatic disease as defined above were
o 63.4 percent for men randomized to ADT + docetaxel-based chemotherapy
o 43.9 percent for men randomized to receive ADT alone
• The study’s independent Data and Safety Monitoring Committee recommended that the study results be made public because this planned interim analysis showed prolongation in overall survival.
these data are going to have significant impact on the management of metastatic prostate cancer because they imply that men with a significant extent of metastatic disease will now start to get docetaxel-based chemotherapy much earlier in the course of their disease than previously.
----Courtesy of The "New" Prostate InfoLink.
You are right in the sense that the mechanism proposed by Oncogenex as well as from significant in vitro studies (especially tissue culture studies) is apoptosis enhancement upon clusterin suppression. However, the proapoptotic MOA is not supported by any clinical trials (P1 solid tumors, P2 prostate and breast) or genetic evidence. On the other hand, genetic association studies as well as epidemiological studies unequivocally established the connection between clusterin and immune regulation. If the MOA of OGX-011 is proapoptotic, then we should have seen more robust response rate difference as well as PFS difference. Another key point I would like to make is that if the Synergy follows the P2 survival curve, then the trial is doomed. In the P2 survival curve, the P value did not change from 10 months to 36 months. On the other hand, if the mechanism is through immune regulation, then the p-value should decrease with time. Right now we can only hope for the best.
Have a good weekend.
You are absolutely right. However, if you struck your neck out for a projection, why not struck all the way out. Evidently I made a lot of assumptions in order to plug everything into the software to run the statistical simulation. I think the 4 months survival advantage is going to be very close (Phase 2 second line trial supports the assumption as well (15.8 months for OGX-011 plus docetaxol and 11.2 for OGX-011 and mito, assuming OGX-011 only works well with taxol derivatives). The next assumption is that only 35 to 40% patients respond to clusterin suppression (using clusterin overexpression for immune evasion, the rest use other pathways. I conducted extensive review of the literature to arrive at this number). The third assumption is that the survival curve start to separate at about 8 months (most immunotherapies). The projected median survival are 25~ and 29~ months. With the above assumptions with a typical CRPC population, the overall survival p value is about 0.04 at 18 months median follow-up ( interim?) and 0.02 at 27 months and 0.01 at 36 months. I put all the numbers spitted out by the software in my projection.
The P2 trial that produced 7 months survival advantage is not balanced between the two arms (it was a non-comparative trial anyway). The control arm had too many patients died within the first 12 months. The most telling statistics come from the "time from disease progression to death". In the P2 trial, the treatment arm gave a median of 18 months, whereas the control arm only produced a median of 10 months. The recent large clinical trials on CRPC are amazingly consistent, especially the medians from the control arms. The median from various second line treatment trials ranges from 10 (Yervoy) to 13.6 (Xtandi); however 13.6 is an outlier. 10 (Yervoy, 9/22/2013), 11.2 (alpharadin), 11.5 (OGX-011 and pred), and 10.9 (Zytiga, second line) are very consistent, with an average of 10.9±0.65 months. In general, median time from disease progression (from docetaxol treatment, front line) to subsequent treatment is 2.5 to 3.5 months (from progression to enter clinical trials: 3 months). Therefore, the median survival from disease progression (after front line docetexol treatment) to death should be around 14 (3 (from progression to treatment)+11 (10.9 average for the median)) months. In the phase 2 trial, in the docetaxol with OGX-011 arm, the median from disease progression to death is 18 months. Since there is no difference in PFS, the overall survival advantage should be close to 4 months (18 minus 14). My projection for synergy trial (final survival) would be (months) 25.5 (control) and 29.6 (treatment) with HR of 0.72 and p=0.019. The PFS would be (months) 7.5 (control) and 9.2 (treatment) with HR of 0.86 and p=0.063.
The news about the interim analysis was disappointing, but not unexpected. Through extensive literature research for the last two weeks, I realize that the MOA of reducing clusterin level is not what scientists at Oncogenex or TEVA expected. The primary function of clusterin is to regulate the complement branch of innate immunity. Therefore, reduction of clusterin will enhance the immune activities through the complement cell killing, most likely the non-specific pathway, which is supported by the fact that reduced levels of clusterin associate with various autoimmune diseases. The activation of complement pathway will not affect the tumor mass (no effect on PFS) or undamaged tumors, therefore OGX-011 can only work with chemotherapy or radiation. The most significant effect of clusterin suppression is to slow down or prevent new micro-metastases to form new tumors. The activation of complement pathway will kill new micro-metastases (cancer cells are foreign to new organs, just like infection. The purpose of overexpressing clusterin is to suppress the activation of complement (similar to suppression of rejection in transplantation. Not surprisingly, recombinant clusterin was used in this fashion in the literature in animal studies)). Therefore, the effect of OGX-011 is most likely appear later during the treatment cycle (similar to Tvec in melanoma).
However, it would be nice to know more specifics of the interim analysis (such as the p value), so that we can analyze the data and make some predictions in six months.
Very well said. My interest in OGX-011 comes from the fact that the data supporting the role of clusterin in immune regulation (autoimmunity, organ transplant rejection, etc) are quite strong. The difference in survival in the P2 trial came from the difference from progression to death between two arms (reminds me Yervoy). There are still couple of confounding factors I need to figure out before fully commit.
That's my guesstimate as well. To be conservative, say, 25 and 30 months with curve similar to P2 and 1023 patients, the trial should be able to get a very strong p value. The PII second line is quite strong as well (median of 15.8 months, compares favorably with 14.8 months with Zytiga). Of course, with small sampling size, a lot of numbers could be outliers.