Your idea is to license rindo to the Chinese as a new placebo?
The trial showed that adding it to the standard of care did not benefit patients. The trial did not show that rindo alone was as effective as the current drug/radiation.
The 2011 study of the role of EGFRvIII in glioblastoma patients in Rome found results that should have been a warning: mean OS = 19 months for patients with EGFRvIII(+) tumors, significantly LONGER than patients without v3+ tumors.
Remember the boast that rindo was eliminating EGFRvIII in 80% of the recurrent tumors? For these patients in Rome "relative to GBMs at primary surgery, the level of EGFRvIII in the recurrent tumors decreased by approximately 50%on average".
Montano etal Expression of EGFRvIII in Glioblastoma: Prognostic Significance Revisited
"1) possibility one: patient selection bias,"
yes, these are two vastly different studies, recruiting different types of patients. need for gross total resection and not progressing in the first 3 months are the big differences in favor of longer survival in in the ACT IV control arm. Most would argue it would be lowered by exclusive use of v3+ pts, but that is not written in stone.
2) "Then it would be really a breakthrough for both rindo and the control. It would be an interesting case put in front of FDA. "
Maybe for the suppliers of KLH, not for CLDX. No need to add rindo to the mix, KLH works fine in that case without the need of adding the proprietary peptide.
"AM should have stood up to the DMC."
The DSMB works only on instructions from their boss ie CLDX. They only follow the rules CLDX has given them.
Now if CLDX should have put in place a futility check that required a sign of efficacy is debatable. With enrollment already finished they don't save a lot of money by stopping early.
I'll just say this: At these price levels CLDX has almost turned into a value stock. Consider that they paid about $40 million for glemba when there was much more uncertainty about its activity, and we know that BMS was willing to pay millions just for the right to exclusively test its PD1 antibody with CD27. Also look at the upfront payments for partnerships in the immunotherapy space.
The table showing the 16 to 17 month expected in control arm vs historic 21 month for Rindo has been removed from the CLDX web site, but Marucci discussed it in 2014:
"...all the way over to the exact match on the n=29, these are people that had a resection, have gotten to 5 out of 28-day regimen, you survive 16 months. So we think that conclusively this study proved that no matter if you had a resection or you don't, if you're a vIII patient, you don't do very well.
And then when you match that up against the ACT III data, we see a median survival of 21.8 months, "
As Marucci has said many times, the study was powered to go after a 3 month survival advantage. I feel they didn't find it because 1) the small numbers of matched patients from previous studies give a low survival time, and 2) bad luck in the control arm - with these relatively small numbers (patients and expected benefit) type II error can easily creep in.
1. Your numbers are way low. After accounting for no progression in first 3 months, resection, v3+, .... CLDX was quoting they expected 16 to 17 months mOS in the control arm. That number was based on small numbers of patients that were part of larger studies (ie less than 30) . Could very well be that a better value for such patients is around 20 months as this new, more robust, data indicate. That Italian group that found a POSITIVE correlation between v3+ and survival may have been right all along.
4. Both arms received KLH, just conjugated to the peptide in the active arm, and separate in a smaller dose in the control. Even if it is found that KLH is supplying a benefit, this studied clearly found that adding rindo to it does not help. And don't give me that tail argument, if it was an important effect it would be showing up in the data unless rindo is worse than the control the first 2 years.
best course going forward is to see if they can reach higher and faster elevated titers with faster dosing and with different companion drugs and/or combine it with other vaccines targeting other antigens.
"do the have the talent in house to get to the bottom of this"
I'm home right now, but will be heading back out in a minute.
Short answer is the stopping limits are much more relaxed at first look - essentially it is just a safety check.
This second look required a bit of benefit to proceed (HR about 0.9). Instead, rindo comfortably failed that check.
"it shows a level of poor management that is hard to believe"
Wasn't the lack of partnering considered a good thing on this board just a couple of weeks ago? Because the programs are wholly-owned the launch of the share price could go to the moon.
BTW, they partnered with Pfizer after the Avant/CLDX merger.
Indeed true, but if you have a loss in CLDX likely better to harvest it at the time of the buyout by selling than just letting sit in the new basis for the acquirors stock you will receive. If you sell and then buy the buyer you get both tax loss and the possible stock appreciation.
"stock versus cash transaction. That way we are able to participate in any upside via stock appreciation of the acquiring company."
Unless you have sizable gains in CLDX, wouldn't it be better to take the cash and buy stock of the acquiror?
That way you get the tax loss and get the potential for stock appreciation of the acquiring company.
So you would rather sell now, with a cash value of $2.7/share, to a cash hungry biotech (SGEN does not fit the mold) than wait a year and sell with a cash value of say $1.90/share.
You give up only $0.80/share if the main attraction to an outside firm is the cash but completely throw away the possible upside if the CR011 (now called glemba) TNBC trial is a success. The same management that gave up half the company to acquire the drug and cash will not likely be willing to abandon it now so close to a possibly pivotal readout.
Celldex has also traded for at just the cash value - right after the merger with Curagen.
In many ways, Celldex today is more Curagen than CLDX - Curagen shareholders received more than 50% of the shares and now the lead product is a former Curagen product.
Why would it matter to CLDX? KLH was in both arms of the study - solo in the control arm and conjugated to the CLDX-exclusive peptide in the active arm. If it really is true that KLH is providing the extra few months compared to historical controls then ACT IV has shown that adding the peptide provides no additional benefit.
No reason to develop an expensive vaccine when generic limpet blood is doing all the work.
Also, remember that KLH was made the control after the first Phase III trial had to be aborted after most of the control patients withdrew consent when they could tell they weren't getting the vaccine. CLDX was questioned at the time about their choice for the control but seemed confident the low dose and past not so remarkable history of using it as a general immune booster wouldn't matter.
Have to remember the rindo arm received a higher dose of KLH than the control arm.
It will be interesting to see what the effect of treatments after patients left the study might have had on confounding the results.
Many of these patients likely went on to other experimental treatments that are showing promise after progressing. One patient on a forum claims to have gone on to NWBOs treatment after leaving the CLDX trial.
The EGFRVIII antibody study by ABBV also was accepting patients apparently from the ACT IV study.
(search for Reardon ABT-414).
Just as with the much-discussed stopping for efficacy parameters, the cut-off to stop for futility is always much more strict at the first look. I don't know the actual numbers, usually it requires a clear sign the treatment is worse than the control. If about the same, as the case here, trial continues.
May want to reread those pr's - it was not compared to chemo. Both the control arm without the vaccine and the Rintega arm received standard very toxic chemo therapy and radiation.
Furthermore, the treatment did not work at all compared to the control.
"As of December 31, 2015, we had cash, cash equivalents and marketable securities of $289.9 million."
The evidence for KLH being effective in newly diagnosed v3+ GBM is indeed now stronger than that of all the Rindo studies to date. Same mean OS benefit compared to historical controls, but in many more patients and medical centers.
Limpets everywhere are nervous.