owtside - you are incorrect - read the CYTR press release announcing the results - they state it is "first line" therapy. However, that is one of the problems with the way the trial was conducted - the enrollment criteria allowed prior "adjuvant" chemotherapy ( i.e. used in conjunction with surgery), including three cycles of Dox. Dox has a lifetime dose cap of 6 cycles, so I'm not sure how they could enroll any patient that had prior Dox therapy into a controlled trial where they would potentially be targeted to receive 6 cycles of Dox, if randomized into the placebo group. Combine this pseudo-front line issue with the trial sites in eastern Europe and Russia and it starts to seem a little flaky - why would you need to go outside the US to enroll a 105 patient trial?
That's the fallacy in the assessment they gave to SRPT last month - i.e. that the "disease is variable", so the stability seen in the Etep boys can be written off as random chance. It isn't the disease that is variable, it is the patients that are in various stages of disease and trying to enroll a homogeneous patient population (one where every boy is at the same stage of progression) is almost impossible. SRPT tried to do it (via age and 6MWT distance) and got two boys that were within 6 months of losing ambulation. But that is why the Etep data is so compelling - the idea that they somehow were lucky and enrolled 10 Exon 51 boys over age 7 that wouldn't progress over two years is almost impossible, if you believe the natural history data. If McDonald's research/testimony and GSK's placebo group data don't convince the FDA of that, then they are hopeless. Beyond the lack of "clinical" progression, you have the parents' testimony that their boys are improving on Etep - improvement is never part of the "variability" of the disease.
Is that you, Pasteur - same moronic arguments under a different mb name? Weren't you getting enough thumbs down under your original name?
dawg - I agree there is something that doesn't seem right about the CYTR Aldox trial - I thought historical response rates for Dox in front-line STS were in the 10%-15% range, so the reported 5% response rate in the Dox arm seemed out of line. The other thing was that they spoke about the trial as being a "front-line" comparison, but the enrollment criteria allowed prior adjuvant chemotherapy, including Dox up to 3 cycles (cumulative dose of 225mg/m2) - not sure how they could enroll someone to potentially receive 6 cycles of Dox in the control arm, if they had already received 3? Finally, some of the trial sites were over in eastern Europe - I get a little leery when I see eastern European or Russian trial sites - why they would need to go overseas for a trial of only 105 patients seems a little strange, as well. I had a small stake in Cytr and cashed out a third on the run-up, so I am playing with house money on the rest. I have no faith in their CEO - he sounds like a huckster and the company issued over 3 million options to the execs and board members right before announcing the results from the trial - that's more than 5% dilution from a single option grant, so these guys are not shy about lining their pockets. I'm going to ride it out another 6-12 months to see if they partner one of the indications or get any interesting results from the GBM trial.
I checked the annual option award the previous year and it was done on the 11th of December, so the timing didn't change from the prior year, but that doesn't mean they didn't hold the data back before doing the grant. In the prior year, the CEO received options on 500,000 shares (with an exercise price of $1.83) - not sure what warranted them granting almost twice as many options in the current year. Unfortunately, this is nothing unusual - execs lining their pockets with shareholder money. That's what nauseates me when the 1%ers talk about the moochers and takers in this country, while a big chunk of them are effectively stealing through the protection of the boardroom - as if this is some sort of "free market" process.
Your assessment of median survival is not accurate - when you say the median endpoints in each arm are reached when 21 and 42 deaths occur, that assumes that every patient was enrolled at the same time. Enrollment from this trial began in Jan 2011 and was completed in Sep 2012, so it is not true that the first 21 or 41 patient deaths establish the median for each arm. That is what is so strange about this trial - why would they assess the data after roughly half of the enrolled patient deaths - every other cancer trial I have seen have waited until at least 75%-80% of the patient deaths to unlock the data.
Beyond that issue, with cancer vaccines, there are always some patients who, because of weakened immune systems or other factors, do not generate an immune response, and so realize no benefit. That is why you especially have to wait for a greater percentage of enrolled deaths in a vaccine trial, because if 1/3rd of the patients don't generate a meaningful immune response, then the first third of patient deaths are effectively comparing placebo to "non-responders". This is the "long tail" issue that they alluded to in the call - the "responders" to the vaccine can have a dramatically higher survival benefits, but that won't be reflected until the bottom half of the KM survival curves - the long tail. They were stupid to unlock the trial after only 67 deaths and they were doubly stupid to not have the data showing immune responses for those 67 deaths to be able to put the results in context, but that does not mean that in the end the trial will be a failure or ICT-107 does not work. You may have to wait a year+ for a sufficient number of deaths and related immune response data to clarify the picture, but having 8 of 16 patients living longer than 5 years in the Phase I trial is no fluke - what do you think the results of that trial would have shown if they assessed the median survival based on the first 8 patients to die?
There was a lot of commentary and discussion at the conference about risk-reward and what level of risk the parents are willing to take with a new, unproven drug. A number of parents gave impassioned arguments for taking great risk, because of the known outcome of doing nothing is horrific for their child, while the FDA reps spoke hypothetically about their willingness to accept significant risk when dealing with deadly diseases, but only in the context of the acceptance of potential side effects. What was not discussed specifically by the FDA, and is the elephant in the room, is that Etep has shown no meaningful side effects, so that risk is a non-factor. The risk that the FDA won't accept at seemingly any level, but was unspoken, is the risk that Etep doesn't work. They seem to be caught in their own self-created box, where the AA rules say they can accept a surrogate measure that is "reasonably likely" to predict clinical benefit, but because there are issues with the measurement of the surrogate, they are uncomfortable going down that road. You would think the AA rules would give them the flexibility to say that (despite the small N in the trial) the clinical results to date and natural history evaluations make it "reasonably likely" that Etep works, but they seem unwilling or unable to accept that risk.
I was listening to the PPMD conference live - I assume at some point a recording will be available. I'm actually surprised they would admit some of the things they did - it is clear from their comments that they had a knee-jerk reaction to the Drisa Phase III failure. They assumed from the Phase II trial (I'm not familiar w the details of that trial, so I'm not sure how "robust" that data was) that the Phase III trial would be a success, so when it wasn't, they concluded that dystrophin production does not correlate with clinical benefit (based on 6MWT), without having the detailed data to analyze individual treated patients on their dystrophin measurements, age, baseline 6MWT, etc. They also dismissed any natural history comparison without having a detailed analysis of the Drisa placebo group, which based on the overall stats that GSK has disclosed clearly shows a significant decline over 48 weeks in the age 7+ placebo group.
What was clear from the conference today is that because of the small sample sizes (due to limited patient numbers) and variability among patients (regardless of how tightly you try to enroll a homogeneous patient group), it is almost impossible to generate meaningful patient group stats - you need to assess each patient individually. As Terri Ellsworth stated in her 2-minute talk - the improvements her son Billy has experienced over the 2+ years in the trial are NEVER seen in the "natural history" of the disease. I'm sure they could get similar assessments from each of the parents of the 10 boys - the boy that broke his ankle and recovered to continue the 6MW tests is a perfect example. How can the FDA ignore these individual assessments/results, but rely on group data from the Drisa trial to dismiss the data from the Etep trial?
FWIW, I wrote to Investor Relations and they confirmed that the patients in the Phase III study have the option of continuing on TH-302 as a monotherapy (after the max 6 cycles of combo therapy with Dox), assuming they have not progressed. As a side note, CYTR just published Phase II data in their STS study showing their modified version of Dox (Aldox) performs better (in response and PFS) and eliminates the dose cap, so TH-302 will have a better version of Dox to combo with down the road.
Nothing new disclosed at the conference. The same problem still plagues this company - they have a very expensive marketing launch coming up in 2014 for OMS302, so they either need to do another capital raise or partner something. Nobody will believe the value of their pipeline until they partner something - why haven't they partnered OMS302 in Europe, yet. A couple of their pipeline drugs are ripe for partnering - they keep bragging about the value of their drug discovery platform - they've "unlocked" 52 orphan GPCR's - how about selling the rights to one of them and maybe people will believe you're just not #$%$ shareholder money away!
When the made the decision to shelve AA for Etep. The FDA rep indicated that they did not yet have the detailed Drisa patient data to determine if there was a "subgroup" of patients that produced dystrophin and had a clinical benefit. Their decision was based on the overall Phase III results that there was no clinical benefit and assuming that there was dystrophin production due to the Phase II results. Making decisions about Etep based on summary conclusions on Drisa without detailed data - nice work FDA!
The comment was they had no problem approving a drug that was proven effective in a rare disease, even if it had toxicity - they would just label it. Drisa has not proven to be effective - its Phase III trial failed. All the FDA reps talk in hypotheticals, which on the surface would give you the impression that the Etep results would be approvable, but they are restricted by law in discussing the specifics of Etep, so they are protected from saying one thing hypothetically and doing another in reality.
This was alluded to in the call yesterday, but they really didn't cover it very well. The idea being that not all patients are going to generate a robust immune response from the vaccine, so for those that don't the survival curves will look comparable to placebo, while for those that do, the survival impact is extraordinary - e.g. the number of patients from the first trial that have survived beyond five years. So, if you are analyzing the survival impact based on the first half of patients to die, you aren't going to capture the patients that have had a robust immune response and the potential for a dramatic survival impact. I'm actually surprised they set this up to have a survival readout based on only 67 (out of 124 total) patients - most cancer trials I have seen did not assess survival until at least 75-80% of the patients had passed, and it is even more important for vaccine therapies that you wait. So, the bottom line is that the survival story still has a while to play out.
When they made the decision to shelve the Etep AA plan. She just said they recently received the Drisa data and soon she will be getting the placebo natural history analysis for the first time. Sorry, but this woman sounds like a twit - if we are counting on her to guide the FDA's process, it is not a good thing.
I agree - this situation was a dicey one for Lpath - based on their comments in announcing the sale by Pfizer, you knew Lpath's bid was on the low end and if Pfizer took it, they would have to raise money. So, if Lpath's bid was accepted, it meant major pharma took a look and passed and dilution was on the horizon - two things I think would have trashed the stock? I think when the dust settles, this will be a positive - depending on who the partner is, it could be very positive. Either way, I doubt they will announce the sale price that Pfizer gets for the sale.
Is how they discuss that no other single agent has been able to beat regular Dox in a side-by-side trial for front-line STS patients, yet the partial response rate for Dox in the trials they reference is less than 10% and the side effect profile is horrible. Just shows you how horrible certain cancers are and what a breakthrough Aldox is - nothing has been able to beat this drug in 30 years, and this small, unknown biotech did it. If Kriegsman didn't sound like such a huckster, we'd probably have better analyst coverage and be trading in double digits!?
Everyone is forgetting that they have already announced interim results from this trial - out of the targeted 105 patients (70 Aldox and 35 Dox) they had response rate results from 82 patients - 22% of Aldox patients had a partial response vs 0% for Dox - hard to imagine that PFS would fail with those prelim stats. As has been pointed out, even if the PFS benefit for Aldox is not statistically significant, the safety profile and elimination of dose cap on Dox will make Aldox a winner.
How bad could it be - based on the interim analysis of 82 patients (out of the 105 targeted enrollment), Aldox had a 22% response rate vs 0% for Dox, so even if they got no more responses in the Aldox arm, the response rate would still be better. If the PFS benefit is not statistically significant, the safety profile and elimination of the dose cap on Dox would give Aldox the upper hand.
beach - I wasn't placing much hope on the interim STS generating a statistically significant OS benefit, as it is only based on about half the events targeted for the final analysis (434). One thing from the Oppenheimer presentation that could change that is the impact of maintenance dosing with TH-302 - slide 14 - how they got an addiitional 10% response rate (5 of the 48 patients that elected to go on to maintenance therapy in the Phase II trial responed, after being stable on TH-302 + Dox). I don't recall ever seeing this before, although it is not clear whether the Phase III trial includes maintenance dosing in the TH-302 arm. If it does, that could push the OS benefit of TH-302 to where it may be statistically significant at the interim?