GNTA What the AGENDA trial needs for Approval!
Alright Genta fans, today I am going to run through what kind of statistics I think Genta needs to produce to garner approval from the FDA in the upcoming release of the AGENDA trial results.
First a quick backgrounder on Genasense
Genasense, as most of you already know is in a Phase III trial named AGENDA for patients with normal LDH levels that have melanoma. The drug is designed to be used in patients with cancer that are resistant to certain types of treatment, in this case dacarbazine. It is believed that these patients are resistant to standard cancer treatments because their cancer has a gene called Bcl-2 that resides in the mitochondrial membrane of the cancer cells that blocks the standard therapy’s ability to kill cancer cells. That gene is specifically targeted by Genasense to be inhibited from performing its function which then allow the dacarbazine to kill the cancer. Genta believes that the drug works best in patients with a normal LDH level (LDH is is often used as a marker of tissue breakdown).
So what kind of results will we need to see out of the AGENDA trial for approval. I am going to be bluntly honest with you, they need some pretty startling results, because Genasense has twice previously been in front of the FDA for approval with this drug and in both instances has been shot down. So let’s run through some quick stats that I think will be important indicators for approval.
The Primary Endpoint: Overall Survival or Progression Free Survival?(of course this is always the most important!!!)
Previously, Genta ran a clinical trial in melanoma patients called the GM301 trial, the trial however did not even come close to meeting the primary endpoint of statistical significance in Overal Survival (OS). Genasense only increased overall survival by an average of 1.2 months over dacarbazine with a statistical significance level of only p-0.077, keep in mind when they met with the FDA the p statistic was at p- 0.18. Not surprisingly the FDA’s ODAC shot them out of the water with these kind of numbers and voted for non-approval. However, Genasense has identified a patient subgroup that responds well and released those figures recently. So let’s take a look at them, from the previous trial Genta extracted a subset of patients with a normal LDH level that appeared to respond much better. In fact these patients overall survival (OS) Genta claims is 12.3 months (here slide 14/15) which would put it at 2.4 months longer than dacarbazine’s 9.9 months. See here is the thing that investors should be aware of, there are other studies out there that show that a cocktail that contains cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 had an overall survival of 11.8-11.9 months (journal here). And these are the studies used in the NCNN melanoma practice guidelines (page 17/41), however it doesn’t seem to be known why these combo therapies work. And they don’t always work the with the same results. So maybe Genta has found the holy grail in that normal LDH patients respond better with their drug. One thing is for sure, THEY NEED TO REPLICATE AT LEAST an 11.8 and up Overall Survival rate in their patient group to garner approval from the FDA. Otherwise the FDA will simply say, “hey why don’t we just give the patients this cocktail, that appears to work better some of the time?”
Next let’s talk about the Progression Free Survival Statistics, because Genta is claiming that the PFS should increase to 3.6 months on Genasense, while patients taking dacarbazine will last 1.6 months. Again a great number, but there are other therapies (paclitaxel plus carboplatin) out there that produce up to 4+ months of PFS in patients with advanced melanoma (journal here), also note this therapy has a ORR of 11% too).
What about the Overall Response Rate
In the GM301 study (here) Genasense actually met this goal, in fact, they completely destroyed dacarbazine by itself. Genasense’s overall response rate (ORR) was 6% higher than dacarbazine’s alone at 13.5% of patients achieving an ORR. It is my belief that this should have been enough to get the go ahead from the FDA’s advisory board, but they voted against it. Why? Recall that previous study I showed you, well read the results again (here). In that study patients have a WHOPPING 64% ORR, I mean seriously that is some tough potatoes to contend with. So keep that number in mind, because even in the normal LDH population Genta only achieves a 20.8% ORR. The other study with the 64% ORR is probably why Genta did not include ORR as one of the endpoints in the AGENDA trial.
What about approval?
So which is the better indicator of approval, OS or PFS? Alright, I’ll just be as quick to the point as I can here. The MOST important thing that matters here is the Overall Survival (OS) rate. You see Genta has already tried the PFS arguement before in melanoma and it blew up in their face. Remember they were rejected by the FDA’s advisory board for a melanoma indication and they were trying to use the PFS as a reason for approval. Add to that, that the other competitor treatments have a PFS of 4+ months and you are really pushing the issue here. We already know that Genasense works to improve the PFS and the FDA rebuffed that, so investors should treat that number as a by-product of the AGENDA trial.
What is really important here though is the OS rate. I know I said earlier that they should have an OS of at least 11.8 months, but to gain approval I think Genasense is going to have to blow the tops off of this one. So if I was investing in this company I would want at least an OS rate of 12.5+ months in the AGENDA trial. Anything less and I would immediately sell the stock. Why? Genta has already tried going in front of the FDA with other endpoints with good data and been shot down. They are not as important, that is why Genta has choosen the OS as their primary endpoint. You see, Genta knows that with the other combo therapies out there showing great ORR (64% in combo sequential therapy) and PFS rates (4+ in some therapies) it will be hard to argue that their drug is better than just plain old dacarbazine. Because in reality patients are going to be attempting the other therapies with the better PFS and ORR rates. I mean who can argue with the 64% ORR that the cocktail data revealed. So for a sure play on the stock, be looking at the primary endpoint to completely smash expectations.
How to read their Press Release when the time comes
Ok, the morning of the press release if you read it and they are only focusing on the ORR and PFS and barely happen to mention the OS rate, then you know the gig is up. The Press Release out of this company should highlight the fact that the OS rate met and beat expectations, anything else will be hogwash. OS rate, remember that is all that matters here.
Wait hold on a minute, what about safety and efficacy?
Ah, you thought I would forget about this, huh? Nope, this is where I am highly critical of Genta, because they aren’t being very forthcoming with the toxicity data in the LDH patients. I have seen snippets here and snippets there, but not enough data to draw conclusions. If you remember correctly in the original GM301 trial (FDA slides 28-30/41 here) you will notice that Genasense increases neutropenia, thrombocytopenia and discontinuation of treatment, none of this bodes well for approval. However, the sequential/cocktail treatment that I have been discussing is actually as rough or even rougher on patients. So what would I be worried about? Safety and Efficacy will not be a concern if Genta smashes the OS rate, it is that simple, these symptoms, while not great, are not enough for a non-approval if the OS rate completely destroys expectations.
Source Geccowire.com
