cxs - moving to a negative view

CXS moving to negative

I have had the opportunity to read through the FDA transcript from 22 March and there are some major concerns.

CXS's press release to the ASX doesn't really tell the whole picture - or at least avoids the negatives.

I have pasted below some passages from the document and you can read them and make your own decision.

There are issues with the submission, the data interpretation, the efficacy and then the diagnostic test which hasnt been sorted out over years.... - how is it going to be suddenly sorted out over months. Maybe they will go for a very limited listing - but even that looks perilous.

There are some problems:

1) Does the drug work - efficacy:

We have seen some great releases on efficacy from CXS - but the FDA represents the first peer review and they had concerns. Admittedly they only have 66 patients and there is now data on 97 patients but the data efficacy submitted and reviewed by the FDA was regarded as low. In fact this summary paragraph is of concern:

"I will now discuss the efficacy results of this trial. Our main concerns with the efficacy are the following: a small sample size, preventing robust and reliable conclusions about the efficacy; uncertainty in the response determination and duration; uncertainty about the clinical meaningfulness of the response rates and questions not only about the eligibility of the patients based on their mutational status, but about the assays performance characteristics."

"Because of the markedly lower response rates noted with omacetaxine compared with dasatinib and nilotinib, it is imperative to have an in vitro diagnostic tool established with known performance characteristics that would identify patients who would respond to omacetaxine. The applicant has not submitted an in vitro diagnostic for review by FDA."

The concern is the use of "markedly lower response rate" meaning the drug is less effective in this trial than the data available for the other TKI drugs that came before it.

for that reason they insist on the need for a diagnostic.


2) lack of a diagnostic: Statements like:


"In addition, and perhaps more importantly, false-positive results for the presence of the T315I mutation would deny patients an opportunity to receive effective therapies for their imatinib-resistant or intolerant disease, such as dasatinib or nilotinib."

"This suggests widely varying test performance, when tests are offered through many different laboratories. Approval of this drug without an approved mutation test has the potential to inappropriately deny patients access to more effective therapies because of high test false positive rates. Conversely, false-negative test results would lead to patients receiving ineffective therapies."

"Testing for mutations in the Bcr/Abl transcripts has evolved more recently due to recognized importance of those mutations for effectiveness of imatinib. Some laboratories report only the presence or absence of detectable mutations. Other laboratories report the prominence of the detected mutation as a percentage of Bcr/Abl transcripts or sometimes in a way that also reflects the overall load of mutated cells."

"According to one NCI recommendation consensus group, mutant clones at low level may not necessarily have the same clinical significance as clones that are detected in the context of a rising disease burden. These analytical and clinical uncertainties mean that test results and their impact surely vary from laboratory to laboratory. "

"There is currently no test specifically designed to optimize Omapro therapy, and none of the tests that I have described is cleared or approved by FDA."

3) The format of the trial: In the opening analysis the reviewer states:

"Overall, there are multiple problems with this NDA.

The first concern is that the applicant did not complete the trial prior to NDA submission. The planned enrollment was 100 patients, and the applicant submitted the NDA when 66 patients were enrolled.

They have informed us that 97 patients are now enrolled. Thus, we are missing data for one-third of the patients in this incomplete trial.

The second concern is that there were multiple protocol violations in assessing response and duration, such that the applicant's response determination is questionable. Therefore, the clinical meaningfulness of the response rate is unclear.

The third concern is that there were multiple tests to detect the T315I mutation at the central laboratories, a key eligibility criterion, and a third of the patients did not have this mutation confirmed at one of the central laboratories at enrollment.

In addition, there were no bridging studies between these two tests to establish concordance/discordance rates, equivalent cutoff, and equivalent reliability. Hence, there is uncertainty regarding the performance of these assays, including reliability, reproducibility and the possible effect of external factors.

Finally, we have safety concerns with the vial size submitted by the applicant. The vials currently contain 5 milligrams of omacetaxine for each dose. However, the average dose in the efficacy trial was 2.4 milligrams. We are concerned about the potential for overdose, as well as for the environmental impact of drug disposal. "

and

"Let me finish my presentation by drawing your attention once again to our concerns with this NDA on the next two slides. An inadequate clinical development plan has resulted in an incomplete single-arm trial with low response rates, in a population with no known historical control. "

"The applicant did not meet this criterion for an adequate and well controlled trial. First, the homogeneity of the population is in doubt, as 35 percent of patients did not have mutation confirmation at enrollment at the central laboratories. Ten of the 66 patients enrolled who had the T315I mutation identified at an outside lab had a negative result at a central lab, and 5 of the 11 responders did not have confirmation of the mutation at enrollment at the central lab. "

"There were two different assays used to detect the T315I mutation and there were no bridging studies between these two tests to establish concordance/discordance rates for liability and reproducibility. Even less is known about the myriad other tests used to detect the mutation in the 23 patients who did not have central laboratory
confirmation. "

"Finally, we have concerns about the false-positive and false-negative rates with in vitro diagnostics that were not validated. False-positive results may incorrectly identify patients who are candidates for effective and less toxic therapies, such as dasatinib or nilotinib. Conversely, patients with a false-negative test result would receive an ineffective therapy. "

4) Is it going to be easy to get a diagnostic test ?

This is from the guy who said just approve it

"DR. BERMAN: I voted no. I'm the no vote. I think the drug should be approved based on the data that we heard today. I think that the likelihood of having a standardized test that will identify this mutation will be long in coming because we have not yet standardized Bcr-Abl among the laboratories.

Sloan Kettering does it different than M.D. Anderson, that does it different than Hammersmith. So knowing how a more crucial test Bcr-Abl is, how more widely used it is and yet we still don't have a standardized way, a likelihood of having a standardized way to detect 315I is, I believe, years in coming.

Based on that, there is an immediate need for a drug in this patient population. I believe that the FDA has parsed very closely the data and, to their credit, they have. However, in the wider context, we see on page 8 of what the drug company has presented, which we saw just recently, that the median survival is not reached in these patients. So the drug does have activity. "

and

"DR. WILSON: I'm Wyndham Wilson. I voted yes. If the presence of this mutation is so profound and so powerful, it shouldn't take years to develop an assay. It's not a matter of developing an assay. That's not what's at issue here.

It is knowing where the cutoffs are and knowing what having the presence of it means and in how many cells. And the fact that we don't have that yet indicates to me that the community out there doesn't really know where that lies. Hence, if it is easy, then the test would be out there. "

"DR. ECKHARDT: Gail Eckhardt. I voted yes. I agree with Dr. Berman and others that this is an active drug; in particular, potentially in this population. But I think that, again, we're not talking about very complicated assay development. We're talking about very standard procedures that people undergo to have companion diagnostics.

With all the caveats aside, I think that this is something that just represents fairly sloppy drug development, and I think it's important that we do develop these assays as we develop more and more drugs that are being recommended for patients with a molecular subtype."