$MSTX Does the EPIC Ph 3 have a 99.9999% chance of failure?

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"The treatment difference between vepoloxamer and placebo only starts to become apparent after 80-120 hours. My investor source views this delayed response as an insurmountable problem because vepoloxamer is administered only for the first 48 hours of the study. The drug's half life is 4-6 hours. Mast's study also doses vepoloxamer for 48 hours."

"There's simply no way vepoloxamer could be responsible for the separation of the treatment curves at 80-120 hours given the exposure profile of the drug, my investor source believes."

I am glad someone, anyone, has finally given a bearish view on the science, but to me this seems like a fairly simplistic view. This is a complex story and one needs to dig into all the publicly available information on the development of Vepoloxmer to properly review the current phase 3 trial known as EPIC.

Firstly, the "investor source" is looking at the VERY poorly designed phase 3 of Poloxamer-188, published in JAMA 2001. Despite all of its shortcomings and vs EPIC: 1) The trial was underpowered as it was designed to enroll 350 patients and only enrolled 255 due to capital constraints. 2) The primary endpoint was limited to 168 hours. 3) Only 29% of those enrolled were under 15 yrs old 4) Only 21% were on concurrent Hydroxyurea + P-188 and 5) Muddy endpoint of "time to discharge, the trial barely missed hitting its primary endpoint , N=249 p=.072, however among the 255 randomized patients, the results were deemed statistically significant, N=255, p=.04. Incidentally, the curves actually start to separate at around 70 hrs for the peds and those on concurrent Hydroxyurea and a subgroup analysis for these 2 groups showed statistically significant results that were "very encouraging" (according to JAMA)

"VERY ENCOURAGING"
"Nevertheless, the decrease in the duration of vaso-occlusive crisis and increase in the proportion of patients able to achieve crisis resolution, particularly in children, are very encouraging. It is possible that children exhibit a better response to PP188 because they have less overall tissue and organ damage due to previous crises and experience less chronic pain, thereby making more evident the rheologic and anti-inflammatory effects of PP188. A beneficial effect was also observed in patients who received hydroxyurea along with PP188. This could be due to a cooperative or even a synergistic effect between these 2 agents, one that might be a result of decreased adhesion of sickle erythrocytes to the microvascular endothelium or to some other less well-defined mechanism. Future studies of PP188 in sickle cell crisis would be useful to confirm the efficacy observed in children and to determine the nature of the interaction between PP188 and hydroxyurea.
http://jama.jamanetwork.com/article.aspx?articleid=194337

The "investor source" is looking at the primary endpoint in the JAMA study, "time to patient hospital discharge", which was a very muddy endpoint and based upon the availability of the treating ER physician to allow the patient to leave, which could of been many hours longer ( 5, 10, 20 hrs??)then necessary. Also in this study, the physician could keep the SCD patient hospitalized for any reason, SCD related or not. EPIC has a very pure primary endpoint that is driven by pain "time from last opioid use"(measured via patient controlled analgesia, PCA etc) not "time to discharge". EPIC has no mandatory pain scale measurements

Secondly, a healthy circulatory system is imperative in maintaining healthy organ function, and adequate bloodflow, this is especially important in Sickle Cell patients where blood flow in the microcirculation can often be comprised, especially during a Vaso Occlusive Crisis. Vepoloxamer is NOT a pain drug it is a drug that is designed to improve microvascular blood flow and hence to shorten the duration of the Vaso Occlusive Crisis which in turn should reduce organ damage (and perhaps increase survival materially over a lifetime?)

Yes Vepoloxamer (a rheologic agent) is administered for "only" 48 hours, but it adheres, seals (patches) and repairs the ruptured cell membranes, restoring the cells non adhesive properties and improving microvascular blood flow. It then releases from the membrane when density normalizes and it is cleared renally, unmetabolized. Vepoloxamer reduces the degree of adhesion to the walls of the vessels and to other ruptured red blood cells, which should lead to less occlusion and less pain. So a "delayed" response to the drug to fully engage seems not only plausible but totally reasonable. .
https://www.youtube.com/watch?v=wd4axOmxp8E

Publications (Vepoloxamer-Microvascular activity)
Vepoloxamer improved microvascular blood flow in sickle cell disease patients
during vasoocclusive crisis (prior Phase 3 sub-study) Double blind assessment of
red cell velocity (mm/s) measured in nine sickle cell patients with vaso occlusive
crisis (p=.00003)
http://www.ncbi.nlm.nih.gov/pubmed/15612454
https://ash.confex.com/ash/2015/webprogram/Paper84168.html
https://ash.confex.com/ash/2015/webprogram/Paper86647.html
http://masttherapeutics.com/wp-content/uploads/2015/07/JSCDH-S-15-00089.pdf
http://masttherapeutics.com/wp-content/uploads/2015/07/Is-There-a-Role-for-a-Rheologic-Agent-in-Transfusion-April-17-2013.pdf
http://masttherapeutics.com/wp-content/uploads/2015/07/MastThera_-2014-ASH-MST-188-Abstract.pdf

Has the "investor source" ever seen data showing that the Vepoloxamer "patch" becomes "unattached" after 48 hours from the damaged RBC membranes? Is it not possible that Vepoloxamer's RBC repair may well exceed the drugs half life of 4-6 hours? Is it possible Vepoloxamer has a durable and cumulative effect of improving microvascular blood flow and that's why it's working for SCD patients, especially kids and those on concurrent HU? Why does the "investor source" even assume that the assessment of the endpoint in the JAMA study was even allowed prior to completion of the 48-hr drug administration? Vepoloxamer is not WD-40, it is not just a lubricant, it repairs(patches) ruptured RBCs.

What about the P-188 Phase 2 trial which showed statistically significant shorter crisis and less opioid use?? (for which the placebo didn't even reach 96hrs) See subgroup 3, full dose patients N=31, duration of painful crisis 44hrs vs placebo 80 hrs, or a 36 hr decrease. P=.02.
http://www.bloodjournal.org/content/90/5/2041?sso-checked=true

What about Vepoloxamer in chronic heart failure which showed statistically significant improvements lasting up to two weeks! (I guess Vepo can have an effect after 80-120 hrs??)
"The Company previously announced that a single, two-hour infusion of MST-188 improved left ventricular systolic function that was significant immediately (at the end of MST-188 administration) and remained significant at one week (and, in some cases, at two weeks) after MST-188 administration. In particular, MST-188 demonstrated a statistically significant improvement in left ventricular ejection fraction, end-systolic volume, stroke volume and cardiac output."
http://masttherapeutics.com/investors/news/?releaseid=1900672


Why EPIC should be positive:

1)Vepoloxamer worked very well in the 1st failed phase 3 trial for children,(duration of crisis 21 hours less; P = .01) This makes sense because vessels are less damaged and more accessible in younger patients. After 250 patients enrolled in EPIC, 79% are children with average an average age of 15. The 1st failed Phase 3 only had 29% under 15 yrs old.

2) In the 1st failed phase 3 trial those patients taking concurrent Hydroxyurea (HU) +P-188 showed a duration of crisis of 16 hours less ; P =.02. In EPIC, 60% of patients are on Vepoloxamer +(HU) vs only 21% in the failed Phase 3. If 30% had been on HU in the 1st failed trial, the trial would of hit statistical significance on this one metric alone.

3) The first Phase 3’s endpoint was limited to a maximum of 168 hours. The JAMA exhibits shows that there was a clear, increasing separation between Vepoloxamer and placebo arms and that a majority of enrolled patients were not resolved after 168 hours, but marked as a censored value. It's very interesting to note that 72% of the peds in the placebo group were still in the hospital AFTER 168 hrs. It would appear vepoloxamer would have continued to show superiority after 168 hours, yet those results were not reflected in the first Phase 3. In EPIC there is no such cutoff, patients are marked when they leave the hospital.

JAMA Comments on the 168 hr cutoff:
"It is important to emphasize that in an earlier phase 2 study, even greater benefits with PP188 had been observed.19 This disparity may be explained at least in part by the assumptions used in our definition of crisis duration, the primary end point in this study. Specifically, we observed that fewer patients achieved crisis resolution within 168 hours than patients in the earlier pilot study had led us to anticipate.19 The current study used a very stringent definition of crisis resolution, one that required repeated assessments of pain throughout the entire hospitalization, including the period following discontinuation of parenteral analgesics. In a number of instances, patients were discharged from the hospital before pain relief had been confirmed by a second pain assessment. In still other instances, study patients were discharged before the criteria for crisis resolution had been met. In either case, the analysis plan required that these patients be considered as treatment failures and that the worst-case duration of crisis (ie, 168 hours) be imputed for them"

"Use of an extremely stringent definition of crisis resolution represented a very conservative approach to the analysis of the data. Because the proportion of patients achieving crisis resolution within 168 hours was lower than anticipated, the ability of this study to detect differences in the length of crisis was correspondingly smaller than expected.39 The work reported here also differed from the earlier phase 2 study in that treatment assignment was made according to the stratified dynamic randomization method of Pocock and Simon.28 For these reasons, the statistical analysis methods used in this study were conservative. While less conservative methods might have shown substantially greater differences between the study populations, such an analysis plan would have required taking into account the use of the randomization method.

4) EPIC was designed based upon the assumption that the mean duration of VOC would be 96 hours with a standard deviation of 51 hours. The interim look in October after 250 patients showed the mean duration of patients on I.V. Opioids to be 79 hours, with a standard deviation of 47 hrs. The three doctors on the recent expert calls all said, the 79 hour mean duration is "encouraging". If the 96 hour assumption holds up, EPIC results should be highly positive
FYI- (1998 hospital stay was 5.38 days and in 2008 was 5.18 days,(overall) Peds right at 96 hrs(see Figure F3))
http://europepmc.org/articles/PMC4177169

Evaluation of EPIC
http://masttherapeutics.com/wp-content/uploads/2015/07/EPIC-An-Ongoing-Pivotal-Phase-3-Study-in-Patients-with-Sickle-Cell-Disease-Aug-21-2013.pdf

Although the stock certainly trades poorly and appears to have a total EPIC miss nearly priced in, I certainly do not believe that Vepoloxamer has a "99.9999%" chance of failure. In fact, if you seriously look at all the Vepoloxamer information publicly available for the last 15-20 years , it would appear to have a very high chance of success. Mast has completed enrollment in the largest placebo-controlled clinical SCD trial conducted to date when most said they couldn't even do that, yet they receive zero recognition. The Company appears to be preparing to file a very robust NDA package. Julie Kanter, Hematologist and lead investigator running the EPIC trial at MUSC recently used a few adjectives to describe Vepoloxamer, "incredible potential", "game changer". Two other SCD experts on recent calls also had very positive things to say about the drug as well. These SCD experts seem to see something they like. I personally have never seen such a disconnect in my life, we will know all of the answers shortly. Good luck to anyone involved.

Disclosure: I am long MSTX. I may Buy or Sell MSTX at any time and for any reason at my sole discretion without any notice.This tweet may contain omissions and errors, all information must always be verified before making any investment decision. I wrote this tweet myself, this is NOT investment advice, it is informational ONLY, it expresses my own opinions. This is not a recommendation to Buy, Sell or hold any security. I am not receiving compensation for it. I have no business relationship with Mast Therapeutics.

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