Reading the tea leaves but description of Shan's Dec. 5th presentation indicates bavi is progessing to "late stage clinical development"... which usually means Phase III. Any comments?

Clinical Development of Bavituximab, a Phosphatidylserine (PS)-Targeting Monoclonal Antibody

Bavituximab, an investigational monoclonal antibody, localizes selectively on tumor vasculature, synergizes with chemotherapy, causes vascular shut down in tumors and reactivates innate and adaptive tumor immunity. In clinical trials to date, bavituximab has been well-tolerated both as a single agent and in combination with approved therapies. Bavituximab has demonstrated promising anti-tumor activity as an adjunct to standard chemotherapy in several solid tumor indications and is advancing to late-stage clinical development in non-small cell lung cancer.
Joseph Shan, MPH, Vice President, Clinical and Regulatory Affairs, Peregrine Pharmaceuticals, Inc

Tumor Associated Macrophages are already on. One proposed mechanism of bavi is not to active macrophages, but utilize their plasticity to turn from a M2 suppressor type to a M1 inflammatory state.

What I can say after reviewing all of PPHM's MOA data presented in 2011 and 2012 is that there definitely appears to be a shifting to inflammatory cytokines (IL-12, IL-1, TNF-alpha) and a depression of suppressive cytokines (IL-10, TNF-beta). These stimulatory cytokines have been shown by multiple other (non-pphm affiliated) researchers to shift the M2/M1 balance.

What is interesting is that up to 50% of tumors are comprised of these Tumor Associated Macrophages (TAM), mostly in a M2 immunosuppresive state. The problem isn't stimulating the innate (macrophages, dendritic cells) in cancer, it is trying to have the pro-inflammatory types be more prevalent.

From the data that has been presented on Bavi, I can say that I am 'slightly convinced' that there is shifting of this microenvironment. It should be noted that all of these pathways are interlinked, and if you shift from M2 to M1, then you get additional CD4+ TH1 cells, and more IL-12, less IL-10, which stimulates more M1, etc.. etc. Also, dendritic cells are allowed to mature in the presence of less IL-10, and can act as APCs (antigen presenting cells).

PPHM has been keen to talk about PS exposure on endothelia cells lately, and the science holds as growth factors (e.g. VEGF - target of Avastin) are downregulated in a pro-inflammatory environment. Also note that cytotoxic T cells and Natural Killer (NK) cells are activated, which are key players in the body's anti-tumor defense system.

If Bavi works by slowly shifting this mass of macrophages within the microenvironment to an inflammatory state over time, I can appreciate OS as the best marker of activity. Note that no Bavi human trial has had a clear negative OS result to my knowledge. Also, one last point, there has been research done (outside of pphm) showing long-term (5 yrs or longer) NSCLC survivors had higher M1 to M2 macrophage ratio than short-term survivors (1 yr or less). This study was looking at a mix of stages and ECOG performance, so not directly applicable to pphm's NSCLC indication (stage IV - 1st or 2nd line), but still encouraging nevertheless.

Estimating the % survival, evented, and censored at each 3 month interval. If you use the Kaplan Meier curve (with the barely visible tic marks) and more importantly the cumulative overall survival at each 3 month interval and patients at risk you can estimate when the censors occur, how many have evented, and how many patients are left at risk. How this is possible is that you use the at risk patients and the survival % at each interval (you can back calculate the survival at each interval by using cumulative survival and multiplying the successive survival %'s). For example, if 90% of patients live from 0-3 months, and 80% of those exiting 0-3 months survive until at least 6 months, then 90% x 80% = 72% cumulative survival to 6 months (which would be the line in Kaplan meier at that data point).

Using this methodology, I found the following (AR=at risk, EV=evented(death), CE=censored, CS%=cumulative survival at month, match to Kaplan Meier):

Please feel free to comment on these findings. I am interested to hear your analysis. These findings indicate 23/40 bavituximab patients (1mg + 3mg) were censored after 9 months, and7 of the 1mg were censored after 12 months. If those patients are added back to the OS calculation once evented (e.g. evented at 14 months), then it would positively impact OS results. Bascially, the reason for censoring is likely survival, and not anything malicious by management. As said, 1mg arm is much better with censoring later than 3mg, but if 3mg is acting like 1mg, then we can assume that these patients are living longer also.

Docetaxel survival data
Mo AR EV CE CS%
0 38 0 0 100%
3 32 6 0 84%
6 18 20 0 47%
9 9 25 4 31%
12 6 26 6 26%
13 3 28 7 16%
14 1 29 8 8%
15 0 29 9 0%


Bavituximab 1mg survival data
months AR EV CE CS%
0 40 0 0 100%
3 35 5 0 88%
6 27 11 2 72%
9 21 14 5 63%
12 10 18 12 45%
13 4 19 17 36%
14 2 19 19 36%
15 2 19 19 36%


Bavituximab 3mg survival data
months AR EV CE CS%
0 39 0 0 100%
3 29 6 4 82%
6 21 12 6 64%
9 14 13 12 60%
12 7 14 18 53%
13 3 15 21 41%
14 3 15 21 41%
15 3 15 21 41%

AF clearly points to the high number of censor patients as a major flaw for this study, but he first uses an incorrect date of unblinding (Dec 2011) vs. actual May 2012. Also, if you use the Kaplan Meier curve and patients at risk you can estimate when they were censored as the graph shown is hard to spot the actual tic marks (despite AF's claim that he can see them all).

My estimate is that for the 1mg arm there were 14/19 total censored patients at 9 months or longer and at least 7 of those at 12 months or longer. The 3mg is less clear with 15/21 at longer than 6 months and 9 of those at possibly longer than 9 months.

Still, you clearly are seeing patients live longer than historical average with docetaxel (possibly 23 of the 40 censored patients living past 9 months). I have a strong feeling that the high censor rate is due to the extended survival and point of follow-up. At less than 50% evented in both bavi arms, it is too early to start counting censored patients in my opinion.

Outside investigation is likely FDA investigating the CRO.. If PPHM management is correct and this is the fault of an independent contractor, then this is a CRO that has assumed sponsor responsibilities.

From the FDA:

"A contract research organization that assumes any obligation of a sponsor shall comply with the specific regulations in this chapter applicable to this obligation and shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under these regulations. Thus, all references to "sponsor" in this part apply to a contract research organization to the extent that it assumes one or more obligations of the sponsor."

Perhaps PPHM can't comment publicly on the details of the discrepancy until the investigation has been completed.

Also, if investigational drug = investigational drug then

If Peregrine's definition of investigational drug in the PR is the same as the FDA's in the regulations stated on testing drugs in humans (which I assume it is as this could be used against them in lawsuit if term is used improperly), then this discrepancy should be limited to the treatment arms. Impact is that x number of pts will need to be censored, but MOS for bavi might still show advantage for pooled data.

From PR:
"A subsequent review of information has determined that the source of these discrepancies appear to have been associated with the independent third-party contracted to code and distribute investigational drug product."

From the FDA (CFR 21 part 312 - laws governing IND applications to use product in human trials):
"Investigational new drug means a new drug or biological drug that is used in a clinical investigation. The term also includes a biological product that is used in vitro for diagnostic purposes. The terms "investigational drug" and "investigational new drug" are deemed to be synonymous for purposes of this part."

Analysis of the PR and some potential outcomes. The PR indicates that pphm used multiple contractors to (1) code the product (2) distribute the product and (3) to assign treatment group assignments. PPHM clearly states the problem is with the contractor responsible for (1) and (2).

This means that the patient groups are likely assigned correctly. Docetaxel alone (placebo) MOS results were available last April, and it could be that these patients did actually receive only placebo as response rate, PFS, and MOS results followed historical averages. If some bavi got into this patient group, it likely isn't many patients or the MOS would be affected to a greater extent, because...

We know that a large percent (over 50%) of both bavi arms were alive as recently as early sept, again patient coding is likely correct. Patient enrollment for this trial completed in Oct 2011, and historically docetaxel alone has about a 30% one-year survival. The 1mg strength was outperforming the 3mg according to Kaplan meier curve at 3, 6, and 9 months according to my analysis after removing censored patients. This means that the discrepancies are likely between the 1mg and 3mg treatment arms.. possibly leading to a lower 1mg MOS result and a higher 3mg.

This would also align with the fact that management probably didn't analyze the bavi results until MOS was met, which was probably recently for at least one treatment arm.

Conclusion: this will probably mean that pphm will have to censor patients affected and lower power of study to point where statistical significance is lost. However, if problem is only restricted to treatment arms, then positive MOS signal with bavi could still be salvaged.