August 2, 2012

Intralesionally-Delivered Local Agents with Potential Systemic Benefits: PV-10, Allovectin-7 and T-Vec (formerly OncoVEX)

As you will recall, Vical's Allovectin-7 and BioVex's OncoVEX, now Amgen's T-Vec (or talimogene laherparepvec), were profiled by Dr. Merrick Ross in his Update on Intralesional Ablative Therapies presentation at The HemOnc Today Melanoma and Cutaneous Malignancies meeting in April.

Dr. Robert, Andtbacka, in his Intralesional Therapy for Systemic Disease: Where Will it Fit in? presentation at the same conference, presented the critical comparison table for these three emerging therapies (PV-10, Allovectin-7 and T-Vec):

Clearly, each of the companies with a dog in this hunt -- Provectus, Vical and Amgen -- are pursuing local agents they believe to have systemic benefits.

Vical & Allovectin-7. One month ago, Theodore Cohen wrote an article at SeekingAlpha about Vical's pivotal MM Phase 3 trial for Allovectin-7. The author has written a few articles on Vical, including a more recent interview with this company's CEO. I encourage you to read them. Author Cohen wrote about the delay in Vical releasing data from its MM P3 trial. This trial began enrolling patients in January 2007 and completed enrollment by February 2010 (a total of 390 patients). Final treatments were completed in February 2012.Trial results are slated for late-2012, although timing may see a 2013 release of information depending on the trial reaching the target number of event deaths.

Mr. Cohen theorizes the delay is due to the trial using healthier patients. An historical review of dacarbazine (DTIC) or temozolomide (TMZ) use shows patients given this treatment have a median overall survival in the range 6 to 11 months. It is possible the median overall survival in the control arm could be greater than 11 months.

It also makes you wonder why the trial has not been stopped by now. According to Mr. Cohen, the trial's safety board only had access to safety data, not efficacy data: "Put another way, the board did not have the ability to halt the trial except for serious safety issues."

In reading and re-reading Mr. Cohen's articles and Vical's CEO's explanations, as well as asking the author about the design of the trial's primary endpoint, I come away more skeptical.

Most studies have large patient numbers because their effect size is lower, which means very incremental improvement. Vical probably did not design an interim analysis or efficacy read into their design (and, thus, did not provide patients in the control arm with a cross-over benefit) because it probably would have put a greater burden on the trial's efficacy outcome. If Vical were supremely confident about the fundamental improvement and significance of the drug's results (vis a vis the primary endpoint), management would have included an interim look. Ultimately, for Allovectin-7, it probably will boil down to [median] overall survival, the original assumption for which was 18 months.

I cannot help but think the primary endpoint was not well designed and wonder if the endpoint was indeed met. As the analyst from Cowen & Company asked on yesterday's Q2 earning's call, paraphrasing: If overall survival (the secondary endpoint) is good, isn't this a drug you would expect to be approved regardless of the success on the primary endpoint. Vice versa, if the overall survival is poor, does primary endpoint data have any chance of rescuing Vical?

Amgen & T-Vec.
 Similar to The Curious Case of Benjamin Button, T-Vec gets smaller and smaller. Amgen acquired BioVex for $1B, more than 80% of which was an upfront payment. It later shut down OncoVEX's head & neck cancer P3 trial, and delayed the release of the drug's pivotal MM P3 trial results into 2013. Amgen, it would seem, makes less and less mention of T-Vec in its earnings calls. 1 mention on the Q2 call. 2 mentions on the Q1 call. 2 mentions on the Q4 2011 call.  3 mentions on the Q3 2011 call. 6 mentions on the Q2 2011 call.

While one might question whether Allovectin-7 met its primary endpoint (it's possible the company met it's secondary endpoint), T-Vec's shrinking causes one to question whether the drug met either its primary or secondary endpoints.

Nevertheless, all things being equal from when Amgen acquired BioVex in January 2011 to now, nearly 18 months later, I think Amgen would have paid a higher price for the local agent it believed would have systemic benefits.

Which brings us back to Provectus and PV-10. The comparison of the Company's contemplated pivotal MM Phase 3 trial to Allovectin-7 and T-Vec's is stark. A primary endpoint of progression free survival. 180 patients; a higher effect size drives a lower study size, meaning a fundamentally large improvement. A response assessment after 12 weeks, which allows patient cross-over from the comparator arm to the PV-10 treatment arm. An historical review of DTIC/TMZ use shows progression free survival in the range 2 to 3 months.

Given the apparent challenges facing Allovectin-7 and T-Vec, it seems clear PV-10 is pulling ahead because it is swimming faster and the others are falling behind because they are swimming slower.

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