When Vical reported third quarter 2012 earnings on November 7, the company commented on its financial results and progress in key development programs. Vical management effectively guided the eventual release of results for the company's pivotal MM Phase 3 trial would be delayed (again) to mid-2013 or into 2H13.
Amgen's talimogene laherparepvec or T-Vec (formerly BioVex's OncoVEX), Vical's Allovectin-7 and Provectus' PV-10 are emerging intralesional immunotherapies the melanoma community has wanted to see more results for and now want to be combined with other immunomodulatory agents.
Dr. Robert Andtbacka profiled these therapies and compared their local-regional and systemic efficacy at the HemOnc Today conference in his presentation entitled Intralesional Therapy for Systemic Disease: Where Will It Fit In?
More potentially promising therapies and options than less are better for cancer-stricken patients. With Vical's announcement on Wednesday, however, it seems another promising therapy is going to fall by the wayside.
I previously wrote about Amgen and T-Vec here. Amgen acquired BioVex in early-2011 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 makes less and less mention of T-Vec in its earnings calls. No mention on the Q3 call. 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. T-Vec's shrinkage causes one to question whether the drug met either its primary or secondary endpoints.
In the same blog post, I also suggested Vical's Allovectin-7 primary endpoint, and thus the trial, was not well designed and wondered if the primary or secondary endpoints were met. Like with Amgen's T-Vec, it appears Allovectin-7 did not meet it primary endpoint -- objective response rate at ≥24 wks. The historical response rate for comparator DTIC at ≥24 weeks is <4%. Allovectin-7's Phase 2 response rate at ≥24 weeks was 11.8% and its Phase 2 response rate for the Phase 3 target population was 17%. The Phase 3 trial was 90% powered to detect a ≥10% difference in response rate.
Vical appears to be hoping it can eke out a survival advantage to meet their secondary endpoint -- overall survival: the historical median OS for DTIC is ~9 months. The median OS for Allovectin-7 in Phase 2 was 18.8 months and the median OS for the Phase 3 target population was 22.5 months. The Phase 3 trial was 90% powered to detect a survival difference; hence, the focus now on the number of events, where the goal is to have is to have sufficient deaths or events to read out the secondary endpoint. This is complicated because Vical would have needed to modify the trial design because they presumably did not meet the primary endpoint and are, therefore, relying on the secondary endpoint. Then, there has to be a delta on the Kaplan-Meier survival curves that is statistically significant to therefore meet the modified secondary endpoint.
Which brings me back to the focus on the trial design for PV-10 and Provectus management's strategy. The pivotal MM Phase 3 trial paves the way for the drug to be approved for a focused label and just reinforces what is already known: PV-10's tremendous local-regional benefit. The company selected Progression Free Survival (PFS) as the trial's primary endpoint PFS, carefully and thoughtfully designed certain others aspects of the trial, and understands the failure of DTIC/TMZ in the comparator arm should occur within 2 to 3 months because the comparator cannot prevent the progression of the disease. By virtue of the pivotal trial designed to focus on loco-regional demonstration, management ensures (through past experience in trials and from the compassionate use program) the near certainty of how and when the trial would end.
There is a belief Allovectin-7's benefit is marginal when compared to DTIC. As a result, that is why a statistical advantage in terms of the number of events has not been reached. Adam Feuerstein summed it up this way: "The latest delay tells you the melanoma assumptions upon which Vical designed the phase III study are worthless. The study is a mess. If allovectin manages to demonstrate a survival benefit (miracles happen occasionally) it will be small and clinically meaningless."
Nevertheless, OncoVEX (T-Vec) and Allovectin-7 historically were important to beginning the conversation of local-regional treatments having systemic benefits. While their MM Phase 2 trial results were good enough locally, their systemic potential captivated the melanoma community. The local benefit is not key for either T-Vec or Allovectin-7, it is their systemic potential.
Provectus leaves to Moffitt and historical trial data to explore and demonstrate the systemic benefit.
A important preparatory observation for when the trial commences, and one I will return to at the appropriate time, is the the number of patients that ultimately are needed to be enrolled and treated before the trial is stopped. The number of patients is driven more from the hazard ratio and powering. Patients will have events, which is bad. Since PV-10 works so well, it has much less events as a result, and events in the Phase 3 trial's PV-10 arm should come much less quickly. More events should occur in the DTIC/TMZ arm, which will enroll and treat 1 patient for every two that are enrolled and treated in the PV-10 arm.
How many patients ultimately would be required to be enrolled and treated, out of the contemplated 180 patient study size, before the study could be be terminated on the basis of an interim read-out concluding the unquestioned superiority of PV-10? 20, 40, 90, etc.?