tyrhenian's  Instablog

Allovectin-7 (A-7) is made up of small segments of DNA that can enter human cells right through the tiny holes in the cell membrane that nutrients use to enter. A-7 is injected directly into tumors. Once inside a cancer cell A-7's genes produce signals (antigens) to the immune system that this cell is foreign and should be attacked. The immune system is designed to make associations between an antigen that it knows is bad (foreign) and others that are associated with it which were previously ignored. Given enough time, it will (hopefully) learn that the cancer's antigens are associated with A-7's antigens and attack untreated cancer cells anywhere in the body.

Vical started a large phase 2 trial in 2001 for metastatic melanoma (one of the toughest cancers there is) and got the results in 2004. The results were very good compared with what chemo typically produces. The responses were long lasting compared to chemo and the side effects were much less debilitating. Despite only being a phase 2 trial they asked the FDA for marketing approval because the results were so encouraging. The FDA (notoriously conservative) was impressed with the results but denied approval on the grounds that the trial wasn't large enough and Vical was instructed to run a larger phase 3 trial.

Vical didn't just run a larger version of the phase 2 trial but instead designed a phase 3 trial using what it had learned from that trial. The phase 2 trial was run under the normal rules for chemo, which typically works very fast but the patient usually relapses quickly as the tumors develop resistance. An immuno-therapy like A-7 can take months to start working but once it does it keeps working for a very long time.

Most of A-7 subjects were dropped from the phase 2 trial at the first sign of disease progression (which is the typical criteria in a chemo trial) before A-7 had a chance to start working. Almost all of the phase 2 systemic  'responders' needed at least 3 months of treatment before they responded but almost 2/3's had already been dropped from the trial by 1-2 months. In the phase 3 trial all subjects will keep receiving treatments for 4-6 months even if there is early progression. In theory (best case scenario) the phase 3 results could be almost 3 times better than the phase 2 because of this FDA approved change in treatment duration.

The phase 2 trial also had 42% of its subjects having already failed chemo before enrolling in the trial. Chemo is known to compromise the immune system (infections are a common side effect of chemo) and A-7 depends on a strong immune system to work properly. The phase 3 trial has enrolled only subjects who have never had chemo so their immune systems should be strong.

Finally, most cancer trials count a subject as having responded if their tumors shrink by half (even if only for a brief time). In metastatic melanoma by 6 months half of early chemo responders have typically relapsed. In A-7's phase 2 trial all responses were still working at 6 months. Vical has gotten the FDA to agree to only count the responses that last at least 6 months in the phase 3 trial. This means they have a very low bar to hurdle to be successful.

Although A-7 only needed to match its phase 2 results in a larger phase 3 trial, with these immuno-friendly changes in trial protocol (agreed to by the FDA) it's hard to imagine the results won't be significantly improved.

Vical started recruiting subjects in 2007 and completed enrollment of its phase 3 trial in February 2010. It was supposed to enroll 375 subjects but there was a surge of applications by oncologists to get their patients into the trial before it completed enrollment and they ended up with 390 subjects. Although the FDA has mandated that all results are blinded to Vical until the database is locked, the treating oncologists know what kind of results they've been getting....so the last minute surge of enrollees is probably an excellent sign.

Vical has stated their intention to lock the database in the next 4 or 5 months. It's been left open this long in order to accumulate overall survival data which is a secondary trial endpoint. Dendreon's Provenge immuno-therapy extended prostate cancer survival by only 4 months (despite demonstrating almost no clinical response)  and yet still won FDA approval and the stock quickly rose from $2.50 to $30.00 a share (the market was anticipating FDA rejection). Vical believes A-7 will extend melanoma survival by a minimum of 7 months (or maybe much longer) simply based on the phase 2 results (even with the old unfriendly immuno rules).

Once the database is locked results should be released within a few months and stocks that have a good chance of success in a phase 3 trial typically keep rising the closer they get to results. Right now there is a lot of ignorance in the investment community about A-7's chances for success...but word is beginning to spread.

Once a treatment wins FDA approval any doctor can use it for any purpose...this is known as off-label use. Some cancer treatments generate as much as 2/3's of their revenues from off-label treatments. Medicare and most insurance companies foot the bill for off-label treatments as long as there is evidence of efficacy. Some states have even mandated that insurance companies cover off-label treatments. Unlike Dendreon's Provenge which is specific for prostate cancer A-7 can be used in any solid tumor. If A-7 wins approval for a tough cancer like melanoma there is likely to be a big off-label demand since it has none of the harsh side effects (nausea, fatigue, infection, hair loss) of traditional chemo treatments.

Here is a Vical link that explains A-7's mechanism of action,  phase 2 results, and improvements in the phase 3 protocol-

     

http://www.vical.com/Theme/Vical/files/doc_presentations/101109_Allovectin_Rolland.pdf