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    • Mon Jan 21st 14:16 PM | Rating: 0 0
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      GenVec, Inc.: The Biggest Little Biotech
      Your theories on Genvec are hogwash.

      Currently, gemcitabine (Gemzar) and erlotinib (Tarceva) are the only FDA-approved treatments for pancreatic cancer. Gemzar was approved in 1996 on the basis of a pivotal study comparing treatment to 5Fu, which was standard of care at the time of approval of Tarceva. Median survival in the pivotal trial was 5.7 months and 1-year survival was 18% in the study arm (compared to 4.4 months and 2%). In 2005, Tarceva was approved on the basis of a 6.37 month median survival and 24% one-year survival. Prior to the approval of Tarceva no drug, including gemcitabine, had been demonstrated to positively affect survival. Between 1996 and 2005 ten phase II studies comparing new drugs to Gemzar and two phase III studies failed to show any significant survival advantage. In addition, eight phase III trials were conducted comparing new drugs+gemcitabine to gemcitabine alone and all failed to demonstrate a survival advantage. Pancreatic cancer continues to be among the most lethal and difficult to treat cancers.
      GenVec has previously conducted two phase I studies of TNFerade (a total of 50 patients) in various locally advanced solid tumors and soft tissue sarcoma of the extremities. More recently, the company conducted a dose-escalation study in 50 patients with unresectable locally advanced pancreatic cancer with four dose levels of TNFerade studied in combination with standard chemoradiation. This study was followed by a 74-patient randomized trial that was subsequently amended in March 2006 to become what GenVec expects to be a single pivotal phase II/III (the “PACT” trial). Target enrollment in the trial is 330 patients of which 75 are estimated to have enrolled to date. Patients with locally advanced unresectable pancreatic cancer will be treated with either TNFerade + standard of care or standard of care alone. Standard of care will include radiation therapy, 5Fu, and maintenance therapy with Gemzar or Tarceva. The primary endpoint of the “PACT” trial is 12-month survival with an expected 20% survival advantage over standard of care.
      On December 14, 2006 GenVec announced that a DSMB recommended continuation of the phase II trial after an interim safety analysis. Data was available for 40 patients, 25 of which had received TNFerade. Only 5 days later the company issued a press release highlighting “updated” efficacy results from the trial pursuant to an “initial interim efficacy analysis”. The imminence of this analysis was not mentioned in the press release five days earlier and the press release does not indicate the nature of the analysis as it relates to the protocol. However, a preplanned interim survival analysis on 15% of the targeted enrollment is unlikely and while the company’s press release refers to confidence intervals there is no reference to significance. Moreover, the data released in that press release is inconsistent with previously described plans. A year earlier the investigators indicated that an “interim analysis of the objective response rates at three months after therapy will be carried out on the first 51 patients.” In any event, the fresh data from the December 19, 2006 press release included an analysis of the first 51 patients enrolled in the trial. In this case, data was available for 33 patients treated with TNFerade.

      In any event, one-year survival was reported as 71% in the treatment arm versus 28% in the standard of care group. In comparison, Tarceva was approved based on a 24% response rate (Tarceva + Gemzar) vs. 19% with Gemzar alone. However, although the TNFerade figures have been compared to Tarceva and Gemzar data by some, they are entirely incomparable. The pivotal Tarceva trial enrolled all-comers, including patients with locally advanced unresectable and metastatic disease; pre-specified covariates in the statistical analysis plan included performance status, extent of disease and pain intensity reflective of the prognostic significance of these variables.

      In the Tarceva pivotal trial, 60% of patients had metastatic disease. Exploratory analyses demonstrated that median survival of patients with locally advanced disease was almost double that of patients with metastatic disease (8.2 months compared to 4.2 months). It should be no surprise, therefore, that GenVec’s data, all based on the treatment of patients without metastases, and are compelling on the surface. In fact, prior progression free survival data presented by GenVec excluded patients enrolled in the trial with metastatic disease at baseline as well as one or more patients who died for reasons deemed not relevant to the analysis by investigators and/or GenVec. More interestingly, this same prior data defined progression free survival based on injected tumor (not patient) response. Disease progression, in other words, was a function of response of the injected tumor and not the patient. One must also ask whether progression free survival at 6 months is a relevant endpoint.

      Similarly, median survival in the investigational arm of the study supporting approval of Gemzar in pancreatic cancer in 1996 showed median survival of 5.7 months and 1-year survival of 18%. A study reported in the Journal of Clinical Oncology in 2005 comparing gemcitabine+oxiliplati... vs. gemcitabine alone showed a 7.1 month, or a 24% difference compared to 5.7 months. However, 70% of patients in the gemcitabine arm had metastatic disease. These patients had median survival of 6.7 in the gemcitabine arm vs. 10.3 months in patients with locally advanced disease. The list goes on, however. A phase III study or irinotecan+gemcitabine vs. gemcitabine reported in the JCO in 2004 demonstrated an almost 7-fold higher response rate in patients with locally advanced disease compared to those with metastatic disease. While the survival difference between the two groups was not as large, median survival in the combination arm was almost twice as long when comparing local vs. metastatic patients (9.8 months vs. 5.4 months) and in the monotherapy arm (11.7 months vs. 5.9 months).
      In addition, preliminary data from the TNFerade trial indicates that mean Karnofsky Performance Status (KPS) in the 4 x 1011 dose cohort was 85% (the dose being studied in the ongoing pivotal trial), which is likewise not comparable to the demographic profile in the Tarceva trial. In the Tarceva pivotal trial, 17% of patients had ECOG performance status at baseline of 2, which is a significant negative prognostic factor. In June 2006, GenVec reported mean KPS of patients enrolled to date in the TNFerade arm of 89% (inclusion criteria allow for patients with KPS of >70%). Was the enrollment of patients with similar baseline performance scores to continue in a manner consistent with the initial patient population one might expect results similar, but again not comparable, to prior data. Of multiple exploratory analyses conducted on the Tarceva pivotal data, only performance status had a statistically relevant interaction with treatment effect. For example, patients with baseline ECOG PS of 0-1 had median survival of 6.6 months compared to 4.2 months in patients with baseline ECOG PS of 2; this translates into a 57% relative survival advantage.
      Based on these facts, the hazards of comparing the reported uncontrolled GenVec TNFerade data with historical data is manifest.

      In the 50-patient dose escalation study of TNFerade GenVec reported dose-dependent improvements in the ability to surgically resect previously unresectable disease. At the maximum tolerated dose GenVec reported successful resection in 45% of patients. These figures are superficially impressive relative to historical data. In a study conducted at the New England Deaconess Hospital, 16 patients who had locally advanced, unresectable pancreatic cancer were treated with EBRT and infusional 5-FU to enhance respectability. Two (13%) of the 16 patients were able to undergo resection. A study at Duke University reported that two (8%) of 25 patients with locally advanced pancreatic cancer treated with EBRT and 5-FU were able to undergo complete resection with negative margins. In addition, some studies gemcitabine in combination with radiation have demonstrated adequate down-staging to allow for complete resection. Nonetheless, both the GenVec data and data from other studies need to be interpreted with caution. Over time, the very definition of locally advanced pancreatic cancer has been relaxed making the ability to compare results difficult and the ability to see positive results in this regard when no difference is just as likely.
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