|Week Ending September 27 2013|
|By Rajesh Patel, Ph.D.|
|Monday, 30 September 2013 07:43|
This Monday, IMUC and AGEN participated in a joint investor conference call covering Glioblastoma Multi Forme (GBM) immunotherapies. This conference call, organized by Proactive capital was directed primarily at retail investors (Pro Active Capital is handling retail investor relations for IMUC). The call did not reveal anything new. IMUC reiterated that they would not be announcing the 64th event in their ongoing phase 2 trial of ICT-107. Last week we indicated that we recently doubled our IMUC position and that we would provide details about why we did so as well as more details on GBM immunotherapies in general.
GBM Immunotherapies Still Unproven
There have been many company presentations and analyst reports touting the unusually long median overall survival (OS) seen in open-label single-center phase 1 trials from IMUC and Northwest Biotherapeutics (NASDAQ:NWBO) as well as the recent phase 2 trial update for AGEN. While these early studies are encouraging, it is important to understand that immunotherapy for GBM is far from proven. Let's try to understand why.
Cross trial comparisons are always problematic. Trial enrollment criteria are different, trial protocols are different, and statistical analysis methods can sometimes differ as well. All of these factors mean that comparing a median statistic such as overall survival from one trial to another is just not accurate. Some have argued that because several different companies using several different approaches all have show remarkable OS numbers, that there MUST be something to the GBM immunotherapy approach. While this is a facile argument to make, proper analysis would then require an investigation into other possible explanations for the long OS in these trials.
IMUC, AGEN and NWBO all compare their phase 1 & 2 results to the Stupp trial of Temozolomide in GBM. The 2005 New England Journal of Medicine paper by Stupp et. al. was the gold standard for GBM treatment. This clinical trial tested radiotherapy alone vs radiotherapy plus Temozolomide in 573 newly diagnosed GBM patients. The Temozolomide arm demonstrated a median OS of 14.6 months while the radiotherapy only arm had OS of 12.1 months.
Based on the Stupp trial, all 3 of these companies claim that their respective therapies show much stronger overall survival than the current standard of care. However; there are important differences between the trial described by Stupp et. al. and the trial run by IMUC, NWBO, and AGEN. First, the Stupp trial enrolled sicker patients. Fully 15% of the patients in that trial had inoperable tumors. This means that ~86 of the 573 patients did not undergo tumor debulking surgery at all. Degree of tumor resection has been shown to have a dramatic impact on survival. Comparing the full Stupp trial's OS numbers to the IMUC, NWBO and AGEN trials where all of the patients underwent debulking and only those patients whose tumors were at least 90% resected were enrolled, is clearly improper.
The overall survival from IMUC's phase 1 trial was 38.4 months meaning that over half the patients lived more than 3 years. Some 3% to 5% of GBM patients are inherently long term survivors who live longer than 3 years. Factors that predict long term survival include age, Karnofsky performance status and MGMT (a gene related to DNA repair) methylation status. When MGMT is methylated, tumors are less able to repair themselves after chemotherapy induced cell damage, thus for these patients chemo is more effective leading to improved survival.
Our view is that the GBM immunotherapy space, especially the approaches of autologous dendritic vaccines, is unproven at the present time. Nevertheless, valuations for these companies may be low if their drug candidates show improved overall survival in double-blind placebo controlled trials. With top-line data reading out in late Q4 2013 or early Q1 2014, we believe Immunocellular represents an interesting trade. Should their phase 2 trial demonstrate a significant overall survival benefit (the trial has 80% power to detect a 9 month OS advantage over an assumed placebo median OS of 18.8 months), then IMUC's stock is significantly undervalued. The caveats above must be kept in mind. Investors should not be fooled by single-center open label phase 1 trials that show very large OS "benefits" vs inappropriate historical controls.