Much has been written Galena Biopharma (NASDAQ:GALE), and their strategic transformation into a late-stage oncology company from a preclinical RNAi company. One voice that has been heard over most others is TheStreet's Adam Feuerstein. Feuerstein has written a few critical articles about Galena, latest being the most perplexing, as he raises his own red flags concerning NeuVax, the company's lead cancer vaccine.
Galena's story begins in March 2011, when RXi Pharmaceuticals (RXII) acquired Apthera, Inc. The agreement called for Apthera's shareholders to initially receive approximately 4.8 million shares of RXi's common stock, which was worth $7.2 million at the time of the deal. In a parallel development, RXI President and CEO Noah D. Beerman was replaced by board member Mark Ahn in both roles. In September 2011, RXi restructured while renaming itself as Galena, and CEO Ahn announced that the company will focus on beginning a Phase III study for NeuVax, a cancer vaccine acquired as part of the deal with Apthera. Galena's management team also revealed their intent to spin out the RNAi part of the company, which was accomplished a couple of weeks ago. In this short time period, the company has been completely transformed, and the goal of starting a Phase III study for NeuVax was reached early this year.
NeuVaX is a synthetic breast cancer vaccine currently being studied in a large scale Phase III trial under a Special Protocol Assessment awarded by the FDA. I have written about NeuVax numerous times in the past, dating back to when Apthera was being formed to help fund future studies, while Ahn was the CEO of Hana Biosciences, when RXi was still a full part of CytRx Corporation, and NeuVax was only known as E75. My main focus was an attempt at an ongoing comparative analysis with a competitive peptide vaccine, the AE37 HER2/neu vaccine being developed by Antigen Express, which I still greatly feel is the most promising vaccine in the burgeoning field of active immunotherapy. However, I surely view the advances of NeuVax to be very promising, and most important as more is learned from the groundbreaking research of using the NeuVax HER2/neu peptide vaccine to prevent breast cancer recurrence in high-risk patients.
As numerous bloggers have noted, new data from NeuVax's prior Phase II studies will be presented at the 48th Annual Meeting of the American Society of Clinical Oncology in Chicago from 1 - 5 June 2012. The accepted NeuVax abstract is titled "Safety and Long-Term Maintenance of Anti-HER2 Immunity Following Booster Inoculations of the E75 Breast Cancer Vaccine", abstract #2529. Click on the abstract number to view the abstract, or go to ASCO.ORG to find a link to the abstract page, and input E75 in a keyword search. This abstract is part of an ASCO Poster Discussion, and most recently was the subject Feuerstein's latest article, titled "Galena Biopharma's Breast Cancer Vaccine Sprouts More Red Flags", published at TheStreet on May 23rd. In the article, Feuerstein opined,
Updated, 60-month follow-up results from a NeuVax Phase II study scheduled for presentation next month at the American Society of Clinical Oncology (OTC:ASCO) annual meeting don't appear to be new or consistent with previously reported data. Galena presented the same 60-month NeuVax analysis last December at the San Antonio Breast Cancer Symposium except the numbers are different.
In reality, the SABCS abstract released in December details overall 60 month findings for the Phase I/II studies of NeuVax, plus information on a subset of 53 patients who received at least one booster dose. (The NeuVax findings are a retrospective analysis of dose escalation studies). You can view the SABCS poster by clicking here. Simply sign in as a guest, and input E75 into the search box for a keyword search. Slightly different, the new ASCO abstract details 5 year safety and efficacy data specifically for this subset of 53 subjects from the booster group. In both abstracts, the recurrence rate for the booster group is the same at 3.8%.
In his May 23rd article, Feuerstein notes that Galena issued a news release related to December's SABCS poster, where they noted a statistically significant disease-free survival rate of 95.9% was seen in the booster group versus 79.7% in the control group. He explains that the disease free survival rate from December's analysis of the 53 NeuVax patients is not the same as the disease free survival rate outlined in the ASCO abstract, and wonders how can that be, while raising his first red flag. He continues to state,
It's easy to switch back and forth between recurrence rate and the disease free survival rate since the disease free survival rate equals 100 minus the recurrence rate. In Galena's ASCO abstract, therefore, the disease free survival rate for the 53 optimally dosed NeuVax patients is 96.2% versus a disease free survival rate of 81.1% for the control arm patients.
However, there is no disease free survival rate noted within the ASCO abstract.
So, one of the main red flags that Feuerstein raises is due to his own analysis that the investigators studying NeuVax are presented conflicting sets of data for the booster group at 60 months, with a disease free survival rate that is higher in the ASCO abstract, if you accept his statistical equation.
I'm no statistician, or oncology expert, but I believe that his analysis has a fatal flaw. Disease free survival in the NeuVax studies are measured by Kaplan-Meier curves using log rank tests, which I don't think is as simple as 100 minus the recurrence rate. Keep in mind that the recurrence rate data for the booster group is the exact same in the SABCS poster from December as the ASCO abstract for this week's Annual Meeting, or 3.8%, as explicitly stated in the text provided by the investigators.
If disease free survival measured by Kaplan-Meier curves was "100 minus the recurrence rate", than the disease free survival rate in the same group at 60 months as presented at SABCS in December wouldn't have been 95.9%, since 100 - 3.8 equals the same 96.2% which Feuerstein guestimates as being the disease free survival rate for the newer ASCO abstract. Instead, the investigators report the disease free survival measured by Kaplan-Meier curves to be 95.9% in the booster group, with a recurrence rate of 3.8%, which doesn't correspond with Feuerstein's math.
Feuerstein raises another of his red flags while assessing the patient demographics for the overall Phase II studies of NeuVax, as detailed in Table 1 of the SABCS poster from December. He notes that 49.1% of patients in the studies in the NeuVax group are node positive vs. 55.7% in the control arm, 34.3% of patients in the NeuVax group have a tumor size described as T2-T4 vs. 46.2% in the control group, 31% of subjects in the NeuVax group overexpress HER2 vs. 26.8% in the control group, and that 11.1% of patients in the NeuVax arm received prior Herceptin therapy vs. 3.8% in the control group.
In considering the demographics, Feuerstein argues that these differences in demographics for the NeuVax group vs. the control group create an imbalance in the baseline patient characteristics, which easily skewed the DFS/recurrence rate in favor of NeuVax. He argues,
That's a big difference and could easily explain away the DFS/recurrence seems to favor NeuVax in the Phase II study. Control-arm patients are sicker, have more aggressive breast cancer and were treated less often with Herceptin, therefore, their breast cancer is recurring at a faster rate. Galena is conducting a larger Phase III study which if done correctly will not have these types of serious imbalances between NeuVax-treated patients and control patients. When the results eventually read out, NeuVax's benefit seen in the Phase II will likely disappear, as will the vaccine's chance of being approved.
Feuerstein may raise valid points to consider in his analysis, so I'm not discounting his entire body of work. Also, while I'm certainly not qualified to understand all of the factors pertaining to higher risk of recurrence of cancer, I feel he appears to cherry pick at available information to support his rigid conclusion that a Phase III study which just started is "doomed to fail".
In support of my theory, consider another item as noted in the SABCS poster detailing the demographics within the overall studies stating that 31.1% of patients treated with NeuVax are ER/PR negative vs. 17.7% of patients in the control group. ER/PR negative is associated with a much higher risk for recurrence, which Feuerstein overlooks in his analysis of patient demographics. This statistical difference in the demographics appears to be larger than any he sites.
In prior articles about NeuVax, Feuerstein argued that the data being presented was cherry picked down in order to find a subset of patients that appear to respond well to NeuVax in order to help validate further testing, which serve in allowing the management team to collect large salaries. Yet, there is more important reasons researchers look at subsets of data, and independent researchers are not concerned with such matters.
The Phase III target patient population has been identified as HLA A2/A3, node positive, HER2 1+ and 2+ patients, receiving the optimal dose and booster regimen, which describes a subset of patients within USMCI Clinical Trials Group Study I-01. That group consists of 18 patients in the NeuVax group vs. 27 patients serving as a control. These subjects are not eligible for Herceptin, so Feuerstein can't attribute a lower recurrence rate for this NeuVax group in Study I-01 to prior Herceptin therapy, or in any new data that eventually emerges from the PRESENT Phase III. The subset of patients in Study I-01 is indeed small, and obviously the larger Phase III is needed to confirm the findings, as they are doing.
One other item of interest relating to the SABCS poster from December, and the ASCO poster that will be presented this week at the ASCO Annual Meeting- the SABCS data and ASCO data are not exactly the same for the booster group. The results sections for both abstracts reveal that certain patients in December's abstract were an inoculation or two ahead of schedule as compared to the newer ASCO abstract, specifically subjects who received their third of fourth booster shot, although in both abstracts 53 subjects received at least one. I'm not sure, but that could also potentially have an effect within a Kaplan-Meier curve analysis, but I'll leave that and all findings to the experts.
One thing is for certain, the true oncology experts don't write blogs on Seeking Alpha, or snarly articles for TheStreet. Please keep in mind that I am not an expert, and far less so than Feuerstein. I am a layman from far outside the world of oncology expressing an opinion. My own interest in NeuVax only stems from my overall interest in the Cancer Vaccine Development Program headed by Col. George Peoples. I have no financial interest in GALE, nor I have never owned their stock, and I don't foresee myself taking a position. I'd love to see the CVDP succeed in bringing from bench to bedside all of the HER2/neu based peptide vaccines they currently help in studying, so breast cancer patients have more treatment options to enable long and healthy lives.
These cancer patients live with enough real raised red flags, and don't need to become needlessly frightened from false ones, especially if those patients are one of the heroes taking part in CVDP clinical studies, such as the NeuVax PRESENT Phase III.