GALE-301 and GALE-302 are folate binding protein-derived vaccines, under development by Galena Biopharma ( GALE), which aim to prevent the recurrence of ovarian and endometrial cancer in women who have undergone standard of care therapy, including surgery and chemotherapy. The U.S. Food and Drug Administration (FDA) recently granted Galena two orphan-drug designations to further develop and ultimately deliver the vaccines to women in need. These compounds, along with the breast cancer vaccine NeuVax, constitute Galena's pipeline of cancer immunotherapy agents.
Galena is a biopharmaceutical company with all the attendant issues of an extended timeframe without commercial revenue and high development costs. The current balance sheet cash position for Galena is $34.7 M as of March 31, 2016 with a quarterly burn rate of $9 M to $11 M (Year-End 2015 Earnings Conference Call). With the settlement of overhanging shareholder derivative and securities class action lawsuits, a major remaining downside risk is the possible failure of its drug pipeline. In the balance, FDA approval of the first-in-class GALE-301 vaccine points to annual sales in the U.S. market alone of one billion dollars (extrapolated from Galena presentation January 4, 2016).
Slide from Galena-Presentation-8-Feb-16.pdf
In January and March of this year I published three articles, " NeuVax Vaccine: A Matter of Signal Integrity", Part 2 and an Addendum. The goal of that series was to develop a model of Galena's Phase 3 NeuVax PRESENT trial in order to provide perspective to the upcoming interim analysis now anticipated in June 2016. The goals of this evidence-based analysis are (1) to filter the noise surrounding GALE-301, and (2) to develop a model for GALE-301 in anticipation of the 24-month Phase 2 readout expected in early 2017.
Ovarian cancer arises from several different cell lines within the ovary; the most common types are known as epithelial ovarian cancers. Because ovarian cancer may not cause any specific symptoms, tumors are often diagnosed in advanced stages and result in lower overall survival rates. In fact, ovarian cancer causes more deaths than any other cancer of the female reproductive system, despite the fact that it accounts for only about 3% of cancers among women ( American Cancer Society).
Folate Binding Protein (FBP) is an immunogenic protein with limited expression in epithelial cells of normal tissues such as kidney, lung, and thyroid (Weitman et al., Cancer Res 52(12): 3396-3401); however, it is over-expressed 20- to 80-fold in greater than ninety percent of ovarian and endometrial cancers (Li et al., J Nucl Med 37(4):665-672), making it an ideal target for immunotherapeutic agents. GALE-301 (designated E39 in the literature) is an HLA-A2 restricted 9-mer peptide vaccine representing the immunodominant epitope of FBP. GALE-302 (designated E39', EIWTFSTKV) is a synthetic 9-mer peptide version of GALE-301 (FBP191-199, EIWTHSYKV) attenuated by virtue of two amino acid substitutions. Both vaccines, combined with the immunoadjuvant GM-CSF, generate CD8+ cytotoxic T-lymphocytes (CTLs) specific for FBP-expressing tumors. They are currently in a Phase I/IIa trial to prevent recurrence in women with endometrial and ovarian cancer ( NCT01580696).
Slide from Galena-Presentation-4-Jan-16.pdf
The schema for the GALE-301 Phase I/IIa trial reveals a study design similar to that of the successful Phase 2 NeuVax vaccine trials. After standard-of-care treatment of their ovarian or endometrial cancer to render themselves disease free, the HLA-A2+ women volunteers received six monthly vaccinations with GALE-301 plus GM-CSF followed by two booster injections of either GALE-301 or GALE-302 in six month intervals; HLA-A2- volunteers served as untreated controls. The underlying assumptions are similar to those proven correct in HER2 studies (per conference call with Dr. George Peoples March 24, 2016): (1) HLA-A2+ and HLA-A2- patients have similar observed recurrence rates, and (2) GM-CSF-only treated controls have similar recurrence rates to controls not treated with GM-CSF. The most recent results were reported at two 2016 presentations: the American Association for Cancer Research Annual Meeting, and American Society of Clinical Oncology Annual Meeting.
Figure from Comparing an attenuated booster (E39 ) vs E39 booster to potentiate the clinical benefit of the folate binding protein-derived vaccine (E39 + GM-CSF) in a phase I/IIa trial to prevent recurrence in endometrial and ovarian cancer
The results after a median follow-up of sixteen months for the Phase I/IIa E39 trial are summarized in two Kaplan-Meier charts. While the following calculations are tedious, they illuminate the effect of censoring. Starting with the left-hand figure which corresponds to the effect of at least one booster vaccination, the 22 women volunteers in the HLA-A2- control group suffered 12 recurrences of their cancer; the steep decline of the DFS curve vividly reveals the inexorable nature of the cancer. To calculate their final DFS rate, the following equation must be evaluated (note the two censored patients, represented by tick marks, in the 1st month and four censored patients in the 16th to 19th month):
The 9 women volunteers in the HLA-A2- E39 booster group suffered 2 recurrences of their cancer after receiving at least one booster vaccination (note the four censored patients in the 17th to 19th month):
This corresponds to an efficacy of 34.9%.
Finally, the 8 women volunteers in the HLA-A2- E'39 booster group also suffered 2 recurrences of their cancer after receiving at least one booster vaccination (note the four censored patients in the 16th to 22nd month):
This corresponds to an efficacy of 47.9%.
The right-hand figure, corresponding to the effect of two booster vaccinations, utilizes the same HLA-A2- control group of women volunteers. Although the two booster DFS curves are superimposed, they can be deduced by comparison with the previous one-booster figure. The 7 women volunteers in the HLA-A2- E39 booster group suffered only a single recurrence of their cancer after receiving two booster vaccinations (note the four censored patients in the 17th to 19th month):
This corresponds to an efficacy of 47.9% (p=0.023).
Similarly, the 7 women volunteers in the HLA-A2- E39' booster group suffered only a single recurrence of their cancer after receiving two booster vaccinations (note the four censored patients in the 16th to 22nd month):
This also corresponds to an efficacy of 47.9% (p=0.023).
Comparison of the one-booster to two-booster GALE-301 data suggests the booster vaccinations effectively reject the recurrence of ovarian cancer in these women and pass on a distinctly higher DFS signal.
To begin modeling GALE-301, the hazard function was derived from a large study of women with primary epithelial ovarian carcinoma (A Prognostic Model for Ovarian Cancer by Clark et al., Br J Cancer 85(7):944-952); the independent variable for the model is FIGO stages from I to IV. As can be seen, the historical recurrence curve (shown in red) closely follows the DFS curve from the Phase I/IIa GALE-301 trial (95% confidence intervals are shown for the 22-patient control group). The similar number and timing of recurrences for the two-booster E39 and E39' trial arms suggests that combining data from the two groups could provide a useful estimate of efficacy while reducing the uncertainty in the DFS curve - the results are shown in blue for the 14-patient combined two-booster vaccine group. This Monte Carlo simulation reaffirms the positive findings of the Phase 2 GALE-301 trial.
Revisiting the GALE-301 Phase I/IIa two-booster data now provides an opportunity to anticipate the 24-month readout of data expected in early 2017. There are eight remaining women volunteers in the combined two-booster vaccine group who have not reached 24 months of follow-up; their censored progress is represented by tick marks on the Kaplan-Meier chart. If the DFS rate for these eight patients were to remain the same as the six women who have already recurred or reached 24 months disease free, the model predicts the average fraction surviving disease free at 24 months for the group as a whole will be 80% (69% efficacy, 95% CI: 50% to 78%). Indeed, the GALE-301 vaccine appears to be a highly effective filter for producing disease-free survival in these women with ovarian cancer!
In closing, I hope I have filtered some of the noise surrounding GALE-301 so you too can clearly appreciate the signs of success coming from its Phase 2 trial. The stakes are high: Each and every day, nineteen American women experience the soon-to-be preventable nightmare of their ovarian cancer recurring, and less than half of them will survive this horrible fate. Galena's NeuVax and GALE-301 vaccines are game changers which promise to skew the odds for cancer and help these women live rich and full lives.
David M. Fujii, M.D.
Pediatric Cardiac Anesthesiologist and Electrical / Mechanical / Aeronautics & Astronautics Engineer
Disclosure: I am/we are long GALE.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.