The cancer immunotherapy field is finally coming of age, with a number of companies pushing promising drug candidates into Phase II/III clinical trials. Although this space has historically been littered with failures, second generation immunotherapies generally have a better handle on how to evade a tumor's ability to suppress the immune system, making these potential drugs worth a look by speculative investors. Of the plethora of therapies under development, vaccines indicated for the treatment of cervical cancer might be the most promising for patients and investors alike. In this article, I compare two vaccines being developed by Inovio Pharmaceuticals, Inc. (INO) and Advaxis (ADXS) indicated for the treatment of cervical cancer, and give my opinion as to which will be the winner in this space.
Cervical Cancer Market Opportunity
Cervical cancer is the second largest killer of women worldwide, with over 250K deaths per year. In 2012, U.S. women spent over $6 B on cervical cancer diagnosis and treatments, and the preventative vaccines Gardasil and Cervarix grossed over $2.3 B in sales in 2011. Furthermore, analysts are projecting that preventative vaccines sales revenues could reach a whopping $5.2B by 2017. Nonetheless, preventative vaccines have no effect on women already infected with HPV, making cervical cancer a largely unmet medical need. The market opportunity for an effective vaccine indicated for the treatment of patients already infected with HPV is therefore believed to be somewhere in the neighborhood of $3-5B annually. As such, cancer immunotherapies are pushing to meet this unmet medical need.
Advaxis: ADXS11-001 (ADXS-HPV)
Drug mechanism: ADXS-HPV is an immunotherapy that is designed to target cells expressing the HPV gene E7. Expression of the E7 gene from high-risk HPV variants is responsible for the transformation of infected cells into dysplastic and malignant tissues. Eliminating these cells can eliminate the dysplasia or malignancy. ADXS-HPV is designed to infect antigen-presenting cells and direct them to generate a powerful, cellular immune response to HPV E7. The resulting cytotoxic Tcells infiltrate and attack the tumors while specifically inhibiting tumor Tregs and MDSCs in the tumors that are protecting it.
Three ongoing Phase II studies (2 in the U.S. and 1 in India):
Clinical trial info
1. Title: A Phase II Evaluation of ADXS11-001 (NSC 752718, BB-IND#13,712) in the Treatment of Persistent or Recurrent Squamous or Non-Squamous Cell Carcinoma of the Cervix
Total enrollment: 67
Start date: September 2011
Estimated completion date: October 2013
Primary outcomes: dosing toxicity levels (safety issue), frequency and severity of adverse events, and overall survival at 12 months.
Secondary outcomes: survival distribution, disease free survival, and proportion of patients with a complete or partial tumor response
2. Title: A Randomized, Single Blind, Placebo Controlled Phase 2 Study to Assess the Safety of ADXS11-001 for the Treatment of Cervical Intraepithelial Neoplasia Grade 2/3
Total enrollment: 120
Start date: April 2010
Estimated completion date: June 2013
Primary outcomes: Histological assessment of whether the tumor has regressed or not
Secondary outcomes: Estimating levels of HPV DNA in treated vs. untreated patients
3. Title: A Randomized, Active Therapy Controlled Phase 2 Study to Assess the Safety and Efficacy of ADXS11-001 with and without Cisplatin as 2nd Line Therapy for the Treatment of Recurrent Cervical Cancer (India trial)
Total enrollment: 110
Start date: November 2010
Estimated completion date: 3rd Quarter 2013
Endpoints: Safety and overall survival up to 18 months
Key preliminary results for ADXS-HPV
With 80% of the India study now complete, long term survival for patients treated with ADXS-HPV have shown improved survival at 12 months (33%) compared to historical controls (0-22%). Moreover, 17% of patients were still alive at the 18 month benchmark, as of October 2012. However, CEO Thomas Moore stated at a recent investor conference that the 12 month survival has actually improved as the study has progressed, although the 18 month survival is slightly down from the October 2012 data release. The company will update the survival data in June 2013 at the ASCO meeting.
In terms of tumor burden, twelve patients treated with ADXS-HPV thus far have shown a significant reduction in tumor burden, with six being complete responses (i.e., total elimination of the tumor). For patients treated with ADXS-HPV alone, the rate of serious adverse events (SAEs) is below 3%, which is considerably lower than that seen for approved chemotherapies. The India trial also showed that no synergy existed between ADXS-HPV and Cisplatin (chemotherapy) for cervical cancer patients. Finally, Advaxis is expected to release mid-dosing results from its U.S. Phase 2 clinical trial by the end of February.
Drug mechanism(s): VGX-3100 is designed to stimulate a T-cell immune response strong enough to cause the rejection of cells infected infected with the HPV virus. Potential indications for VGX-3100 include the treatment of precancerous dysplasias (CINs), cervical cancers, and head and neck/anogenital cancers.
Clinical trial info
Title: Phase II Placebo Controlled Study of VGX-3100, (HPV16 E6/E7, HPV18 E6/E7 DNA Vaccine) Delivered IM Followed by Electroporation With Cellectra-5P for the Treatment of Biopsy-proven CIN 2/3 or CIN 3 With Documented HPV 16 or 18.
Total enrollment: 148
Start date: April 2011
Estimated completion date: March 2014
Primary outcomes: Reduction in cervical lesions to CIN1
Secondary outcomes: Reduction in HPV load
Key preliminary results for VGX-3100
In a completed Phase I trial of VGX-3100, Inovio reported that 100% of study participants (18/18) exhibited a positive immune response to at least two vaccine antigens, and 94% (17 of 18) reported positivity to three antigens; 56% (10 of 18) were positive to all four antigens. An ELISpot analysis ofT-cell immune data showed that 78% (14 of 18) subjects showed T-cell responses to at least one vaccine antigen, 72% (13 of 18) responded to at least two antigens, and 50% (9 of 18) responded to all four antigens. Moreover, analysis of T-cell immune data 24 weeks after the last immunization showed that the responses were still detectable in 86% of evaluable patients, indicating that T-cell responses, in addition to antibody responses, persist for at least 6 months after the final immunization at month 3.At a recent retail investor conference, Dr. Kim gave a brief update on the ongoing Phase II trial for VGX-3100, saying that preliminary efficacy data from trial would be available in the 4th Quarter of 2013. No further updates were available at this time, showing that the trial is still in its early stages.
I am not a big fan of Inovio as evinced by my last article, and believe the company continually misleads investors about the promise of its DNA vaccine platform. The recent statements by Dr. Kim during his presentation to retail investors provided further evidence that the company isn't telling the whole story about the prospects of its clinical candidates. Specifically, Mr. Kim failed to even note that ADXS-HPV is close to finishing its Phase II trials, and even left them off of the list of possible competitors in the space. I find this astonishing given that ADXS-HPV actually won the best therapeutic vaccine at the Annual Vaccine Industry Excellence Awards in 2011, making it highly unlikely that Dr. Kim is simply unaware of ADXS-HPV.
Moreover, Dr. Kim stated that VGX-3100 has been "proven" to be safe and the most powerful vaccine in this space, despite the fact that VGX-3100 just started its Phase II trial. So his proffer of "proof" is based on 18 patients in a Phase I trial, which is disconcerting to say the least. By contrast, ADXS-HPV has shown astonishing therapeutic results in its three Phase II trials thus far, with several patients having tumors completely disappear, despite the fact that these patients were literally knocking on death's door when they entered the clinical trial. Surprisingly, Dr. Kim even went as far to say that listeria vaccines exhibit "low immune responses in human clinical trials". I think the Phase II data presented above on ADXS-HPV, coupled to the industry's positive view of ADXS-HPV, refutes that statement quite dramatically, and leaves me wondering why Inovio's executive team continually makes such statements.
Based on the state of the current Phase II trials, ADXS-HPV looks to be well on track to enter a Phase III trial in 2014, whereas VGX-3100 will still be in the Phase II stage. And if history is any guide, VGX-3100 will fail to meet its primary and secondary endpoints in Phase II, making a Phase III unnecessary. This direct comparison strong suggests that ADXS-HPV will be the winner in the cervical cancer vaccine space, despite the optimistic statements by Inovio's executive team. As such, ADXS looks to be an excellent speculative buy this year, although the company's dire financial picture remains a major risk with this stock. Even so, investors new to ADXS should take note that the company plans on licensing out ADXS-HPV to a big pharma, and these negotiations are underway according to CEO Thomas Moore's recent public statements.
In truth, the company cannot financially take ADXS-HPV into Phase III trials alone, so a licensing deal is the only realistic option for Advaxis. With that said, I have a strong suspicion that ADXS.OB will simply be sold to Bristol-Myers Squibb (BMY) upon the successful completion of the current Phase II trials for ADXS-HPV. Backing up this claim, a number of interesting business relationships exist between the two companies, and BMY has a strong interest in pursuing cancer immunotherapies in general. I have additional reasons for this belief, but they are beyond the scope of this article. Overall, it's not a stretch to think the BMY wouldn't gobble up a promising developmental immunotherapy for a few hundred million, which would be a windfall for current ADXS shareholders given its current market cap of $56 M. In conclusion, I believe INO is promising more than the history of DNA vaccines warrants, and ADXS's management has been auspiciously quiet in terms of boasting about the clinical trial successes (with the exception of a handful of investor conferences). As a result, my horse in the cervical cancer vaccine race is Advaxis.