The pink ribbon was officially adopted as the symbol for breast cancer awareness in 1992 and has had a storied history of use (and misuse) to raise awareness and funds to combat the disease physically and psychologically devastating hundreds of thousands of women. Although the disease does affect men at a rate of 1:1000, the overwhelming majority of patients are women to the tune of about 288,000 new cases in 2011 with a current rate of diagnosis of about 1:8 women developing the disease over their lifetime. These are stunning numbers topped in incidences of diagnoses in women only by skin cancers and in fatalities only by lung cancer. According to the American Cancer Society, 2012 will witness approximately 290,000 new cases of breast cancer in the U.S. with about 40,000 associated deaths.
The current standard of care treatment regimen for treating breast cancer varies depending on how localized or metastasized the disease is. Advances have been made in surgery with options consisting of a partial mastectomy, a total mastectomy or a modified radical mastectomy depending on the disease's progression. Radiotherapy can consist of either external radiation or internal radiation with the latter given via a substance by needles, catheters, wires or seeds placed in or near the tumor. Hormone therapy and chemotherapy is also advancing with varying degrees of success with tradeoffs in each of efficacy versus safety profile. The long list of FDA-approved drugs for breast cancer can be construed as a partial failure as the mechanisms by which these work are varied and none as of yet seen as a "magic bullet" with each having varying degrees of safety concerns at the necessary dosage levels. These chemotherapy drugs even when initially effective often do little in terms of total eradication as the cancer often returns and at times with more aggression and more resistance to the drug that destroyed the predecessor cells.
Advances in the immunotherapy approach for cancers are rapidly giving patients and physicians more hope against the disease with the first regulatory approval in the U.S. via Dendreon's (DNDN) Provenge with its 2010 approval for treating prostate cancer. There are now hosts of clinical trials using an immunotherapy approach either as an adjuvant (usually follow up to a standard of care) or as a first-line treatment for attacking cancer, and breast cancer treatment is on the forefront of the technology. Following are three emerging biotechs at different levels of development in the immunotherapy approach to fighting this disease. Each of these companies is using a novel mechanism by which to teach the immunity system to identify and attack the cancer cells and to prevent recurrence. There probably will not be a single mechanism for all cancers, but a magic bullet for one with true eradication of cancer cells and prevention of recurrence will be a huge boost for the sector and will have a cascading effect with additional successes and hope coming down the line.
AE37's HER2 +1 +2 Targeting Approach with Modified Antigens
Generex Biotechnology Corporation (OTCQB:GNBT) reported a regulatory update on its Phase IIb AE37 breast cancer vaccine study on January 3rd. According to the president of its Antigen Express subsidiary, the interim Phase II data was impressive enough with a 46% reduction in low HER2 expressing tumors with a good safety profile to justify requesting an end of Phase II meeting with the FDA thereby giving them an opportunity to move onto the Phase III program. AE37 is an "off-the-shelf" or allogeneic drug meaning that it does not have to be made specifically tailored to each patient and as a result is much less expensive than Provenge's $93K price tag for its patient-specific approach. AE37 is manufactured from a peptide fragment of the human epidermal growth factor receptor 2 (HER2) protein that is expressed in about 75% of breast cancers, although the initial indication will be for about 50% of breast cancer patients, those with low-to-intermediate levels of HER2 expression. The HER2 expression is critical as it is the means by which the body's CD4+ T helper cells target and generate an immune response. What differentiates AE37 from other vaccines also using the HER2 targeting approach is Antigen Express' Ii-Key Hybrid technology platform the company says modifies the fragments of the antigens to increase their potency in stimulating the CD4+ T helper cells.
As of the publishing date for this article, Generex hasn't spoken with the FDA about ending the Phase II trial and doesn't know if it will receive the coveted "Special Protocol Assessment" (SPA) designation for its Phase III trial when/if it is allowed. This designation would define the trial's endpoints that if met would be sufficient for regulatory approval for the drug. These guidelines are critical and will help lead the company through the expensive and time-consuming Phase III regulatory path toward approval. FDA permission to terminate the Phase II trial, (to be requested before the end of Q1 2012), begin Phase III trial and the possible achieve SPA designation are three key catalysts for the company as it moves forward in 2012 and will directly impact shareholder value in the company.
CDX-1401's NY-ESO-1 Targeting Approach with Immune Stimulant Assistance
Celldex Therapeutics (CLDX) has a robust immunotherapy platform including a portfolio of monoclonal antibodies, antibody-targeted vaccines, antibody-drug conjugates and immunomodulators to create disease-specific drug candidates. Their CDX-1401 breast cancer candidate is an off-the-shelf fully human monoclonal antibody targeting the tumor-associated antigen, NY-ESO-1 to DEC-205 receptor with the human mAb 3G9. It is in a Phase I/II dose escalation trial for the treatment of cancers expressing NY-ESO-1. A more detailed description of the mechanism may be found here. Since cancer cells primarily manufacture the NY-ESO-1 protein, it is a potential target against which to stimulate an immune response that may destroy cancer cells. To enhance the immune response, CDX-1401 is administered with 1 or 2 immune stimulants, Resiquimod and/or poly-ICLC (Hiltonol). According to the clinicaltrials.gov website, the estimated completion date for the trial is February 2012, so an update from the company is expected soon. Positive data with a good safety profile at increased doses would be a good catalyst for the company and would indicate the drug's potential as increased dosages often represent increased efficacy and the ability for patients to keep receiving booster doses to prevent recurrence over their lifetimes. Although a small patient set, efficacy there in tumor shrinkage or progression free survival statistical improvement will likely bring the company and the drug much attention. The company is already having success with CDX-011 (GPNMB-targeting antibody, CR011, that is linked to a potent cytotoxic, monomethyl auristatin E) for advanced breast cancer using ADC technology licensed from Seattle Genetics (SGEN). However, CDX-1401 could potentially have a better safety profile than CDX-011 due to the nature of the latter's cytotoxic mechanism. Also, CDX-011 also doesn't fit perfectly into the immunotherapy theme as it does not create an immune response via targeting dendritic cells but rather releases MMAE upon internalization into GPNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Simply put, it is an antibody-drug conjugate, a hybrid chemotherapy/antibody approach. For this reason alone it is not listed as one of the three promising breast cancer immunotherapy drugs, but should certainly be watched as its Phase I/II progresses. Meanwhile, success in CDX-1401 using the novel NY-ESO-1 approach would really capture investor and Big Pharma attention with several possible indications in addition to breast cancer coming out of the drug with this novel approach.
Neuvax E75's HER2 Targeting Approach with Immune Adjuvant Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)
Galena Biopharma's (GALE) Neuvax E75 immunogenic peptide of HER2 stimulates cytotoxic T lymphocytes (CD8+ T cells) to attack and kill HER2 1+ and 2+ (low to intermediate) expressing breast cancer cells. 5-year data on a prospective Phase II trial presented in December indicated an excellent safety profile with both node positive and node negative groups showing improvement versus the control groups. For the combined patient set in the patients receiving NeuVax, a good correlation was observed with the vaccine treated patients demonstrating a disease-free survival rate of 89.4% versus 79.7% in the control group (p = 0.098), impressive but needing more statistical significance to be considered a strong data set. Waning efficacy was observed in the patient set months after the drug treatment protocol had completed. A 53 patient subset received at least one booster inoculation (once every six months) with a dramatic increase in efficacy as evident in a statistically significant disease-free survival rate of 95.9% versus 79.7% in the control group (p = 0.016). With radiotherapy, hormone therapy and chemotherapy, this additional dosing could have detracted from the safety profile with the additional dosages meaning additional toxicities. The safety profile of Neuvax is such that the additional doses don't appear to compromise the drug's safety profile.
The Phase II data set of the 53 patient subset receiving the booster doses was significant enough to justify a Phase III trial with the study receiving the FDA's coveted Special Protocol Assessment designation. On January 20th, the initiation of the Phase III trial was announced with a targeted 100 investigator sites in the U.S. and beyond. The patients in the trial will receive a booster dose every six months after the initial treatment period to hopefully match the 53-patient subset in the Phase II with the statistically significant efficacy values. The trial will enroll approximately 700 patients giving only 7 patients needed per site average, greatly expediting the process if all 100 sites are chosen and enroll fairly rapidly. The targeted patient set will be breast cancer patients with tumors that are HER2 +1 or +2. These patients are not eligible to receive Roche-Genentech's (OTCQX:RHHBY) Herceptin (trastuzumab) therapy that is currently approved for patients with HER2 3+ expression representing only 25% of breast cancer patients. Of note pertaining to marketability, about 75% of breast cancer patients are HER2 +1 +2 or +3. Herceptin's $5 billion in revenue it achieved in 2010 was on the HER2 +3 patient set only. The remaining HER2 +1 or +2 patient set represents the sales potential for Neuvax. The upside for this $45 million market capitalization stock could be substantial with success here.
What Happens Next?
The marketing potential for each of these drugs is substantial with a huge need in the treatment protocol. Currently Neuvax has the upper hand in time as it's already initiated its SPA-designated Phase III trial with an aggressive 100 clinical sites needing only 7 patients per site. Generex will request permission to terminate its Phase II trial on AE37 sometime before the end of March. Once the FDA renders its decision, investors will be watching closely to see if the company receives the SPA designation for the trial. The Neuvax Phase II trial data is a more mature data set as it represents a 5-year trial while AE37 data is based on a median of 22 months with many patients not yet reaching the 2-year mark as of the poster. This may not be significant if the AE37 trial is allowed to terminate and permission is given for the Phase III trial. However, a decision to carry out the trial another year or more will make all the difference as this would put them another year behind Neuvax with additional costs associated with the trial. Celldex's CDX-1401 will likely complete its Phase II before AE37 as a recent press release indicated completion in February 2012. This makes it the company with the next likely significant catalyst, as its data presentation will likely soon follow. Like AE37, the data will determine if a Phase III trial would be allowed with the SPA designation decision coming soon thereafter. Eyes will be on Celldex in the upcoming days as solid interim data would be a boost for the approach in breast and other cancers if an acceptable safety profile and efficacy is observed.
Each of these three candidates is an off-the-shelf drug that is not tailor made for each patient and is desirable for Big Pharma and physician acceptance as this benefits the cost structure and the speed of administration of the drugs. Each of these companies will be gaining increased investor and Big Pharma attention over the coming days and weeks in 2012 due to the upcoming decisions and data being presented. Increased scrutiny of and attention to each will also be heightened due to a February 8th announcement by Roche Holdings that that the FDA has accepted the company's Biologics License Application for pertuzumab and granted Priority Review. The targeted indication is pertuzumab in combination with Herceptin and docetaxel chemotherapy for people with HER2-positive metastatic or locally recurrent, unresectable breast cancer, who have not received previous treatment or whose disease has recurred after adjuvant therapy. The PDUFA date for the drug is June 8th of this year and will likely garner much attention for the immunotherapy approach for breast cancer in the coming weeks up to the decision. Much like Dendreon's Provenge approval gave a boost to the sector in 2009 and 2010, a Roche approval for breast cancer using a an immunotherapy approach could likely do the same for these three companies further accentuating any positive data/decisions coming out of them in the upcoming months.
On the other side of the coin, the FDA revoked its approval for Genentech's Avastin in November of 2011 for metastatic breast cancer due to the drug not helping patients live longer or having a meaningful effect on the tumors along with some safety concerns (poor efficacy/risk ratio in other words). The revocation was an example that although the immunotherapy approach will likely work in fighting breast cancer, the proper mechanism(s) must still be found. Neuvax, AE37 and/or CDX-1401 may very well have the right approaches in mind. Whether it is one of these three immunotherapy drugs or another, the approach is hopeful and could some day change the symbolism of the pink ribbon from "breast cancer awareness" to "breast cancer, battle won". Millions of affected women, their families and physicians are awaiting that day.