By Vanessa Burns, B.S., Ofir Goldberger, Ph.D., and Nick Mordwinkin, PharmD., Ph.D.
OXiGENE (OXGN) is an oncology pharmaceutical company that is developing small molecules to disrupt existing tumor vasculature. Its leading product is ZYBRESTAT, a Combretastatin A-4 phosphate prodrug that targets existing tumor vasculature. To date, such Vascular Disrupting Agents (VDAs) have struggled to show clinical efficacy. OXiGENE is strategically focused on orphan diseases to mitigate regulatory burden; however, it has so far been unable to use invested capital ($225 million) to generate returns for investors. Symphony Capital LLC, a strategic partner, supported OXiGENE's efforts since 2009 and invested $30 million to allow a clinical trial to proceed. In addition, on April 11, 2013, OXiGENE reported an extra $5 million in private placement, and the company predicts it will run out of cash by Q1 2014.
Although OXiGENE's oncology pipeline has been disappointing, ZYBRESTAT Topical, a reformulation aimed at ophthalmological disorders has the potential to address a market of $390 billion in age related macular degeneration (AMD) and Polypoidal Choroidal Vasculopathy (PCV). Since OXiGENE does not have ophthalmology capabilities in-house, potential can only be realized by partnering with an established ophthalmology company, so the savvy investor would be wise to monitor such future partnerships. Since May 2011 the stock has been losing value and on April 9, 2013, closed at a 52-week low of $3.38. The exercise price on the recent private placement is $3.40, and being set so close to the current market price indicates that OXiGENE is not confident about its ability to attract investment. Given the troubled past of VDAs and OXiGENE's limited resources, we believe the stock will remain weak unless the company pursues a new indication or partnership.
Vascular Disrupting Agents (VDAs) for Cancer Therapy
VDAs target existing tumor vasculature and destabilize blood vessel walls, resulting in tumor cell death by starvation. The principle of action was convincingly demonstrated by OXiGNE (and others) in preclinical rodent models, where tumor vasculature was indeed disrupted and tumor cell death ensued. However, after therapy was stopped, residual (peripheral) tumor cells continued to grow. VDAs are therefore not expected to act as a monotherapy in oncology.
As a therapeutic class, VDAs have seen significant challenges in recent years. Most of the products in this category were discontinued, including Sanofi's Ombrabulin, AstraZeneca's ZD6126, Antisoma's Vadimezan, Myrexis's Verubulin, and Abbot's ABT-751. Nereus's clinical trial with Plinabulin ended in 2011, but results remain unpublished, suggesting a less than stellar outcome. Finally, the fate of EpiCept's Crolibulin remains unclear as the company is being merged with Immune Therapeutics while the National Cancer Institute is sponsoring a clinical trial for solid tumors (Phase I/II).
Currently, OXiGENE and Bionomics are the only remaining companies actively pursuing VDAs in clinical trials. Bionomics is investigating BNC105 for renal cell carcinoma (Phase II) and ovarian cancer (Phase I/II) in combination with drugs that target non-angiogenic pathways. OXiGENE is investigating ZYBRESTAT (combretastatin A-4 phosphate) and a second generation analog OXi4503 (combretastatin A1 di-phosphate).
Recent reports from OXiGENE have described a refocusing strategy, specifically OXiGENE pursuing regulatory approval to use ZYBRESTAT for anaplastic thyroid cancer (ATC) only in Europe, and the primary focus of their U.S. efforts on the use of ZYBRESTAT as second- or third- line combination therapy for advanced ovarian cancer. In the U.S. market, their first aim is ZYBRESTAT in combination with Avastin, in a study in collaboration with Genentech (GOG 186I). Enrollment for this Phase II trial is currently in progress, with an expected interim analysis in Q2 2013 to determine if the trial will stop or continue to full enrollment. OXiGENE is currently blinded to the study results. They have just completed study enrollment as of April 2013, and anticipate preliminary results available by the first half of 2014. If study results are positive, OXiGENE anticipates proceeding to phase III, with a NDA filing in 2016-2017.
The second aim is ZYBRESTAT in combination with the tyrosine kinase inhibitor, pazopanib (marketed by GSK). They would like to support a clinical Phase Ib/II trial for advanced ovarian cancer patients, aiming at a start date in the second half of 2013. Last is the combination of ZYBRESTAT plus paclitaxel, which would be building on Phase II studies of this combination. Pending the availability of financial resources, the target start date would be in the second half of 2013, with a final read-out (go/no-go) for the trial sometime in 2015.
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ZYBRESTAT Topical has the potential to treat PCV. Current therapy is injection of Lucentis (a VEGF-A inhibitor by Genentech) into the eye. Data from OXiGENE shows that ZYBRESTAT Topical is tolerated in primates, rabbits, and rodents when applied to the surface of the eye. The market for Lucentis is $390 billion, presenting an opportunity for OXiGENE. However the company is not currently continuing independent development of the drug, but is seeking partnering opportunities. We think ZYBRESTAT Topical could be a promising product provided adequate funding is available.
U.S. Market Size by Drug and Indication
Industry Partners / Sponsors
(Non-Small Cell Lung Carcinoma)
Estimated using 84% of 230,000
Not planning to pursue further.
Estimated using 80% of 31,000
Estimated using 80% (source) of 22,000
Orphan drug - US
Genentech (GOG 186I)
GSK (ZYBRESTAT + pazopanib)
Finished Phase 2 enrollment
(Anaplastic Thyroid Cancer)
Estimated using 2% of 60,000
Orphan drug - US/EU
Special Protocol Assessment
Azanta (EU compassionate use)
Not planning to market in US because of regulatory hurdles. Seeking EMA advice for Europe.
OXiGENE Q-10 2013 SEC filing
Partnership with Angiogene Pharmaceuticals Ltd. (UK)
Licensed, but no current trials.
Acute Myelogenous Leukemia (AML)
20-40% refractory AML of
University of Florida
Recruiting for Phase I (AML & MDS)
Myelodysplastic Syndrome (MDS)
University of Florida
Recruiting for Phase I (AML & MDS)
ARMD (age related macular degeneration
Estimated using 1.6% of 105M (people age 43 and over; 2010 census)
PCV (Polypoidal Choroidal Vasculopathy)
Estimated using 7.8% of ARMD patients (source).
As a therapeutic class, VDAs have had limited success in clinical trials, and ZYBRESTAT is not an exception. OXiGENE's regulatory strategy in pursuing orphan indications backfired when it was unable to continue a clinical trial for ATC in the U.S. due to a small patient population. The prospect of regulatory approval in the EU is unclear and expected to come through no sooner than 2015. However, without a significant influx of cash, partnership, or acquisition, OXiGENE will be unable to sustain their clinical trials and research past Q1 2014.
- OXiGENE has spent $225 million pursuing VDAs as cancer drugs since 1998, with the first paper published in 2000 and the first clinical trial in 2004.
- ZYBRESTAT, the lead molecule, has not been successful in clinical trials.
- The current cash and equivalents will be exhausted by Q1 2014 (self-reported).
- OXiGENE does not expect to have preliminary results from a crucial clinical trial (GOG 186I) until Q2 2014.
- OXiGENE is currently seeking to raise additional capital (maximum $15 million at the current price) by selling 4.29 million shares of common stocks (April 2013).