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A Portfolio Focused On Orphan Oncology Indications

CA4P (Combretastatin A4-phosphate or fosbretabulin)

CA4P is our lead investigational drug and is a potent, tubulin-binding vascular disrupting agent (VDA). Compared to other tubulin-binding VDAs, we believe that CA4P has shown the most robust and consistent evidence of tumor blood flow shutdown in clinical trials to date. We are studying CA4P in platinum-resistant ovarian cancer (prOC). We are also exploring its potential use in other tumor types, such as neuroendocrine tumors (NETs), glioblastoma multiforme (GBM), hepatocellular carcinoma, and gastric cancer. Because its mechanism of action (MOA) is different than any approved drug for the treatment of cancer, its success in the clinic could potentially advance the treatment of many cancers.

CA4P exerts its antitumor effect by targeting tumor blood vessels, ultimately depriving tumors of oxygen and essential nutrients, leading to the death of interior tumor cells, but sparing some cells on the outer rim of the tumor, where the tumor cells are able to derive their nutrients from blood vessels in the proximal normal tissue. This is in contrast to the MOA of currently available anti-angiogenic agents (AAs), which prevents vascular endothelial growth factor (VEGF)-driven angiogenesis, mostly occurring at the rim of tumors. For this reason, combination therapy with agents that inhibit the VEGF pathway of angiogenesis will be the focus of the company’s clinical studies moving forward. Initial clinical data support the therapeutic potential of combining CA4P with AAs in a range of tumor types.

In Recurrent Ovarian Cancer

In combination with bevacizumab (Avastin®)—Results from the GOG-01861 clinical study

Data from the Phase 2 (GOG-0186I) clinical study were published online in the Journal of Clinical Oncology, the official journal of the American Society of Clinical Oncology. This is the first published report of the beneficial effects of combination vascular targeted therapy (VTT) for women with recurrent ovarian cancer. The open-label randomized Phase 2 study was conducted in the United States and enrolled a total of 107 patients at 67 sites. Patients were randomized to receive either CA4P (fosbretabulin) plus bevacizumab (CA4P combination) or bevacizumab alone (control). The Gynecologic Oncology Group (GOG), a member of NRG Oncology, conducted the study with support from the National Cancer Institute.

The study met its primary endpoint by demonstrating a statistically significant improvement in progression-free survival (PFS) for patients receiving the CA4P combination compared to the control (7.3 vs 4.8 months, respectively; Hazard Ratio [HR]=0.69; P=0.05 pre specified one-sided analysis). Preliminary median overall survival (OS) was longer for patients receiving the CA4P combination than for the control (24.6 vs 22.0 months, respectively; HR=0.85; data as of April 2015).

The improvement in PFS for patients receiving the CA4P combination was greater for patients with measurable disease than it was for patients without measurable disease, suggesting, along with the findings of improved PFS in patients with platinum-resistant disease, that CA4P combination therapy is more effective in those with more advanced disease. Treatment-emergent adverse events (AEs) associated with the CA4P combination were relatively low, and no serious AEs were observed. The most common AE associated with CA4P combination was hypertension, occurring in 18 patients (35%) compared to 10 patients (20%) in those receiving control (grade 3 and above).

In combination with pazopanib (Votrient®)

A Phase 1b/2 (PAZOFOS – NCT02055690) clinical study of CA4P in combination with pazopanib, compared to pazopanib alone, in advanced recurrent ovarian cancer. The study is sponsored by The Christie Hospital NHS Foundation Trust and coordinated by the Manchester Academic Health Science Centre, Trials Coordination Unit, or MAHSC-CTU, with additional support from The University of Manchester, the Royal Marsden NHS Foundation Trust, and Mount Vernon Cancer Centre (part of the East and North Hertfordshire NHS Trust). The trial design consists of a Phase 1b dose escalation portion with the combination of pazopanib and CA4P, which was completed at the end of 2015, and a randomized Phase 2 portion comparing pazopanib alone and pazopanib plus CA4P in patients with recurrent ovarian cancer that is expected to initiate enrollment in mid 2016. The study is expected to enroll approximately 128 patients at sites in the United Kingdom. The primary endpoint of the trial is PFS, and secondary endpoints include safety, overall survival, objective response rate, and CA125 response rate. For more information please go to clinicaltrials.gov.

In Platinum-resistant Ovarian Cancer (prOC):

A Phase 2/3 study of CA4P for the treatment of platinum-resistant ovarian cancer. This clinical study, called FOCUS (NCT02641639), will test whether CA4P improves PFS when combined with bevacizumab (Avastin) and physician’s choice chemotherapy (PCC). If the trial is successful, data from FOCUS would be used as the basis for a new drug application to the FDA.

FOCUS is a randomized double-blind placebo-controlled study divided into 2 parts to maximize the speed of data collection. During part 1 (n=80 patients), several interim analyses will be conducted to initially assess the efficacy and safety of the combination regimen when compared to standard-of-care. Part 2 (n=356 patients) is a confirmatory Phase 3 study which would begin immediately after evidence of safety and efficacy are initially demonstrated in part 1.

FOCUS is designed to build upon data from the GOG-0186I study, which demonstrated that CA4P improves PFS in women with recurrent ovarian cancer when combined with bevacizumab compared to bevacizumab alone. The treatment effect observed in this study was strongest in the subgroup of ovarian cancer patients with platinum-resistant disease. For more information please go to focusclinicalstudy.com.

In Neuroendocrine Tumors (GI-NETs and PNETs):

Gastrointestinal and pancreatic neuroendocrine tumors (GI-NETs and PNETs) are highly vascularized tumors that cause a cascade of disease symptoms, resulting in significant morbidity for the patient. Preclinical data have evaluated the efficacy of systemic administration of CA4P for the treatment of functional insulinomas in a transgenic mouse model of PNETs. In the model, treatment with CA4P resulted in a significant and sustained decrease in circulating insulin, with maximum effect seen by day 17 (P<0.0001). Treatment with CA4P disrupted tumor vasculature, induced apoptosis and inhibited tumor cell proliferation, and appeared to be well tolerated, with no obvious toxicity.