Ovarian Cancer and Prolanta

Ovarian cancer is the fourth leading cause of cancer-related death in women in the US and the leading cause of gynecologic death. Despite being one tenth as common as breast cancer, ovarian cancer is three times more lethal. The American Cancer Society (2017) estimates 22,240 women will be diagnosed with ovarian cancer, and 14,080 will die from this disease in the US. The incidence of ovarian cancer in Europe is 45,000 and worldwide is 225,000. The prevalence in the US is 188,167. The prevalence in Europe is approximately twice that of the US.

Because of the difficulties with the early detection of ovarian cancer, approximately 80% of patients are diagnosed with advanced stage disease. Of these patients, 80% to 90% will initially respond to chemotherapy, but less than 10% to 15% will remain in permanent remission. Although advances in treatment have led to an improved five-year survival rate approaching 45%, overall survival has not improved. The five-year survival rate for patients with distant disease is only 28%.

The current standard of care for ovarian cancer is surgical debulking, with a total hysterectomy and oophorectomy typically performed at the same time. The majority of patients require postoperative chemotherapy to eradicate residual disease.

Six cycles of a taxane, such as paclitaxel, combined with a platinum-based therapy, such as carboplatin or cisplatin, is now standard treatment. Even in patients that respond to therapy by going into remission, relapse still occurs in the majority of those patients with advanced disease, and only 10% to 30% of such patients have long-term survival. For these patients, there is a need for second-line therapies capable of controlling recurrent disease for prolonged periods of time. Approximately 20% to 30% of patients never have a clinical remission despite receiving highly active first-line chemotherapy. This residual or progressive disease is generally not curable with current treatments.Both paclitaxel and the platinum-based regimens cause severe side effects, including progressive neuropathy, cumulative thrombocytopenia, anemia, neutropenia, platinum allergy, cardiovascular effects, nausea and renal toxicity. Severe or cumulative side effects can necessitate a switch to alternative therapies, such as liposomal doxorubicin, topotecan, gemcitabine, etoposide and vinorelbine, however, the response rate for each of these drugs is only 10% to 20% in patients with platinum-resistant disease. Thus, there is a great need for more effective therapeutic options for patients with relapsed disease.

Prolanta Potential in Ovarian Cancer. We believe Prolanta has the potential to be a major breakthrough in the treatment of ovarian cancer. Prolanta targets multiple signaling pathways related to both prolactin (~80% of patients) and HER2 (~20% of patients) activity, offering a broad approach to the treatment of ovarian cancer. Prolanta’s novel mechanism of action (autophagocytosis or autophagy) clearly separates this drug from current and other therapies in clinical development. Currently, cytotoxic drugs (chemotherapy) are the only drugs approved for this deadly disease in the US, but these drugs have limited efficacy.

Prolanta has also shown to have an additive effect when used with docetaxel in a mouse xenograft model of ovarian cancer. One million SKOV3 human ovarian cancer cells were injected intraperitoneally into immunodeficient mice on Day 1 and treatment was begun on Day 8. Treatment consisted of 100 µg of Prolanta (G129R) daily, 25 µg of docetaxel (DCT) weekly, or both. The control group mice received mannitol buffer only. Mice were treated for 38 days, until the control mice were moribund. Both tumor weight and number of tumor nodules were reduced when Prolanta was added to docetaxel. In addition, there is substantial evidence that Prolanta will enhance the effectiveness of platinum therapy, providing a significant opportunity to be part of a combination first-line treatment.

While the five-year survival rate is 75% when diagnosed in an early stage, once the disease has spread, the five-year survival rate is reduced to 20%. Most women are diagnosed after the disease has spread. The incidence of ovarian cancer in Europe is 45,000 and 225,000 worldwide. The prevalence in the US is 177,578 and approximately twice as high in Europe.

Targeted therapies are expensive treatments. In the US, Herceptin sells for $64,000 per year (Source: Genentech) and the annual cost of Avastin is $55,000 to more than $80,000 per year, depending on income. If Prolanta could achieve a 5% market share of the US and European prevalence of ovarian cancer, at least $35,000 per patient per year, revenues would surpass $1 billion per year.

Prolanta has the potential to treat the majority of ovarian cancer patients because an estimated 80% of ovarian cancer patients’ tumors express the PRLR. Preclinical data in mouse models of ovarian cancer indicate that: (i) monotherapy with Prolanta and (ii) combination therapy of Prolanta and taxol are both highly effective in reducing metastatic tumor burden. Animal models have also demonstrated that in HER2 positive cancers, PRL can cross-activate the same intracellular signaling pathways activated by HER2, an oncogene found in 20% of ovarian cancers that is correlated with a more aggressive type of cancer.

Regulatory Plans. Oncolix has an FDA-cleared IND to commence the Phase I study of Prolanta to treat ovarian cancer. Furthermore, Prolanta was granted orphan designation by the FDA for the treatment of ovarian cancer. Because of the unmet medical needs in ovarian cancer, Oncolix will seek accelerated approval after the Phase IIb study, or will roll the Phase IIb results into a Phase III study. Studies in other indications (breast, endometrial cancer and others) are deferred until later in the clinical development process unless the Company receives additional funding to commence these trials or the Company enters into a strategic partnership with a large pharmaceutical company.