The FDA has granted breakthrough therapy designation for Lucentis (ranibizumab; Genentech) for the treatment of diabetic retinopathy, according to a company statement (External Source Eyewire , Genentech, DEC 15, 2014, View Source [SID:1234501195]).

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A medicine may be designated as a breakthrough therapy by the FDA if it is intended to treat a serious or life-threatening disease or if preliminary clinical research suggests it will provide a significant improvement over existing therapies. The designation will expedite the development and review of Lucentis for diabetic retinopathy and reflects the unmet need for treatment options for diabetic retinopathy patients, according to Genentech.

In September, the FDA accepted the supplemental biologics license application for Lucentis and granted the medicine priority review for the treatment of diabetic retinopathy.

There are currently no approved ocular medications for diabetic retinopathy, which is estimated to affect 7.7 million Americans.

The FDA decision is based on the phase 3 RISE/RIDE trials, which showed meaningful improvements in diabetic retinopathy in a clinically significant proportion of patients treated with Lucentis at 2 years compared to patients treated with sham injections. Benefits of Lucentis treatment were maintained during year 3 of treatment. The safety in the RISE and RIDE phase 3 trials was consistent with previous studies.

The FDA’s confirmed action date for its biologics license application is February 6, 2015.

On December 12, 2014 Oncothyreon reported that the positive preliminary data from two ongoing Phase 1b trials of ONT-380 (ARRY-380), an orally active, reversible and selective small molecule HER2 inhibitor, will be presented at the San Antonio Breast Cancer Symposium (Press release Oncothyreon, DEC 12, 2014, View Source [SID:1234501172]).

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The first trial (ClinicalTrials.gov Identifier NCT02025192) is a parallel dose-escalation study of ONT-380 in combination with Xeloda (capecitabine) and/or Herceptin (trastuzumab) in patients previously treated with Herceptin and Kadcyla (ado-trastuzumab emtansine or TDM-1) for metastatic breast cancer. Interim data will be presented for 21 patients, including seven in the ONT-380 plus Xeloda cohort, eight in the ONT-380 plus Herceptin cohort, four in the ONT-380 plus Xeloda and Herceptin cohort, and two in an ongoing expansion cohort in patients with untreated or progressive central nervous system (CNS) metastases, both treated with ONT-380 plus Herceptin.

Seventeen of the patients were evaluable for best overall response using RECIST 1.1 criteria. In the ONT-380 plus Xeloda cohort, four patients had a partial response (PR) and three patients had stable disease (SD), for an overall clinical benefit rate of 100 percent (defined as either PR/CR or stable disease for > 6 months). In the ONT-380 plus Herceptin cohort, best response has been a complete response (CR) in one patient, PR in two patients, SD in four patients, and progressive disease (PD) in one patient. Two patients in the ONT-380 plus Xeloda and Herceptin cohort are currently evaluable, one of whom had a PR and one PD. One patient in the CNS expansion cohort had a PR and the other SD.

Fourteen of the 21 patients in this trial had a history of CNS metastases, of whom six had evaluable target lesions per modified RECIST 1.1 at the time of entry into the trial. Of these, best initial response has been SD, with decreases in CNS target lesions in four patients. Five of these six patients remain active on study.

The second trial (ClinicalTrials.gov Identifier NCT01983501) is a dose-escalation study of ONT-380 in combination with Kadcyla in patients who have been previously treated with Herceptin and a taxane for metastatic breast cancer. Data will be presented for 17 patients, of whom 16 were evaluable for response. Patients in this trial were heavily pre-treated, having received a median of two prior systemic treatments for metastatic disease, including prior pertuzumab in six, and prior lapatinib in five. Best overall response has been PR in five patients, SD in seven patients, and PD in four patients. Nine patients in this trial had a history of CNS metastases, of whom four had measurable disease per modified RECIST 1.1 at the time of entry into the trial. Three of these four patients have SD in the CNS and remain active on the study, including two with decreases in measurable target lesions.

ONT-380 was well-tolerated in both studies and in all combinations tested. The most common adverse events included nausea and vomiting, diarrhea, fatigue and elevated liver function tests. Most adverse events were grade 1 or 2 in severity. Elevated liver function tests were more common in patients also receiving Kadcyla. No grade 3 diarrhea was seen in either trial; anti-diarrheal prophylaxis was not a study requirement.

A maximally tolerated dose (MTD) for ONT-380 has not been identified to date in any of the combinations tested in either trial. An improved tablet formulation of ONT-380 with increased absorption was used in these trials compared to the powder in capsule formulation used in the previously reported Phase 1 trial. All patients in both current trials received an initial dose of 300 mg twice per day. At that dose, measured drug levels were similar to those seen with 600 mg twice per day (the single agent MTD) of the prior formulation. Drug exposure in the current trials was well above the level needed for 90 percent inhibition of HER2.

"The preliminary signs of efficacy in both of these trials are encouraging for the further development of ONT-380," said Stacy Moulder, M.D., Associate Professor, Breast Medical Oncology, University of Texas MD Anderson Cancer Center. "These patients were heavily pre-treated, with the majority already having a history of CNS metastases. Nevertheless, meaningful responses and prolonged stable disease have been observed and many patients currently remain on study. Importantly, ONT-380 has been well-tolerated, with a toxicity profile that facilitates its combination with other agents."

"We are continuing to enroll patients in both of these Phase 1b trials," said Diana Hausman, M.D., Chief Medical Officer of Oncothyreon. "We are currently testing an increased dose level of ONT-380 of 350 mg twice daily in both trials. We are also enrolling cohorts of patients in both trials with CNS metastases from HER2+ breast cancer that are either asymptomatic and untreated or progressive following treatment to better define the potential role of ONT-380 in treating patients with this serious unmet medical need."

About ONT-380

ONT-380 is an orally active, reversible and selective HER2 inhibitor invented at Array BioPharma Inc. In multiple preclinical tumor models, ONT-380 was well tolerated and demonstrated significant dose-related tumor growth inhibition that was superior to Herceptin (trastuzumab) and Tykerb (lapatinib). Additionally, in these models, ONT-380 demonstrated synergistic or additive tumor growth inhibition when dosed in combination with the standard-of-care therapeutics Herceptin or Taxotere (docetaxel). ONT-380 has also demonstrated superior activity, based on overall survival, compared to Tykerb and to the investigational drug, neratinib, in an intracranial HER2 positive breast cancer xenograft model.

A Phase 1 trial of ONT-380, with both dose-escalation and expansion components, has been completed in 50 patients, 43 of whom had HER2 positive metastatic breast cancer. All HER2 positive breast cancer patients had progressed on a Herceptin-containing regimen. In addition, over 80 percent had been treated with Tykerb, with many having progressed on therapy. In this study, ONT-380 demonstrated an acceptable safety profile; treatment-related adverse events were primarily Grade 1. Because ONT-380 is selective for HER2 and does not inhibit EGFR, there was a low incidence and severity of treatment-related diarrhea, rash and fatigue. Additionally, there were no treatment-related cardiac events or Grade 4 treatment-related adverse events reported. Twenty-two HER2 positive breast cancer patients with measurable disease were treated with ONT-380 at doses greater than or equal to 600 mg BID. In this heavily pretreated patient population, there was a clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) of 27 percent.

On December 12, 2014 Novartis reported on results of the BOLERO-1 (Breast cancer trials of OraL EveROlimus-1) trial of Afinitor (everolimus) tablets in combination with trastuzumab (Herceptin*) and paclitaxel as a first-line treatment in women with human epidermal growth factor receptor-2 positive (HER2+) advanced breast cancer at the 2014 San Antonio Breast Cancer Symposium (SABCS) (Press release Novartis, DEC 12, 2014, View Source [SID:1234501181]).

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The trial was conducted in HER2+ advanced breast cancer patients, a population that represents approximately 20% of advanced breast cancers and differs from the hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer patients for whom Afinitor in combination with exemestane following a non-steroidal aromatase inhibitor is approved worldwide. The study did not meet the threshold of statistical significance for the primary objectives of progression-free survival (PFS) among women with HER2+ advanced breast cancer or the pre-defined hormone-receptor negative, human epidermal growth factor receptor-2 positive (HR-/HER2+) subgroup.

"For more than two years, Afinitor has positively impacted the HR positive treatment landscape as an important therapy for women living with advanced breast cancer," said Alessandro Riva, Global Head, Oncology Development and Medical Affairs, Novartis Oncology. "The results of this trial in HER2 positive support our research approach of investigating various treatment combinations targeting the PI3K/AKT/mTOR pathway in advanced breast cancer and we thank all of the researchers and patients who participated in the BOLERO-1 study."

The results of BOLERO-1, a Phase III, randomized, double-blind, placebo-controlled multicenter trial of 719 patients with HER2+ locally advanced or metastatic breast cancer, showed that the median PFS with everolimus plus trastuzumab and paclitaxel was 15.0 months versus 14.5 months with placebo plus trastuzumab and paclitaxel, a difference of 0.5 months (hazard ratio=0.89 [95% CI: 0.73 to 1.08]; p=0.1166).

In the HR- subgroup of women with HER2+ advanced breast cancer, a second primary objective, everolimus plus trastuzumab and paclitaxel treatment demonstrated benefit over the placebo arm prolonging median PFS by 7.2 months. The median PFS was 20.3 months with everolimus plus trastuzumab and paclitaxel and 13.1 months with placebo plus trastuzumab and paclitaxel. While this difference was clinically relevant, the results did not demonstrate statistical significance.

The combination of everolimus, trastuzumab and paclitaxel was generally well-tolerated. Adverse events were consistent with the known safety profile of everolimus with the most common all-grade adverse reactions (incidence >= 35%) being stomatitis, diarrhea, alopecia, rash, cough, pyrexia, neutropenia and fatigue. The most common Grade 3-4 adverse reactions (incidence >= 2%) were neutropenia, stomatitis, diarrhea, anemia, hypokalaemia, leukopenia, hyperglycemia, fatigue, pyrexia and dyspnea.

Afinitor is currently approved in more than 90 countries across the globe, including the countries of the European Union and the United States, to treat postmenopausal women with HR+/HER2- advanced breast cancer in combination with exemestane after recurrence or progression following a non-steroidal aromatase inhibitor. The specific indications vary by country. HR+/HER2- advanced breast cancer is the most common form of the disease. Approximately 70% of all invasive breast cancers are positive for HR expression at the time of diagnosis.

On 10 December, 2014 the USA Food and Drug Administration (FDA) approved Gardasil 9 (Human papillomavirus 9-valent Vaccine, Recombinant) for the prevention of certain diseases caused by nine types of Human Papillomavirus (HPV). Covering nine HPV types, five more HPV types than Gardasil (previously approved by the FDA), Gardasil 9 has the potential to prevent approximately 90% of cervical, vulvar, vaginal and anal cancers (Press release, US FDA, DEC 10, 2014, View Source [SID1234607427]).

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Gardasil 9 is a vaccine approved for use in females ages 9 through 26 and males ages 9 through 15. It is approved for the prevention of cervical, vulvar, vaginal and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52 and 58, and for the prevention of genital warts caused by HPV types 6 or 11. Gardasil 9 adds protection against five additional HPV types—31, 33, 45, 52 and 58— which cause approximately 20% of cervical cancers and are not covered by previously FDA-approved HPV vaccines.

"Vaccination is a critical public health measure for lowering the risk of most cervical, genital and anal cancers caused by HPV," said Dr Karen Midthun, director of the FDA’s Center for Biologics Evaluation and Research. "The approval of Gardasil 9 provides broader protection against HPV-related cancers."

A randomised, controlled clinical study was conducted in the USA and internationally in approximately 14,000 females ages 16 through 26 who tested negative for vaccine HPV types at the start of the study. Study participants received either Gardasil or Gardasil 9. Gardasil 9 was determined to be 97% effective in preventing cervical, vulvar and vaginal cancers caused by the five additional HPV types (31, 33, 45, 52, and 58). In addition, Gardasil 9 is as effective as Gardasil for the prevention of diseases caused by the four shared HPV types (6, 11, 16, and 18) based on similar antibody responses in participants in clinical studies.

Due to the low incidence of anal cancer caused by the five additional HPV types, the prevention of anal cancer is based on Gardasil’s demonstrated effectiveness of 78% and additional data on antibodies in males and females who received Gardasil 9.

The effectiveness of Gardasil 9 in females and males ages 9 through 15 was determined in studies that measured antibody responses to the vaccine in approximately 1,200 males and 2,800 females in this age group. Their antibody responses were similar to those in females 16 through 26 years of age. Based on these results, the vaccine is expected to have similar effectiveness when used in this younger age group.

Gardasil 9 is administered as three separate shots, with the initial dose followed by additional shots given two and six months later. For all of the indications for use approved by the FDA, Gardasil 9’s full potential for benefit is obtained by those who are vaccinated prior to becoming infected with the HPV strains covered by the vaccine.

The safety of Gardasil 9 was evaluated in approximately 13,000 males and females. The most commonly reported adverse reactions were injection site pain, swelling, redness, and headaches.

Gardasil 9 is manufactured by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., based in Whitehouse Station, New Jersey.

Avanir has filed a 10-K – Annual report [Section 13 and 15(d), not S-K Item 405] with the U.S. Securities and Exchange Commission .

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