Author: [email protected]

Novartis gains FDA approval for Signifor® LAR to treat patients with acromegaly, a rare and life-threatening hormonal disorder

On December 16, 2014 Novartis reported that the US Food and Drug Administration (FDA) has approved Signifor long-acting release (LAR)* (pasireotide) for injectable suspension, for intramuscular use, for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option (Press release Novartis, DEC 15, 2014, View Source [SID:1234501194]). The approval of Signifor LAR, a next-generation somatostatin analog (SSA), helps address a critical unmet need among the acromegaly patient population. Signifor LAR has been studied and found effective in both medically naïve patients with acromegaly who have had prior surgery or for whom surgery was not an option, as well as patients whose disease is not fully controlled on first generation SSAs[2].

Acromegaly is a rare, debilitating endocrine disorder caused by the excess production of growth hormone (GH) and insulin-like growth factor-1 (IGF-1)[1],[3]. In the majority of cases, the disease is caused by a non-cancerous tumor on the pituitary gland. Prolonged exposure to GH and IGF-1 may cause patients to experience extreme physical changes including the enlargement of hands, feet and facial features[1]. Acromegaly is also associated with two- to three-fold increased mortality rates and serious health complications, including heart disease, hypertension, diabetes, arthritis and colon cancer[1],[4],[5]. In fact, heart disease is responsible for approximately 60% of deaths among people with acromegaly[6].

“Treating acromegaly can be extremely challenging and the consequences of inadequate normalization of hormone levels can be serious for patients,” said Dr. Monica Gadelha, Professor, Federal University of Rio de Janeiro and pivotal trial study author. “With the approval of Signifor LAR, physicians now have a new acromegaly therapy that provides an enhanced mechanism to address elevated hormone levels. This is a significant achievement and much welcomed news for patients with acromegaly.”

Worldwide, the prevalence of acromegaly is estimated to be 60 cases per million, with an annual incidence of 3 to 4 new cases per million[1]. However, recent studies suggest that pituitary adenomas may be more prevalent than previously thought, and that the prevalence of acromegaly may be between 115 and 295 cases per million[3]. On average, patients experience a delayed diagnosis of 6 to 10 years from disease onset[7]. Once diagnosed, the primary objective when treating acromegaly is to achieve biochemical control of the disease, as measured by both the reduction of GH levels and normalization of IGF-1 levels[8]. Notably, a recent meta-analysis using more sensitive assays and more stringent evaluation criteria showed that 45% of patients with acromegaly fail to achieve recommended levels of GH or normalized levels of IGF-1[9]. Reduction of tumor volume and minimization of clinical manifestations are other important treatment goals[8].

This FDA approval was based on two multicenter Phase III studies, C2305 and C2402, which respectively examined medically naïve patients who have had prior surgery or for whom surgery was not an option and patients with acromegaly inadequately controlled on first generation SSAs. In both studies, higher rates of full biochemical control (defined as mean GH level <2.5mcg/L and normal IGF-1 levels) were achieved with Signifor LAR compared to a first generation SSA[2]. "The FDA approval of Signifor LAR for acromegaly marks an important day for physicians and patients living with difficult-to-treat pituitary conditions and underscores our continued commitment to helping patients manage rare diseases," said Bruno Strigini, President, Novartis Oncology. "We are pleased that a new treatment option is now available to help address the serious impact of uncontrolled acromegaly, and are optimistic about providing this much needed treatment to other patients worldwide in the near future." Signifor LAR is an SSA administered intramuscularly once-monthly that exerts its pharmacological activity via binding to somatostatin receptors (SSTRs). Signifor LAR has the potential to stimulate both SSTR2 and SSTR5 subtype receptors, which are relevant for inhibition of GH and IGF-1 secretion, making Signifor LAR a more effective treatment for acromegaly compared to other SSAs currently used to treat this disease[2]. In the US, Signifor LAR has orphan drug designation for acromegaly. Orphan drug designation is granted for products that treat a condition that affects fewer than 200,000 people in the US[10],[11]. In November 2014, the European Medicines Agency (EMA) approved Signifor* to treat adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with a first-generation SSA. Novartis has also submitted additional regulatory applications for Signifor LAR worldwide.

8-K – Current report

On December 15, 2014 Sorrento Therapeutics reported that it has entered into a binding agreement with NantWorks founder, physician scientist, and biotechnology entrepreneur Dr. Patrick Soon-Shiong (Filing 8-K , Sorrento Therapeutics, DEC 15, 2014, View Source [SID:1234501189]).

Under the terms of the agreement, NantWorks and Sorrento will establish a global strategic collaboration to jointly develop next generation immunotherapies for the treatment of cancer and auto-immune diseases. NantWorks, through a subsidiary, and Sorrento intend to establish the first joint venture – “The Immunotherapy Antibody JV” – as an independent biotechnology company with $20 million initial joint funding. As part of a strategic investment, Dr. Soon-Shiong’s affiliated entity will acquire a 19.9% equity stake in Sorrento by purchasing common stock priced at $5.80 per share, Sorrento’s closing sale price on Friday, December 12, 2014. In addition, Sorrento granted the purchaser a 3-year warrant to purchase 1,724,138 shares of common stock at an exercise price of $5.80 per share.

The Immunotherapy Antibody JV will focus on accelerating the development of multiple immuno-oncology monoclonal antibodies (mAbs) for the treatment of cancer, including but not limited to anti-PD-1, anti-PD-L1, anti-CTLA4 mAbs, and other immune-check point antibodies as well as antibody drug conjugates (ADCs) and bispecific antibodies. The immuno-oncology field has emerged as the one of most exciting and fastest developing pharmaceutical market. Immunomodulatory antibodies help the cancer patient’s own immune system to fight the disease and are being developed for the treatment of a number of solid tumors. They have demonstrated therapeutic potential in difficult-to-treat cancers, such as metastatic melanoma and non-small cell lung cancer (NSCLC). A recent forecast by Citigroup predicts this market to become the biggest blockbuster drug class in history with potential sales of up to $35 billion a year over the next 10 years.

“We are extremely pleased to be working with Dr. Patrick-Soon Shiong and NantWorks. The investment into Sorrento and future formation of the JV with NantWorks further validate our G-MAB antibody technology and underscore Sorrento’s commitment to seeking strategic alliances in bringing its diverse portfolio of fully human monoclonal antibodies, ADCs, and bispecific antibodies into the clinic,” said Dr. Henry Ji, President and CEO of Sorrento. “Our innovative collaboration will unite Sorrento’s capability to develop complex biologics with NantWorks proprietary genomic and personalized medicine technologies. We share NantWorks’ enthusiasm for the potential of our JV to produce a pipeline of immuno-oncology products to address unmet needs of cancer treatment.”

“Combining NantWorks’ cutting edge expertise in genomic and molecular profiling of cancer patients and Sorrento’s industry-leading G-MAB antibody technology, we believe will enable us to develop multiple novel therapies for malignant disorders where there is currently a significant unmet need. Through this partnership, it is our goal to provide relief for millions of people who today have limited treatment options. This will be a model relationship aligned to accelerate development and production of novel cancer immunotherapies. We look forward to working closely with Sorrento’s team,” said Dr. Patrick Soon-Shiong, CEO and Founder of NantWorks.

Novartis announces results of trial evaluating the use of Afinitor® in first-line treatment in HER2+ advanced breast cancer at SABCS

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

Oncothyreon Announces Presentation of Positive ONT-380 Data at San Antonio Breast Cancer Symposium

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]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.

Ramucirumab (Cyramza)

On December 12, 2014, the U. S. Food and Drug Administration approved ramucirumab (Cyramza Injection, Eli Lilly and Company) for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy (External Source US FDA , Eli Lilly, DEC 12, 2014, View Source [SID:1234501177]). Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving ramucirumab. Ramucirumab was previously approved as a single agent and for use in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma after disease progression on first line therapy.

The approval of ramucirumab in combination with docetaxel in NSCLC was based on the demonstration of improved overall survival (OS) in a multicenter, double-blind, placebo-controlled study (I4T-MC-JVBA) that enrolled 1253 patients with previously treated metastatic NSCLC. Patients were randomized to receive either ramucirumab (10 mg/kg every three weeks) in combination with docetaxel (75 mg/m2 every 3 weeks) on day 1 of a 21-day cycle (n=628) or matching placebo plus docetaxel (n=625).

A statistically significant prolongation of OS was demonstrated [HR 0.86; (95% CI: 0.75, 0.98); p=0.024]; median OS was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm. Progression-free survival was also significantly longer for patients receiving ramucirumab plus docetaxel [HR=0.76 (95% CI: 0.68, 0.86); p<0.001)]. Safety data was evaluated in 1245 patients who received at least one dose of study drug. The most frequently reported adverse reactions with ramucirumab plus docetaxel (incidence greater than or equal to 30%) were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. The most common serious adverse reactions with ramucirumab plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The recommended dose and schedule for ramucirumab in combination with docetaxel for NSCLC is ramucirumab 10 mg/kg intravenously and docetaxel 75 mg/m2 intravenously administered every 3 weeks. Full prescribing information is available at: View Source