On March 17, 2015 Novartis reported that the European Commission has approved Jakavi (ruxolitinib) for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea. Jakavi is the first targeted treatment approved by the European Commission for these patients[2] (Press release, Novartis, MAR 17, 2015, View Source [SID:1234502302]).

PV is a rare and incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as blood clots, stroke and heart attack[1]. Approximately 25% of patients with PV develop resistance to or intolerance of hydroxyurea and are considered to have uncontrolled disease[3]. This is typically defined as hematocrit levels greater than 45%, elevated white blood cell count and/or platelet count, and may be accompanied by debilitating symptoms and/or an enlarged spleen[3],[4],[5].

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 European Commission’s approval of Jakavi is encouraging news for patients," said Dr. Claire Harrison, study investigator and Consultant Hematologist, Guy’s and St. Thomas’ NHS Foundation Trust, London. "Jakavi will fill an unmet need as the first treatment shown to significantly improve hematocrit, as well as symptom control and reduce spleen size in patients with polycythemia vera resistant to or intolerant of hydroxyurea."

The approval is based on data from the pivotal Phase III RESPONSE clinical trial demonstrating that a significantly greater proportion of patients achieved the composite primary endpoint of hematocrit control without use of phlebotomy and spleen size reduction, key measures of disease control, when treated with Jakavi compared to best available therapy (21% compared to 1%, respectively; p<0.0001)[1],[2]. In the study, a 50% or more improvement in PV-related symptoms was seen in 49% of Jakavi-treated patients compared to 5% of patients treated with best available therapy[2].

"The approval of Jakavi in polycythemia vera underscores what’s possible in today’s era of precision oncology research," said Bruno Strigini, President, Novartis Oncology. "Jakavi specifically targets the JAK-STAT pathway, which regulates blood cell production and is known to play a key role in the underlying mechanism of this disease, bringing patients and physicians a new way to treat polycythemia vera."

Overall, non-hematologic adverse events (AEs) were consistent with those previously seen in other Jakavi studies in PV and myelofibrosis[2],[6],[7]. Within the first 32 weeks of treatment, the most common Grade 3 or 4 hematologic AEs in the Jakavi-treatment arm were anemia (1.8%) and thrombocytopenia (5.5%)[2]. The most common non-hematologic AEs were dizziness (15.5%), constipation (8.2%) and herpes zoster (6.4%)[2]. The three most frequent non-hematological laboratory abnormalities (any Grade) were hypercholesterolemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate aminotransferase (20.9%), which were mainly Grade 1 and 2[2].

The European Commission approval applies to all 28 EU member states, plus Iceland, Norway and Liechtenstein. Additional regulatory applications for ruxolitinib in PV are currently ongoing in countries worldwide, and further regulatory filings are under review by health authorities. Ruxolitinib, which is marketed in the US by Incyte Corporation as Jakafi, received approval in December 2014 from the US Food and Drug Administration (FDA) for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea.

About the Pivotal Clinical Trial
RESPONSE is a global, randomized, open-label trial conducted at more than 90 trial sites. 222 patients with PV resistant to or intolerant of hydroxyurea were randomized 1:1 to receive either Jakavi (starting dose of 10 mg twice daily) or best available therapy, which was defined as investigator-selected monotherapy or observation only. The Jakavi dose was adjusted as needed throughout the trial. In the Jakavi arm, patients had a PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median of approximately three years. Most patients (>80%) had received at least two phlebotomies in the last 24 weeks prior to screening[2]. Patients were classified as intolerant or resistant to hydroxyurea based on the modified European LeukemiaNet (ELN) defined criteria[8].

The primary endpoint of the trial was the proportion of patients whose hematocrit was controlled without phlebotomy eligibility from week 8 through 32 (with no more than one phlebotomy eligibility between randomization and week 8) and whose spleen volume was reduced by 35% or more from baseline as assessed by imaging at week 32. Patients in the trial who were deemed to be eligible for phlebotomy had hematocrit that was greater than 45% and had increased three or more percentage points from the time they entered the trial (e.g., at baseline), or hematocrit greater than 48%. In addition, efficacy was further assessed using two key secondary endpoints: durable primary response and complete hematological remission. Other endpoints include safety and symptom improvement (as measured by the MPN-SAF 14-item total symptom score)[2].

About Polycythemia Vera
PV is a rare and incurable blood cancer associated with an overproduction of blood cells in the bone marrow that affects roughly one to three people per 100,000 globally[1[,[9]. The disease is driven by the dysregulation of the JAK-STAT pathway[10]. It is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count[1]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[11]. Additionally, patients with PV may have an enlarged spleen and symptoms that are frequent and burdensome, with an overall impact on quality of life similar to that seen with myelofibrosis[5],[12].

A common PV treatment includes phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, which is used to help maintain a hematocrit level below 45%[1],[11]. However, phlebotomy is usually unsuitable as a permanent treatment option due to its inability to control symptoms or effectively manage the overproduction of red blood cells, therefore cytoreductive agents, such as hydroxyurea, may be added[11]. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time[13]. Unfortunately, approximately 25% of PV patients become resistant to or intolerant of hydroxyurea treatment according to ELN criteria, resulting in inadequate disease control and an increased risk of progression[3].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Jakavi is approved in more than 80 countries for patients with myelofibrosis, including countries in the European Union, Canada, Japan and some countries in Asia, Latin and South America. Additional worldwide regulatory filings are underway in myelofibrosis and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk myelofibrosis.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in myelofibrosis is 15 mg twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for myelofibrosis and PV patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[2].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indication.

Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and Polycythemia Vera (PV)
Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with any hepatic impairment or severe renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended, and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed. Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-melanoma skin cancer (NMSC) has been reported in Jakavi treated patients. Periodic skin examination is recommended. Very common adverse reactions in MF (>10%) include urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising and weight gain. Common adverse reactions in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%) include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, dizziness, alanine aminotransferase increased and aspartate aminotransferase increased. Common adverse reactions in PV (1 to 10%) include urinary tract infections, herpes zoster, weight gain, constipation and hypertension.

On March 17, 2015 Myriad reported an expansion of the Company’s collaboration with BioMarin Pharmaceutical Inc. Under the expanded collaboration, BioMarin will use Myriad’s myChoice HRD companion diagnostic test to prospectively identify patients with metastatic breast, ovarian and potentially other tumor types that may be sensitive to talazoparib(Press release, Myriad Genetics, MAR 17, 2015, View Source [SID:1234502301]). Financial terms were not disclosed.

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!

Talazoparib is an investigational poly-ADP ribose polymerase (PARP) inhibitor being developed by BioMarin. In the expanded relationship, the companies also will collaborate under FDA regulations and guidelines for the development and potential regulatory approval requirements for both talazoparib and myChoice HRD.

"Myriad is a pioneer in personalized medicine. Our companion diagnostics are providing clinicians with valuable biological data to accelerate and improve healthcare for their patients," said Mark Capone, president of Myriad Genetic Laboratories. "With cancer treatments, there is no one-size-fits-all approach for patients. We are excited to be working with BioMarin to help identify the patients who are most likely to benefit from talazoparib based on their own genetic makeup and biology."

The expansion adds to an ongoing collaboration that began in September 2013, when BioMarin began using Myriad’s BRACAnalysis CDx companion diagnostic test in its pivotal Phase 3 EMBRACA and Phase 2 ABRAZO clinical studies of talazoparib for advanced or metastatic breast cancer patients carrying BRCA mutations.

On March 17, 2015 Kite Pharma reported that it has further strengthened its TCR product platform and established a European presence through the acquisition of T-Cell Factory B.V. (TCF), a privately held Dutch company, which has been renamed Kite Pharma EU (Press release, Kite Pharma, MAR 17, 2015, View Source [SID:1234502299]). Founded by preeminent scientists, including Professor Dr. Ton N. M. Schumacher, Ph.D., of the Netherlands Cancer Institute (NKI) and Professor Dr. Dirk H. Busch, M.D., of the Technische Universität München (TUM), TCF has the ability to discover and develop tumor-specific TCRs for broad application in cancer treatment based on its proprietary TCR-GENErator platform. Professor Schumacher will assume the role of Chief Scientific Officer of Kite Pharma EU, and maintain his position as Deputy Director of the NKI. Through this acquisition, Kite Pharma has obtained license agreements with IBA GmbH, Sanquin Blood Supply Foundation, and the NKI that include rights to certain new intellectual property in the TCR space developed by Professor Schumacher at the NKI. In addition, the acquisition provides access to European clinical manufacturing facilities, launching a base for Kite to build its global presence and initiate clinical programs in the EU.

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 acquisition of TCF follows the announcement earlier this month of Kite’s expanded Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI) to develop new TCR candidates, including against tumor neo-antigens, truly tumor-specific antigens generated as tumors accumulate genetic mutations. TCRs broaden the approach to cancer treatment by allowing targeting of tumor antigens found inside cancer cells, as well as surface antigens.

"The acquisition of TCF and its novel discovery and development platform provides Kite with a strong position in TCR gene therapy for cancer. In addition, with our strategic plans for expanding clinical operations to ex-US sites, Kite’s relationship with NKI, an internationally renowned research and clinical institution, provides an important operational platform and potential access to investigators, clinical sites and manufacturing facilities in Amsterdam," said Arie Belldegrun, M.D., FACS, Kite’s President and Chief Executive Officer. "Kite plans to leverage its access to intellectual property, know-how, and a network of collaborators across the continent to build a robust pipeline of TCR gene therapies."

"Through the tight link between our research institute and dedicated cancer hospital, we are in a unique position to discover, develop and manufacture cellular gene therapies for cancer," said Professor René Medema, Director of NKI. "NKI’s goal is to become the leader in T cell gene therapy in Europe, and we are expanding our clinical and manufacturing capacities. We are excited about partnering with Kite and potential future R&D collaborations with the company. We will continue to support Professor Schumacher in his new role with Kite Pharma EU in addition to his ongoing relationship with NKI."

"T cell based gene therapy products will have a profound role in treating currently intractable diseases. We believe the combination of TCF’s leading technology platform, the translational and development capabilities at the Netherlands Cancer Institute, and Kite’s expertise in advancing immune-oncology products, will rapidly bring important TCR-based gene therapies to patients," stated Professor Schumacher.

David Chang, M.D., Ph.D., Kite Pharma’s Executive Vice President, Research and Development, and Chief Medical Officer, commented, "In addition to expanding our capabilities in TCR, this acquisition is an important first step in our goal of global clinical expansion outside the US, applying our leadership and in-house clinical expertise in both CAR and TCR therapies. We are pleased with the accelerating momentum of our programs and look forward to additional clinical, operational, and manufacturing progress and accomplishments this year."

Financial terms of Kite’s acquisition of TCF include an upfront payment of up to €20.0M (approximately $21.0M USD) to TCF shareholders, licensors and employees, of which €3.8M (approximately $4.0M USD) will be paid in Kite stock. Kite is obligated to make certain milestone payments upon the achievement of clinical, regulatory and sales milestones relating to TCR-based product candidates.

On March 17, 2015 Celldex Therapeutics reported that it has entered into a clinical trial collaboration with Roche to evaluate the safety, tolerability and preliminary efficacy of varlilumab, Celldex’s CD27 targeting investigational antibody, and MPDL3280A (anti-PDL1), Roche’s investigational cancer immunotherapy in a Phase 1/2 study in renal cell carcinoma (Press release, Celldex Therapeutics, MAR 17, 2015, View Source [SID:1234502298]).

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!

Varlilumab and MPDL3280A are part of a new class of investigational medicines known as cancer immunotherapies that are designed to harness the body’s own immune system to fight cancer through separate yet complementary mechanisms of action that may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells. Preclinical data suggest the combination of these two mechanisms are synergistic and may enhance anti-tumor immune response compared to either agent alone. In Celldex’s Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity in patients with refractory renal cell carcinoma were observed, including a durable partial response (11.0+ months) that has continued to decrease in tumor volume over time and prolonged stable disease (4 patients with a range of 5.3 to 30.7+ months).

"This collaboration with Roche furthers our ongoing initiative to investigate varlilumab’s potential in combination with a broad range of mechanisms and across multiple tumor types," said Thomas Davis, MD, Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "Varlilumab is currently being studied in two Phase 1/2 combination studies and we expect it will enter at least another four combination studies this year. This latest trial is supported by promising signs of single-agent activity observed in our Phase 1 study in patients with renal cell carcinoma. We believe combining an immune activator with a checkpoint inhibitor in this disease setting may augment this activity and the synergy demonstrated in our preclinical varlilumab/anti-PDL1 combination models provide further support for this approach."

Under the terms of this agreement, Roche will provide study drug and Celldex will be responsible for conducting and funding the study, which is expected to begin in 2015.

About Varlilumab

Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs. Varlilumab is currently being studied in two Phase 1/2 combination studies and several additional combination studies will be initiated in 2015.

About MPDL3280A (anti-PDL1)

MPDL3280A (also known as anti-PDL1 and RG7446) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. MPDL3280A is designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PD-L1, MPDL3280A may enable the activation of T cells, restoring their ability to effectively detect and attack tumor cells.