On December 6, 2015 Takeda Pharmaceutical Company Limited (TSE: 4502) reported post-treatment follow up data from the pivotal phase 2 study of single-agent brentuximab vedotin for the treatment of relapsed or refractory Hodgkin lymphoma following autologous stem cell transplantation (ASCT) (Press release, Takeda, DEC 6, 2015, View Source [SID:1234508435]). The data demonstrated that the estimated five-year overall survival (OS) rate among ADCETRIS-treated patients was 41 percent (95% CI: 31%, 51%); median OS was 40.5 months (95% CI: 28.7, 61.9 [range 1.8 to 72.9+]) and median progression-free survival (PFS) was 9.3 months (95% CI: 7.1 to 12.2 months). The safety profile of ADCETRIS was generally consistent with the existing prescribing information.These results were presented today at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting in Orlando, FL.

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"The five year overall survival rates reported in this pivotal trial are very promising in improving the long-term outlook for patients in this setting as outcomes have historically been very poor," said Professor Andreas Engert, M.D., University Hospital of Cologne, Germany. "These data further reinforce the emergence of ADCETRIS as a standard of care for patients with Hodgkin lymphoma who experience relapse or disease progression following salvage therapy and ASCT."

Also presented today at the ASH (Free ASH Whitepaper) annual meeting, data from the phase 3 AETHERA trial of brentuximab vedotin consolidation therapy in Hodgkin lymphoma patients at high risk of relapse following ACST demonstrated that after three years of follow-up, patients treated with brentuximab vedotin continued to show a significant improvement in PFS per investigator assessment (61%; 95% CI:53%, 68% HR 0.52) compared to placebo (43%; 95% CI:36%, 51% HR 0.52). The safety profile of ADCETRIS was generally consistent with the existing prescribing information.

ADCETRIS (brentuximab vedotin) is an antibody-drug conjugate (ADC) directed to CD30, a defining marker of classical Hodgkin lymphoma. ADCETRIS is currently approved in more than 55 countries for the treatment of relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma (sALCL). The utility of ADCETRIS is currently being explored across a number of types of cancer, and data from six studies in the ADCETRIS clinical trial program were presented at the ASH (Free ASH Whitepaper) meeting, including four as oral presentations.

"With more than 45 clinical trials across multiple lines of therapy underway and ongoing research focused on understanding the underlying pathogenesis of Hodgkin lymphoma, our commitment to advancing the care of people battling this disease is far-reaching," said Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

"The positive long-term results from these two pivotal studies are very important in our work to advance the care of people living with Hodgkin lymphoma whose disease has progressed."

About the Studies

Study 1: Five-year Survival Data Demonstrating Durable Responses from a Pivotal Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma [Abstract 2736, presented December 6, 2015]
Five-year follow up data from the pivotal phase 2 study evaluating the safety and efficacy of brentuximab vedotin in heavily pre-treated patients with relapsed/refractory Hodgkin lymphoma post-ASCT were presented as a poster by Robert Chen, M.D., City of Hope National Medical Center, California. In the study, the 102 enrolled patients received 1.8 mg/kg brentuximab vedotin once every three weeks as a 30 minute outpatient intravenous (IV) infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Key secondary endpoints included complete response (CR) rate, duration of response, PFS, OS, safety and tolerability. Survival and disease status were assessed every three months for two years and then every six months through year five. A study protocol amendment removed the requirement of routine CT scanning during follow up, and so disease status was assessed by the investigator. At the time of the amendment, 18 patients were still being assessed for progression; these patients had been in long-term follow-up for a median of over 30 months.

Patients received a median of nine cycles (range, 1-16) of brentuximab vedotin. The study met its primary endpoint demonstrating 72 percent ORR and a CR rate of 33 percent. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Grade 3 or higher adverse events occurred in ≥5 percent of patients and included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.

Fifteen of the 102 enrolled patients remained in follow-up and in remission at study closure. Of the 15 patients, six received consolidative allogeneic SCT and nine received no further therapy since completing treatment with brentuximab vedotin.
Study 2: Updated Efficacy and Safety Data from the AETHERA Trial of Consolidation with Brentuximab Vedotin After Autologous Stem Cell Transplant (ASCT) in Hodgkin Lymphoma Patients at High Risk of Relapse [Abstract 3172, presented December 6, 2015]
Updated efficacy and safety data from the phase 3 AETHERA trial were presented as a poster by John Sweetenham, M.D., Huntsman Cancer Institute, University of Utah. The AETHERA trial was designed to evaluate the potential of single-agent brentuximab vedotin to extend PFS post-ASCT in patients with Hodgkin lymphoma with at least one risk factor for progression. In addition to the primary endpoint of PFS, secondary endpoints included OS, safety and tolerability. Eligible patients must have had a history of refractory Hodgkin lymphoma, have relapsed within one year from receiving frontline chemotherapy and/or had extranodule disease at the time of pre-ASCT relapse. These factors are consistently reported to be associated with poor prognosis after transplant. Patients received brentuximab vedotin or placebo every three weeks for up to approximately one year. This international multi-center trial was conducted at 78 sites in the United States, Eastern and Western Europe and Russia.

A total of 329 Hodgkin lymphoma patients at risk of relapse were enrolled, including 165 on the brentuximab vedotin arm and 164 on the placebo arm. Patients received a median of 15 cycles of treatment on both arms.

As reported at the ASH (Free ASH Whitepaper) annual meeting in 2014, the AETHERA trial met its primary endpoint, demonstrating significant improvement in PFS among patients who received brentuximab vedotin compared to patients who received placebo (median of 43 months versus 24 months, respectively; HR=0.57; p=0.001). Approximately three years after the last patient was randomized, consolidation therapy with ADCETRIS continued to show an improvement in PFS. At three years, PFS was 61 percent (95% CI:53–68) for patients in the brentuximab vedotin arm compared to 43 percent (95% CI 36-51) for the placebo arm.

At three years, treatment-emergent peripheral neuropathy resolved for most patients, and no additional secondary malignancies were observed in either treatment arm.

Among the 112 patients in the brentuximab vedotin arm who experienced treatment-emergent peripheral neuropathy, 99 patients (88%) experienced some improvement (23%) or complete resolution (65%) of neuropathy symptoms at the time of analysis.

Secondary malignancies were comparable between the two treatment arms (n=4 brentuximab vedotin, n=2 placebo).
Discontinuation of treatment due to an adverse event (AE) occurred in 54 patients (33%) who received ADCETRIS, most commonly due to peripheral sensory and motor neuropathies (14% and 7%, respectively). Patients who discontinued brentuximab vedotin treatment as a result of an AE received a median of 9.5 cycles (range, 1 to 15). The two-year PFS rate in these patients was 69 percent (95% CI 54–79) versus 82 percent (95% CI 71–89) for patients who completed all 16 treatment cycles.

Six PFS events (2 progressions and 4 deaths) were recorded after the 24-month evaluation period in the brentuximab vedotin arm versus three in the placebo arm (2 progressions and 1 death). The hazard ratio (HR) for PFS per independent review was 0.57 (95% CI 0.41–0.82).

About ADCETRIS

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE). The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

ADCETRIS was granted conditional marketing authorization by the European Commission in October 2012 for two indications: (1) for the treatment of adult patients with relapsed or refractory CD30-positive Hodgkin lymphoma following autologous stem cell transplant (ASCT), or following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option, and (2) the treatment of adult patients with relapsed or refractory sALCL. ADCETRIS has received marketing authorization by regulatory authorities in more than 55 countries. See important safety information below.

ADCETRIS for intravenous injection has received approval from the FDA for three indications: (1) regular approval for the treatment of patients with classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates, (2) regular approval for the treatment of classical Hodgkin lymphoma patients at high risk of relapse or progression as post-auto-HSCT consolidation, and (3) accelerated approval for the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. The sALCL indication is approved under accelerated approval based on overall response rate. Continued approval for the sALCL indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Health Canada granted ADCETRIS approval with conditions for relapsed or refractory Hodgkin lymphoma and sALCL.

ADCETRIS is being evaluated broadly in more than 30 ongoing clinical trials, including the phase 3 ALCANZA trial and two additional phase 3 studies, one in frontline classical Hodgkin lymphoma and one in frontline mature T-cell lymphomas, as well as trials in many additional types of CD30-expressing malignancies, including B-cell lymphomas.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS Global Important Safety Information
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory (r/r) CD30+ Hodgkin lymphoma (HL):

Following autologous stem cell transplant or
Following at least 2 prior therapies when autologous stem cell transplantation is not a treatment option
ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

ADCETRIS is contraindicated for patients who are hypersensitive to ADCETRIS. In addition, combined use of bleomycin and ADCETRIS causes pulmonary toxicity, and is contraindicated.

ADCETRIS can cause serious side effects, including:

Progressive multifocal leukoencephalopathy (PML): John Cunningham virus (JCV) reactivation resulting in PML and death has been reported in patients treated with ADCETRIS. Patients should be closely monitored for new or worsening neurological, cognitive, or behavioral signs or symptoms, which may be suggestive of PML.

Pancreatitis: Acute pancreatitis has been observed in patients treated with ADCETRIS. Fatal outcomes have been reported. Patients should be closely monitored for new or worsening abdominal pain.

Pulmonary Toxicity: Cases of pulmonary toxicity have been reported in patients receiving ADCETRIS. In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed.

Serious infections and opportunistic infections: Serious infections such as pneumonia, staphylococcal bacteraemia, sepsis/septic shock (including fatal outcomes), and herpes zoster, and opportunistic infections such as Pneumocystis jiroveci pneumonia and oral candidiasis have been reported in patients treated with ADCETRIS. Patients should be carefully monitored during treatment for emergence of possible serious and opportunistic infections.

Infusion-related reactions: Immediate and delayed infusion-related reactions, as well as anaphylaxis, have occurred with ADCETRIS. Patients should be carefully monitored during and after an infusion.

Tumor lysis syndrome (TLS): TLS has been reported with ADCETRIS. Patients with rapidly proliferating tumor and high tumor burden are at risk of TLS and should be monitored closely and managed according to best medical practice.
Peripheral neuropathy (PN): ADCETRIS treatment may cause PN that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. Patients should be monitored for symptoms of PN, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness.

Hematological toxicities: Grade 3 or Grade 4 anemia, thrombocytopenia, and prolonged (equal to or greater than one week) Grade 3 or Grade 4 neutropenia can occur with ADCETRIS. Complete blood counts should be monitored prior to administration of each dose.

Febrile neutropenia: Febrile neutropenia has been reported. Patients should be monitored closely for fever and managed according to best medical practice.

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): SJS and TEN have been reported. Fatal outcomes have been reported.

Hyperglycemia: Hyperglycemia has been reported during trials in patients with an elevated body mass index (BMI) with or without a history of diabetes mellitus. Any patient who experiences an event of hyperglycemia should have their serum glucose closely monitored.

Renal and hepatic impairment: There is limited experience in patients with renal and hepatic impairment. Population pharmacokinetic analysis indicated that MMAE clearance might be affected by moderate and severe renal impairment, and by low serum albumin concentrations. Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported. Liver function should be routinely monitored in patients receiving brentuximab vedotin.

Sodium content in excipients: This medicinal product contains a maximum of 2.1 mmol (or 47mg) of sodium per dose. To be taken into consideration for patients on a controlled sodium diet.

Serious adverse drug reactions were: neutropenia, thrombocytopenia, constipation, diarrhea, vomiting, pyrexia, peripheral motor neuropathy and peripheral sensory neuropathy, hyperglycemia, demyelinating polyneuropathy, tumor lysis syndrome, and Stevens-Johnson syndrome.

ADCETRIS was studied as monotherapy in 160 patients in two Phase 2 studies. Across both studies, adverse reactions defined as very common (≥1/10) were: infections, neutropenia, peripheral sensory neuropathy, diarrhea, nausea, vomiting, alopecia, pruritis, myalgia, fatigue, pyrexia, and infusion-related reactions. Adverse reactions defined as common (≥1/100 to <1/10) were: upper respiratory tract infection, herpes zoster, pneumonia, anemia, thrombocytopenia, hyperglycemia, peripheral motor neuropathy, dizziness, demyelinating polyneuropathy, cough, dyspnea, constipation, rash, arthralgia, back pain, and chills.

These are not all of the possible side effects with ADCETRIS. Please refer to Summary of Product Characteristics (SmPC) before prescribing.

BI 836909 is a Bispecific T cell Engager (BiTE), designed to redirect the body’s endogenous T cells towards cells expressing B cell maturation antigen (BCMA) on the cell surface (Presentation, ASH (Free ASH Whitepaper), DEC 6, 2015, View Source [SID:1234510960]).
BCMA is a highly plasma cell specific antigen and shows homogeneous expression on the cell surface of multiple myeloma, plasma cell leukemia and plasmacytoma cells. In normal tissues, BCMA expression is restricted to plasma cells, while other normal tissues do not express BCMA. This highly selective expression pattern makes BCMA an ideal target for T cell redirecting therapy.

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The pharmacological effect of BI 836909 depends on its simultaneous binding to both the CD3 epsilon subunit of the T cell receptor complex on T cells as well as to BCMA on multiple myeloma cells, resulting in the lysis of the BCMA-expressing cells.

In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several multiple myeloma cell lines and increasing concentrations of BI 836909, and tumor cell lysis, T cell activation, and induction of cytokine release were assessed. BI 836909 induced dose-dependent redirected lysis of human multiple myeloma cell lines with EC90 values ranging from 16 to 810 pg/mL. Viability of BCMA-negative cells was not affected, demonstrating the specificity of BI 836909 for BCMA. The expression of the activation markers CD69 and CD25 on T cells and the release of cytokines by T cells were target-dependent and occurred only in the presence of BCMA-positive cells.

In vivo anti-tumor activity of BI 836909 was assessed in NOD/SCID mice reconstituted with human T cells and bearing subcutaneous or orthotopic xenografts derived from human multiple myeloma cell lines.

In the subcutaneous NCI-H929 xenograft model, animals were treated with BI 836909 by daily intravenous or subcutaneous bolus injections. Statistically significant dose-dependent anti-tumor activity was observed at doses of 50 µg/kg/day and higher. The efficacy of BI 836909 was comparable after intravenous and subcutaneous administration, when the difference in bioavailability of the different routes was considered.

In an orthotopic L-363 xenograft model, treatment with BI 836909 resulted in a statistically significant prolonged survival at doses of 5 µg/kg/day and higher.

BI 836909 shows comparable cross-reactive binding to both BCMA and CD3 epsilon of human and macaque origin at picomolar and low nanomolar affinities respectively, thus allowing the assessment of pharmacodynamics, pharmacokinetics, and safety in non-human primates. In toxicity studies, cynomolgus monkeys were administered doses of up to 135 µg/kg/day of BI 836909 via continuous intravenous infusion, and up to 405 µg/kg/day via daily subcutaneous injection for up to 28 days. A dose- dependent decrease in plasma cells was observed in the bone marrow of treated animals compared to the vehicle control group, consistent with BCMA expression on cynomolgus monkey plasma cells, this demonstrated the pharmacological activity of BI 836909.

These pre-clinical data demonstrate that BI 836909 is a highly potent, efficacious and BCMA-selective T cell redirecting agent and support clinical testing of BI 836909 in multiple myeloma patients.

On December 5, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported updated data from the pivotal CLL11 study confirming that Gazyva/Gazyvaro (obinutuzumab) plus chlorambucil reduced the risk of disease worsening or death by more than half compared to MabThera/Rituxan (rituximab) plus chlorambucil (progression-free survival, PFS; HR=0.46, median PFS 28.7 months versus 15.7 months; p<0.0001) (Press release, Hoffmann-La Roche , DEC 5, 2015, View Source [SID:1234508417]). New results to be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting from a secondary endpoint that measured time to next treatment (TTNT) showed that, after completing the set six-month Gazyva/Gazyvaro regimen, people remained treatment-free for nearly four years on average before needing the next treatment for their cancer (TTNT; 51.1 months, including the six month initial treatment period). No unexpected safety signals were observed with Gazyva/Gazyvaro.

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"These updated CLL11 data confirmed that Gazyva/Gazyvaro helped people with previously untreated chronic lymphocytic leukaemia live significantly longer without disease worsening or death compared to MabThera/Rituxan," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "After a fixed course of therapy with Gazyva/Gazyvaro, people remained treatment-free for nearly four years on average. Time free from treatment is an important consideration for a disease like CLL, which occurs in older adults who frequently have other health issues. "

In the GREEN safety study, data from a subgroup analysis showed there were no unexpected safety signals when Gazyva/Gazyvaro was combined with bendamustine. In addition, nearly 80 percent of people responded to treatment with Gazyva/Gazyvaro plus bendamustine (overall response, ORR), and a third of people (32.3 percent) achieved a complete response (CR). A substantial number of people were also minimal residual disease (MRD) negative when measured in the bone marrow or blood (28 percent and 59 percent, respectively), which means no cancer can be detected using a specific test. Overall response rate and MRD were secondary endpoints of the study.

Gazyva/Gazyvaro in combination with chlorambucil is approved in the United States for use in people with previously untreated CLL and in the EU for use in people with previously untreated CLL who have comorbidities making them unsuitable for an intensive therapy (full-dose fludarabine based therapy).

About the CLL11 study
CLL11 is a Phase III, multicentre, open-label, randomised three-arm study investigating the efficacy and safety profile of Gazyva/Gazyvaro plus chlorambucil, MabThera/Rituxan plus chlorambucil and chlorambucil alone in 781 people with previously untreated CLL. Stage 1a (n=589) compared Gazyva/Gazyvaro plus chlorambucil to chlorambucil alone and MabThera/Rituxan plus chlorambucil to chlorambucil alone. Stage 2 (n=663) compared Gazyva/Gazyvaro plus chlorambucil with MabThera/Rituxan plus chlorambucil.

The primary endpoint of the study was PFS and secondary endpoints included overall response rate (ORR), overall survival (OS), complete response rate (CR), response duration, disease free survival (DFS), time to next treatment (TTNT), minimal residual disease (MRD) negativity and safety profile.

The updated analysis from CLL11 will be presented at a poster session on Saturday 5 December at 5:30 pm EST (Abstract #1733).

About the GREEN study
GREEN is an ongoing Phase IIIb safety study. This multicentre, open-label, single-arm study is evaluating the safety and efficacy of Gazyva/Gazyvaro alone or in combination with chemotherapy, including bendamustine, in people with previously untreated or relapsed/refractory CLL. The primary endpoint of the study was safety with secondary endpoints including overall response rate (ORR) and minimal residual disease (MRD) negativity.
The study included a subgroup of people who were previously untreated and who received treatment with Gazyva/Gazyvaro in combination with bendamustine. Data from this subgroup analysis will be presented at an oral presentation on Monday, 7 December at 7:00 am EST (Abstract #493).

About Gazyva/Gazyvaro (obinutuzumab)
Gazyva/Gazyvaro is an engineered monoclonal antibody designed to attach to CD20, a protein found only on B-cells. Gazyva/Gazyvaro is designed to attack and destroy targeted B-cells both directly and together with the body’s immune system.
Gazyva/Gazyvaro is currently approved in more than 60 countries in combination with chlorambucil, for people with previously untreated CLL. The approval was based on the CLL11 study, showing significant improvements with Gazyva/Gazyvaro plus chlorambucil across multiple clinical endpoints, including progression-free survival (PFS), overall response rate (ORR), complete response rate (CR), and minimal residual disease (MRD) when compared head-to-head with MabThera/Rituxan plus chlorambucil.
Gazyva is marketed as Gazyvaro in the EU and Switzerland.

Gazyva/Gazyvaro is being studied in a large clinical programme, including the Phase III GOYA and GALLIUM studies. GOYA is comparing Gazyva/Gazyvaro head-to-head with MabThera/Rituxan plus CHOP chemotherapy in first line diffuse large B-cell lymphoma (DLBCL) and GALLIUM is comparing Gazyva/Gazyvaro plus chemotherapy followed by Gazyva/Gazyvaro maintenance head-to-head with MabThera/Rituxan plus chemotherapy followed by MabThera/Rituxan maintenance in first line indolent non-Hodgkin’s Lymphoma (NHL). Additional combination studies investigating Gazyva/Gazyvaro with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, are planned or underway across a range of blood cancers.

About CLL
CLL is the most common type of leukaemia in the Western world. It accounts for 25-30% of all leukaemias1, equating to over 80,000 cases of CLL being diagnosed each year2.

On December 5, 2015 Incyte Corporation (Nasdaq:INCY) reported data from two Phase 3 studies evaluating the long-term safety and efficacy of Jakafi (ruxolitinib) in patients with Myeloproliferative Neoplasms (MPNs) (Press release, Incyte, DEC 5, 2015, View Source;p=RssLanding&cat=news&id=2120390 [SID:1234508420]). In myelofibrosis (MF), results of a five-year follow-up from the COMFORT-II study demonstrate a continued survival benefit in patients originally randomized to ruxolitinib compared with patients randomized to best available therapy (BAT), with a 33 percent reduction in the risk of death (HR, 0.67; 95%CI, 0.44-1.02; P=.06). Because patients in the BAT arm had crossed over to receive ruxolitinib therapy (median 17 months after randomization), these data may suggest that earlier treatment with ruxolitinib may be associated with improved long-term survival in patients with intermediate-2 or high-risk MF. Additionally, 53 percent of patients treated with ruxolitinib (n=78/146) achieved at least a 35 percent reduction in spleen volume from baseline that was sustained over time (median duration 3.2 years).

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"These data from the COMFORT-II study reinforce the positive and long-term clinical benefits seen in patients with myelofibrosis who are treated with Jakafi," said Rich Levy, MD, Chief Drug Development Officer, Incyte. "The reduction in the risk of death and the sustained improvements in spleen volume are meaningful and important results for the community of patients with this rare blood cancer."

An analysis of the RESPONSE study is also planned for presentation at ASH (Free ASH Whitepaper). Previously published results in the New England Journal of Medicine showed that treatment with ruxolitinib, compared to standard therapy improved hematocrit control and reduced spleen volume in patients with polycythemia vera (PV) who had an inadequate response to or had unacceptable side effects from hydroxyurea (HU). The data at ASH (Free ASH Whitepaper) demonstrate that in patients with elevated white blood cell (WBC) counts at baseline, a greater proportion of patients in the ruxolitinib treatment arm (45%) achieved normalization of their WBC counts (achieving a WBC ≤10×109/L or a ≥50% reduction from baseline) compared to BAT (22%) or HU (9%) at week 32.
These data are scheduled for presentation at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place December 5-8, 2015 in Orlando, FL.

Results from the COMFORT-II Study

Data from a five-year follow-up of the COMFORT-II trial, a randomized, open-label Phase 3 study evaluating long-term safety and efficacy of ruxolitinib in patients with intermediate-2 or high-risk primary myelofibrosis, post-PV myelofibrosis, or post-ET myelofibrosis, allowing crossover from the BAT arm to ruxolitinib after 48 weeks upon protocol-defined progression, revealed that 53 percent of patients treated with ruxolitinib (n=78/146) achieved at least a 35 percent reduction in spleen volume from baseline while on treatment during the study. Additionally, approximately one-third of evaluable JAK2 V617F-positive patients had more than a 20 percent reduction in allele burden at 3.2 years (38%) and 3.7 years (31%). Patients treated with ruxolitinib also experienced improvements in bone marrow fibrosis (15.8%) with 32.2 percent reporting stable fibrosis scores.

Overall, 59 (40%) and 35 (48%) deaths were reported in the ruxolitinib and BAT arms, respectively. Median overall survival (OS) was not reached in the ruxolitinib arm and was 4.1 years in the group of patients originally receiving BAT. There was a 33 percent reduction in risk of death with ruxolitinib (HR, 0.67; 95 percent CI, 0.44-1.02; P=.06). The estimated probability of survival at 5 years was 56 percent with ruxolitinib and 44 percent with patients originally receiving BAT. At week 48, BAT patients were allowed to cross over to receive ruxolitinib upon protocol-defined progression and after week 48 all BAT patients, irrespective of their progression status, were allowed to crossover to receive ruxolitinib; therefore, a confounding effect on OS was observed. An analysis correcting for crossover will be presented.

Adverse events (AEs) were consistent with those reported in previous studies of ruxolitinib and there was no increase in the incidence of AEs with longer exposure to treatment.

COMFORT-II is scheduled for presentation as an oral session by Dr. Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, Guy’s Hospital, Saturday, December 5, 2015, 9:30-11:30 AM EST, Room W224.

Results from the RESPONSE Study
The RESPONSE trial is a Phase 3 open-label study evaluating long-term safety and efficacy of ruxolitinib in patients with PV compared to BAT who had an inadequate response to or had unacceptable side effects from HU. The analysis from RESPONSE to be presented at ASH (Free ASH Whitepaper) shows that patients who received ruxolitinib had greater mean reductions in WBC counts compared with BAT or the HU subgroup of the BAT arm, and these reductions were maintained over time. In patients with baseline WBC counts ≥11×109/L, worsening WBC counts were observed in 10.8 percent of patients in the ruxolitinib arm versus 35.4 percent in the BAT arm (P=0.0002) and 47.8 percent in the HU subgroup (P<0.0001). In this same subgroup of patients with elevated WBC counts at baseline, a greater proportion of patients in the ruxolitinib arm (45%) normalized their WBC counts (achieving a WBC ≤10×109/L or a ≥50% reduction from baseline) compared with BAT (22%) or HU (9%) at week 32. The median time to achieve this response with ruxolitinib therapy was 8 weeks.

These data are scheduled for presentation as a poster session by Dr. Carole Miller, Saint Agnes Cancer Institute, Monday, December 7, 2015, 6:00-8:00 PM EST, Hall A.

About Myelofibrosis
MF is part of a group of related rare blood cancers known as myeloproliferative neoplasms (MPNs) where a patient’s bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge1. As a result, patients with MF may suffer from debilitating symptoms and have a poor quality of life2. After diagnosis, patients with MF have a decreased life expectancy, with an average survival of approximately five to six years3. Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5% of patients who are young and fit enough to undergo the procedure4.

About Polycythemia Vera
Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) and 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 count5. Patients with PV who fail to consistently maintain appropriate blood count levels, including appropriate hematocrit levels, have an approximately four times higher risk of major thrombosis (blood clots) or cardiovascular death6. Patients with PV can also suffer from an enlarged spleen and a significant symptom burden which may be attributed to thickening of the blood and lack of oxygen to parts of the body7. These symptoms commonly include fatigue, itching, night sweats, bone pain, fever, and weight loss8.

Approximately 100,000 patients in the U.S. are living with PV9. Current standard treatment for PV is phlebotomy (the removal of blood from the body) plus aspirin. When phlebotomy can no longer control PV, chemotherapy such as hydroxyurea, or interferon, is utilized10,11. Approximately one in four patients with PV are considered uncontrolled12,13 because they have an inadequate response to or are intolerant of hydroxyurea, the most commonly used chemotherapeutic agent for the treatment of PV.

About Jakafi (ruxolitinib)

Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. Food and Drug Administration, for treatment of people with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea.

Jakafi is also indicated for treatment of people with intermediate or high-risk myelofibrosis (MF), including primary MF, post–polycythemia vera MF, and post–essential thrombocythemia MF.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States.

Important Safety Information

Jakafi can cause serious side effects, including:
Low blood counts: Jakafi may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you experience unusual bleeding, bruising, fatigue, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.
Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

The most common side effects of Jakafi include: anemia, low platelet count, bruising, dizziness, headache.
These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had liver or kidney problems, are on dialysis, had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider. Do not drink grapefruit juice while on Jakafi.

Women should not take Jakafi while pregnant or planning to become pregnant, or if breast-feeding.

Full Prescribing Information, including a more complete discussion of the risks associated with Jakafi, is available at www.jakafi.com.

On December 5, 2015 Novartis reported that five-year treatment with Jakavi (ruxolitinib) suggested an overall survival advantage for patients with myelofibrosis (MF), despite crossover to Jakavi from the best available therapy arm after the primary analysis at 48 weeks (intent-to-treat analysis: 33% reduction in risk of death, hazard ratio=0.67 [95% confidence interval (CI), 0.44-1.02], crossover-corrected hazard ratio=0.44 [95% CI, 0.18-1.04]) (Press release, Novartis, DEC 5, 2015, View Source [SID:1234508421]). In the COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) Phase III study, more than half of the patients with MF (53.4%) also experienced significant reductions (>=35%) in spleen size with Jakavi therapy, and sustained this benefit over prolonged periods of time (median duration of 3.2 years)[1]. Findings from this study were presented at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting (ASH) (Free ASH Whitepaper) in Orlando, Florida.

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"Given that patients with myelofibrosis have shortened survival expectations and are at an increased risk of complications, the five-year findings from COMFORT-II demonstrate a long-term benefit with Jakavi therapy that is meaningful to the community," said Claire Harrison, MD, study investigator and Consultant Hematologist, Guy’s and St. Thomas’ NHS Foundation Trust, London. "These data help to confirm the important role Jakavi plays in these difficult-to-treat patients."

In addition to the Jakavi data presented at ASH (Free ASH Whitepaper), Novartis announced that a separate Phase III study met its primary endpoint-patients with polycythemia vera (PV) resistant to or intolerant of hydroxyurea who did not have an enlarged spleen who were treated with Jakavi maintained hematocrit control without the need for phlebotomy. In the Phase III RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) study, the safety profile of Jakavi was consistent with previous studies. Full results from the trial continue to be evaluated and will be presented at a future medical congress.

"The growing body of research confirms the benefit of Jakavi for patients with rare blood cancers, such as myelofibrosis and polycythemia vera, who have limited treatment options," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "In addition to exhibiting long-term benefits in myelofibrosis, Jakavi also showed potential to benefit a broader population of patients with polycythemia vera, bringing hope to another underserved patient community."

About the COMFORT-II Study
COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) is a randomized, open-label, Phase III study of 219 patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) in 56 study locations in Europe. Two-thirds of patients (146) received Jakavi twice daily and one-third of patients (73) received best available therapy, which was administered at doses and schedules determined by the investigator. Best available therapy was selected by the investigator for each patient and could have included a combination of available agents to treat the disease and/or its symptoms. Of the patients on the best available therapy arm, 61.6% crossed over to receive Jakavi upon protocol-defined progression following the primary analysis after week 48. All patients randomized to best available therapy have crossed over or discontinued. An analysis of the study at five years was performed to evaluate the safety and efficacy of Jakavi in patients with MF[1].

In the Phase III trial, fibrosis grades, a key indicator of disease control in MF, improved (15.8%) or were maintained (32.2%) in nearly half of patients with long-term Jakavi treatment. Nearly one-quarter of patients (26.7% from Jakavi treatment arm; 24.4% who crossed over from best available treatment arm) remained on treatment with Jakavi for five years. All adverse events (AEs) were consistent with previous analyses of treatment with Jakavi in patients with MF. The most common AEs in Jakavi-treated patients either after randomization or after crossing over from best available therapy were thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%) and peripheral edema (33.0%). The most common grade 3/4 AEs included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%) and shortness of breath (4.2%)[1].

About the RESPONSE 2 Study
RESPONSE 2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) is a multi-center, open label, randomized, Phase IIIb study evaluating the efficacy and safety of Jakavi versus best available therapy. The trial randomized 149 patients with PV who were resistant to or intolerant of hydroxyurea, dependent on phlebotomy for hematocrit control and did not have an enlarged spleen. Patients were randomized 1:1, by stratification (based on hydroxyurea resistance or intolerance) to receive either Jakavi (10 mg twice daily) or best available therapy, which was defined as investigator selected monotherapy or observation only. The dose was adjusted as needed throughout the study.

About Myelofibrosis
MF is part of a group of related rare blood cancers known as myeloproliferative neoplasms (MPNs) where a patient’s bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge[2]. As a result, patients with MF may suffer from debilitating symptoms and have a poor quality of life[4]. After diagnosis, patients with MF have a decreased life expectancy, with an average survival of approximately five to six years[5]. Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5% of patients who are young and fit enough to undergo the procedure[6].

About Polycythemia Vera
Also an MPN, PV is associated with an overproduction of blood cells in the bone marrow and affects roughly one to three people per 100,000 globally[3],[7]. The disease is driven by the dysregulation of the JAK-STAT pathway[8]. 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[3]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[9]. Approximately 60 to 70% of patients with PV do not have enlarged spleen[10].

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%[3],[9]. However, for a subset of patients, including those with high-risk PV, 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[9]. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time[11]. Unfortunately, approximately 25% of patients with PV become resistant to or intolerant of hydroxyurea treatment according to European LeukemiaNet (ELN) criteria, resulting in inadequate disease control and an increased risk of progression[12].

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 (MF) (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is approved in more than 95 countries for patients with MF, including countries in the European Union, Canada, Japan and countries in Asia, Latin and South America, and in 49 countries for patients with PV, including countries in the European Union, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF 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 MF.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF 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 MF 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[13].

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 indications.

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.