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ARIAD Announces Long-Term Safety and Efficacy Data of Ponatinib from Phase 2 Pace Clinical Trial

On June 13, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ:ARIA) reported long-term follow-up data from its pivotal Phase 2 PACE clinical trial of Iclusig (ponatinib), its approved BCR-ABL inhibitor, in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (Press release, Ariad, JUN 13, 2016, View Source [SID:1234513239]). Responses have been maintained long-term in chronic phase CML (CP-CML) patients. The study shows that patients treated with Iclusig continued to demonstrate anti-leukemic activity with a median follow-up of 4.0 years for CP-CML. Additionally, 96 percent of CP-CML patients who underwent ponatinib dose reductions while in response maintained their responses (MCyR) at the four year timepoint.

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"We remain very pleased by these continued responses in the PACE study in such a heavily pretreated patient population, as 59 percent of patients had previously received three or more approved tyrosine kinase inhibitors (TKIs). Altogether, 82 percent of CP-CML patients who achieved MCyR are estimated to remain in MCyR at four years," stated Jorge E. Cortes, M.D., professor and deputy chair, department of leukemia, University of Texas MD Anderson Cancer Center. "These data showing long-term major cytogenic response offer the optimism of favorable outcomes for many patients who previously had no or very limited treatment options available."

The data were featured at the 21st Conference of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

PACE Trial Update

The efficacy and safety of ponatinib in CML and Ph+ ALL patients resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation, were evaluated in the PACE trial. A total of 449 patients were treated with ponatinib at a starting dose of 45 mg/day. An estimated 93 percent of patients received two or more approved tyrosine kinase inhibitors (TKIs), and 59 percent of all patients received three or more approved TKIs. Enrollment in the PACE trial was completed in October 2011.

Updated data on CP-CML patients (n=270) from the ongoing trial indicate that with a median follow-up of 48.2 months (data as of August 3, 2015), 110 patients (41%) continued to receive ponatinib. Additional data for CP-CML patients include:

59 percent of CP-CML patients achieved MCyR (primary endpoint) at any time.
82 percent of patients who achieved MCyR are estimated to remain in MCyR at four years by Kaplan-Meier analysis.
39 percent of patients achieved a major molecular response (MMR) or better at any time.
By Kaplan-Meier analysis, progression-free survival at four years is estimated to be 56 percent.
Overall survival at four years is estimated to be 77 percent.
23 percent of CP-CML patients experienced arterial occlusive events (AOE) that were designated a serious adverse event (SAE), and 29 percent of CP-CML patients experienced any AOE.
4 percent of CP-CML patients experienced a venous thromboembolic SAE, and 5 percent of all patients experienced a venous thromboembolic SAE.
The most common any-grade treatment-emergent adverse events occurring in ≥ 20 percent of CP-CML patients included abdominal pain (46%), rash (47%), thrombocytopenia (45%), headache (43%), constipation (41%), and dry skin (42%).
"These data continue to show that ongoing CP-CML patients in the PACE trial have retained long-term cytogenetic and molecular responses at a median of four years follow-up," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "We currently have two additional trials underway evaluating Iclusig. Our OPTIC randomized trial evaluating Iclusig at starting doses of 45 mg/day or lower, is currently enrolling patients. Outside the U.S., we initiated our randomized Phase 3 trial of Iclusig in second-line patients with CP-CML called OPTIC-2L in December of 2015 and expect full enrollment in the trial in 2018."

Efficacy Update Following Dose-Reduction Recommendations

(Data from October 10, 2013 to August 3, 2015)

On October 10, 2013, dose-reduction recommendations were provided by ARIAD to investigators for patients remaining on the PACE trial. The following dose reductions were recommended, unless the benefit-risk analysis warranted treatment with a higher dose:

CP-CML patients who already achieved a MCyR should have their ponatinib dose reduced to 15 mg/day,
CP-CML patients who had not already achieved MCyR should have their dose reduced to 30 mg/day, and
Advanced-phase patients should have their dose reduced to 30 mg/day.
As of August 3, 2015, with an additional 1.9 years (22 months) of follow up after these recommendations, maintenance of response (MCyR) in CP-CML patients was 95 percent (56 of 59) and 100 percent (25 patients), respectively, for patients who were either at 15 mg/day in October 2013 or were reduced to 15 mg/day after October 2013.

Of the 69 patients who were in MCyR as of October 10, 2013 and had a dose reduction, 66 patients (96%) maintained their response at 1.9 years following prospective dose reduction.
Of the 51 patients who were in MMR as of October 10, 2013 and had a dose reduction, 46 patients (90%) maintained MMR at 1.9 years following dose reduction.
35 patients in MCyR did not undergo any dose reductions (the majority of which were already at a reduced dose of 30 mg/day or 15 mg/day as of October 10, 2013); of these, 33 patients (94%) maintained MCyR after 1.9 more years of ponatinib treatment.
Safety Update Following Dose-Reduction Recommendations (Data from October 10, 2013 to August 3, 2015)

Of the patients who underwent dose reduction, six of 75 patients (8%) without prior AOEs had a new AOE during the 1.9-year interval following dose reduction.
31/75 patients reduced from 45 mg to 15 mg
25 /75 patients reduced from 30 mg to 15 mg
19/75 patients reduced either other doses (45 mg to 30 mg or not specified)
Of the patients who did not undergo dose reduction, 10 of 62 patients (16%) without prior AOE had a new AOE in the same time interval.
36 /62 patients were at 15 mg
26/62 were at 45 mg or 30 mg
About Iclusig (ponatinib) tablets

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Limitations of use: Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.
Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent Iclusig 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to singe agent imatinib 400 mg once-daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension and skin and subcutaneous tissue disorders. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP CML.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4).

Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning.

Pfizer Announces Final Results from Inotuzumab Ozogamicin Pivotal Phase 3 Study in Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia

On June 12, 2016 Pfizer Inc. today reported the publication of findings from the Phase 3 INO-VATE ALL study in the online issue of The New England Journal of Medicine (Press release, Pfizer, JUN 12, 2016, View Source [SID:1234513240]). The study, also known as Study 1022, is an open-label, randomized, Phase 3 study evaluating the safety and efficacy of inotuzumab ozogamicin as compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). Results showed improvement over chemotherapy on a number of measures including complete hematologic remission and progression-free survival (PFS). Updated results and newly available overall survival (OS) data were also presented as a late-breaking oral presentation (#LB2233) today at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) 2016 Annual Meeting in Copenhagen, Denmark.

"Relapsed or refractory ALL is an aggressive leukemia in urgent need of new treatment options as about half of adult patients will not respond to chemotherapy or will see their disease return," said Hagop M. Kantarjian, M. D., lead study investigator and professor, The University of Texas MD Anderson Cancer Center. "The efficacy results seen in patients treated with inotuzumab ozogamicin in this study are impressive, particularly median progression-free survival, high rates of hematological remission and absence of minimal residual disease. These results suggest inotuzumab ozogamicin, if approved, could be a valuable new addition to currently available treatment options for ALL patients, including as a bridge to stem cell transplantation, which is the best chance for a cure at this stage of the disease."

The INO-VATE ALL study had two independent primary endpoints, complete response with or without hematologic remission and OS. INO-VATE ALL met its first primary endpoint of complete response, which was significantly better with inotuzumab ozogamicin compared to chemotherapy (80.7% [95% CI, 72%-88%] vs. 29.4% [95% CI, 21%-39%], P<0.001). Inotuzumab ozogamicin also significantly extended PFS compared to chemotherapy (HR: 0.45 [97.5% CI, 0.34-0.61], P<0.001; median PFS, 5.0 vs. 1.8 months, in their respective arms). The second primary endpoint of OS showed a strong trend toward longer OS for patients treated with inotuzumab ozogamicin compared to chemotherapy, but did not reach the level of statistical significance (p < 0.0104) for the trial (HR: 0.77 [97.5% CI, 0.58-1.03], one-sided P=0.0203; median OS, 7.7 months [95% CI, 6.0-9.2] vs. 6.7 months [95% CI, 4.9-8.3]). The two-year OS rate for inotuzumab ozogamicin was 23 percent (95% CI, 16%‒30%) compared to chemotherapy at 10 percent (95% CI, 5%‒16%).

"Adult patients with relapsed or refractory ALL have a five-year survival rate of less than 10 percent, making these patients particularly difficult to treat. To see remission rates and two-year survival rates that are more than doubled compared to standard of care chemotherapy is very gratifying. We believe these data add to the growing body of evidence that supports inotuzumab ozogamicin as an important potential treatment option in adults with relapsed or refractory ALL," said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.

Results from INO-VATE ALL also showed patients treated with inotuzumab ozogamicin achieved high rates of minimal residual disease (MRD) negativity (78.4% [95% CI, 68%-87%; P<0.001]), and experienced a duration of response (DOR) of 4.6 months (95% CI, 3.9-5.4; HR: 0.55; P<0.034). In comparison, 28.1 percent (95% CI, 14%-47%; P<0.001) of patients treated with chemotherapy achieved MRD negativity and median DOR was 3.1 months (95% CI, 1.4-4.9; HR: 0.55; P<0.034). More patients also proceeded to stem-cell transplant with inotuzumab ozogamicin compared to standard chemotherapy (41% vs. 11%, P<0.001).

The most common adverse events (AEs) observed for both inotuzumab ozogamicin and chemotherapy were cytopenias, including febrile neutropenia (16% vs. 22%). Common nonhematologic treatment-emergent AEs with inotuzumab ozogamicin included nausea (32%), headache (28%) and pyrexia (27%). Patients in the chemotherapy arm experienced nausea (47%), pyrexia (43%) and diarrhea (40%).

Additionally, any-grade veno-occlusive liver disease (VOD) occurred more frequently in patients treated with inotuzumab ozogamicin compared to chemotherapy (11% vs. 1%). Five patients taking inotuzumab ozogamicin developed VOD during treatment and 10 patients developed VOD after subsequent stem cell transplant. Among those taking chemotherapy, one patient developed VOD after transplant; no cases of VOD occurred during treatment with chemotherapy.

Inotuzumab ozogamicin received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for ALL in October 2015. Pfizer is working closely with the FDA and other regulatory authorities with the aim of making inotuzumab ozogamicin available for adult patients with relapsed or refractory CD22-positive ALL.

About Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia with a poor prognosis in adults.1 The current foundational treatment is intensive, long-term chemotherapy.2 In 2016, it is estimated that 6,590 cases of ALL will be diagnosed in the United States, with about 2 in 5 cases in adults.3 Approximately 20 to 40 percent of newly diagnosed adults with ALL are cured with current treatment regimens.4 For patients with relapsed or refractory adult ALL, the five-year overall survival rate is less than 10 percent.5

About Inotuzumab Ozogamicin

Inotuzumab ozogamicin is an investigational antibody-drug conjugate (ADC) comprised of a monoclonal antibody (mAb) targeting CD22, a cell surface antigen found on cancer cells in almost all B-ALL patients, linked to a cytotoxic agent. 1,6 When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is thought to be internalized into the cell, where the cytotoxic agent calicheamicin is released to destroy the cell.7

Inotuzumab ozogamicin originates from a collaboration between Pfizer and Celltech, now UCB. Pfizer has sole responsibility for all manufacturing and clinical development activities for this molecule.

Results of Phase III study of volasertib for the treatment of acute myeloid leukaemia presented

On June 11, 2016, Boehringer Ingelheim reported the results of the Phase III POLO-AML-2 trial (NCT01721876) investigating volasertib plus chemotherapy (low dose cytarabine LDAC), in the treatment of elderly acute myeloid leukaemia (AML) patients, did not meet the primary endpoint of objective response (Press release, Boehringer Ingelheim, JUN 11, 2016, View Source [SID1234535646]).1 Boehringer Ingelheim is committed to further investigating volasertib with a revised research strategy based on the learnings of the trial, which demonstrated the compound’s anti-leukaemic activity and an increased response rate.
The results presented at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) 2016 showed the percentage of patients with an objective response was higher with volasertib plus LDAC, compared to placebo plus LDAC but the difference was statistically not significant.1 The data showed an unfavourable overall survival trend for the experimental treatment arm, with the safety profile of the volasertib plus LDAC dosing regimen considered as the main reason for the trend.1

Martin Stefanic, Medical Head, Early Clinical Development, Boehringer Ingelheim commented: "We are disappointed with the findings of the POLO-AML-2 trial after the encouraging results we observed in the Phase II trial. However, we believe in the potential of volasertib and new clinical studies have been initiated for AML patients, in addition to other areas of high unmet need such as higher risk myelodysplastic syndromes (MDS). The goal of these studies is to improve tolerability with modified dosing and scheduling of volasertib, while not compromising on efficacy, in order to achieve the best outcome for patients."

POLO-AML-2 (NCT01721876) is a randomised, double-blind, multi-centre, controlled Phase III clinical trial of volasertib in combination with LDAC in 666 patients aged 65 years and older with newly diagnosed AML, not suitable for intensive induction therapy.1 The primary analysis showed a higher number of patients responded to volasertib plus LDAC (25.2%) than placebo plus LDAC (16.8%) but the overall result was not statistically significant.1

There was a higher incidence of severe adverse events with volasertib plus LDAC, with a fatal infection frequency of 16.6% (volasertib plus LDAC) vs 5.1% (placebo plus LDAC) which was considered the main reason for a negative overall survival trend in the volasertib plus LDAC treatment arm compared to placebo plus LDAC (primary OS analysis: HR 1.26 [95% CI 0.95–1.67; p=0.113]; updated OS analysis (Nov 2015): HR 1.06 (95% CI 0.88–1.28; p=0.552).1 The unblinded trial is still ongoing and updated results will be presented at a future scientific meeting when they are available.
Boehringer Ingelheim has a substantial programme in haematological cancers with five investigational compounds in early clinical development.

References
1 Döhner H et al. Phase III randomized tial of volasertib plus low–dose cytarabine (LDAC) versus placebo plus LDAC in patients aged ≥65 years with previously untreated AML, ineligible for intensive therapy. Abstract # S501 presented at the 2016 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting, Copenhagen, Denmark, 9-12 June 2016

Janssen’s EPREX® (epoetin alfa) Demonstrates Effectiveness as a Treatment for Anaemia in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes

On June 11, 2016 Janssen-Cilag International NV reported results from the international Phase 3, randomised, double-blind, placebo-controlled, multicentre study, EPOANE 3021 (Press release, Janssen-Cilag International, JUN 11, 2016, View Source [SID:1234513282]).The study demonstrated the efficacy and safety of EPREX (epoetin alfa) as a treatment for anaemia, in adult patients with low or intermediate-1 risk myelodysplastic syndromes (MDS), as classified by an International Prognostic Scoring System (IPSS).1 EPOANE 3021 data were presented at the 21st Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Abstract P248).

These data, along with three registry studies from across Europe, have been submitted to the French health authority Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM), as the reference health authority for EPREX (epoetin alfa) within the mutual recognition procedure, to extend the existing marketing authorisation in Europe. A decision is expected in the coming months.

EPOANE 3021 was designed to evaluate whether epoetin alfa improves anaemia in patients with MDS, versus placebo over 24-weeks of treatment. It consisted of 130 randomised patients, with 85 patients receiving epoetin alfa. Results showed that compared to placebo, patients in the epoetin alfa arm demonstrated a statistically significantly higher erythroid response rate (according to IWG2006 criteria) in the first 24 weeks, the primary endpoint of the study (31.8 percent vs. 4.4 percent, p<0.001). Significantly fewer patients required transfusion on epoetin alfa (24.7 percent vs. 54.1 percent).1 Additional analysis, accounting for dose adjustments within the protocol, also confirmed a statistically significant erythroid response for epoetin alfa (45.9 percent) compared to placebo (4.4 percent) (p<0.001).1 Quality of life for responding patients in the epoetin alfa arm improved significantly compared to non-responders (FACT-An p=0.025, EQ-5D index score p=0.007, EQ-5D VAS p=0.037). There were no new safety signals for epoetin alfa from the study and safety findings were consistent with the known safety profile of epoetin alfa.1

"Anaemia affects the vast majority of patients with MDS and contributes substantially to their symptoms. However, there are currently no approved erythropoiesis stimulating agents approved for treating anaemia in lower-risk MDS patients," said Pierre Fenaux, M.D., PhD., principal investigator of EPOANE 3021, and Professor of Hematology, Hôpital St Louis/Université, Paris, France. "These data provide important evidence that epoetin alfa can effectively manage lower risk MDS-related anaemia, beyond transfusion, and without any impact on progression to acute myeloid leukaemia (AML)."

"EPREX (epoetin alfa) has shown great potential across a range of indications throughout its clinical development programme. We are excited to be building on this evidence base once again, with the findings of this new study demonstrating the meaningful difference this medicine can make to patients with MDS-related anaemia. We’re also extremely pleased to see the improvements in quality of life offered by EPREX, where alternative treatment options have so far been limited," said Jane Griffiths, Company Group Chairman, Janssen Europe, Middle East and Africa.

For more information on the EPOANE 3021 data presented at EHA (Free EHA Whitepaper) 2016, please view the abstract online.

About the EPOANE 3021 Study1

EPOANE 3021 was a randomised, double-blind, placebo-controlled, multicentre clinical trial investigating the efficacy and safety of EPREX (epoetin alfa) as a treatment for anaemia, in adult patients with low or Intermediate-1 risk myelodysplastic syndromes (MDS), as classified by an International Prognostic Scoring System (IPSS). Results demonstrated that 31.8 percent of patients treated with epoetin alfa achieved the primary endpoint of erythroid response versus 4.4 percent of placebo patients (p<0.001). An ad hoc analysis, accounting for the dose adjustments as per the protocol, confirmed a statistically significant erythroid response for epoetin alfa, with 45.9 percent of epoetin alfa patients, versus 4.4 percent of placebo patients achieving an erythroid response (p<0.001). Median erythroid response duration for epoetin alfa patients was 197 days. The number of patients needing transfusion in the epoetin alfa arm steadily decreased from 51.8 percent in the 8 weeks prior to baseline, to 24.7 percent by week-24. Transfusion need remained unchanged in the placebo patients (48.9 percent – 54.1 percent) over the same interval. Time to first transfusion was longer in the epoetin alfa group (p=0.046). Epoetin alfa demonstrated a statistically significant improvement of quality of life in responding patients.

There were no new safety signals for epoetin alfa from the study and safety findings are consistent with the known safety profile of epoetin alfa. The proportion of patients with at least one treatment emergent adverse event (TEAE) was numerically higher in the placebo group compared with the epoetin alfa group (88.9 percent vs. 77.6 percent). Drug discontinuation due to adverse events was 10.6 percent in the epoetin alfa group versus 13.3 percent in placebo. Four patients in the epoetin alfa arm (4.7 percent) and none in placebo reported a thrombovascular event (TVE). There were four fatal outcomes in the epoetin alfa arm versus one in the placebo arm; none were reported to be related to the study drug. During the study, progression to acute myeloid leukaemia (AML) was similar between groups (3.5 percent in epoetin alfa; 4.4 percent in placebo).

About Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) are a group of diverse bone marrow disorders in which the bone marrow does not produce enough healthy blood cells.2 The low numbers of normal blood cells (cytopenias) eventually cause symptoms, including infection, anaemia, spontaneous bleeding, or easy bruising.2,3 The natural course of MDS is highly variable, with overall survival ranging from a few weeks to several years.4 MDS is primarily a disease of the elderly with a median age at diagnosis of 70 years, but it can affect younger patients as well.4 The incidence in Europe is about four cases per 100,000 per year, reaching 40-50 per 100,000 in patients aged 70 years and over.4

Approximately 60-80 percent of patients with MDS experience symptomatic anaemia,5 which can significantly reduce quality of life and often requires repeated blood transfusions.2 Controlling anaemia and improving quality of life are the principal aims of treatment in lower risk MDS patients.4 At present, blood transfusions are currently the only approved treatment option; however these lead to iron overload, which is associated with significant morbidity and mortality.4,5

About EPREX (epoetin alfa)

EPREX (epoetin alfa) is an erythreopoiesis-stimulating agent (ESA) that works by stimulating the production of red blood cells (RBCs).6 ESAs are an important treatment option for patients with certain types of anaemia, including chemotherapy-induced anaemia and anaemia due to chronic kidney disease. Without ESAs, patients with certain types of anaemia may require regular blood transfusions to maintain RBCs at concentrations necessary to sustain normal oxygen levels throughout the body.4

EPREX is currently indicated for the treatment of:6

Symptomatic anaemia associated with chronic renal failure (CRF):
In adult and paediatric patients aged 1 to 18 years on haemodialysis and adult patients on peritoneal dialysis.
In adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients.
Adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient’s general status (e.g. cardiovascular status, pre-existing anaemia at the start of chemotherapy) for the treatment of anaemia and reduction of transfusion requirements.
Adults in a predonation programme to increase the yield of autologous blood. Treatment should only be given to patients with moderate anaemia (haemoglobin concentration range between 10 to 13 g/dl [6.2 to 8.1 mmol/l], no iron deficiency) if blood saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).
Non-iron deficient adults prior to major elective orthopaedic surgery having a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions. Use should be restricted to patients with moderate anaemia (e.g. haemoglobin concentration range between 10 to 13 g/dl) who do not have an autologous predonation programme available and with expected moderate blood loss (900 to 1,800 ml).
About the Janssen Pharmaceutical Companies

Seattle Genetics Highlights Vadastuximab Talirine (SGN-CD33A) Data in Acute Myeloid Leukemia (AML) at the 21st Congress of the European Hematology Association

On June 11, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported data at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place in Copenhagen, Denmark, June 9-12, 2016, evaluating vadastuximab talirine (SGN-CD33A; 33A) in combination with hypomethylating agents (HMAs; azacitidine, decitabine) in frontline patients with acute myeloid leukemia (AML) who had declined intensive therapy (Press release, Seattle Genetics, JUN 11, 2016, View Source;p=RssLanding&cat=news&id=2176948 [SID:1234513211]). 33A is an investigational antibody-drug conjugate (ADC) targeted to CD33 utilizing Seattle Genetics’ newest technology, comprising an engineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA binding agent called a pyrrolobenzodiazepine (PBD) dimer. CD33 is expressed on leukemic blasts in nearly all AML patients with expression generally consistent regardless of age, cytogenetic abnormalities or underlying mutations.

Based on data from the ongoing phase 1 clinical trial, a phase 3 clinical trial, called CASCADE, was recently initiated evaluating 33A in combination with HMAs in previously untreated AML patients not candidates for intensive induction chemotherapy. Seattle Genetics is also evaluating 33A broadly across multiple lines of therapy in patients with myeloid malignancies, including ongoing and planned phase 1 and 2 clinical trials for newly diagnosed or relapsed AML and for previously untreated myelodysplastic syndrome (MDS). More information about 33A and ongoing clinical trials can be found at www.ADC-CD33.com.

"Hypomethylating agents, or HMAs, are the current standard of care for AML patients who are not able to tolerate intensive therapy. HMAs have limited benefit, with low response rates and median overall survival of 10 months or less," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "We believe that adding 33A to HMAs may improve efficacy and has the potential to redefine the treatment of AML. The clinical data at ASH (Free ASH Whitepaper) showing high response rate, manageable tolerability profile and low early mortality reported have been maintained in this larger data set, and support our recently initiated phase 3 CASCADE clinical trial, which is now enrolling patients."

"There is a dire need to improve outcomes for patients with AML," said Amir Fathi, M.D., investigator of the phase 1 trial who will present the data at EHA (Free EHA Whitepaper). "The anti-leukemic activity we have observed in the phase 1 clinical trial evaluating 33A combination therapy in AML patients continues to be encouraging. This is an incredibly difficult disease to treat and the results to-date continue to show a balance of activity and tolerability together with low early mortality rates. The data presented suggest that the addition of 33A improves the rates of response and durable remissions in comparison to that seen historically from using the current standard of care alone."

SGN-CD33A in Combination with Hypomethylating Agents: A Novel, Well-Tolerated Regimen with High Remission Rate in Older Patients with AML (Abstract #S503, oral presentation on Saturday, June 11, 2016 at 4:30 p.m. CEST)

Outcomes for AML patients who are not candidates for intensive chemotherapy or allogeneic stem cell transplant are dismal. Low intensity treatment options, including HMAs (azacitidine and decitabine), are limited. Interim results from the first 25 patients in the ongoing phase 1 study evaluating 33A in combination with HMAs in frontline AML were presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. Updated interim results from the ongoing phase 1 study were presented in an oral session at EHA (Free EHA Whitepaper).

Data were reported from 53 frontline unfit AML patients with a median age of 75 years and intermediate or adverse cytogenetic risk who had declined intensive therapy. Forty-five percent of patients had evidence of underlying myelodysplasia. Key findings presented by Dr. Fathi include:

Of 49 efficacy-evaluable patients treated with 33A combined with either azacitidine or decitabine, the overall response rate was 76 percent. Complete remission (CR) or complete remission with incomplete platelet or neutrophil recovery (CRi) was observed in 35 patients (71 percent). The remission rate (CR+CRi) was similar between the two 33A and HMA combination treatment groups (71 percent combined with azacitidine and 72 percent combined with decitabine).
Responses were observed in higher-risk patients, with remissions achieved in 16 of 22 patients (73 percent) with underlying myelodysplasia and 15 of 18 patients (83 percent) with adverse cytogenetics.
Patients who achieved minimal residual disease included eight of 19 (42 percent) CR patients and five of 15 (33 percent) CRi patients.
The median overall survival for all patients in the phase 1 trial is interim and expected to evolve. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months, with a median follow-up of 12.58 months.
Median relapse-free survival was 7.7 months (range, 0.0+ and 11.3+) with 27 patients (51 percent) remaining alive and on study as of last follow-up. The 30- and 60-day mortality rates were two and eight percent, respectively.
The most common treatment-related adverse events of any grade occurring in 20 percent or more of patients were fatigue (57 percent), thrombocytopenia (53 percent), nausea (49 percent), febrile neutropenia (45 percent), and constipation and anemia (42 percent each). The most common Grade 3 or 4 treatment-emergent adverse events occurring in 20 percent or more of patients were febrile neutropenia, thrombocytopenia, neutropenia, anemia and fatigue.
About Acute Myeloid Leukemia
Acute myeloid leukemia, also called acute myelocytic leukemia or AML, is an aggressive type of cancer of the bone marrow and blood that progresses rapidly without treatment. AML is a cancer that starts in the cells that are supposed to mature into different types of blood cells. AML starts in the bone marrow (the interior part of bones, where new blood cells are made) and quickly moves into the blood. According to the American Cancer Society, in 2016 approximately 20,000 new cases of AML (mostly in adults) will be diagnosed and nearly 10,500 deaths will occur from AML (almost all will be in adults).

About Vadastuximab Talirine (SGN-CD33A)
Vadastuximab talirine (SGN-CD33A; 33A) is a novel investigational ADC targeted to CD33 utilizing Seattle Genetics’ newest ADC technology. CD33 is expressed on most AML and MDS blast cells. The CD33 antibody is attached to a highly potent DNA binding agent, a pyrrolobenzodiazepine (PBD) dimer, via a proprietary site-specific conjugation technology to a monoclonal antibody with engineered cysteines (EC-mAb). PBD dimers are significantly more potent than systemic chemotherapeutic drugs and the site-specific conjugation technology (EC-mAb) allows uniform drug-loading of the cell-killing PBD agent to the anti-CD33 antibody. The ADC is designed to be stable in the bloodstream and to release its potent DNA binding agent upon internalization into CD33-expressing cells.

33A was granted Orphan Drug Designation by both the U.S. Food and Drug Administration (FDA) and the European Commission for the treatment of AML. FDA orphan drug designation is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States.