Onconova Moving Forward with Phase 3 INSPIRE Pivotal Trial with Increased Sample Size Following Promising Interim Analysis

On January 17, 2018 Onconova Therapeutics, Inc. (Nasdaq:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing small molecule drug candidates to treat cancer, reported that it is moving forward with its Phase 3 INSPIRE pivotal trial following the interim analysis, consistent with the DMC’s recommendation (Press release, Onconova, JAN 17, 2018, View Source [SID1234523237]). The DMC recommended continuation of the trial with a one-time expansion in enrollment, using a pre-planned sample size re-estimation, consistent with the Statistical Analysis Plan (SAP). The INSPIRE pivotal trial is studying intravenously-administered (IV) rigosertib in patients with higher-risk myelodysplastic syndromes (MDS) who have progressed on, failed to respond to, or relapsed after prior hypomethylating agent (HMA) therapy. The Company remains blinded to the interim analysis results.

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Guillermo Garcia-Manero, M.D, Professor and Chief of the MDS Section at the MD Anderson Cancer Center, a lead investigator on the INSPIRE study, commented, "Choices are very limited for higher risk MDS patients after failure of HMA therapy and no second-line therapy has ever been approved by the Health Authorities for these patients. These patients have a very short life-span and there is a tremendous unmet medical need. We remain highly supportive of Onconova’s efforts. After the interim analysis, continuation of the INSPIRE study is encouraging for patients."

The SAP for the INSPIRE trial featured an adaptive trial design, permitting several options following the interim analysis, which included continuation of the trial as planned, discontinuation of the trial for futility, trial expansion using pre-planned sample size re-estimation, and trial continuation for only the pre-defined treatment subgroup of patients classified as VHR based on the Revised International Prognostic Scoring System (IPSS-R).

The expanded INSPIRE study will continue to enroll eligible patients based on the current trial design of the overall ITT population and will increase enrollment by adding 135 patients to the original target to reach a total enrollment of 360 patients, with the aim of increasing the power of the trial. Due to the adaptive trial design and the DMC’s assessment, the INSPIRE trial will continue to analyze both the ITT and the VHR population for the primary endpoint of overall survival. The design of the trial with the expanded study enrollment will be identical to the current study design and will include the analysis of the overall survival endpoint in the ITT and the pre-specified VHR subgroup.

Steve Fruchtman, M.D., Chief Medical Officer of Onconova, added, "With no FDA approved therapies for many patients with higher-risk MDS who are refractory to HMAs, we are encouraged by these results and pleased to be at the forefront of advances in this treatment landscape. The DMC’s recommendation based on the pre-planned interim analysis includes the expansion of the INSPIRE trial and retains the analysis of survival in both the ITT and the VHR pre-defined subgroups. Patients with MDS who are refractory to HMAs have the highest unmet medical need due to an extremely poor prognosis following failure of HMA therapy. We look forward to completing enrollment and for the opportunity to analyze overall survival in the higher-risk MDS patients who have failed prior HMA therapy."

Currently, the INSPIRE study is active at approximately 175 trial sites in 22 countries across four continents, and has enrolled more than 170 patients. In Japan, patients have been enrolled to this study by SymBio Pharmaceuticals, our collaboration partner for Japan and Korea. Onconova believes that this trial is the most advanced study for a new therapeutic agent in this indication, and there are no FDA approved therapies specifically for MDS patients after failure of front-line HMAs.

The Company will host a conference call today, January 17th at 8:30 a.m. Eastern Time to discuss the interim results and answer any questions. Interested parties may access the call by dialing toll-free (855) 428-5741 from the US, or (210) 229-8823 internationally and using conference ID: 8899928.

The call will also be webcast live. Please click here to access the webcast.

A replay will be available at this link until April 30, 2018.

BioLineRx Announces Partial Monotherapy Results from Phase 2a COMBAT Study in Pancreatic Cancer

On January 17, 2018 BioLineRx Ltd. (NASDAQ: BLRX) (TASE: BLRX), a clinical-stage biopharmaceutical company focused on oncology and immunology, reported partial results from the monotherapy portion of BL-8040’s Phase 2a COMBAT study showing that BL-8040 increases infiltration of T cells into the tumor in patients with metastatic pancreatic cancer (Press release, BioLineRx, JAN 17, 2018, View Source;p=RssLanding&cat=news&id=2326963 [SID1234523236]). The data will be presented as a poster titled "Evaluation of Pharmacodynamic Biomarkers in Patients with Metastatic Pancreatic Cancer Treated with BL-8040, a Novel CXCR4 Antagonist (Abstract 276)" at the ASCO (Free ASCO Whitepaper) 2018 Gastrointestinal Cancers Symposium, on January 19, 2018 in San Francisco, CA.

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The partial results from the BL-8040 monotherapy portion of the COMBAT trial show that BL-8040 was safe and well-tolerated. BL-8040 also induced an increase in the number of total immune cells in the peripheral blood, while the frequency of peripheral blood regulatory T cells (Tregs), known to impede the anti-tumor immune response, was decreased. In addition, analysis of available biopsies (N = 7) showed infiltration of various types of effector T cells, known to attack cancer cells, into the tumor periphery and tumor micro-environment (TME). In this regard, the results show up to a 15-fold increase in CD3+ T cells, and up to a 2-fold increase in CD8+ T cells, in the TME of 43% (3/7) of the patients, after five days of BL-8040 monotherapy.

Dr. Manuel Hidalgo, Chief of Hematology Oncology and Co-Director of the Pancreatic Cancer Research Program at Beth Israel Deaconess Medical Center in Boston, commented, "This is the first time we see results of BL-8040 in pancreatic cancer patients. The results of the monotherapy part of the COMBAT trial are extremely encouraging as they confirm the mechanism of action of BL-8040 in this difficult-to-treat patient population, resulting in T-cell infiltration into the tumor after only 5 days of monotherapy with BL-8040. These results support the rationale for combining BL-8040 with checkpoint inhibitors, and I am looking forward to the topline results of the COMBAT study expected later this year."

"The results show that BL-8040 induces robust infiltration of anti-tumor T cells into liver metastases in almost half of the pancreatic cancer patients who underwent a biopsy, effectively transforming these tumors from immunologically ‘cold’ to ‘hot’, which is seen as key in the objective of improving the responsiveness of patients with pancreatic cancer to front-line immunotherapy" stated Philip Serlin, Chief Executive Officer of BioLineRx. "These results support the mechanism of action proposed by pre-clinical studies, namely that BL-8040 mobilizes immune cells into the peripheral blood and promotes T cell infiltration into tumors. As previously reported, enrollment of the study has been completed and we expect to meet our timelines for conclusion of the study and topline results by the second half of 2018."

The Phase 2a study, named the COMBAT study, is an open-label, multicenter, single-arm trial designed to evaluate the safety and efficacy of the combination of BL-8040 and KEYTRUDA (pembrolizumab), an anti-PD-1 therapy marketed by Merck & Co., Inc., Kenilworth, N.J., USA (known as MSD outside the United States and Canada), in over 30 subjects with metastatic pancreatic adenocarcinoma. The study is primarily designed to evaluate the clinical response, safety and tolerability of the combination of these therapies. In addition, the study evaluates multiple pharmacodynamic parameters, including the ability to increase infiltration of T cells into the tumor, for both BL-8040 as a monotherapy, as well as for the combination of BL-8040 and KEYTRUDA. The study is being conducted in the US, Israel and additional territories.

The COMBAT study is being conducted by BioLineRx under a collaboration agreement signed in 2016 between BioLineRx and MSD, through a subsidiary, to support a Phase 2a study investigating BioLineRx’s BL-8040 in combination with KEYTRUDA in patients with metastatic pancreatic cancer.

BL-8040, BioLineRx’s lead oncology platform, is a CXCR4 antagonist that has been shown in several clinical trials to be a robust mobilizer of immune cells to peripheral blood and to be effective at inducing direct tumor cell death. Additional findings have suggested that CXCR4 antagonists may be effective at increasing the infiltration of anti-tumor T cells into tumors that were previously immunologically "cold" and devoid of immune cell infiltrate. Checkpoint inhibitors (such as KEYTRUDA) produce anti-cancer effects by increasing the activity of T cells through blockade of the interaction between the immunosuppressive elements PD-1, on T cells, and PD-L1, on tumor cells. Pancreatic cancers have very little T-cell infiltrate, making them less susceptive to checkpoint blockade than other tumors that are infiltrated by T cells. Therefore, combining BL-8040 with checkpoint blockade is predicted to increase the responsiveness of pancreatic cancer patients to immunotherapy.

About BL-8040

BL-8040 is a short peptide for the treatment of acute myeloid leukemia, solid tumors, and stem cell mobilization. It functions as a high-affinity antagonist for CXCR4, a chemokine receptor that is directly involved in tumor progression, angiogenesis, metastasis and cell survival. CXCR4 is over-expressed in more than 70% of human cancers and its expression often correlates with disease severity. In a number of clinical and pre-clinical studies, BL-8040 has shown robust mobilization of cancer cells and immune-cells from the bone marrow, thereby sensitizing cancer cells to chemo- and bio-based anti-cancer therapy, as well as a direct anti-cancer effect by inducing cell death (apoptosis) and mobilizing immune-cells. In addition, BL-8040 has also demonstrated robust stem-cell mobilization, including the mobilization of colony-forming cells, T, B and NK cells. BL-8040 was licensed by BioLineRx from Biokine Therapeutics and was previously developed under the name BKT-140.

FDA Approves Addition Of Overall Survival Data To KYPROLIS® (carfilzomib) Label

On January 17, 2018 Amgen (NASDAQ:AMGN) reported that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) to add overall survival (OS) data from the Phase 3 head-to-head ENDEAVOR trial to the Prescribing Information for KYPROLIS (carfilzomib) (Press release, Amgen, JAN 17, 2018, View Source;p=RssLanding&cat=news&id=2327111 [SID1234523235]). Data added to the label demonstrated that KYPROLIS and dexamethasone (Kd) reduced the risk of death by 21 percent and increased OS by 7.6 months versus Velcade (bortezomib) and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (median OS 47.6 months for Kd versus 40.0 months for Vd, HR=0.79; p=0.01).

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"Overall survival is generally considered to be the gold standard of endpoints because it clearly demonstrates a drug’s value in extending a patient’s life, 1,2" said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "Blood cancer therapies approved by the FDA between 2003 and 2013 only improved overall survival by an average of 2.61 months.3 KYPROLIS and dexamethasone improved overall survival by 7.6 months, underscoring that this regimen is a significant advancement and should be considered a standard of care for patients with relapsed or refractory multiple myeloma."

The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines) list Kd as the only preferred doublet regimen at relapse for multiple myeloma. Full OS results from the ENDEAVOR trial were published earlier this year in The Lancet Oncology.

Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were anemia, diarrhea, pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia and headache.

Since its approval in 2012, more than 50,000 patients worldwide have received KYPROLIS. The KYPROLIS clinical program continues to focus on providing treatment options for physicians and patients for this frequently relapsing and difficult-to-treat cancer. KYPROLIS is available for patients whose myeloma has relapsed or become resistant to another treatment and continues to be studied in a range of combinations and patient populations.

About ENDEAVOR
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated KYPROLIS in combination with low-dose dexamethasone, versus Velcade with low-dose dexamethasone in relapsed or refractory patients who previously received at least one, but not more than three, prior therapeutic regimens. The primary endpoint of the trial was progression-free survival, defined as the time from treatment initiation to disease progression or death. The primary analysis was published in The Lancet Oncology and is described in the Prescribing Information.

Patients received treatment until progression with KYPROLIS as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treatment cycles, along with low-dose dexamethasone (20 mg). For cycle one only, KYPROLIS was administered at 20 mg/m2 on days 1 and 2, and if tolerated was escalated to 56 mg/m2 from day 8 of cycle one onwards. Patients who received Velcade (1.3 mg/m2) with low-dose dexamethasone (20 mg) were treated with Velcade administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regional regulatory approval of Velcade. More than 75 percent of the patients in the control arm received Velcade subcutaneously. This study was conducted at 235 sites worldwide. For information about this trial, please visit www.clinicaltrials.gov under trial identification number NCT01568866.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.4 It is a rare and life-threatening disease that accounts for approximately one percent of all cancers.5,6 In the U.S., there are more than 118,000 people living with, or in remission from, multiple myeloma.7 Approximately 30,280 Americans are diagnosed with multiple myeloma each year and 12,590 patient deaths are reported on an annual basis.7

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.8 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.8 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.8,9

KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and the European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. It is recommended to control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS.
Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant‐ineligible Patients

In a clinical trial of transplant‐ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KYPROLIS in combination with melphalan and prednisone is not indicated for transplant‐ineligible patients with newly diagnosed multiple myeloma.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see full prescribing information at www.kyprolis.com.

About Amgen’s Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen’s supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

Overall Survival Analysis From KYPROLIS® (Carfilzomib) Phase 3 ASPIRE Trial Published in the Journal of Clinical Oncology

On January 17, 2018 Amgen (NASDAQ:AMGN) reported that the Journal of Clinical Oncology published positive overall survival (OS) findings from the final analysis of the Phase 3 ASPIRE trial, which demonstrated that the addition of KYPROLIS (carfilzomib) to lenalidomide and dexamethasone (KRd) reduced the risk of death by 21 percent versus lenalidomide and dexamethasone alone (Rd) and extended OS by 7.9 months in patients with relapsed or refractory multiple myeloma (median OS 48.3 months for KRd versus 40.4 months for Rd, HR = 0.79, 95 percent CI, 0.67 – 0.95; 1-sided p=0.0045) (Press release, Amgen, JAN 17, 2018, View Source;p=RssLanding&cat=news&id=2327105 [SID1234523234]). Notably, an OS improvement of 11.4 months was observed for patients at first relapse (47.3 versus 35.9 months [HR = 0.81, 95 percent CI, 0.62 – 1.06]), supporting early use of KRd.

"Results from the final analysis of the Phase 3 ASPIRE trial published today in the Journal of Clinical Oncology are significant, as they further validate carfilzomib, lenalidomide and dexamethasone as a standard of care regimen for patients with relapsed or refractory multiple myeloma," said Keith Stewart, M.B., Ch.B., Mayo Clinic in Arizona and principal investigator of the ASPIRE trial. "Furthermore, these data showed that early use of carfilzomib, lenalidomide and dexamethasone at first relapse provided nearly one additional year of survival for patients regardless of prior treatment with bortezomib or transplant."

"As seen in two different Phase 3 studies, KYPROLIS-based regimens are the first and only therapy combinations to demonstrate a significant overall survival advantage for patients with relapsed or refractory multiple myeloma versus recent standards of care," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "We look forward to continuing conversations with regulatory authorities in the U.S. and Europe to add these results to the KYPROLIS label."

The safety data from ASPIRE was consistent with the known safety profile of KYPROLIS. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were diarrhea, anemia, neutropenia, fatigue, upper respiratory tract infection, pyrexia, cough, hypokalemia, thrombocytopenia, muscle spasms, pneumonia, nasopharyngitis, nausea, constipation, insomnia and bronchitis.

The final analysis of ASPIRE included subgroup analyses by prior lines of therapy, prior Velcade (bortezomib) exposure at first relapse, and prior transplant at first relapse. Among these three groups, there was an 18 to 29 percent reduction in the risk of death for KRd versus Rd, consistent with findings in the overall population. Median OS was 11.4 months longer for KRd versus Rd in patients who had received one prior line of therapy and 6.5 months longer for patients with two or more prior lines (48.8 versus 42.3 months [HR = 0.79, 95 percent CI, 0.62 – 0.99]). Among patients who had received one prior line, median OS was improved by 12 months with KRd versus Rd in those with prior Velcade exposure (45.9 versus 33.9 months [HR = 0.82; 95 percent CI, 0.56 – 1.19]) and by 7.9 months in those without prior Velcade (48.3 versus 40.4 months [HR = 0.80, 95 percent CI, 0.55 – 1.17]). Median OS was also improved by 18.6 months with KRd versus Rd among patients with prior transplantation at first relapse (57.2 versus 38.6 months [HR = 0.71, 95 percent CI, 0.48 –1.05]).

The KRd regimen used in this trial is currently approved in the U.S., European Union and other countries based on primary analysis of progression-free survival (PFS) in the ASPIRE study. Amgen has submitted a supplemental New Drug Application to the U.S. Food and Drug Administration and a variation to the marketing application to the European Medicines Agency to include the OS data from ASPIRE in the product information for KYPROLIS.

About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated KYPROLIS in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed or refractory multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included OS, overall response rate, duration of response, disease control rate, health-related quality of life and safety. Patients were randomized to receive KYPROLIS (20 mg/m2 on days 1 and 2 of cycle one, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of subsequent cycles), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, seven days off) and low-dose dexamethasone (40 mg per week in four-week cycles), versus lenalidomide and low-dose dexamethasone alone. The study randomized 792 patients at sites in North America, Europe and Israel.

Patients treated with KRd reported improved global health status, with higher Global Health Status/Quality of Life (QoL) scores compared with Rd over 18 cycles of treatment (2‑sided p<0.0001) measured with the EORTC QLQ‑C30, an instrument validated in multiple myeloma.

Overall survival by Revised International Staging System (R-ISS) stage was also assessed. For R-ISS stage I (KRd, n = 42; Rd, n = 46), median OS was not reached for KRd and was 58 months for Rd (HR = 0.49, 95 percent CI, 0.26 – 0.92). For patients with R-ISS stage II (KRd, n = 194; Rd, n = 195), median OS was 45.4 months for KRd and 41.2 months for Rd (4.2 months; HR = 0.86, 95 percent CI, 0.68 – 1.10). For the small number of patients with R-ISS stage III (KRd, n = 37; Rd, n = 47), median OS was 23.3 months for KRd and 18.8 months for Rd (4.5 months; HR = 1.05, 95 percent CI, 0.66 – 1.68).

For the overall study population, treatment discontinuation due to an adverse event occurred in 19.9 percent of patients treated with KRd and 21.5 percent of patients receiving Rd. Fatal adverse events were reported in 11.5 percent of KRd-treated patients and 10.5 percent of patients treated with Rd. Grade ≥3 adverse event rates were 87 percent for KRd and 83 percent for Rd. Selected grade ≥3 adverse events of interest (grouped terms; KRd vs Rd) included acute renal failure (3.8 percent versus 3.3 percent), cardiac failure (4.3 percent versus 2.1 percent), and hypertension (6.4 percent versus 2.3 percent).

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse.1 It is a rare and life-threatening disease that accounts for approximately one percent of all cancers. 2,3 Worldwide, approximately 114,000 people are diagnosed with multiple myeloma each year and 80,000 patient deaths are reported on an annual basis.2

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.4 KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells.4 In some cells, KYPROLIS can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins. 4,5

KYPROLIS is approved in the U.S. for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
KYPROLIS is also approved in Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and the European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

IMPORTANT SAFETY INFORMATION

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.
Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (including renal failure) have occurred in patients receiving KYPROLIS. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.
Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving KYPROLIS. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold KYPROLIS until TLS is resolved.
Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving KYPROLIS. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.
Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) was reported in patients treated with KYPROLIS. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment.
Dyspnea

Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Hypertension

Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with KYPROLIS. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart KYPROLIS based on a benefit/risk assessment.
Venous Thrombosis

Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with KYPROLIS. Thromboprophylaxis is recommended for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions

Infusion reactions, including life-threatening reactions, have occurred in patients receiving KYPROLIS.
Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.
Hemorrhage

Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia

KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving KYPROLIS. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or withhold dose as appropriate.
Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, including fatal cases, have been reported during treatment with KYPROLIS. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.
Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome have occurred in patients receiving KYPROLIS. Monitor for signs and symptoms of TTP/HUS. Discontinue KYPROLIS if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS therapy in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving KYPROLIS. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue KYPROLIS if PRES is suspected and evaluate. The safety of reinitiating KYPROLIS therapy in patients previously experiencing PRES is not known.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant‐ineligible Patients

In a clinical trial of transplant‐ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KYPROLIS in combination with melphalan and prednisone is not indicated for transplant‐ineligible patients with newly diagnosed multiple myeloma.
Embryo-fetal Toxicity

KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.
Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.
ADVERSE REACTIONS

The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.
Please see full prescribing information at www.kyprolis.com.

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Aeterna Zentaris Enters into Licensing and Assignment Agreement with Strongbridge for Macrilen™ (macimorelin) in the U.S. and Canada

On January 17, 2018 Aeterna Zentaris Inc. (NASDAQ:AEZS) (TSX:AEZS) reported that it has, through a wholly-owned subsidiary, entered into a license and assignment agreement with a wholly-owned subsidiary of Strongbridge Biopharma plc (NASDAQ:SBBP) to carry out development, manufacturing, registration and commercialization of Macrilen (macimorelin) in the United States and Canada (Press release, AEterna Zentaris, JAN 17, 2018, View Source [SID1234523233]).

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"We are very excited to partner with Strongbridge on the commercialization of Macrilen (macimorelin) in the U.S. and Canada," said Michael Ward, Chief Executive Officer of Aeterna Zentaris. "We look forward to exploring the various alternatives to monetizing our rights to Macimorelin outside the United States and Canada."

Aeterna Zentaris will receive an upfront cash payment of US$24,000,000 from Strongbridge, and, for as long as Macrilen (macimorelin) is patent-protected, Aeterna Zentaris will be entitled to a 15% royalty on net sales up to US$75,000,000 and an 18% royalty on net sales above US$75,000,000. Following the end of patent protection in United States or Canada for Macrilen (macimorelin), Aeterna Zentaris will be entitled to a 5% royalty on net sales in that country. In addition, Aeterna Zentaris will also receive one-time payments from Strongbridge following the first achievement of the following commercial milestone events:

US$4,000,000 on achieving US$25,000,000 annual net sales,
US$10,000,000 on achieving US$50,000,000 annual net sales,
US$20,000,000 on achieving US$100,000,000 annual net sales,
US$40,000,000 on achieving US$200,000,000 annual net sales, and
US$100,000,000 on achieving US$500,000,000 annual net sales.
Upon approval by the U.S. Food and Drug Administration ("FDA") of a pediatric indication for Macrilen (macimorelin), Aeterna Zentaris will receive a one-time milestone payment of US$5,000,000 from Strongbridge.

Strongbridge will fund 70% of the costs of a worldwide pediatric development program to be run by Aeterna Zentaris with customary oversight from a joint steering committee. The joint steering committee will be comprised of four persons, two of whom will be appointed by each of Strongbridge and Aeterna Zentaris.

The decision to license Macrilen (macimorelin) in the U.S. and Canada was made following a detailed review process undertaken by a committee of independent directors of Aeterna Zentaris. The committee of independent directors of Aeterna Zentaris was advised by Stifel, Nicolaus & Company, Incorporated. Aeterna Zentaris is continuing to explore various alternatives to monetizing its rights to Macimorelin in other countries around the globe, including whether to find other license partners in these jurisdictions or to use its internal resources to commercialize Macimorelin in one or more of these countries.

The Agreement will be filed on SEDAR at www.sedar.com. The foregoing description of the terms of the Agreement does not purport to be complete and is qualified in its entirety by reference to the Agreement.

Macrilen (macimorelin) is an orally-active ghrelin agonist that stimulates the secretion of growth hormone. Macrilen (macimorelin) has been granted orphan drug designation by the FDA for the evaluation of growth hormone deficiency. On December 20, 2017, the FDA granted Aeterna Zentaris marketing approval for Macrilen (macimorelin) to be used in the diagnosis of patients with adult growth hormone deficiency ("AGHD").

AGHD reportedly affects approximately 60,000 adults across the U.S. and Canada. Growth hormone not only plays an important role in growth from childhood to adulthood, but also helps promote a hormonally-balanced health status. AGHD mostly results from damage to the pituitary gland. It is usually characterized by a reduction in bone mineral density, lean body mass, exercise capacity, and overall quality of life as well as an increase of cardiovascular risks.