On September 27, 2016 Amgen (NASDAQ:AMGN) reported top-line results of the Phase 3 CLARION trial, which evaluated an investigational regimen of KYPROLIS (carfilzomib), melphalan and prednisone (KMP) versus Velcade (bortezomib), melphalan and prednisone (VMP) for 54 weeks in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem-cell transplant (Press release, Amgen, SEP 27, 2016, View Source [SID:SID1234515424]). The trial did not meet the primary endpoint of superiority in progression-free survival (PFS) (median PFS 22.3 months for KMP versus 22.1 months for VMP, HR = 0.91, 95 percent CI, 0.75 – 1.10). While the data for overall survival, a secondary endpoint, are not yet mature, the observed hazard ratio (KMP versus VMP) was 1.21 (95 percent CI, 0.90 – 1.64). Neither result was statistically significant. Schedule your 30 min Free 1stOncology Demo! Overall, the adverse events in the KMP arm were consistent with the known safety profile of KYPROLIS. The incidence of Grade 3 or higher adverse events was 74.7 percent in the KMP arm and 76.2 percent in the VMP arm. Fatal treatment-emergent adverse events occurred in 6.5 percent of KMP patients and 4.3 percent of VMP patients. The incidence of Grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5 percent in the KMP arm and 35.1 percent in the VMP arm.
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These data will be submitted to a future medical conference and for publication.
"Based on studies in the KYPROLIS label, including the ENDEAVOR study, a head-to-head comparison of KYPROLIS to Velcade in patients with relapsed or refractory multiple myeloma, we know KYPROLIS to be a major advance in proteasome inhibitor therapy," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we’ve seen in the second-line setting. However, the myeloma landscape has changed dramatically since the design of the CLARION study with very few newly diagnosed patients treated with melphalan-based regimens, particularly in the U.S. We remain committed to exploring KYPROLIS in combination with other agents to advance the treatment of multiple myeloma."
Amgen supports a number of investigator-sponsored studies, and a Phase 3 study evaluating KYPROLIS in combination with lenalidomide plus dexamethasone (KRd) versus Velcade in combination with lenalidomide plus dexamethasone (VRd) in newly diagnosed multiple myeloma patients. This trial, called E1A11 or ENDURANCE, is underway independently by the ECOG-ACRIN Cancer Research Group with funding provided by the National Cancer Institute (NCI) and its National Clinical Trials Network. Over 750 institutions nationwide are currently enrolling patients in the study (NCT01863550).
The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating 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 the CLARION Study
The CLARION study was a Phase 3 head-to-head multicenter, open-label, randomized study in transplant-ineligible patients with newly diagnosed multiple myeloma. A total of 955 patients were randomized 1:1 to receive KYPROLIS, melphalan and prednisone or Velcade, melphalan and prednisone for 54 weeks. The median patient age was 72.
The KMP regimen consisted of KYPROLIS as a 30 minute intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29 and 30 during each 42-day cycle (20 mg/m2 on days 1 and 2 of cycle 1; 36 mg/m2 thereafter), melphalan 9 mg/m2 on days 1–4, and prednisone 60 mg/m2 on days 1–4.
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 very aggressive disease that accounts for approximately one percent of all cancers.2,3 In the U.S., there are nearly 95,000 people living with, or in remission from, multiple myeloma.4 Approximately 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.4
MiNA Therapeutics Announces Presentation of Pre-Clinical Data Supporting On-Target Mechanism of Action of Clinical Candidate MTL-CEBPA
On September 27, 2016 MiNA Therapeutics, the pioneer in RNA activation therapeutics, reported the presentation of data supporting the on-target mechanism of action of drug candidate MTL-CEBPA (Press release, MiNA Therapeutics, SEP 27, 2016, View Source [SID:SID1234515421]). MTL-CEBPA is the first development candidate to emerge from MiNA’s RNA activation platform and is currently being evaluated in a Phase I clinical study in patients with liver cancer. Schedule your 30 min Free 1stOncology Demo! The data were presented at the 2016 Annual Meeting of the Oligonucleotide Therapeutics Society on September 26 in Montreal, Canada, in a poster titled "Development and mechanism of a small activating RNA targeting CEBPA, a novel therapeutic in clinical trials for patients with liver cancer".
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"Through a range of methods MTL-CEBPA has been validated to up-regulate the CEBP-a protein through an on-target and highly specific mechanism of transcriptional activation" commented Robert Habib, CEO of MiNA Therapeutics. "This data supports the potential of our RNA activation platform to up-regulate therapeutically ‘undruggable’ proteins in a highly specific manner."
MTL-CEBPA is a SMARTICLES liposomal formulation of CEBPA-51, a small activating RNA targeting the CEBPA gene. In the experiments covered by the presentation, CEBPA-51 was shown in cell lines to transcriptionally activate expression of CEBPA gene resulting in increased levels of CEBPA mRNA as well as CEBP-a protein. Mutations and modifications to the sequence of CEBPA-51 demonstrated this mechanism to be sequence specific as well as strand specific. Incorporation of 2’O-Me modifications in CEBPA-51 was shown to abrogate immune stimulation without loss of on-target activity. In addition, CEBPA-51 was shown to co-localise with, and require for activity, Argonaute 2 – an enzyme involved in a cell’s innate regulation of gene expression.
The poster presented at the Oligonucleotide Therapeutics Society Annual Meeting is available on the Company’s website in the publication section under "Media".
About MTL-CEBPA
MTL-CEBPA consists of a double stranded RNA formulated into a SMARTICLES liposomal nanoparticle and is designed to activate the CEBPA gene. By restoring CEBPA expression to normal levels, MTL-CEBPA has been demonstrated to attenuate or reverse liver disease in a range of pre-clinical studies including models of liver cancer, liver cirrhosis, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). MTL-CEBPA is currently under evaluation in OUTREACH, a first-in-human Phase I clinical study in patients with severe liver cancer. The multi-centre Phase I study will assess the safety and tolerability of MTL-CEBPA in patients with advanced primary or metastatic liver cancer who are ineligible or resistant to standard therapies. To learn more about the OUTREACH clinical study, please visit our listing at clinicaltrials.gov
Ibrutinib (IMBRUVICA®) Supplemental New Drug Application Submitted to the U.S. Food and Drug Administration (FDA) for Marginal Zone Lymphoma (MZL)
On September 26, 2016 Janssen Research & Development, LLC reported that a supplemental New Drug Application (sNDA) for ibrutinib (IMBRUVICA) has been submitted to the U.S. Food and Drug Administration (FDA) for the treatment of patients with marginal zone lymphoma (MZL) who require systemic therapy (Press release, Johnson & Johnson, SEP 26, 2016, View Source [SID:SID1234515474]). The filing is based on data from the multi-center, open-label Phase 2 PCYC-1121 trial assessing the use of ibrutinib, a BTK inhibitor, in patients with MZL who have received at least one prior therapy. IMBRUVICA is jointly developed and commercialized by Janssen and Pharmacyclics LLC, an AbbVie company.
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"We are encouraged by the results of this study of ibrutinib in yet another type of B-cell malignancy," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. "This FDA submission represents an 2 exciting and important step towards a potential new treatment option for MZL patients who currently have a great unmet need. Currently there are no therapies approved for this rare form of cancer."
The PCYC-1121 international trial enrolled 63 patients with MZL who had received at least one prior therapy, including splenic MZL (SMZL), nodal MZL (NMZL) and extranodal MZL (EMZL). Patients received ibrutinib 560mg orally, once daily until progression or unacceptable toxicity. The primary endpoint of the study was overall response rate as assessed by an Independent Review Committee. Key secondary endpoints included duration of response and overall response rate. The data have been submitted for publication in a peer-reviewed journal and presentation at an upcoming medical conference. More information about the study can be found on www.clinicaltrials.gov (NCT01980628).
IMBRUVICA is currently approved to treat patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including patients with 17p deletion, patients with mantle cell lymphoma (MCL) who have received at least one prior therapy and patients with Waldenström’s macroglobulinemia (WM). Accelerated approval was granted for MCL based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Janssen and Pharmacyclics are continuing an extensive clinical development program for IMBRUVICA, including Phase 3 study commitments in multiple patient populations.
About Marginal Zone Lymphoma (MZL)
MZL is a B-cell lymphoma arising from white blood cells (lymphocytes) at the margins, or edges of lymph nodes and various tissues, including the stomach, salivary glands, thyroid gland, eyes, lungs and spleen. 1 MZL accounts for approximately 12 percent of all cases of non-Hodgkin lymphoma in adults, and the median age of diagnosis is 65 years old. There are currently no approved treatments or established standards of care specifically indicated for patients with MZL.
About IMBRUVICA
IMBRUVICA was one of the first therapies to receive U.S. approval after having received the FDA’s Breakthrough Therapy Designation. IMBRUVICA works by blocking a specific protein called Bruton’s tyrosine kinase (BTK).2 The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.3 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread. For more information, visit www.IMBRUVICA.com.
Additional Information about IMBRUVICA
INDICATIONS 3 IMBRUVICA is indicated to treat people with:
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
o Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA . Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA .
The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days preand postsurgery depending upon the type of surgery and the risk of bleeding.
Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA . Evaluate patients for fever and infections and treat appropriately.
Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 9%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA . Monitor complete blood counts monthly.
Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA , particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an 4 ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.
Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA . Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.
Second Primary Malignancies – Other malignancies (range, 5% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA . The most frequent second primary malignancy was non-melanoma skin cancer (range, 4% to 13%).
Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
ADVERSE REACTIONS The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, and WM) were neutropenia* (64%), thrombocytopenia* (63%), diarrhea (43%), anemia* (41%), musculoskeletal pain (30%), rash (29%), nausea (29%), bruising (29%), fatigue (27%), hemorrhage (21%), and pyrexia (21%).
*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%). Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse reactions.
5 Approximately 4%-10% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse reactions. Most frequent adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each) in CLL patients and subdural hematoma (1.8%) in MCL patients.
DRUG INTERACTIONS
CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.
SPECIFIC POPULATIONS
Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.
Please see Full Prescribing Information: View Source A
Advaxis’ Lm Technology Immunotherapies to be Showcased in Three Poster Presentations at SITC Annual Meeting
On September 26, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported three poster presentations have been accepted by the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 31st Annual Meeting & Associated Programs taking place from Nov. 9-13 at Gaylord National Hotel & Convention Center in National Harbor, Md (Press release, Advaxis, SEP 26, 2016, View Source [SID:SID1234515427]). The poster presentations showcase the potential of Advaxis’ Lm Technology immunotherapies for monotherapy and combination therapy in difficult-to-treat cancers.
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The poster presentations featuring Advaxis immunotherapies at SITC (Free SITC Whitepaper) 2016 include:
"AIM2CERV: a randomized Phase 3 study of adjuvant AXAL immunotherapy following chemoradiation in patients who have high-risk locally advanced cervical cancer (HRLACC)"
"A Phase 1/2 study of durvalumab alone or in combination with AXAL in recurrent/persistent or metastatic cervical or human papillomavirus (HPV)+ squamous cell cancer of the head and neck (SCCHN): preliminary Phase 1 results"
"Combination of Listeria-based human papillomavirus (HPV) E7 cancer vaccine (AXAL) with CD137 agonist antibody provides an effective immunotherapy for HPV-positive tumors in a mouse model"
Cambrex to Acquire PharmaCore Inc., to Expand Clinical Stage API Capabilities
On September 26, 2016 Cambrex Corporation (NYSE: CBM), a leading manufacturer of small molecule innovator and generic Active Pharmaceutical Ingredients (APIs), reported that it has agreed to acquire PharmaCore Inc., a privately-owned company specializing in developing, manufacturing and scaling up small molecule APIs for clinical phase projects, for approximately $25 million (Press release, Cambrex, SEP 26, 2016, View Source [SID:SID1234515425]). PharmaCore was founded in 1999 and occupies a 35,000 sq. ft. GMP site in High Point, North Carolina, USA.
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PharmaCore develops and produces complex APIs and intermediates requiring multi-step synthetic processes in batch sizes from milligrams to 100 kg to support clinical trials from Phase I to Phase III. The company is licensed with the US Drug Enforcement Administration (DEA) to manufacture Schedule II to Schedule V controlled substances. PharmaCore has more than 60 full time employees, focused on projects at laboratory and pilot plant scale, with nearly 40 lab-based Process and Analytical Chemists, the majority of whom hold PhDs.
The acquisition will enhance Cambrex’s portfolio of small molecule API services and complements its existing large scale, multi-purpose manufacturing facilities in the US and Europe. PharmaCore is currently generating $15 to $17 million per year in revenues and just over two million dollars per year in EBITDA. Cambrex expects the transaction, net of deal fees, to have a neutral impact on earnings per share in 2016 and to be accretive in 2017.
"We are excited to announce our acquisition of PharmaCore, which we believe underlines our commitment to continually enhancing our service offering to our global pharmaceutical and biotech customers. The acquisition will provide the capability and expertise to efficiently develop early clinical phase products and new technologies. We expect PharmaCore’s substantial customer base and robust project pipeline to broaden our potential late stage clinical development and commercial manufacturing opportunities," commented Steven Klosk, CEO of Cambrex.
He added, "Through the end of 2016, Cambrex will have invested over $200 million in capital projects within our existing facilities, including a recently completed $50 million production and warehousing expansion of our large scale US API facility in Charles City, Iowa, and a $9 million investment to expand large scale manufacturing capacity at our Karlskoga facility in Sweden, which we expect will be completed shortly."
Rob Maddox, President of PharmaCore added, "PharmaCore is proud of the reputation we have developed, both as a trusted CMO and a company with a strong track record of innovative chemistry. We are thrilled to be joining Cambrex’s global network and to have the opportunity to participate in Cambrex’s growth strategy."
PharmaCore’s NC facility has a 15,000 sq. ft. chemistry laboratory and a 13,000 sq. ft. pilot plant, with reactor capacity ranging from 20L to 2000L, with supporting GMP analytical services.
The completion of the transaction is subject to customary closing conditions, and is expected to occur within 30 days. PharmaCore was advised on this transaction by Wombat Capital Markets, LLC.