On April 23, 2018 Eli Lilly and Company (LLY) and Incyte Corporation (INCY) reported that the U.S. Food and Drug Administration’s (FDA) Arthritis Advisory Committee recommended approval of the 2-mg dose of baricitinib, a once-daily oral medication for the treatment of moderately-to-severely active rheumatoid arthritis (RA) for adult patients who have had an inadequate response or intolerance to methotrexate (Press release, Incyte, APR 23, 2018, View Source [SID1234525686]). While the Advisory Committee unanimously supported the efficacy of the 4-mg dose of baricitinib, it did not recommend approval of the 4-mg dose of baricitinib for the proposed indication based on the adequacy of the safety and benefit-risk profiles.

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"We are confident that baricitinib, if approved, can help people in the U.S. manage the challenges of living with RA," said Christi Shaw, president of Lilly Bio-Medicines. "While we are disappointed with the Advisory Committee’s assessment of the data for the 4-mg dose, we are confident in the positive benefit-risk profile of both the 2-mg and the 4-mg doses. We look forward to continuing our work with the FDA on our New Drug Application (NDA) and are hopeful that baricitinib will receive approval in the coming months."

Baricitinib 2-mg and 4-mg doses are approved in more than 40 countries, including the member states of the European Union and Japan.

For both doses, the Advisory Committee voted to support the assessment that baricitinib’s data provide substantial evidence of efficacy. For the 2-mg dose, the Advisory Committee voted in favor of the assessment that baricitinib’s safety data adequately support its approval. For the 4-mg dose, the Advisory Committee voted against the assessment that baricitinib’s safety data was adequate to support its approval based on the proposed indication.

The Advisory Committee’s recommendation was based on baricitinib’s global development program, which included four completed Phase 3 studies. In total, 3,492 patients, who represented a range of treatment experiences, received baricitinib in the global RA development program. The Phase 3 studies evaluated baricitinib’s treatment impact related to RA signs and symptoms, physical function, joint damage progression and other patient-reported outcomes. The Phase 3 program also evaluated recognized risks for RA patients, including serious infection, malignancy, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and gastrointestinal perforations, along with key laboratory changes. The safety profile of baricitinib is based on 7,860 patient-years of exposure.

"Despite advances in the management of RA over the last 20 years, which include early treatment, optimized use of traditional therapies for rheumatic disease and the advent of newer medications such as biologics, many patients are still struggling to meet treatment targets, and live with debilitating pain, fatigue and other symptoms of RA," said Peter Taylor, MA, PhD, professor, University of Oxford, an expert who attended the Advisory Committee Meeting. "Baricitinib could be a promising option for RA patients in the U.S. who are not achieving adequate disease control with currently available treatments."

The FDA is not required to follow the Advisory Committee’s recommendation, but will consider it during its review of the NDA for baricitinib.

About Baricitinib
Baricitinib is a once-daily oral JAK inhibitor currently in clinical studies for inflammatory and autoimmune diseases. There are four known JAK enzymes: JAK1, JAK2, JAK3 and TYK2. JAK-dependent cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases, suggesting that JAK inhibitors may be useful for the treatment of a broad range of inflammatory conditions, including rheumatoid arthritis.

In December 2009, Lilly and Incyte announced an exclusive worldwide license and collaboration agreement for the development and commercialization of baricitinib and certain follow-on compounds for patients with inflammatory and autoimmune diseases. Baricitinib was submitted for regulatory review seeking marketing approval for the treatment of rheumatoid arthritis in the U.S., the European Union and Japan in 2016. Baricitinib was approved in the EU in February 2017 and in Japan in July 2017. In April 2017, the U.S. Food and Drug Administration issued a Complete Response Letter on the New Drug Application for baricitinib. To date, baricitinib has been approved in more than 40 countries and remains under review in several other markets.

On April 23, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas" ) reported that it submitted on March 23, 2018, a new drug application (NDA) for marketing approval of gilteritinib (generic name) in Japan for the treatment of adult patients with FLT3 mutation-positive (FLT3mut+) relapsed or refractory acute myeloid leukemia (AML) (Press release, Astellas Pharma US, APR 23, 2018, View Source [SID1234525608]). Astellas also submitted a NDA for approval of gilteritinib in the same patient population to the U.S. Food and Drug Administration (FDA) on March 29, 2018 (U.S. time) following the submission in Japan. The applications for marketing approval for gilteritinib are based on data from the ongoing pivotal Phase 3 ADMIRAL study investigating gilteritinib in adult patients with FLT3mut+ relapsed or refractory AML.

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Astellas is a pharmaceutical company dedicated to improving the health of people around the world. (PRNewsFoto/Astellas Pharma Inc.)

AML is a cancer that impacts the blood and bone marrow, and its incidence increases with age. In Japan, approximately 5,500 patients are diagnosed with AML each year1. Gilteritinib is an investigational compound that has demonstrated inhibitory activity against both internal tandem duplication (ITD) and tyrosine kinase domain (TKD), FLT3 mutations that are seen in approximately one-third of patients with AML.

In October 2015, the Japanese Ministry of Health, Labor and Welfare (MHLW) announced the selection of gilteritinib as one of the first products designated for SAKIGAKE2.

(1)

KantarHealth. TREATMENT ARCHITECTURE: JAPAN LEUKEMIA, ACUTE MYELOID. CancerMPact Japan, February 2017.

(2)

SAKIGAKE: SAKIGAKE designation system can shorten the review period with the following 3 approaches: 1) Prioritized Consultation, 2) Substantial Pre-application Consultation and 3) Prioritized Review.

And also, the system will help promote the development with the following 2 approaches: 4) Review Partner System (to be conducted by the Pharmaceuticals and Medical Devices Agency) and 5) Substantial Post-Marketing Safety Measures.

About Gilteritinib
Astellas is currently investigating gilteritinib in various FLT3 mutation-positive AML patient populations through several Phase 3 trials. Visit View Source to learn more about ongoing gilteritinib clinical trials.

Gilteritinib was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and potentially commercialize gilteritinib. Gilteritinib has been granted Orphan Drug and Fast Track designation by the U.S. FDA, Orphan Drug Designation by the European Commission, and SAKIGAKE Designation and Orphan Drug Designation by the Japan Ministry of Health, Labor and Welfare.

About the ADMIRAL Study
The Phase 3 ADMIRAL trial is an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy. The co-primary endpoints of the trial are OS (Overall Survival) and CR (complete remission) / CRh (CR with partial hematological recovery) rate and the study is still ongoing. The study enrolled 371 patients with FLT3 mutations present in bone marrow or whole blood, as determined by central lab. Subjects have been randomized in a 2:1 ratio to receive gilteritinib (120 mg) or salvage chemotherapy.

On April 23, 2018 Advaxis, Inc. (NASDAQ:ADXS), a late-stage biotechnology company focused on the discovery, development and commercialization of immunotherapy products, reported that Kenneth A. Berlin has been appointed as President and Chief Executive Officer, effective April 23, 2018, and will also serve as a Director of the company (Press release, Advaxis, APR 23, 2018, View Source [SID1234525582]). Interim CEO Anthony Lombardo will remain with Advaxis for a period of time to ensure a smooth transition to Mr. Berlin.

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In addition, Andres A. Gutierrez, M.D., Ph.D. has been named Executive Vice President, Chief Medical Officer, effective April 23, 2018. Advaxis also announced that CFO Sara Bonstein will be leaving the company as of April 30, 2018 to pursue a new professional opportunity. The Company is actively engaged in the search for a new CFO, and will announce an interim appointment shortly.

"After a comprehensive and methodical search, we are very pleased to announce that Ken Berlin has agreed to join Advaxis as President and CEO, and that Dr. Andres Gutierrez is joining our team as CMO. Both of these executives are eminently qualified for their new positions, and we expect to benefit greatly from their expertise. Under their leadership, we look to the future of the company with excitement and confidence," stated David Sidransky, M.D., Chairman of the Board. "On behalf of the Board, I would like to take this opportunity to sincerely thank Sara Bonstein and Anthony Lombardo for their valued service to the company as CFO and interim CEO, respectively, and extend best wishes to both of them."

Mr. Berlin joins Advaxis from Rosetta Genomics, where since 2009 he was President and Chief Executive Officer. During his tenure at Rosetta, Mr. Berlin spearheaded the effort of repositioning the company for commercial success with various microRNA-based oncology diagnostic products and raised nearly $100 million in capital to fund these efforts. Prior to Rosetta Genomics, Mr. Berlin was Worldwide General Manager at cellular and molecular cancer diagnostics developer Veridex, LLC, a Johnson & Johnson company. At Veridex he grew the organization to over 100 employees, launched three cancer diagnostic products, led the acquisition of its cellular diagnostics partner, and delivered significant growth in sales as Veridex transitioned from an R&D entity to a commercial provider of oncology diagnostic products and services. During Mr. Berlin’s tenure, Veridex received numerous awards including recognition from the Cleveland Clinic and Prix Galien for the use of its innovative CellSearch technology in the fight against cancer.

Mr. Berlin joined Johnson & Johnson in 1994 and served as corporate counsel for six years. He led and participated on the legal team that oversaw several mergers, acquisitions, divestitures and commercial transactions. He then held positions of increasing responsibility within Johnson & Johnson and a number of its subsidiary companies. From 2001 until 2004 he served as Vice President, Licensing and New Business Development in the pharmaceuticals group, and from 2004 until 2007 served as Worldwide Vice President, Franchise Development, Ortho-Clinical Diagnostics. He has been responsible for numerous licensing and/or research collaboration deals in oncology, metabolic disease, cardiovascular disease, CNS and women’s health, including the ex-U.S. license to Millennium Pharmaceutical’s VELCADE, a first-in-class, oncology therapeutic with peak reported sales outside the U.S. of approximately $1.8 billion.

"Ken brings to Advaxis a truly valuable combination of executive leadership experience with large and small, development-stage and commercial companies with a particular expertise in oncology. He has a proven ability to raise capital, launch products, achieve rapid sales growth, build businesses and complete strategic M&A and licensing transactions. We are fortunate to have Ken as our new chief executive," commented Dr. Sidransky.

"The opportunity to join Advaxis at such a pivotal and active time is very exciting," stated Mr. Berlin. "I look forward to building on the company’s strong foundations and to maximize the value of our Lm-based platform technology worldwide and in multiple indications."

Mr. Berlin holds an A.B. degree from Princeton University and a J.D. from the University of California Los Angeles School of Law.

Dr. Gutierrez will be responsible for all global clinical development and regulatory initiatives for Advaxis’ novel Lm-based antigen delivery platform. He has more than 25 years of experience in clinical oncology and drug development and joins Advaxis from Oncolytics Biotech, Inc., where he served as Chief Medical Officer. Prior to Oncolytics, Dr. Gutierrez was Chief Medical Officer at SELLAS Life Sciences Group and was Medical Director, Early Development Immuno-Oncology at Bristol-Myers Squibb, where he oversaw the development of translational and clinical development of immuno-oncology programs in solid tumors and hematological malignancies. Earlier, Dr. Gutierrez was Medical Director for several biotechnology companies including Sunesis Pharmaceuticals, BioMarin Pharmaceutical, Proteolix and Oculus Innovative Sciences, leading key programs with talazoparib and carfilzomib, among others . Prior to Oculus, he served as Director of the Gene & Cell Therapy Unit at the National Institutes of Health in Mexico City and as a consultant physician at the Hospital Angeles del Pedregal.

"We are delighted to welcome Dr. Gutierrez to Advaxis and are confident he will be a valuable addition to our executive team. He is an accomplished leader and physician with a track record of success in developing novel oncology drugs, putting patients first and delivering results," said Dr. Sidransky. "Dr. Gutierrez has played a key role in the advancement of clinical trials in all stages of development, through to drug approvals. We look forward to benefitting from his expertise in oncology drug development as he leads the clinical development of our immune-oncology platform."

"I am excited to be joining Advaxis at this important time in the company’s evolution with multiple clinical programs planned and underway, and look forward to contributing to the impressive progress made to date by the Advaxis team in advancing its innovative Lm-based antigen delivery technology across a number of important cancer indications," said Dr. Gutierrez. "Advaxis has a promising future as we continue to accelerate the development of our pipeline and bring innovative new medicines to patients."

Dr. Gutierrez received his M.D. and a Ph.D. in biomedical science from the National University of Mexico, with board certification in internal medicine and a fellowship in clinical oncology at the Hammersmith Hospital in London. He has presented clinical data at more than 85 scientific and medical meetings, has written numerous peer-reviewed articles, is a contributing author on nine medical textbooks and is named on 20 patents relating to drug development.

On April 21, 2018 Molecular Partners AG (SIX: MOLN), a clinical-stage biopharmaceutical company developing a new class of drugs known as DARPin therapies*, reported that preliminary results from the ongoing Phase 2 study of MP0250 with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) were presented at the 1st European Myeloma Network Meeting in Turin (Press release, Molecular Partners, APR 21, 2018, View Source [SID1234525567]).

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The presentation in Turin focused on results from the first dose cohort of MP0250 with respect to safety and efficacy. Eight patients were treated with 8 mg/kg of MP0250 and five out of these eight patients showed a documented response: Four patients reached a partial response (PR) and one patient reached a very good partial response (VGPR) at the cut-off date. Four out of the five patients are still on treatment with individual treatment durations of 13, 21, 24 and 33 weeks, respectively. The safety profile was consistent with the known safety profiles of bortezomib and MP0250, respectively. The independent dose escalation committee recommended to continue the clinical study at the higher dose of 12mg/kg and the first patient in the second dose cohort has been dosed recently.

Prof. Dr. Hartmut Goldschmidt (Medical Clinic V, University clinic Heidelberg), the Primary Investigator of the phase 2 study, commented: "We are encouraged by the initial efficacy and good tolerability data of MP0250 in combination with bortezomib and dexamethasone. Despite upcoming new treatment options, multiple myeloma remains an incurable disease and new molecules with innovative mechanism of actions are needed."

"We are pleased by the remarkable activity and the good safety profile that we have seen in the first cohort of this study. We are looking forward to patients being treated with the higher dose of MP0250 (12 mg/kg) and the additional phase 1b/2 study of MP0250 in combination with osimertinib in EGFR-mutated NSCLC," said Dr. Andreas Harstrick, Chief Medical Officer at Molecular Partners.

MP0250 is a proprietary DARPin drug candidate neutralizing VEGF and HGF and thus blocking key escape pathways and resistance. Increases in VEGF and HGF are associated with disease progression in multiple myeloma and have been linked to poor prognosis. They are known to be able to stimulate neovascularization, bone destruction, and myeloma proliferation, migration, and adhesion in the bone marrow. MP0250 shows activity in many preclinical tumor models, including in multiple myeloma models in which it enhances the effects of bortezomib on inhibition of M protein production and bone lysis and reduces invasion of tumor cells. MP0250 has shown a favorable safety profile in a phase 1 clinical study in 45 patients with advanced solid tumors.

In the ongoing phase 2 clinical study[1], the safety and efficacy of MP0250 is examined in combination with bortezomib (Velcade) and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) who have failed standard therapies. The study is performed in Germany, Poland and Italy. A total of 40 patients are planned to be treated, 12 patients in the dose-escalation phase (Part 1) to establish a safe dose, and an additional 28 patients in the dose-expansion phase (Part 2) resulting in a total of 34 patients at the target dose.

Additional safety and efficacy data are expected by the end of 2018.

An additional phase 1b/2 study will evaluate MP0250 in combination with osimertinib in patients with EGFR-mutated NSCLC pretreated with osimertinib. The study is conducted in the US and is open for patient enrollment2.

[1] ClinicalTrials.gov identifier NCT03136653
2 ClinicalTrials.gov identifier NCT03418532

Financial Calendar
April 26, 2018 – Q1 2018 Management Statement
August 30, 2018 – Publication of 2018 Half-year Results
November 01, 2018 – Q3 2018 Management Statement
View Source

About the DARPin Difference
DARPin therapeutics are a new class of protein therapeutics opening an extra dimension of multi-specificity and multi-functionality. DARPin candidates are potent, specific, safe and very versatile. They can engage in more than 5 targets at once, offering potential benefits over those offered by conventional monoclonal antibodies or other currently available protein therapeutics. The DARPin technology is a fast and cost-effective drug discovery engine, producing drug candidates with ideal properties for development and very high production yields.
With their good safety profile, low immunogenicity and long half-life in the bloodstream and the eye, DARPin therapies have the potential to advance modern medicine and significantly improve the treatment of serious diseases, including cancer and sight-threatening disorders. Molecular Partners is partnering with Allergan to advance clinical programs in ophthalmology, and is advancing a proprietary pipeline of DARPin drug candidates in oncology. The most advanced global product candidate is abicipar, a molecule currently in Phase 3, in partnership with Allergan.
Several DARPin molecules for various ophthalmic indications are also in development. The most advanced systemic DARPin molecule, MP0250, is in Phase 1 clinical development for the treatment of solid tumors and in Phase 2 development for hematological tumors. In addition, Molecular Partners intends to further evaluate MP0250 for solid tumors in a phase 1b/2 trial for EGFR-mutated NSCLC. MP0274, the second-most advanced DARPin drug candidate in oncology, has broad anti-HER activity; it inhibits HER1, HER2 and HER3-mediated downstream signaling via Her2, leading to induction of apoptosis. MP0274 has moved into Phase 1. Molecular Partners is also advancing a growing preclinical pipeline that features several immuno-oncological development programs. DARPin is a registered trademark owned by Molecular Partners AG.

On April 20, 2018 Dr. Michael Rosenblum and his team at MD Anderson Cancer Center, Houston, TX, reported that presented updated data on TGI (Targeted Granzyme B immunotherapy) at the 2018 American Association of Cancer Research Annual Meeting (AACR) (Free AACR Whitepaper) (Press release, Mirata BioPharma, APR 20, 2018, View Source [SID1234525564]). The research was supported by Mirata Biopharma LLC and conducted by the Clayton Foundation for Research ("Clayton Foundation").

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Dr. Rosenblum’s team developed a fusion protein, GrB-Fc-IT4 (MRT-101), that contains a humanized scFv binding domain targeting the cell surface receptor Fn14, an antigen highly expressed in a variety of solid tumors, and containing the human serine protease granzyme B (GrB) as the cytotoxic payload. The construct includes the IgG hinge Fc domain linker for efficient dimerization and an overall high molecular weight, thereby designed to provide a prolonged serum half-life (~40 h in mice). This unique format mimics human immune effector cell function and induces target cell death through the activation of a variety of well described pro-apoptotic cascade signals.

The poster, entitled "Molecular mechanistic and in vivo efficacy studies of Fn14-targeted fusion constructs containing human granzyme B," demonstrated that Western blot studies on human TNBC cells (MDA-MD-231) have shown that intact MRT-101 is translocated into the cytosol in less than 1 hour after exposure and is detectable in the cytosol for at least 8 hours. The free GrB component is also detected by the Western blot 4 hours after treatment and persists for up to 8 hours. Both of these agents trigger apoptotic cascades through activation of various caspases and induction of mitochondrial damage. Studies demonstrating cytochrome C release and mitochondrial depolarization are ongoing and will be reported. Incubation with the lysosomotropic agent chloroquine did not alter the IC50 of MRT-101, suggesting that the fusion protein is not appreciably held in the endosomal compartment.

In vivo studies have shown that MRT-101 is well tolerated in BALB/c mice after intravenous administration of 5 doses at 20 mg/kg/dose. This dose level showed no evidence of toxicity in any of the major organs such as liver and kidneys. In vivo efficacy studies conducted on NSGNOD scid mice demonstrated significant tumor growth inhibition of established orthotopic breast tumors (MDA-MB-231), with no tumor growth for up to 30 days after implantation. Treatment of nude mice bearing lung PDX tumors showed a 60% tumor growth inhibition when compared to the vehicle control group. These results, in combination with previous in vitro and in vivo studies, demonstrate that the completely human MRT-101 construct is a selective, highly potent, non-toxic and effective antigen-driven drug with significant potential for the treatment of Fn14 positive tumors that acts through a new and unique mechanism of action.

Full poster from the AACR (Free AACR Whitepaper) can be accessed via Mirata Biopharma website: View Source