On May 12, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO) reported that the first patient has been dosed in a Phase 1 trial for ADU-S100 (also known as MIW815), a novel STING (Stimulator of Interferon Genes) pathway activator (Press release, Aduro BioTech, MAY 12, 2016, View Source [SID:1234512325]). Activation of the STING pathway in tumors has been shown to be a critical step to initiate an innate response that may lead to a systemic adaptive tumor-specific immune response. Novartis, Aduro’s collaborator for STING pathway activator compounds in the field of oncology, is conducting the study. The achievement of this milestone triggers a $35 million milestone payment from Novartis to Aduro. Schedule your 30 min Free 1stOncology Demo! "We are thrilled to embark on this landmark Phase 1 study, which we believe is the first clinical trial to specifically target the STING pathway. ADU-S100 (MIW815) has the potential to induce an anti-tumor immune response that is unique to the treated individual, an approach that potentially offers the benefits of a personalized therapy but using an off-the-shelf small molecule," said Thomas Dubensky, Jr., Ph.D., chief scientific officer of Aduro. "ADU-S100 is the first compound to enter the clinic under our collaboration with Novartis, and through this Phase 1 study, we look forward to gaining insight into the safety, tolerability and initial efficacy for several different types of cancer. We have now advanced two differentiated immuno-oncology platforms into the clinic: ADU-S100, with the start of this trial, and our LADD listeria-based immunotherapy strains in clinical studies in multiple indications, including pancreatic, ovarian, lung and prostate cancers, mesothelioma and glioblastoma."
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In preclinical models, direct activation of the STING pathway through intratumoral administration of ADU-S100 (MIW815) overcame immune system suppression within the tumor microenvironment, resulting in significant anti-tumor response. These preclinical studies, which were published in Cell Reports, demonstrated that injecting tumors with ADU-S100 (MIW815) induced profound regression of diverse established tumors in mice, both in the injected tumors and distal, untreated lesions. Importantly, treatment of a single tumor initiated a systemically effective T cell response that prevented outgrowth of untreated tumors in other areas of the body (metastases). The ADU-S100-initiated response was durable and provided lasting immunologic memory and anti-tumor protection.
The Phase 1, multicenter, dose escalation study, which includes dose expansion into designated indications, will enroll patients with cutaneously accessible metastatic solid tumors or lymphomas who are in need of other treatment alternatives. The trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of ADU-S100 (MIW815). For more information about the clinical trial, please visit www.clinicaltrials.gov and use identifier NCT02675439.
In March 2015, Aduro entered into a collaboration with Novartis for the worldwide research, development and commercialization of novel immuno-oncology products derived from Aduro’s STING pathway activator platform. Under the terms of the agreement, Aduro received $200 million upon signing and an additional $50 million equity investment from Novartis. In addition to the $35 million milestone payment triggered by this Phase 1 trial initiation, Aduro is eligible to receive up to an additional $465 million in development and regulatory milestones if all stated objectives of the collaboration are achieved. Aduro will lead commercialization activities and will book sales in the United States for any products developed and commercialized pursuant to this collaboration, with Novartis leading commercialization activities in all other regions. The companies will share in profits, if any, in the United States, Japan and major European countries, and Novartis will pay Aduro a mid-teens royalty for sales in the rest of the world.
About the Tumor Microenvironment
The tumor microenvironment is the cellular environment in which the tumor exists, and, along with cancerous cells, includes support cells, immune cells, surrounding blood vessels, and the extracellular matrix. The tumor cells and the surrounding microenvironment are closely related and interact constantly. Tumors influence the microenvironment by releasing signals that promote tumor growth, immune tolerance and immune suppression. When tumors initially form, the body’s immune system recruits and activates a host of immune cells to fight the invading tumor. However, in cases where cancer develops, tumors are eventually able to evade the immune system by changing their microenvironment to inhibit the ability of the immune system to recognize and destroy the tumor thus allowing for tumor outgrowth and formation of metastasis.
About STING Pathway Activator Platform
The Aduro-proprietary STING pathway activator product candidates, including ADU-S100 (MIW815), are synthetic small molecule immune modulators that are designed to target and activate human STING. STING is generally expressed at high levels in immune cells, including dendritic cells. Once activated, the STING receptor initiates a profound innate immune response through multiple pathways, inducing the expression of a broad profile of cytokines, including interferons and chemokines. This subsequently leads to the development of a systemic tumor antigen-specific T cell adaptive immune response.
Month: May 2016
Selumetinib granted Orphan Drug Designation in the US for adjuvant treatment of differentiated thyroid cancer
On May 12, 2016 AstraZeneca reported that the US Food and Drug Administration (FDA) has granted Orphan Drug Designation for the investigational MEK 1/2 inhibitor, selumetinib (AZD6244, ARRY-142886) for adjuvant treatment of patients with stage III or IV differentiated thyroid cancer (DTC) (Press release, AstraZeneca, MAY 12, 2016, View Source [SID:1234512292]). Schedule your 30 min Free 1stOncology Demo! DTC is diagnosed in approximately 60,000 people in the US each year,1 and radioactive iodine (RAI) is recommended for those with known/suspected metastases at diagnosis and those at high risk of recurrence.2 A small proportion of patients do not benefit from currently available treatment with RAI because they do not express sufficient sodium/iodine symporter (NIS) which is important for RAI uptake into thyroid cells.3,4 Selumetinib is being tested for its ability to increase expression of NIS with the potential to add a treatment option for patients who do not respond well to RAI.
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Sean Bohen Executive Vice President, Global Medicines Development and Chief Medical Officer, at AstraZeneca, said: "Uptake of RAI is crucial for patients with thyroid cancer where no other therapies have proven beneficial. Selumetinib could significantly enhance currently available treatment options for these patients. The Orphan Drug Designation is an important achievement as we advance our development plans for this potential treatment in differentiated thyroid cancer."
The Orphan Drug Designation programme provides orphan status to drugs and biologics, which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US.5
Selumetinib inhibits the MEK pathway in cancer cells to prevent tumour growth. It is being tested in the Phase III ASTRA trial in patients with DTC who are at high risk of recurrence.6 In a Phase II study of selumetinib in patients with advanced thyroid cancer, clinically meaningful increases in iodine uptake and retention were seen in patients with thyroid cancer that was refractory to RAI.7
In addition to DTC, selumetinib is being tested in SELECT-1, a Phase III trial of patients with KRAS-mutant advanced non-small cell lung cancer (NSCLC) and in a Phase II registration trial of paediatric and adolescent patients with neurofibromatosis Type 1 in collaboration with the US National Cancer Institute.
NOTES TO EDITORS
1 American Cancer Society. Key statistics for thyroid cancer. Available at: View Source Accessed May 2016.
2 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Thyroid Cancer. Version 2.2015
3 Worden F. Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer.Ther Adv Med Oncol. 2014 Nov;6(6):267-79.
4 Lakshmanan A et al. Modulation of sodium iodide symporter in thyroid cancer. Horm Cancer. 2014 Dec;5(6):363-73.
5 US Food and Drug Administration. Developing Products for Rare Diseases & Conditions View Source Accessed May 2016.
6 National Institutes of Health. Study Comparing Complete Remission After Treatment With Selumetinib/Placebo in Patient With Differentiated Thyroid Cancer. (ASTRA) View Source Accessed May 2016
7 Ho AL et al. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer N Engl J Med. 2013 February 14; 368(7): 623–632.
8 Durante C et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006 Aug;91(8):2892-9.
About thyroid cancer
Cancer of the thyroid gland is diagnosed in approximately 60,000 people in the US each year.1 Nearly 95% of patients have differentiated tumours with an associated five-year survival of over 90%.2 DTC is usually treated by surgery and thyroxine hormone replacement therapy, and radioactive iodine treatment (RAI) is recommended for patients with known/suspected metastases at diagnosis and for those at high risk of recurrence.2 Up to 30% of patients experience recurrence of DTC after initial treatment.2
Approximately 5-15% of patients with DTC do not respond to RAI.3 Ten year survival in patients who fail to take up radioactive iodine into tumour cells is 10% compared to nearly 60% in those with normal uptake.8 Traditional chemotherapy has minimal efficacy in patients with metastatic DTC.2
About selumetinib
Selumetinib is an oral, potent, selective inhibitor of MEK, part of the mitogen-activated protein kinase (MAPK) pathway which is frequently activated in cancer, including those with the KRAS mutation, which is present in 20% of human cancers and 20-30% of non-small cell lung cancer tumours.
MAPK activation also inhibits expression of thyroid hormone biosynthesis genes, including the sodium/iodine symporter (NIS) which facilitates iodine uptake into cells. 7 Pre-clinical studies have suggested that following MAPK inhibition, iodine uptake by thyroid tumour cells is regained.7
AstraZeneca acquired exclusive worldwide rights to selumetinib from Array BioPharma Inc. in 2003.
About the ASTRA trial
ASTRA is a Phase III randomised, double blind study which is comparing the complete remission rate following a 5-week course of selumetinib or placebo and single dose adjuvant radioactive iodine therapy in patients with differentiated thyroid cancer.5
Ability Pharmaceuticals Enters into a Licensing Agreement with SciClone Pharmaceuticals for the Novel Anticancer Agent ABTL0812 for the China Market
On May 11, 2016 Ability Pharmaceuticals, SL reported that the company has entered into an agreement with the NASDAQ-listed US company SciClone Pharmaceuticals, Inc. (SCLN) granting SciClone an exclusive license to develop and market the novel anticancer ABTL0812 in China and some adjacent territories (Press release, Ability Pharmaceuticals, MAY 11, 2016, View Source [SID1234562099]).
Under the terms of the agreement, AbilityPharma has granted SciClone exclusive rights to develop, promote, market, distribute and sell ABTL0812 in China, as well as Hong Kong, Macau, Taiwan and Vietnam, getting access to follow-up compounds. AbilityPharma will receive an upfront payment and research funding as well as development, regulatory and sales milestone payments, potentially totaling more than $20 million; AbilityPharma will also be eligible to receive royalties on sales. SciClone will be responsible for all aspects of development, product registration and commercialization in the partnered regions, having access to data generated by AbilityPharma.
Carles Domènech, Chief Executive Officer and co-founder of AbilityPharma, stated: "We are excited to partner with SciClone, a NASDAQ US company that has a strong presence in such a rapidly growing market like China, which shares our enthusiasm and sense of urgency for bringing important new cancer therapeutics to patients. The collaboration with SciClone represents meaningful support for our development efforts. This agreement represents the first one signed for China by the Catalan and Spanish Biotech Industry, and we are very proud of it."
About ABTL0812
ABTL0812 is a first-in-class PI3K/Akt/mTOR signaling pathway inhibitor for the treatment of solid tumors. ABTL0812 has a novel mechanism of action, which has shown both in vitro and in vivo high efficacy in tumor settings, including resistant cancer models. It up-regulates TRIB3 leading to inhibition of Akt phosphorylation, which results in decreased activity of mTORC1 (Published in Clinical Cancer Research, Erazo et al., December 2015). ABTL0812 is active in models of multiple solid tumors as single agent and potentiates the anti-cancer effect of chemotherapy as well. The compound plays also a relevant role in tumor stem cells.
AbilityPharma has completed a Phase 1/1b clinical trial of orally administered ABTL0812 in 29 advanced cancer patients with solid tumors and presented the study results at AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Vidal et al.) in Boston in November 2015. This first-in-humans clinical study was designed to explore ABTL0812’s safety and efficacy profile. Outstanding safety and tolerability with several long-term disease stabilizations were demonstrated in patients progressing after previous chemotherapy lines, two of them stabilized over one year. The study showed the inhibition of the PI3K/Akt/mTOR pathway based on biomarkers, with correlation with ABTL0812 plasma levels. A full Phase 2 clinical program has been designed in several advanced tumor indications including endometrial and lung cancer (ongoing). US FDA and Europe EMA granted ABTL0812 Orphan Drug Status for the pediatric cancer neuroblastoma.
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8-K – Current report
On May 6, 2016 La Jolla Pharmaceutical Company (NASDAQ: LJPC) (the Company or La Jolla), a leader in the development of innovative therapies intended to significantly improve outcomes in patients suffering from life-threatening diseases, reported first quarter 2016 financial results and highlighted recent corporate progress (Filing, Q1, La Jolla Pharmaceutical, 2016, MAY 11, 2016, View Source [SID:1234512493]).
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Recent Corporate Progress
• La Jolla’s ATHOS (Angiotensin II for the Treatment of High-Output Shock) 3 trial continued to enroll as planned through the first quarter of 2016. The ATHOS 3 trial is La Jolla’s multicenter, randomized, double-blind, placebo-controlled, Phase 3 clinical trial of LJPC-501, the Company’s proprietary formulation of angiotensin II, in catecholamine-resistant hypotension (CRH), which was initiated in 2015. The Company initiated the ATHOS 3 trial after reaching an agreement with the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA), in which the agreed-upon primary efficacy endpoint in ATHOS 3 is an increase in blood pressure. Results of ATHOS 3 are expected by the end of 2016.
• La Jolla reported interim results in January 2016 of its multicenter, open-label, dose-escalation Phase 1 clinical trial of LJPC-401, the Company’s novel formulation of hepcidin, in patients at risk for iron overload due to conditions such as hereditary hemochromatosis, beta thalassemia, sickle cell disease and myelodysplastic syndrome. These results suggested a dose-dependent reduction in serum iron following a single dose of LJPC-401. Complete results from this Phase 1 clinical trial, which was initiated in October 2015, are expected in the second half of 2016.
"The first quarter was a productive start to 2016 for La Jolla, highlighted by the continued enrollment of our ATHOS 3 trial and encouraging interim data from our Phase 1 clinical trial of LJPC-401," said George Tidmarsh, M.D., Ph.D., La Jolla’s President and Chief Executive Officer. "We look forward to continuing the advancement of each of our exciting programs during the rest of 2016, culminating with the results from the ATHOS 3 trial that are expected by the end of the year."
Results of Operations
As of March 31, 2016, La Jolla had $113.1 million in cash and cash equivalents, compared to $126.5 million as of December 31, 2015. The decrease in cash and cash equivalents was primarily due to net cash used for operating activities. Based on current operating plans and projections, La Jolla believes that its current cash and cash equivalents are sufficient to fund operations into 2018.
La Jolla’s net cash used for operating activities for the three months ended March 31, 2016 was $13.0 million, compared to net cash used for operating activities of $5.5 million for the same period in 2015. La Jolla’s net loss for the three months ended March 31, 2016 was $16.5 million, or $0.96 per share, compared to a net loss of $9.0 million, or $0.59 per share, for the same period in 2015. During the three months ended March 31, 2016, La Jolla recognized contract revenue of approximately $0.2 million, which was pursuant to a services agreement initiated in 2015 under which La Jolla provides research and development services to a related party. The net loss includes non-cash, share-based compensation expense of $3.7 million for the three months ended March 31, 2016, compared to $3.4 million for the same period in 2015.
The increases in net cash used for operating activities and net loss in 2016 as compared to 2015 were primarily due to increased development costs associated with the ATHOS 3 trial and the costs associated with the initiation of the Phase 1 clinical trial of LJPC-401 in iron overload. In addition, there were increases in personnel and related costs, which were mainly due to the hiring of additional personnel and increased facility costs to support the increased development activities.
Onconova Therapeutics, Inc. Reports Recent Business Highlights and First Quarter 2016 Financial Results
On May 11, 2016 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3 clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported a corporate update and reported financial results for the first quarter ended March 31, 2016 (Press release, Onconova, MAY 11, 2016, View Source [SID:1234512298]).
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"We recently reported two important advances in the development of rigosertib for the unmet medical needs of patients with myelodysplastic syndromes (MDS). Foremost is the elucidation of the novel mechanism of action of rigosertib targeting the RAS pathway, recently published in Cell, and the release of detailed clinical data from our ONTIME Phase 3 study in Lancet Oncology. These peer-reviewed papers provide important validation of the mechanistic rationale for rigosertib as a novel treatment option for patients with MDS," said Ramesh Kumar, Ph.D., President and CEO of Onconova. "We are encouraged by the continued progress in the global Phase 3 INSPIRE trial which is now enrolling patients in the U.S. and Europe."
Recent Business Highlights:
Progress in INSPIRE Pivotal Trial of Rigosertib in Higher-risk MDS (HR-MDS)
The global INSPIRE trial is now enrolling patients in the United States and Europe. As of May 3, 2016, 51 sites, including 13 in the U.S., are open and recruiting patients. This pivotal trial was initiated in 4Q2015.
Results from Onconova’s ONTIME trial were published in the top-tier, peer-reviewed journal, Lancet Oncology. The article, entitled, "Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial," appeared in the March 8, 2016 online edition of the journal.
Rigosertib Mechanism of Action
The unique RAS-targeted mechanism of action for rigosertib was published in the prestigious peer-reviewed experimental biology journal, Cell. The paper, entitled "A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling," appeared in the April 21, 2016 edition of the journal.
Proprietary NCE targeting ARK5 and CDK4/6
A presentation at the 2016 American Association of Cancer Research Annual meeting demonstrated the important differentiating features of ON 123300, Onconova’s novel pre-clinical ARK5 and CDK4/6 targeted agent. Results indicated that the inhibitory activity of ON 123300 on ARK5 and CDK4/6 resulted in the activation of programmed cell death in colorectal cancer cells, while treatment with an approved CDK4/6 inhibitor merely resulted in cytostasis.
Upcoming Events
Enrollment of the first patient in the Phase 3 INSPIRE trial in Japan: 2Q2016
Presentation of updated Phase 2 data from oral rigosertib combination trial in MDS: 2Q2016
End of Phase 2 meeting with FDA to discuss data from oral rigosertib combination trial: 2H2016
First Quarter 2016 Financial Results
Cash, cash equivalents, and marketable securities as of March 31, 2016 totaled $16.8 million, compared to $19.8 million as of December 31, 2015.
Total net revenue was $1.5 million for the first quarter of 2016 compared to $0.1 million for the first quarter of 2015.
Research and development expenses were $5.8 million for the first quarter of 2016 compared to $9.5 million for the first quarter of 2015.
General and administrative expenses were $3.2 million for the first quarter of 2016 compared to $3.0 million for the first quarter of 2015.
About Rigosertib
Rigosertib is a small molecule inhibitor of cellular signaling and acts as a RAS mimetic. These effects of rigosertib appear to be mediated by direct binding of the compound to the RAS-binding domain (RBD) found in many RAS effector proteins, including the Raf kinases and PI3K. The therapeutic focus for rigosertib is myelodysplastic syndromes (MDS), a group of bone marrow disorders characterized by ineffective formation of blood cells that often converts into acute myeloid leukemia (AML). Clinical trials for rigosertib are being conducted at leading institutions in the United States, Europe, and the Asia-Pacific region. Rigosertib is protected by issued patents (earliest expiry in 2026) and has been awarded Orphan Designation for MDS in the United States, Europe and Japan.
About INSPIRE
The INternational Study of Phase III IV RigosErtib, or INSPIRE, is based on guidance received from the U.S. Food and Drug Administration and European Medicines Agency and derives from the findings of the ONTIME Phase 3 trial. INSPIRE is a multi-center, randomized controlled study to assess the efficacy and safety of IV rigosertib in HR-MDS patients who had progressed on, failed to respond to, or relapsed after previous treatment with an HMA within the first nine months of initiation of HMA treatment. This time frame optimizes the opportunity to respond to treatment with an HMA prior to declaring treatment failure, as per NCCN Guidelines. The trial will enroll approximately 225 patients randomized at a 2:1 ratio into two treatment arms: IV rigosertib plus Best Supportive Care versus Physician’s Choice plus Best Supportive Care. The primary endpoint of INSPIRE is overall survival and an interim analysis is anticipated. Full details of the INSPIRE trial, such as inclusion and exclusion criteria, as well as secondary endpoints, can be found on clinicaltrials.gov (NCT02562443).