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Aduro Biotech Highlights Preclinical Data for Three Programs Reported at the American Association for Cancer Research Annual Meeting

On April 17, 2018 Aduro Biotech, Inc. (NASDAQ:ADRO) reported that data from three of the company’s programs were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) this week (Press release, Aduro Biotech, APR 17, 2018, View Source;p=RssLanding&cat=news&id=2343034 [SID1234525429]). The poster presentations detailed:

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Updated preclinical data for ADU-S100, a first-in-class small molecule therapeutic in Phase 1 studies targeting the STimulator of INterferon Genes (STING) pathway;
New preclinical data for ADU-1604, an anti-CTLA-4 antibody scheduled to enter clinical development in the second half of 2018; and,
Preclinical data for BION-1301, an anti-APRIL antibody currently in a Phase 1/2 study for the treatment of patients with multiple myeloma.

"These robust and new data continue to elucidate the diverse mechanisms by which our immunotherapies may provide new therapeutic alternatives for the large majority of patients that do not currently benefit from available cancer immunotherapies," said Andrea van Elsas, Ph.D., chief scientific officer of Aduro. "For ADU-S100, we’ve confirmed in preclinical models that signaling through the STING pathway is critical to elicit tumor-reactive CD8+ T cells, the cornerstone of effective, durable and systemic anti-tumor immunity as evident from rejection of distant tumors. Importantly, these preclinical data show that adding checkpoint inhibitors to an ADU-S100 treatment regimen can eradicate tumors unresponsive to anti-PD-1 immunotherapy."

Dr. van Elsas continued, "We also reported data on our anti-CTLA-4 antibody, ADU-1604, and expect to initiate clinical studies based on this data. In addition, our first-in-class antibody BION-1301 blocks APRIL from binding to both BCMA and TACI and may provide a differentiated approach to treating patients with multiple myeloma who do not benefit from or are resistant to current therapies. We look forward to confirming these data through our ongoing Phase 1/2 clinical study."
Presentation Title (Abstract #631): Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8+ T cell immunity that effectively combines with checkpoint inhibitors
On Sunday, April 15, 2018, Sarah McWhirter of Aduro Biotech presented updated preclinical data demonstrating that an optimized dosing regimen of ADU-S100 administered intratumorally activates acute innate immunity as well as adaptive CD8+ T cells necessary and sufficient for systemic and durable anti-tumor immunity. The data show that activation of the STING pathway by ADU-S100 mediates local induction of type I interferon and TNFα and subsequently CD8+ T cell induction to stimulate an immune response sufficient to reduce or eliminate both the injected and distal tumors.

In addition, combining ADU-S100 with checkpoint inhibitors enhances the durable immunity even in tumors that are resistant to anti-PD-1 treatment. Aduro and Novartis are evaluating ADU-S100 in ongoing Phase 1 clinical studies, both as monotherapy for cutaneously accessible tumors and in combination with PDR001, an anti-PD-1 compound in advanced metastatic solid tumors and lymphomas. Additional studies combining ADU-S100 and other checkpoint inhibitors are planned.

Presentation Title (Abstract #1702): Assessment of pharmacology and toxicology of anti-CTLA-4 antibody (ADU-1604) in non-human primates and evolution of local and anti-CTLA-4 application
On Monday, April 16, 2018, Maaike Hendriks of Aduro Biotech presented preclinical data demonstrating that ADU-1604 binds a unique epitope on human CTLA-4 and was well-tolerated, enhanced T cell activation and inhibited tumor growth. Based on these data, Aduro plans to initiate a Phase 1 study in patients with advanced melanoma in the second half of 2018.

Presentation Title (Abstract #3780): Preclinical pharmacokinetics, pharmacodynamics and safety of BION-1301, a first-in-class antibody targeting APRIL for the treatment of multiple myeloma

On Tuesday, April 17, 2018, John Dulos of Aduro Biotech presented preclinical pharmacokinetic and pharmacodynamic data initially announced at the American Society of Hematology (ASH) (Free ASH Whitepaper) demonstrating that BION-1301 was well-tolerated. In addition, the binding of BION-1301 to APRIL (A Proliferation Inducing Ligand), a ligand for the receptors BCMA and TACI, resulted in decreased IgA, IgG and IgM production in a dose-dependent fashion. Aduro is evaluating BION-1301 in an ongoing Phase 1/2 study in patients with multiple myeloma.

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.

Aduro’s lead molecule, ADU-S100/MIW815, is the first therapeutic in development specifically targeting STING. In collaboration with Novartis, it is being tested in a Phase 1 monotherapy clinical trial and in a Phase 1b combination study with PDR001, an anti-PD-1 compound. Both studies are enrolling patients with cutaneously accessible, advanced/metastatic solid tumors or lymphomas. The trials are evaluating the ability of ADU-S100 to activate the immune system and recruit specialized immune cells to attack the injected tumor, leading to a broad immune response that seeks out and kills non-injected distant metastases. Initial clinical data are expected in the second half 2018.

About ADU-1604
Cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) is a negative regulator of T cell responses and is an immune checkpoint. Blocking CTLA-4 using antibodies may produce an anti-tumor response by enhancing T cell activation and their cancer cell killing activity in the tumor. This therapeutic target has been clinically validated by others in advanced melanoma. Aduro is developing a proprietary humanized anti-CTLA-4 antibody called ADU-1604 that binds to a unique epitope and its potency has been demonstrated in vitro and in vivo. Based on preclinical studies, Aduro believes that ADU-1604 when combined with innate and adaptive immune cell stimulators such as STING agonists and cancer vaccines, can display an amplified anti-tumor effect against poorly immunogenic tumors. ADU-1604 is anticipated to enter clinical development in the second half of 2018.

About BION-1301
Aduro is currently evaluating BION-1301, its most advanced proprietary B-select monoclonal antibody, as a novel therapy for multiple myeloma. Despite new treatments recently approved in multiple myeloma, this disease remains incurable as patients relapse, or become resistant to, currently-available therapies. In preclinical studies, Aduro has established that A PRoliferation-Inducing Ligand (APRIL) plays a crucial part in the protective bone marrow tumor microenvironment. In these studies, APRIL, through the B cell maturation antigen (BCMA), was shown to be critically involved in the survival, proliferation and chemoresistance of multiple myeloma, and upregulates mechanisms of immunoresistance, including PD-L1 upregulation. BION-1301, a humanized antibody that blocks APRIL from binding to its receptors, has been shown in preclinical studies to halt tumor growth and overcome drug resistance. In addition, BION-1301 also demonstrated the ability to inhibit immune suppressive effects of regulatory T cells via TACI but not BCMA in multiple myeloma blood and bone marrow. BION-1301 is currently being evaluated in a Phase 1/2 clinical study.

Sierra Late-Breaking Data Demonstrating SRA737 Preclinical Activity with PARPi to be Presented at the AACR 2018 Annual Meeting

On April 17, 2018 Sierra Oncology, Inc. (Nasdaq: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported preclinical results in two posters, including late-breaking data being presented today, for its Checkpoint kinase 1 (Chk1) inhibitor SRA737, at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2018 in Chicago, Illinois (Press release, Sierra Oncology, APR 17, 2018, View Source [SID1234525426]).

"The data presented within these posters demonstrate that SRA737, as monotherapy and in combination with a poly ADP-ribose polymerase inhibitor (PARPi) such as niraparib, has anti-tumor activity across a broad range of settings. Anti-tumor activity was observed both in homologous recombination repair (HRR) proficient cancers which are poor candidates for PARPi alone, and in HRR deficient tumor cells that have acquired resistance to either PARPi and/or platinum agents," said Dr. Christian Hassig, Chief Scientific Officer of Sierra Oncology. "We also observed inhibition of tumor growth in aggressive CCNE1-driven high grade serous ovarian cancer (HGSOC) patient-derived xenografts. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. Analogous to PARPi, which first exhibited robust activity in patients harboring BRCA mutations, Chk1 inhibitors such as SRA737 may prove effective in defined genetic backgrounds of high replication stress, such as CCNE1 amplification."
The efficacy of SRA737 monotherapy is currently being investigated in an ongoing Phase 1/2 clinical trial (NCT02797964) in replication stress-driven cancer including a patient cohort with CCNE1 amplified HGSOC.
Sierra is also planning to investigate SRA737 in combination with niraparib in a multicenter Phase 1b/2 study in subjects with metastatic castration-resistant prostate cancer (mCRPC), anticipated to be initiated in the fourth quarter of 2018. Janssen Research & Development, LLC will supply TESARO’s ZEJULA (niraparib) for the trial, which is to be led by Professor Johann de Bono, Regius Professor of Cancer Research, Head of the Division of Clinical Studies and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.
The two posters will be available on the company’s website at www.sierraoncology.com.
SRA737 AACR (Free AACR Whitepaper) 2018 Late-Breaker: The Novel Oral Chk1 Inhibitor, SRA737, Is Active in Both PARP Inhibitor Resistant and CCNE1 Amplified High Grade Serous Ovarian Cancers
Data being presented in this late-breaking poster is from research conducted in the laboratory of Dr. Fiona Simpkins, Assistant Professor of Obstetrics and Gynecology at The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Approximately 20% of HGSOCs harbor CCNE1 gene amplification. CCNE1 amplification is known to increase replication stress and genomic instability, leading to increased reliance on Chk1. These tumors show intrinsic resistance to PARPi and frequently are, or become resistant to, platinum therapy, leaving patients without effective treatment options. In this research, Chk1 inhibition by SRA737 as monotherapy in CCNE1 amplified ovarian cancer models was shown to: a) increase levels of replication stress and DNA double strand breaks, b) in turn leading to excessive genomic instability, c) resulting in subsequent tumor cell death, tumor regression and a profound survival benefit.

A distinct subgroup comprising approximately 50% of HGSOC have defective HRR genes (e.g. BRCA1/2 mutation). HRR deficient HGSOC are initially sensitive to PARPi but drug resistance ultimately emerges, frequently involving genetic reversion of BRCA mutated genes and partial restoration of HRR. HRR deficiency may also elevate sensitivity to Chk1 inhibition, given the well-established role of Chk1 in HRR, as well as other aspects of the replication stress response. In this research, SRA737 demonstrated activity as a single agent, as well as in combination with PARPi, in acquired PARPi-resistant cells. Furthermore, SRA737 in combination with PARPi demonstrated preliminary evidence of synergistic tumor growth inhibition in a HGSOC patient-derived xenograft model.

SRA737 AACR (Free AACR Whitepaper) 2018 Poster: The Chk1 Inhibitor, SRA737, Synergizes with the PARP Inhibitor, Niraparib, to Kill Carcinoma Cells via Multiple Cell Death Pathways
Sierra presented a second poster at AACR (Free AACR Whitepaper) with data from research conducted in the laboratory of Dr. Paul Dent, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia. The results demonstrate that the combination of SRA737 and niraparib was effective in HRR proficient ovarian and breast tumor cell lines and that both autophagic cell death and apoptotic pathways contribute to SRA737/niraparib-induced tumor cell killing. PARPi monotherapy is known to be substantially less effective in treating patients with HRR proficient tumors, making the combination with SRA737 a novel and potentially more effective treatment option. Moreover, the involvement of multiple cell death mechanisms may decrease the potential for tumors to develop resistance to these agents.

NewLink Genetics Describes the Differentiated Mechanism of Action of Indoximod in AACR Poster Presentation

On April 17, 2018 NewLink Genetics Corporation (NASDAQ:NLNK) reported that it presented a poster entitled "Indoximod modulates AhR-driven transcription of genes that control immune function" in the Immunomodulatory Agents and Interventions session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2018 Annual Meeting in Chicago (Press release, NewLink Genetics, APR 17, 2018, View Source [SID1234525425]).

"The data demonstrate that indoximod has a unique mechanism of action, remarkably differentiated from IDO enzymatic inhibitors. This different mechanism may contribute to antitumor immune responses in the IDO pathway and through activity independent of IDO," said Charles J. Link, Jr., M.D., Chairman and Chief Executive Officer.

The data suggest that indoximod regulates the differentiation of helper T cells toward an immuno-stimulatory helper function and downregulates genes that control the differentiation of T cells into immuno-suppressive regulatory T cells (Tregs) in an AhR dependent manner. This leads to an increase in the ratio of helper T cells to Tregs. Additionally, it was shown that indoximod reduces the level of IDO protein in dendritic cells in vitro, leading to increased stimulation of CD8 T cell proliferation and reduced production of kynurenine. Moreover, indoximod stimulation of mTOR in T cells appears to increase the proliferation of effector T cells in an IDO and TDO-independent manner. Through this mechanism, indoximod may be able overcome the effects of Trp degradation mediated by both IDO and TDO. Thus, in addition to opposing immunosuppression mediated by the IDO pathway, indoximod may drive antitumor immune responses independent from IDO.

In summary, indoximod has immunostimulatory effects involving 4 main cell types: CD8+ T cells, T helper cells, T regulatory cells, and dendritic cells. Indoximod appears to function through three main mechanisms to inhibit the IDO pathway:

Reversing the effects of low tryptophan by increasing proliferation of effector T cells

Increasing the ratio of T helper to T regulatory cells by both favoring differentiation of activated CD4 T cells into helper T cells and directly reprogramming T regulatory cells into helper T cells

Downregulating IDO expression in dendritic cells

About Indoximod

Indoximod is an investigational, orally available small molecule targeting the IDO pathway. The IDO pathway is a key immuno-oncology target involved in regulating the tumor microenvironment and immune escape. Indoximod is being evaluated in combination with treatment regimens including anti-PD-1/PD-L1 agents, cancer vaccines, radiation and chemotherapy across solid and liquid tumors.

Myriad to Announce Fiscal Third-Quarter 2018 Financial Results on May 8, 2018

On April 17, 2018 Myriad Genetics, Inc. (NASDAQ:MYGN), a leader in molecular diagnostics and personalized medicine, reported that it will hold its fiscal third-quarter 2018 sales and earnings conference call with investors and analysts at 7:30 a.m. ET on Tuesday, May 8, 2018 (Press release, Myriad Genetics, APR 17, 2018, View Source [SID1234525424]). During the call, Mark C. Capone, president and CEO and Bryan Riggsbee, CFO, will provide an overview of Myriad’s financial performance for the fiscal third-quarter and provide a business update. Additionally, Dr. Bryan Dechairo, executive vice president of Clinical Research, will discuss the data from the GeneSight randomized controlled trial. The clinical study data will first be presented as a late breaking poster in the exhibit hall at the American Psychiatric Association annual meeting on Monday, May 7, 2018 at 10:00 a.m. ET, and will be presented by the study principal investigator the same day at a satellite symposium at 6:30 p.m. ET at Hudson Mercantile at 500 W. 36th Street in New York City.

To listen to the earnings call, interested parties in the United States may dial 800-699-0623 or +1 303-223-4362 for international callers. All callers will be asked to reference reservation number 21887258. The conference call also will be available through a live webcast and a slide presentation pertaining to the earnings call will also be available under the investor section of our website at www.myriad.com. A replay of the call will be available two hours after the end of the call for seven days and may be accessed by dialing 800-633-8284 within the United States or +1 402-977-9140 for international callers and entering reservation number 21887258.

Johnson & Johnson Reports 2018 First-Quarter Results:

On April 17, 2018 Johnson & Johnson (NYSE: JNJ) reported sales of $20.0 billion for the first quarter of 2018, an increase of 12.6% as compared to the first quarter of 2017 (Press release, Johnson & Johnson, APR 17, 2018, View Source [SID1234525423]).

Operational sales results increased 8.4% and the positive impact of currency was 4.2%. Domestic sales increased 6.1%. International sales increased 19.9%, reflecting operational growth of 10.9% and a positive currency impact of 9.0%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 4.3%, domestic sales increased 1.3% and international sales increased 7.6%.*

Net earnings and diluted earnings per share for the first quarter of 2018 were $4.4 billion and $1.60, respectively. First-quarter 2018 net earnings included after-tax intangible amortization expense of approximately $1.0 billion and a charge for after-tax special items of approximately $0.3 billion. First-quarter 2017 net earnings included after-tax intangible amortization expense of approximately $0.2 billion and a charge for after-tax special items of approximately $0.4 billion. Excluding after-tax intangible amortization expense and special items, adjusted net earnings for the current quarter were $5.6 billion and adjusted diluted earnings per share were $2.06, representing increases of 11.8% and 12.6%, respectively, as compared to the same period in 2017.* On an operational basis, adjusted diluted earnings per share also increased 5.5%.* A reconciliation of non-GAAP financial measures is included as an accompanying schedule.

"We are pleased with the strong and consistent performance delivered by our colleagues around the world, demonstrated by our sales and EPS growth in the first quarter," said Alex Gorsky, Chairman and Chief Executive Officer. "Our Pharmaceutical business continues to deliver robust growth and we are pleased with the improvement in our Consumer business. In our Medical Devices businesses, we have areas of leadership and continue to make investments and portfolio choices to improve performance."
Mr. Gorsky continued, "The U.S. tax legislation passed late last year is creating the opportunity for us to invest more than $30 billion in R&D and capital investments in the U.S. over the next four years, which is an increase of 15%."
The Company increased its sales guidance for the full-year 2018 to a range of $81.0 to $81.8 billion, reflecting expected operational growth in the range of 4.0% to 5.0%. Additionally, the Company reaffirmed its adjusted earnings guidance for full-year 2018 to a range of $8.00 to $8.20 per share, reflecting expected operational growth in the range of 6.8% to 9.6%.

Segment Sales Performance
Worldwide Consumer sales of $3.4 billion for the first quarter 2018 represented an increase of 5.3% versus the prior year, consisting of an operational increase of 1.3% and a positive impact from currency of 4.0%. Domestic sales increased 1.6%, international sales increased 8.2%, which reflected an operational increase of 1.2% and a positive currency impact of 7.0%. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 2.0%, domestic sales increased 1.6% and international sales increased 2.3%*.
Worldwide operational results, excluding the net impact of acquisitions and divestitures, were driven by beauty products primarily NEUTROGENA, AVEENO, and Dr. Ci Labo, and international analgesics in over-the-counter products, partially offset by the negative impact of domestic baby care products.
Worldwide Pharmaceutical sales of $9.8 billion for the first quarter 2018 represented an increase of 19.4% versus the prior year with an operational increase of 15.1% and a positive impact from currency of 4.3%. Domestic sales increased 9.9%; international sales increased 33.1%, which reflected an operational increase of 22.5% and a positive currency impact of 10.6%. Sales included the impact of Actelion Ltd which contributed 7.6%, to worldwide operational sales growth. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 7.5%, domestic sales increased 2.2% and international sales increased 15.3%.*

Worldwide operational results, excluding the net impact of acquisitions and divestitures, were driven by new products and the strength of core products. Strong growth in new products include DARZALEX (daratumumab), for the treatment of patients with multiple myeloma, IMBRUVICA (ibrutinib), an oral, once-daily therapy approved for use in treating certain B-cell malignancies, a type of blood or lymph node cancer and TREMFYA (guselkumab), for the treatment of adults living with moderate to severe plaque psoriasis. Additional contributors to operational sales growth included ZYTIGA (abiraterone acetate), an oral, once-daily medication for use in combination with prednisone for the treatment of metastatic, castration-resistant prostate cancer, STELARA (ustekinumab) and international SIMPONI/SIMPONI ARIA (golimumab), biologics for the treatment of a number of immune-mediated inflammatory diseases, XARELTO (rivaroxaban), an oral anticoagulant, and INVEGA SUSTENNA/XEPLION/TRINZA/TREVICTA (paliperidone palmitate), long-acting, injectable atypical antipsychotics for the treatment of schizophrenia in adults.

During the quarter, the U.S. Food and Drug Administration (FDA) approved an additional indication for ZYTIGA (abiraterone acetate), in combination with prednisone for the treatment of patients with metastatic high-risk castration-sensitive prostate cancer and ERLEADA (apalutamide) an oral androgen receptor inhibitor for the treatment of patients with non-metastatic castration-resistant prostate cancer. In addition, the Committee for Medicinal Products for Human Use issued a positive opinion recommending marketing authorization for JULUCA (rilpivirine and dolutegravir), the first, single-pill, two-drug regimen for the treatment of human immunodeficiency virus type 1 infection.

Also in the quarter, a marketing authorization application was submitted to the European Medicines Agency for apalutamide, an oral androgen receptor inhibitor for the treatment of patients with high-risk non-metastatic castration-resistant prostate cancer.

Worldwide Medical Devices sales of $6.8 billion for the first quarter 2018 represented an increase of 7.5% versus the prior year consisting of an operational increase of 3.2% and a positive currency impact of 4.3%. Domestic sales increased 2.2%; international sales increased 12.7%, which reflected an operational increase of 4.2% and a positive currency impact of 8.5%. Sales included the partial quarter impact of the recently acquired surgical vision business which contributed 3.1%, to worldwide operational sales growth. Excluding the net impact of acquisitions and divestitures, on an operational basis, worldwide sales increased 1.1%, domestic sales decreased 0.2% and international sales increased 2.4%.*

Worldwide operational results, excluding the net impact of acquisitions and divestitures, were driven by ACUVUE contact lenses in the Vision Care business; electrophysiology products in the Interventional Solutions business; endocutters in the Advanced Surgery business; and trauma products in the Orthopaedics business, partially offset by declines in the Diabetes Care business and spine products in the Orthopaedics business.
During the quarter, the acquisition of Orthotaxy S.A.S., a privately-held developer of software-enabled surgery technologies, including a differentiated robotic-assisted surgery was completed. In addition, the Company announced a binding offer from Platinum Equity, a private investment firm, to acquire its LifeScan business for approximately $2.1 billion, subject to customary adjustments.

Subsequent to the quarter, ACUVUE OASYS with Transitions received 510(k) clearance from the FDA and is indicated for vision correction and the attenuation of bright light.
Additionally, Johnson & Johnson plans to implement actions across its global supply chain that are intended to enable the company to focus resources and increase investments in critical capabilities, technologies and solutions necessary to manufacture and supply its product portfolio of the future, enhance agility and drive growth. The Company expects these supply chain actions will include expanding our use of strategic collaborations, and bolstering our initiatives to reduce complexity, improving cost-competitiveness, enhancing capabilities and optimizing our network. Discussions regarding specific future actions are ongoing and are subject to all relevant consultation requirements before they are finalized.

In total, the Company expects these actions to generate approximately $0.6 to $0.8 billion in annual pre-tax cost savings that will be substantially delivered by 2022. The Company expects to record pre-tax restructuring charges of approximately $1.9 to $2.3 billion, which will be treated as a special item.