On April 17, 2018 ArQule, Inc. (NASDAQ:ARQL) reported that it has entered into an exclusive license agreement with Basilea Pharmaceutica International Limited(Basilea, SIX: BSLN) to develop and commercialize derazantinib, a pan-FGFR (fibroblast growth factor receptor) inhibitor in the US, EU, Japan and rest of the world excluding the People’s Republic of China, Hong Kong, Macau and Taiwan, where Sinovant Sciences Ltd., a Roivant Sciences Ltd. subsidiary, has rights to develop and exclusively commercialize the drug (Press release, ArQule, APR 17, 2018, View Source [SID1234525419]).

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Under the terms of the agreement, ArQule will receive an upfront payment of $10 million and is eligible for up to $326 million in regulatory and commercial milestones. ArQule is also entitled to receive staggered single-digit to double-digit royalties on net sales upon commercialization. Basilea will be responsible for all costs and expenses of development, manufacture and commercialization in its territory. Under certain circumstances, ArQule may have the opportunity to promote derazantinib in the US directly.
ArQule is currently conducting a registrational trial for derazantinib in the United States, Canada and Europe as a potential treatment for intrahepatic cholangiocarcinoma (iCCA), a form of biliary tract cancer. As part of the exclusive license agreement, Basilea intends to continue this trial and the further development of derazantinib in iCCA and other tumor types with FGFR dysregulation.

Ronald Scott, Chief Executive Officer of Basilea, said: "We are very excited about this partnership with ArQule. Derazantinib is an ideal match for our existing clinical oncology portfolio. It is a targeted therapy building on a solid biomarker approach in an area where patients currently have limited treatment options. This transaction underscores our continued commitment to expand our R&D portfolio with novel compounds focused on overcoming the clinical problem of resistance in oncology and infectious diseases. Our clinical oncology portfolio now includes three drug candidates in different stages of development. We continue to focus on further broadening our R&D portfolio through internal and external innovation."

"Partnering with Basilea, a company with global drug development experience and expertise, will propel the advancement of derazantinib in ways we could not have achieved independently," said Paolo Pucci, Chief Executive Officer of ArQule. "Basilea will bring a wealth of skills to the expansion of the derazantinib development plan at a time when it will benefit most from these resources, allowing it to reach its full potential in iCCA and beyond."
ArQule will hold a conference call to discuss this agreement tomorrow, April 18, beginning at 9 a.m. EDT. Paolo Pucci, Chief Executive Officer of ArQule, will lead the call. As a result of entering into the exclusive license agreement, ArQule will be updating its financial guidance on the call.

The details of the call are as follows:
Wednesday, April 18, 2018 at 9:00 AM EDT
Audio connection numbers:
US: 1 877-868-1831
Outside US: 1 914-495-8595 PIN: 4089669
A replay of the call will be available two hours after the completion of the call and can be accessed in the "Investors and Media" section of our website, www.arqule.com, under "Events and Presentations." The ArQule investor conference call will be archived and can be accessed in the "Investors and Media" section of ArQule’s website, www.arqule.com, under "Events and Presentations."
About Derazantinib
Derazantinib is a potent, orally administered inhibitor of the fibroblast growth factor receptor (FGFR) family, a key driver of cell proliferation, differentiation, and migration. In a Phase 1/2 study in patients with iCCA harboring FGFR2 gene fusions, treatment with derazantinib resulted in an objective response rate of 21%, nearly 3 times higher than standard-of-care chemotherapy. ArQule is currently conducting a registrational study with derazantinib in patients with FGFR2 fusion-positive second-line iCCA. The open-label single-arm trial is recruiting in the United States, Canada and Europe with objective response rate as the primary endpoint. More information on that program is available here.
About Intrahepatic Cholangiocarcinoma
Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC).1 Depending on the anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). iCCA originates from the intrahepatic biliary ductal system and forms an intrahepatic mass. iCCA is an aggressive cancer, with a median 5-year survival rate of 15% for patients diagnosed with early-stage disease.2 In China, the incidence of cholangiocarcinoma is more than 7 cases per 100,000 people, and the majority of cases are intrahepatic.3

On April 17, 2018 Arcus Biosciences, Inc. (NYSE:RCUS), a clinical-stage biopharmaceutical company focused on creating innovative cancer immunotherapies, reported that it will present data today from its Phase 1 trial for AB928, its dual adenosine receptor antagonist, in healthy volunteers in a poster presentation titled "Clinical Pharmacokinetic-Pharmacodynamic Relationship for AB928, a Dual Antagonist of the A2aR and A2bR Adenosine Receptors," at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, Illinois (Press release, Arcus Biosciences, APR 17, 2018, View Source [SID1234525418]).

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"We are extremely encouraged by the results from our ongoing Phase 1 trial of AB928. The compound has been shown to be safe and well tolerated at all doses evaluated and achieves near complete inhibition of A2aR adenosine receptor activation in blood samples from healthy volunteers," said Terry Rosen, Ph.D., Chief Executive Officer at Arcus. "Importantly, we achieved this level of inhibition under conditions that we believe are representative of the large concentrations of adenosine found in the tumor microenvironment. These results have informed the selection of the starting dose for our clinical trials of AB928 in combination with other anti-cancer agents, and we look forward to starting these trials shortly."

Design of the Phase 1 Trial for AB928 in Healthy Volunteers
The Phase 1 double-blinded, placebo-controlled trial has enrolled 85 healthy volunteers. The trial includes a single-ascending-dose (SAD) portion as well as a multiple-ascending-dose (MAD) portion. In the SAD portion, single doses of 10, 25, 75 and 150 mg and a twice-daily dose of 100 mg have been evaluated. In the MAD portion, doses of 10, 25, 75 and 150 mg QD and 200 mg QD (with food) have been administered to subjects for four consecutive days. In each dosing cohort, 6 subjects received AB928 and 2 subjects received placebo, and dosing in the trial has been completed. Investigators remain blinded regarding subject assignment to the AB928 or placebo arms.
The objective of this trial is to assess the safety, tolerability, pharmacokinetics and pharmacodynamic profile of AB928 and to inform our selection of the starting dose of AB928 for our combination trials in cancer patients.

Summary of the Results Presented
All doses have been safe and well tolerated, and no safety events prevented escalation to higher doses. To assess the pharmacodynamic effects of AB928, blood samples were taken from subjects at different time points following the administration of AB928 or placebo. As of the cut-off date (COD) of March 30, 2018 for the poster presentation, samples from all dosing cohorts, with the exception of the 200 mg QD (with food) MAD cohort, have been evaluated to assess the pharmacodynamic effects of AB928. These samples were treated with NECA (a synthetic analogue of adenosine), which activates A2aR receptors on T cells. The ability of AB928 to block A2aR receptors on T cells was quantified by measuring the levels of pCREB, which is a marker for activation of the A2aR receptor.
When blood samples from the 150 mg MAD cohort were incubated with 5 µM NECA, AB928 achieved complete inhibition of pCREB activation at two hours post-dosing and approximately 90% mean inhibition of pCREB activation at 24 hours post-dosing on day 4. As experiments conducted in vitro by Arcus have demonstrated that NECA is at least 20 times more potent than adenosine at inducing pCREB activation in blood T cells, stimulation with 5 µM NECA should be comparable to stimulation with adenosine concentrations in excess of 100 µM.
The pharmacokinetic profile of AB928 supports once-daily dosing, with a plasma half-life that exceeds 20 hours.
Complete results from this trial, including pharmacodynamic data for the 200 mg BID (with food) dosing cohort, will be released following the unblinding of data in mid-2018.

AB928 Clinical Development Plans
The results from this healthy volunteer trial demonstrate that a safe and well tolerated dose of AB928 can provide near complete inhibition of A2aR receptor activation. Based on these results, Arcus is preparing to initiate clinical trials to evaluate AB928 in combination with three different chemotherapy regimens and in combination with AB122, its PD-1 antibody, in cancer patients. Regulatory submissions to start these trials are underway.
These trials will include a dose-escalation portion to identify the recommended dose of AB928 for each combination regimen. Based on the safety profile of AB928, the initial dose of AB928 for the dose-escalation portion should achieve close to complete inhibition of A2aR receptor activation. Once the recommended dose has been selected, AB928 will be evaluated in 11 expansion cohorts. Each expansion cohort will evaluate the AB928 + chemotherapy combination and/or the AB928 + AB122 combination in one of the following tumor types: non-small cell lung cancer, renal cell carcinoma, gastroesophageal cancer, colorectal cancer, ovarian cancer and triple negative breast cancer. In both the dose escalation portion and expansion cohorts, Arcus will conduct significant biomarker analysis, which will inform patient selection in future trials. Arcus plans to report data from the dose-escalation portion of these trials in the first half of 2019

On March 17, 2018 Zymeworks Inc. (NYSE/TSX: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported that presented preclinical data on ZW49, its lead bispecific antibody-drug conjugate candidate (ADC) and its ZymeLink ADC platform (Press release, Zymeworks, APR 17, 2018, View Source [SID1234525407]). As previously reported, Zymeworks expects to file an Investigational New Drug (IND) application this year in order to begin clinical trials with ZW49 for patients with HER2-expressing cancers.

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Abstract Number: 3914; ZW49, A HER2 Targeted Biparatopic Antibody Drug Conjugate for the Treatment of HER2 Expressing Cancers

Summary: ZW49, which incorporates Zymeworks’ Azymetric bispecific and ZymeLink ADC technology platforms, was shown to be active and well tolerated in a series of preclinical studies. The unique biparatopic (ability to simultaneously bind two distinct locations on a single target) properties of ZW49 enable highly efficient delivery of its cancer cell killing payload while its ZymeLink-enhanced tolerability allows higher doses to be administered leading to improved anti-tumor activity. In models of both high and low HER2-expressing cancers, administration of ZW49 resulted in complete regression of the tumors. Importantly, ZW49 was well tolerated in preclinical safety studies at the same exposure levels that demonstrated efficacy in tumor models, without the toxicities generally associated with this class of ADC payloads.

Abstract Number: 3912; Towards Development of Next Generation Biparatopic ADCs Using a Novel Linker-Toxin with Expanded Therapeutic Window
Summary: Many ADCs in development ultimately fail to demonstrate efficacy in clinical testing due to dose-limiting toxicities. Zymeworks’ approach to ADC development is focused on efficient payload delivery and improving tolerability to enable greater exposures at the tumor rather than the conventional approach of solely increasing ADC potency. Preclinical data demonstrate that ZymeLink improved the tolerability of ADCs against four known clinical targets compared to the corresponding ADC platforms used in clinical trials. This enabled ZymeLink ADC exposures of at least seven-fold higher than benchmark ADCs which translated to increased anti-tumor activity in preclinical models. Ongoing efforts are focused on evaluating biparatopic versions of these ZymeLink ADC candidates to expand the therapeutic window even further.

"Combining our complementary Azymetric and ZymeLink technology platforms gives us a foundation to create active and well tolerated ADCs," said Ali Tehrani, Ph.D., Zymeworks’ President & CEO. "ZW49 is the first of many of ADCs that we plan to develop as part of our diverse pipeline of new medicines to overcome the limitations of current therapies and ultimately, defeat cancer."

About ZW49
ZW49 is a biparatopic (a bispecific antibody that can simultaneously bind two non-overlapping epitopes on a single target) anti-HER2 ADC based on the same antibody framework as ZW25, Zymeworks’ lead clinical candidate being evaluated in a Phase 1 study, but armed with the company’s proprietary ZymeLink cytotoxic (potent cancer-cell killing) payload. ZW49 may mediate its therapeutic effect through a combination of mechanisms, including: increased HER2 receptor-antibody clustering and internalization leading to toxin-mediated cytotoxicity; increased binding and removal of HER2 protein from the cell surface; and potent effector function.

About Antibody-Drug Conjugates
Antibody-drug conjugates (ADC) are a class of anti-cancer therapies intended to precisely target tumor cells in order to avoid the significant toxicities routinely associated with cancer treatments while simultaneously improving their efficacy. An ADC is an antibody that is connected, or conjugated, to a small molecule drug. It has three critical components: the antibody for targeting of specific cells, the cytotoxin (or payload) being delivered to induce cancer cell death, and the linker, which connects the two components together.

About the ZymeLink Platform
The ZymeLink platform is a modular suite of site-specific conjugation technologies, customizable linkers, and proprietary cytotoxic payloads designed for the targeted delivery of therapeutics with optimal tolerability and efficacy. The ZymeLink platform is compatible with traditional antibodies and with the Azymetric platform and is intended to facilitate the development of next-generation therapeutics.

About the Azymetric Platform
The Azymetric platform enables the transformation of monospecific antibodies into bispecific antibodies, giving them the ability to simultaneously bind two different targets. Azymetric bispecific technology enables the development of multifunctional biotherapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering degradation, and increase tumor-specific targeting. These features are intended to enhance efficacy while reducing toxicities and the potential for drug-resistance. Azymetric bispecifics have been engineered to retain the desirable drug-like qualities of naturally occurring antibodies, including low immunogenicity, long half-life and high stability. In addition, they are compatible with standard manufacturing processes with high yields and purity, potentially significantly reducing drug development costs and timelines.

On April 17, 2018 Euronext Paris: FR0010331421 – IPH) reported that new preclinical data of the Company’s broad and innovative portfolio of next generation immunotherapies have been presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 14-18, in Chicago (Press release, Innate Pharma, APR 17, 2018, View Source [SID1234525405]).

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Eric Vivier, Chief Scientific Officer of Innate Pharma, said: "Innate Pharma has always been driven by innovation and we are very proud to present new preclinical data from our broad and innovative portfolio of next generation immunotherapies. These data not only underpin our ongoing clinical program but also highlight the next wave of immunotherapies in cancer."

Innate Pharma has presented four posters featuring new preclinical data at the Immune Checkpoints sessions on 16 April.

Monalizumab in combination with cetuximab:
Data (ID: 1690) demonstrates that squamous cell carcinoma of the head & neck (SCCHN) tumor cells are infiltrated by NK and CD8+ T cells expressing CD94/NKG2A and that these cancer cells express the natural ligand of NKG2A, HLA-E. Blockade of NKG2A potentiated cetuximab induced antibody-dependent cell-mediated cytotoxicity (ADCC) towards SCCHN cell lines. Overall, the data support the Company’s ongoing Phase I/II trial for the combination of monalizumab and cetuximab in recurrent and/or metastatic SCCHN for which first clinical activity data will be presented today at 1:00 PM Chicago time during the "Phase I/II, II, and III Trials in Progress" poster session.

Monalizumab in combination with durvalumab:
New preclinical data (ID: 2714) suggest the combination of monalizumab and durvalumab is a potent immunotherapy for solid tumors. Tumor infiltrating NK and CD8+ T cells expressing NKG2A and/or PD-1 are present in several cancer types.

Blocking both NKG2A/HLA-E and PD-1/PD-L1 pathways enhanced anti-tumor responses of NK and CD8+ T cells in vitro and in vivo in mice. Taken together, these data support the rationale for ongoing clinical trials investigating the monalizumab/durvalumab combination in various solid tumors
.
IPH52 and IPH53, targeting the adenosine pathway:
Additionally, preclinical data (ID: 2718) support the development of anti-CD39 (IPH52) and anti-CD73 (IPH53) neutralizing antibodies targeting the ATP/Adenosine immune checkpoint pathway for cancer immunotherapy, potentially in combination with chemotherapy or immune checkpoint blockade.
These antibodies potently inhibit the enzymatic activity of both the soluble and membrane-associated forms of their respective target enzymes. In vitro, both antibodies efficiently reverse adenosine-mediated T cell suppression in the presence of ATP. IPH52, a first-in-class CD39 blocking antibody, sustains high concentrations of extracellular ATP that promotes immune responses by enhancing dendritic cell (DC) activation and subsequent T cell proliferation. IPH53 is more potent in vitro than benchmark anti-CD73 antibodies currently under clinical development. Additionally, combining IPH52 and IPH53 lead to a strong reversion of immune cell inhibition in the presence of ATP. Humanized IPH52 and IPH53 are currently in preclinical development.

Siglec-9, a new checkpoint for cancer immunotherapy:
In another highlight, preclinical findings (ID: 2713) for a first-in-class antibody program targeting Siglec-9 were presented. Siglecs comprise a family of 15 members of sialic acid-binding receptors. Siglec-9 is an inhibitory receptor of the family that is expressed on a broad range of immune cells of both lymphoid and myeloid origin. Siglec-9 can interact with sialic acids expressed by tumors, leading to dampened immune cell functions. Thus, Siglec-9-sialic acid interaction disruption may promote anti-tumor immunity.
Data show that antibodies against Siglec-9 generated by Innate Pharma enhance NK cell cytotoxicity. This anti-tumor response is improved by the blockade of the immune checkpoint NKG2A. Further, data demonstrate that Siglec-9 is highly expressed on tumor-infiltrating myeloid cells and upregulated on T cells in cancer, suggesting a potential additional role as an inhibitory checkpoint agent.

On April 17, 2018 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for its anti-coagulation factor IXa/X humanized bispecific monoclonal antibody / coagulation factor VIII substitute, "HEMLIBRA" [US generic name: emicizumab-kxwh] for people with hemophilia A without factor VIII inhibitors (Press release, Chugai, APR 17, 2018, View Source [SID1234525404]). Development and distribution of the drug in the US is conducted by Genentech, a member of Roche Group.

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"We are thrilled that HEMLIBRA has been granted its second Breakthrough Therapy Designation," said Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit, Dr. Yasushi Ito. "This will allow us to expedite potential delivery of this new therapy we created to people with hemophilia A without inhibitors in the US following the previous designation for inhibitors. We continue to work closely with Genentech to enable this line extension as soon as possible."

This designation is based on the global phase III HAVEN 3 (NCT02847637) study evaluating HEMLIBRA subcutaneous injection once a week and once every two weeks in people with hemophilia A (12 years of age or older) without inhibitors to factor VIII.

Hemophilia A is a disease presenting repeated severe bleeding symptoms. In this disease, the blood coagulation reaction does not proceed normally due to the deficiency or functional disorder of coagulation factor VIII. For people with hemophilia A without inhibitors, regular factor VIII replacement therapy has been widely used to prevent bleeding. HEMLIBRA is a bispecific monoclonal antibody, which was developed using Chugai’s proprietary antibody engineering technologies. The drug is designed to bind factor IXa and factor X. In doing so, HEMLIBRA provides the cofactor function of factor VIII in people with hemophilia A, who either lack or have impaired coagulation function of factor VIII1, 2). In the HAVEN 3 study, a statistically significant reduction in the frequency of bleeding episodes was observed with HEMLIBRA. With the convenience of subcutaneous administration and the lower frequency of administration, it is expected to be a new treatment option for hemophilia A.
This is the sixth Breakthrough Therapy Designation received for three drugs created by Chugai: ALECENSA (ALK-positive non-small cell lung cancer with disease progression on crizotinib, and first line treatment for ALK-positive non-small cell lung cancer), ACTEMRA (systemic sclerosis and giant cell arteritis), and HEMLIBRA (prophylactic treatment for patients 12 years or older with hemophilia A with factor VIII inhibitors).

Trademarks used or mentioned in this release are protected by law.
References
Kitazawa, et al. Nature Medicine 2012; 18(10): 1570
Sampei, et al. PLoS ONE 2013; 8: e57479
About Breakthrough Therapy
Breakthrough Therapy Designation was adopted as part of the FDA Safety and Innovation Act (FDASIA) enacted in July 2012 aiming at expediting the development and review of drugs for the treatment of severe or life-threatening diseases or symptoms. In order to grant Breakthrough Therapy Designation, preliminary clinical evidence is required demonstrating that the drug may have substantial improvement on at least one clinically significant endpoint over existing therapies. Breakthrough Therapy Designation includes the features of a Fast Track designation, with the addition of intensive guidance on efficient drug development as well organizational commitment from FDA.
Main approval status of the drug

US: In November 2017, the drug (US product name: HEMLIBRA; Genentech) was approved by the U.S. Food and Drug Administration and was marketed for "routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors."

EU: In Europe, the drug (EU product name: HEMLIBRA; Roche) obtained regulatory approval from the European Commission and was marketed for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors in February 2018.
Japan: The Ministry of Health, Labour and Welfare has approved HEMLIBRA for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with congenital factor VIII deficiency (hemophilia A) with factor VIII inhibitors in March 2018.
About the results of HAVEN 3 study
Press release issued on November 20, 2017
View Source