On April 16, 2018 Harpoon Therapeutics, a biotechnology company pioneering a new class of T cell engaging therapeutics based on its proprietary TriTAC platform, reported that preclinical data supporting the ongoing development of the platform and its two lead molecules, HPN424 and HPN536 (Press release, Harpoon Therapeutics, APR 16, 2018, View Source [SID1234525414]). These programs are the first of four programs using TriTAC technology, which has been designed for superior tumor penetration and efficacy in combating solid tumors. The company, which announced a series B financing and a partnership with AbbVie in 2017, anticipates filing investigational new drug (IND) applications and entering the clinic with these two compounds in the next 12 months. Data were presented at the 2018 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago, held April 14-18, 2018.

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"Harpoon created TriTAC as a best-in-class T cell engager platform optimized for the treatment of solid tumors," said Jerry McMahon, PhD, President and CEO, Harpoon Therapeutics. "The platform allows us to bring the success of T cell engagers targeting hematologic malignancies, like Blincyto, to solid tumor treatment. At Harpoon, we have optimized serum half-life, maximized tumor penetration, and engineered superior stability and manufacturability. These features have been the foundation for our discovery and development of a robust pipeline of drug candidates targeting PSMA, mesothelin, BCMA and DLL3."

Harpoon presented preclinical data which highlighted the novel aspects of its proprietary TriTAC platform to potentially overcome the limitations of existing bispecific antibody-based and CAR-T therapies. The TriTAC platform uses a single flexible polypeptide comprised of three binding domains, and is designed to be the smallest, half-life extended T cell engaging format without the potential liabilities associated with conventional bispecific antibodies.

"We are excited to share these preclinical data for HPN424 and HPN536, which are designed to elicit targeted tumor cell destruction for both metastatic castration-resistant prostate cancer (mCRPC) and mesothelin-expressing tumors, respectively, such as lung, ovarian and pancreatic cancers," said Holger Wesche, PhD, Senior Vice President, Research. "We believe our new data underscore the significant impact our approach could make in advancing the field of immuno-oncology, and look forward to evaluating our compounds in clinical testing."

HPN424 Data Showed Potent T Cell Killing of Prostate Cancer Cells and Serum Half-Life Extension

HPN424 is a 50-kD single polypeptide containing three binding domains — for human PSMA, human serum albumin (HSA) and human CD3. In preclinical studies, HPN424 demonstrated single-digit picomolar potency for PSMA-dependent T cell killing in a panel of human prostate cancer cell lines, which translated to in vivo efficacy with efficacious doses in the low µg/kg range. HPN424 was well tolerated in a multi-dose safety study in non-human primates and showed a serum half-life of 80 hours supporting once-weekly administration for a Phase 1 dose-escalation study in mCRPC patients planned to begin this year.

HPN536 Data Showed Potent Destruction of Mesothelin-Positive Cancer Cells and Evidence of Mechanism in a Primate Study

HPN536 is a 50-kD single polypeptide containing three binding domains — for human mesothelin (MSLN), HSA and human CD3. In preclinical studies, HPN536 demonstrated single-digit picomolar potency for MSLN-dependent T cell killing in a panel of human cancer cell lines derived from mesothelioma, pancreatic, non-small cell lung and ovarian tumors, and in vivo efficacy with efficacious doses in the low µg/kg range. An exploratory safety study in non-human primates showed that HPN536 was well tolerated and supported weekly dosing in humans. The compound was also shown to elicit T cell activation resulting in mesothelial hypertrophy and lymphocyte infiltration, which strongly supports tissue penetration, the mechanism of action of the TriTAC platform, and the planned Phase 1 study.

ABSTRACT INFORMATION

Abstract #1773
Title: "HPN424, a half-life extended, PSMA/CD3-specific TriTAC for the treatment of metastatic prostate cancer"
Date and Time: April 16, 2018, 8:00 AM – 12:00 PM CT
Session: Therapeutic Antibodies, Including Engineered Antibodies 1

Abstract #1781
Title: "HPN536, a T cell-engaging, Mesothelin/CD3-specific TriTAC for the treatment of solid tumors"
Date and Time: April 16, 2018, 8:00 AM – 12:00 PM CT
Session: Therapeutic Antibodies, Including Engineered Antibodies 1

Abstract #3814
Title: "TriTACs are novel T cell-engaging therapeutic proteins optimized for the treatment of solid tumors and for long serum half-life"
Date and Time: April 17, 2018, 8:00 AM – 12:00 PM CT
Session: Therapeutic Antibodies, Including Engineered Antibodies 3

On April 16,2018 Dynavax Technologies Corporation (NASDAQ: DVAX) reported data from its ongoing Phase 1b/2 study investigating SD-101, Dynavax’s intratumoral TLR9 agonist, in combination with KEYTRUDA , an anti-PD-1 therapy developed by Merck (known as MSD outside the United States and Canada) (Press release, Dynavax Technologies, APR 16, 2018, View Source [SID1234525507]). These data were presented in a poster session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The results from this dose escalation study showed encouraging response rates in patients with advanced head and neck squamous cell carcinoma. In addition, the combination was well tolerated. The full poster presentation can be accessed at View Source

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"Results from our Phase 1b/2 trial of SD-101 in combination with KEYTRUDA are promising in head and neck cancer, a condition for which patients typically have a poor prognosis," said Eddie Gray, Chief Executive Officer of Dynavax. "This is another tumor type in which SD-101, based on early data, has demonstrated encouraging activity while being well tolerated. As understanding of combination therapy matures we believe an effective immune stimulating agonist with an attractive tolerability profile will play a significant role in a wide range of tumors."

"On Tuesday, April 17, 2018 we are also presenting updated data from our Phase1b/2 study at AACR (Free AACR Whitepaper) from a cohort of melanoma patients, where a durable response was observed in patients naïve to anti-PD-1/L1 therapy as well as patients with prior treatment. We are excited about the overall results to date and believe this underscores the potential breadth of our immuno-oncology platform," Mr. Gray added.

Highlights from Poster Presentation of HNSCC Data

Interim data from evaluable patients showed an ORR of 33% (6 out of 18) (38% among patients who received at least one scan on study)

Well tolerated with no dose limiting toxicities

No increase in frequency or severity of the treatment-related adverse events that have been reported in clinical studies of KEYTRUDA as a monotherapy, nor evidence of a unique safety signal for the combination.

Biomarker analyses showed induced broad immune activity, including increase in CD8 T cells, and Th1 response in the tumor microenvironment, consistent with findings reported in advanced melanoma

Highlights from Abstract of Advanced Melanoma Durability Data

86% of initial responses were ongoing after a median of 18 months of follow up in patients that were naïve to anti-PD-1/L1 monotherapy (n=7)

2 of 12 evaluable patients with progressive disease on prior anti-PD-1/L1 monotherapy achieved a partial or stable disease response for at least 10.5 months

Medianprogression-free survival (PFS), duration of response, and median overall survival have not been reached

Treatment was well tolerated with no Grade 3 or higher treatment-related AEs in longer term follow up

Details for the poster presentation are as follows:

Durability of responses to the combination of SD-101 and pembrolizumab in advanced metastatic melanoma: Results of a phase Ib, multicenter study

Session Title: Phase I Trials in Progress

Abstract: CT139

Poster Board Number: 22

Date/Time: Tuesday Apr 17, 2018 8:00 AM – 12:00 PM CDT

Location: McCormick Place South, Hall A, Poster Section 42

SD-101 in combination with KEYTRUDA generally was well tolerated. The most common treatment-emergent adverse events were injection site reactions and transient grade 1 to 2 flu-like symptoms, including fever, chills and myalgia.

About MEL-01 (KEYNOTE-184)
The dose-escalation and expansion study of SD-101 in combination with KEYTRUDA includes patients with histologically or cytologically confirmed unresectable Stage IIIc/IV melanoma. The primary endpoints of the trial are MTD and evaluation of the safety of intratumoral SD-101 in combination with KEYTRUDA. In addition, the trial is investigating response as assessed by the investigator according to RECIST v1.1, biomarker assessments and duration of response. Patients previously treated with anti-PD-1 and other immunotherapies are included.

About SD-101
SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy, in patients with metastatic melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.

On April 16, 2018 Taiho Pharmaceutical Co., Ltd., a Japanese R&D-driven specialty pharma focused on oncology and Helsinn, a Swiss pharmaceutical group focused on building quality cancer care products, reproted that they are collaborating on the development of an investigational highly-selective RET inhibitor TAS0286/HM05, being evaluated in non-small cell lung cancer and other carcinomas (Press release, Helsinn, APR 16, 2018, View Source [SID1234561171]). Preliminary data regarding TAS0286/HM05 is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting in Chicago, Illinois, U.S.A. Abstracts of the presentations are available at: View Source!/4562/presentation/6785

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In in-vitro preclinical studies, TAS0286/HM05 inhibited the proliferation of various RET fusions and RET-activating mutations positive cells as well as in in-vivo preclinical studies, TAS0286/HM05 was shown to significantly inhibit the growth of tumors harboring various RET fusions and activating mutations at a range of 20 to 100 mg/kg/day without any body weight loss. The antitumor efficacy of TAS0286/HM05 was more potent than pre-existing multikinase inhibitors at their maximum tolerated dose. Primary data in mice studies has shown an effect in tumor growth, providing an induced tumor regression of 40% within 15 days. This study is being presented as a poster on Tuesday, April 17 from 1:00 PM to 5:00 PM CST in Poster Section 36, Poster Board Number 13 (Abstract No. 4784).

"Preliminary data for TAS0286/HM05 suggests it may be a potential agent for future clinical development in patients with RET gene abnormalities," Sergio Cantoreggi, Helsinn Group Chief Scientific Officer commented. "Helsinn and Taiho Pharmaceutical have collaborated over many years on a number of programs and we are delighted to be able to present this promising preclinical data, and we look forward to further collaboration."

"Over the years, Taiho Pharmaceutical has collaborated with Helsinn as an excellent partner in the development and marketing of new drugs. I am excited about the new collaboration with Helsinn on the selective RET inhibitor that was discovered by the Taiho Tsukuba Research Center. I look forward to the success of the program and the strengthening of our partnership." Teruhiro Utsugi, Taiho Managing Director commented.

TAS0286/HM05 was discovered by Taiho Pharmaceutical and it will now be jointly developed by Helsinn and Taiho Pharmaceutical. TAS0286/HM05 is an investigational agent and is not approved for commercial use in any country.

On April 16, 2018 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data demonstrating the robust cell killing ability of CG’806, a pan-FLT3/pan-BTK inhibitor, in multiple types of AML and B-cell malignancies (Press release, Aptose Biosciences, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342648 [SID1234525329]). Data further demonstrated that CG’806 targets multiple pathways and overcomes drug resistance seen with other inhibitors. The data were presented in a poster on Sunday, April 15, 2018 at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference being held April 14-18, in Chicago, IL.

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The poster, entitled CG’806, a first-in-class pan-FLT3/pan-BTK inhibitor, targets multiple pathways to kill diverse subtypes of acute myeloid leukemia and B-cell malignancy in vitro, explores the potency and molecular mechanisms of the pan-FLT3/pan-BTK inhibitor CG’806 in hematologic malignancies relative to other FLT3 or BTK inhibitors commercialized or in development. The Aptose research team led by Dr. Hannah Zhang, Senior Director of Research, demonstrated that in FLT3-ITD AML cells, CG’806 induced apoptosis through inhibition of FLT3 signaling, and CG806 was approximately 10-fold more potent than quizartinib. Although FLT3-ITD is found in approximately 30% of AML patient, most AML patients express wild type (WT) FLT3. CG’806 was superior to quizartinib, gilteritinib and crenolanib FLT3 inhibitors in FLT3-WT AML cell lines. In B cell malignancies, BTK signaling plays a pivotal pathogenic role. CG’806 decreased BTK phosphorylation in all malignant B cell lines tested and inhibited cell proliferation and colony formation 50-6,000 times more potently than ibrutinib, an effect explained by the ability of CG’806 to target multiple rescue pathways rather than merely the exclusive inhibition of BTK signaling.

CG’806 demonstrated the ability to target all wild type (WT) and mutant forms of FLT3 and BTK and to inhibit multiple signaling pathways, producing killing of diverse subtypes of hematologic malignancies driven by different genomic aberrations.

"This study directly compares CG’806 to other FLT3 or BTK inhibitors in development and confirms the potent and extended activity we have seen with the molecule," said William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "As a pan-FLT3/pan-BTK multi-kinase inhibitor that can eliminate tumors in the absence of toxicity in animal models, CG’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways. We are eager to pursue its clinical development."
Separately, Aptose and Oregon Health & Science University (OHSU) Knight Cancer Center researchers also announced new data on CG’806 presented at AACR (Free AACR Whitepaper) (see press release here). Both poster presentations will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The posters can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.

About CG’806
CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK multi-kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates acute myeloid leukemia (AML) tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG’806 may be developed for various B cell malignancy patients (including CLL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. CG’806 is currently in preclinical development in partnership with CrystalGenomics.

On April 16, 2018 Idera Pharmaceuticals, Inc. ("Idera") (NASDAQ:IDRA), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel oligonucleotide therapeutics for oncology and rare diseases, reported it has entered into a clinical development support agreement with Pillar Partners Foundation ("Pillar Partners") (Press release, Idera Pharmaceuticals, APR 16, 2018, View Source [SID1234525345]). Under the terms of the agreement Pillar Partners will provide direct funding to support three investigator initiated clinical trials to further strategically expand the clinical research of IMO-2125, Idera’s toll-like receptor ("TLR") 9 agonist into broader melanoma populations and other solid tumors. For these trials, Idera will provide IMO-2125. Idera is currently enrolling a Phase 3 ("ILLUMINATE-301") trial of intratumoral administration of IMO-2125 in combination with ipilimumab in patients with anti-PD-1 refractory metastatic melanoma.

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The three trials within the terms of this agreement are:
A Phase 1/2 open label study of intratumoral IMO-2125 in combination with intratumoral ipilimumab and IV nivolumab in a protocol open to multiple tumor types including non-small cell lung cancer ("NSCLC"), melanoma, squamous cell carcinoma of the head and neck and urothelial carcinoma. The principal investigator initiating this trial is Aurélien Marabelle, MD, PhD, Clinical Director of the Cancer Immunotherapy Program at Institut Gustave Roussy, Villejuif, France.

A Phase 2 study of intratumoral IMO-2125 in combination with IV pembrolizumab in patients with NSCLC. The principal investigator initiating this trial is Arafat Tfayli, MD, FRCP, Professor of Clinical Medicine, Director of Research, NK Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon.

A Phase 2 placebo controlled study of intradermal administration of IMO-2125 in patients with T3/T4 primary melanoma scheduled to undergo a combined re-excision and sentinel node biopsy procedure. The principal investigators initiating this trial are Bas Koster, MD, Fons van den Eertwegh MD, PhD, and Tanja de Gruijl, PhD, who is Professor of Translational Tumor Immunology and Co-Director of the Cancer Immunology Program at the VU University Medical Center, Cancer Center Amsterdam, The Netherlands.
"We are eager to expand our knowledge and understanding of the various cancer types and combinations in which IMO-2125 can play a significant role in improving outcomes beyond our current registrational focus with our ILLUMINATE 301 program," stated Joanna Horobin, M.B., Ch. B., Idera’s Chief Medical Officer. "We look forward to working with these investigators to provide the support they need to initiate these trials before the end of the year," said Shah Rahimian, MD, Idera’s Oncology Medical Lead. "
"We have long believed and understood that the mechanism for IMO-2125 has broad potential and plays a central role in IO combinations beyond PD-1 refractory melanoma and through this financial grant, we are able to help light the spark to further expand our ability to test this hypothesis in multiple tumor types with expert clinical investigators," stated Youssef El Zein, Managing Partner, Pillar Invest Corporation.