On April 28, 2020 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, reported the presentation of a new off-the-shelf, iPSC-derived, chimeric antigen receptor (CAR)-targeted cell-based cancer immunotherapy program at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 23rd Annual Meeting to be virtually hosted on May 12 – 15, 2020 (Press release, Fate Therapeutics, APR 28, 2020, View Source [SID1234556688]). The new preclinical program targets MHC class I related proteins A (MICA) and B (MICB), and is supported by an exclusive license from the Dana-Farber Cancer Institute to intellectual property covering novel antibody fragments binding MICA/B for iPSC-derived cellular therapeutics. MICA and MICB are stress proteins that are selectively expressed at high levels on many solid tumors.

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"MICA and MICB are emerging as exciting pan-cancer immunotherapy targets, and we are pleased that our engineered iPSC-derived CAR-MICA/B NK cells have shown potent anti-tumor activity in preclinical studies," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "Importantly, since the shedding of MICA/B is a common escape mechanism deployed by many tumors to evade immune cell recognition, we are encouraged that our novel CAR design, which uniquely targets the α3 domain of MICA/B, prevents protein shedding and promotes NK and T cell-mediated tumor immunity."

While it is well known that tumor resistance to cytotoxic T cells is mediated by loss of MHC Class I expression, proteolytic shedding of the α1 and α2 domains of MICA/B expressed on tumor cells is a common mechanism of NK cell evasion. A recent publication in Science (DOI:10.1126/science.aao0505) by Kai W. Wucherpfennig, M.D., Ph.D., Chair of the Department of Cancer Immunology and Virology at the Dana-Farber Cancer Institute and co-leader of the Cancer Immunology Program at Dana-Farber / Harvard Cancer Center, demonstrated that antibody targeting of the MICA/B α3 domains specifically prevents MICA/B shedding and restores NK cell-mediated immunity. Additionally, in a more recent publication in Cancer Immunology Research (DOI: 10.1158/2326-6066.CIR-19-0483), Dr. Wucherpfennig also demonstrated that cancers with B2M and JAK1 inactivating mutations resulting in loss of MHC Class I expression can be effectively targeted with MICA/B α3 domain-specific antibodies to restore NK cell-mediated immunity against solid tumors resistant to cytotoxic T cells.

Using a clonal master induced pluripotent stem cell (iPSC) line previously engineered with an expression cassette introduced into the CD38 locus that encodes for a high-affinity, non-cleavable CD16 Fc receptor and an IL-15 receptor fusion, scientists from Fate Therapeutics introduced a second expression cassette encoding for the novel CAR MICA/B construct. In vitro differentiation of the clonal iPSC lines produced homogeneous NK cell populations with uniform expression of CAR MICA/B, hnCD16, and IL15RF, and without any expression of CD38. The iPSC-derived CAR NK cells displayed enhanced cytokine production and cytotoxicity against MICA/B positive tumor cells compared to non-engineered, iPSC-derived NK cells.

Other Company abstracts selected for presentation at ASGCT (Free ASGCT Whitepaper) include the derivation of clonal master engineered iPSC lines for the Company’s FT576 product candidate, an off-the-shelf, multi-antigen targeted CAR-BCMA NK cell engineered with four anti-tumor modalities for the treatment of multiple myeloma; and a study of various expression systems for the generation, engineering and cryopreservation of clonal master engineered iPSC lines.

About MICA and MICB Proteins
The major histocompatibility complex (MHC) class I related proteins A (MICA) and B (MICB) are induced by cellular stress, damage or transformation, and the expression of MICA and MICB proteins has been reported for many tumor types. Cytotoxic lymphocytes, such as NK cells and CD8+ T cells, can detect and bind the membrane-distal α1 and α2 domains of MICA/B, activating a potent cytotoxic response. However, advanced cancer cells frequently evade immune cell recognition by proteolytic shedding of the α1 and α2 domains of MICA/B. The clinical importance of proteolytic shedding is reflected in the association of high serum concentrations of shed MICA/B with disease progression in many solid tumors. Several recent publications have shown that therapeutic antibodies targeting the membrane-proximal α3 domain strongly inhibited MICA/B shedding, resulting in a substantial increase in the cell surface density of MICA/B and restoration of NK cell-mediated tumor immunity. Therapeutic approaches aimed at targeting the α3 domain of MICA/B therefore represent a potentially promising novel strategy to overcome this prominent evasion mechanism as a means of restoring anti-tumor immunity.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.

On April 28, 2020 Magenta Therapeutics (NASDAQ: MGTA), a clinical-stage biotechnology company developing novel medicines to bring the curative power of stem cell transplant to more patients, reported that data from across its portfolio will be presented at the ASGCT (Free ASGCT Whitepaper) annual meeting, to be held May 12-15, 2020 (Press release, Magenta Therapeutics, APR 28, 2020, View Source [SID1234556687]).

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"Magenta’s pipeline continues to deliver new results and continues our progress toward our goal of allowing all patients who can benefit to receive curative stem cell gene therapy or transplant. Our ASGCT (Free ASGCT Whitepaper) presentations demonstrate the far-reaching potential of our programs to widen availability of and improve the patient experience with stem cell gene therapy and transplant," said John Davis Jr., M.D., M.P.H., M.S., Head of Research & Development and Chief Medical Officer, Magenta Therapeutics. "We are particularly encouraged by the new results on our first-line mobilization and conditioning medicines for patients."

Data from MGTA-145 First-Line Stem Cell Mobilization Program:

Magenta is developing MGTA-145 as the new first-line standard of care for stem cell mobilization in a broad range of diseases, including autoimmune diseases, blood cancers and genetic diseases, such as sickle cell disease. MGTA-145, a CXCR2 agonist, works in combination with plerixafor, a CXCR4 antagonist, to rapidly and robustly mobilize stem cells for collection and transplant.

These data provide further confirmation that MGTA-145, in combination with plerixafor, enables the same-day mobilization of functional hematopoietic stem cells (HSCs) that can be gene-modified and engrafted.

Title: MGTA-145, in Combination with Plerixafor, Rapidly Mobilizes Large Numbers of HSCs in Humans That Can Be Gene Edited with CRISPR/Cas9 and Mediate Superior Engraftment to Standard-of-Care (Abstract #123)
Presenter: Kevin Goncalves, Ph.D., Magenta Therapeutics, Cambridge, Mass.
Date and Time: Tuesday, May 12, 2020 – 3:45-5:30pm

This abstract demonstrates that MGTA-145 plus plerixafor is a rapid, reliable, efficient medicine to obtain high numbers of HSCs that can be gene edited with CRISPR/Cas9 and mediate durable engraftment in preclinical models.

Title: MGTA-145/Plerixafor-Mediated HSC Mobilization and Intravenous Gene Therapy in Mice Allows for Efficient in vivo HSC Transduction and Stable Gene Marking in Peripheral Blood Cells (Abstract #810)
Presenter: Chang Li, Ph.D., Division of Medical Genetics, Department of Medicine, University of Washington
Date and Time: Wednesday, May 13, 2020 – 5:30-6:30pm

This abstract shows, for the first time, that MGTA-145 plus plerixafor can enable robust mobilization of large numbers of stem cells in animals that can be efficiently modified in vivo by gene therapy without transplant.

Data from CD117-ADC Gene Therapy Conditioning Program

Targeted, disease-modifying antibody drug conjugates (ADCs) are designed to precisely and rapidly remove disease-causing cells in the body and enable immune and blood system reset and long-term engraftment, without the need for chemotherapy or radiation. The results to be presented at ASGCT (Free ASGCT Whitepaper) use a tool CD117-ADC molecule to demonstrate the first-ever successful transplant of gene-modified cells in non-human primates without the use of chemotherapy or radiation. Magenta has built on these results to declare its clinical candidate, MGTA-117, for targeted patient preparation for stem cell gene therapy and transplant. Magenta is on track to deliver initial clinical data on MGTA-117 in 2021.

Title: A Single Dose of Fast Half-Life CD117 Antibody Drug Conjugate Enables Hematopoietic Stem Cell-Based Gene Therapy in Nonhuman Primates (Abstract #533)
Presenter: Naoya Uchida, M.D., Ph.D., Cellular and Molecular Therapeutics Branch; National Heart, Lung, and Blood Institute; National Institutes of Health
Date and Time: Wednesday, May 13, 2020 – 3:45-5:30pm

This abstract demonstrates that a single dose of a tool CD117-ADC selectively depleted HSCs in non-human primates while sparing immune cells, which are important for recovery following transplant. A single dose of CD117-ADC in non-human primates enabled successful transplant and long-term engraftment of HSCs modified with a lentiviral vector encoding the β-globin gene, the gene that causes sickle cell disease and β-thalassemia, with none of the side effects associated with busulfan conditioning.

Additional Posters and Presentations

Title: Expansion with E478 Significantly Increases the Rate of CRISPR-Mediated Homology Directed Repair (HDR) and Improves Engraftment of Human Hematopoietic Stem Cells (Abstract #10)
Presenter: Kevin Goncalves, Ph.D., Magenta Therapeutics, Cambridge, Mass.
Date and Time: Tuesday, May 12, 2020 – 10:15am-12:00pm

Title: MGTA-456, A Cell Therapy Utilizing an Aryl Hydrocarbon Receptor Antagonist (AHRa) Culture, Promotes Expansion of CD34+CD90+Cord Blood (CB) Hematopoietic Stem Cells (HSC), Resulting in Rapid Hematopoietic Recovery, Uniform Engraftment and Better HLA Matched Grafts for Larger Recipients (Abstract #120)
Presenter: John Wagner, M.D., Executive Medical Director, Bone Marrow Transplant Program, University of Minnesota, Minneapolis, Minn.
Date and Time: Tuesday, May 12, 2020 – 3:45-5:30pm

Title: High Dose Hematopoietic Stem Cell Therapies, like MGTA-456, Enable Complete Neural, Peripheral and Skeletal Disease Cross-Correction Through Rapid and Robust Engraftment (Abstract #248)
Presenter: Sharon Hyzy, M.S., Magenta Therapeutics, Cambridge, Mass.
Date and Time: Tuesday, May 12, 2020 – 5:30-6:30pm

Title: A Phase 2 Trial of MGTA-456 Cell Therapy Demonstrates Rapid and Durable Long-Term Improvement in Disease-Specific Outcomes in Inherited Metabolic Disease (IMD) Patients (Abstract #1302)
Presenter: John Wagner, M.D., Executive Medical Director, Bone Marrow Transplant Program, University of Minnesota, Minneapolis, Minn.
Date and Time: Friday, May 15, 2020 – 8:00-9:45am

On April 28, 2020 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported that five abstracts were accepted for the 23rd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) (Free ASGCT Whitepaper), taking place virtually from May 12-15, 2020. Abstracts are available on the ASGCT (Free ASGCT Whitepaper) website (Press release, Intellia Therapeutics, APR 28, 2020, View Source [SID1234556686]).

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Intellia’s data include important updates about the company’s progress and platform development activities:

Oral Presentations

"Enhanced tgTCR T Cell Product Attributes Through Process Improvement of CRISPR/Cas9 Engineering"
As a follow-on to data presented at Keystone Symposia’s Engineering the Genome Conference this past February, Intellia’s ASGCT (Free ASGCT Whitepaper) presentation will focus on process improvements in its CRISPR/Cas9-based engineering to deliver T cell therapies with high levels of editing, achieving robust levels of expansion, desirable memory phenotypes, improved function and reduced translocations. These platform advances support NTLA-5001, which is Intellia’s first wholly owned engineered T cell therapy development candidate. NTLA-5001 utilizes a T cell receptor (TCR)-directed approach to target the Wilms’ Tumor 1 (WT1) antigen, obtained through the ongoing research collaboration with IRCCS Ospedale San Raffaele, which is over-expressed in many hematologic and solid tumors. Intellia will focus its initial clinical investigation of NLTA-5001 on acute myeloid leukemia (AML), while exploring in ongoing preclinical studies its application in solid tumors. Intellia plans to submit an IND for NTLA-5001 for the treatment of AML in the first half of 2021.

Presenter: Aaron Prodeus, Ph.D., senior scientist, Cell Therapy
Abstract number: 35
Session: CAR T-Cell Therapies I
Presentation date/time: Tuesday, May 12, 2020, from 11:45 a.m.-12 p.m. ET

"Exploiting CRISPR-Genome Editing and WT1-Specific T Cell Receptors to Redirect T Lymphocytes Against Acute Myeloid Leukemia"
This presentation will focus on Intellia’s ongoing research collaboration with IRCCS Ospedale San Raffaele to apply CRISPR/Cas9 technology to develop engineered T cell therapies to address intractable cancers, such as AML. Researchers will also present data showing a significant decrease in AML tumor burden in mice treated with the WT1-specific TCRs, which are incorporated into Intellia’s lead NTLA-5001 candidate for the treatment of AML.

Presenter: Eliana Ruggiero, Ph.D., Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Italy
Abstract number: 78
Session: CAR T and Other Engineered T Cells Targeting Hematological Malignancies
Presentation date/time: Tuesday, May 12, 2020, from 3:45-4 p.m. ET

"CRISPR/Cas9-Mediated Gene Knockout of KLKB1 to Treat Hereditary Angioedema"
Intellia will present data updates on its potential hereditary angioedema (HAE) therapy, which uses the company’s modular lipid nanoparticle (LNP)-based CRISPR/Cas9 delivery system to knock out the prekallikrein B1 (KLKB1) gene and reduce kallikrein activity. HAE is a rare genetic disorder characterized by recurring and unpredictable severe swelling attacks in various parts of the body, and is significantly debilitating or even fatal in certain cases. This presentation will include results from the company’s ongoing collaboration with researchers at Regeneron and also will build on initial data released at Keystone Symposia’s Engineering the Genome Conference in February. Intellia expects to nominate a development candidate for HAE in the first half of 2020.

Presenter: Jessica Seitzer, director, Genomics
Abstract number: 1320
Session: Gene Regulation and Delivery Technologies
Presentation date/time: Friday, May 15, 2020, from 10:30-10:45 a.m. ET

Poster Presentations

"Validation of CRISPR/Cas9 Off-Target Discovery Profiles from In Silico Prediction, Cell-Based and Biochemical-Based Assays with Targeted Off-Target Sequencing"
This presentation will highlight Intellia’s approach to assess off-target activity to identify highly specific CRISPR/Cas9 guides. Researchers demonstrated that potential off-target editing profiles discovered through empirical data from biochemical approaches were the most sensitive and accurate.

Presenter: Nishit Patel, Ph.D., senior associate scientist, Informatics, Computational Biology and Genomics
Abstract number: 203
Session date/time: Tuesday, May 12, 2020, from 5:30-6:30 p.m. ET

"In Vivo Model Development for Genome-Edited T Cell Therapeutics"
Researchers will present improved murine models used to assess safety, efficacy and persistence of therapeutic modalities in cell-based therapies. Together with biotechnology company Taconic Biosciences, Intellia developed two in vivo mouse models, which allow for enhanced monitoring of graft-versus-host disease and human natural killer cytotoxicity.

Presenter: Yong Zhang, Ph.D., principal scientist, Cell Therapy
Abstract number: 1174
Session date/time: Thursday, May 14, 2020, from 5:30-6:30 p.m. ET

Workshop and Symposia

"Building a Modular CRISPR/Cas9 Platform for Human Therapeutic Applications"
Intellia will participate in the ASGCT (Free ASGCT Whitepaper) Translational Science Genome Editing Pre-Meeting Workshop, which will include an overview on important factors to consider in building a modular CRISPR/Cas9 platform for human therapeutic applications.

Presenter: Jessica Seitzer, director, Genomics
Session: Gene Editing Workshop
Presentation date/time: Monday, May 11, 2020, from 4:10-4:30 p.m. ET

Industry Sponsored Symposia

Intellia will participate in an industry lunchtime panel discussion during ASGCT (Free ASGCT Whitepaper).

Panelist: Laura Sepp-Lorenzino, Ph.D., chief scientific officer
Panel date/time: Wednesday, May 13, 2020, from 12-1:30 p.m. ET

On April 28, 2020 Karyopharm Therapeutics Inc. (Nasdaq:KPTI) reported that it will report first quarter 2020 financial results on Tuesday, May 5, 2020 (Press release, Karyopharm, APR 28, 2020, View Source [SID1234556685]). Karyopharm’s management team will host a conference call and audio webcast at 8:30 a.m. ET on Tuesday, May 5, 2020, to discuss the financial results and other company updates.

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To access the conference call, please dial (855) 437-4406 (local) or (484) 756-4292 (international) at least 10 minutes prior to the start time and refer to conference ID 9936655. A live audio webcast of the call will be available under "Events & Presentations" in the Investor section of the Company’s website, View Source An archived webcast will be available on the Company’s website approximately two hours after the event.

On April 28, 2020 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage, oncology therapeutics company developing drugs to treat cancers with the greatest medical need for new treatment options, including colorectal cancer, prostate cancer and leukemia, reported new positive results from its ongoing Phase 1b/2 clinical trial of onvansertib in combination with FOLFIRI and Avastin (bevacizumab) for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC) (Press release, Trovagene, APR 28, 2020, View Source [SID1234556684]). The data were featured in a virtual oral presentation, delivered by Dr. Afsaneh Barzi, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) conference on Monday, April 27th, 2020.

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There is a significant, unmet medical need to develop a safe and effective second-line treatment option for patients with KRAS-mutated mCRC. Currently available treatments have limited efficacy with only a 4% response rate and a median of 5.5 months PFS. Other compounds currently in clinical development that target KRAS-mutated cancers have shown minimal activity in mCRC.
"We are encouraged by the level of activity that we are observing with the combination of onvansertib and standard-of-care FOLFIRI and bevacizumab in our patients with KRAS-mutated colorectal cancer," said Dr. Afsaneh Barzi, principal investigator, who led the trial as an associate professor of clinical medicine at Keck School of Medicine of USC and medical oncologist at USC Norris Comprehensive Cancer Center. "So far we are observing what we had hoped for in this trial – lack of toxicity and positive signs of efficacy. We remain optimistic because we are observing anti-tumor effects of onvansertib, which could present the opportunity for a new treatment designed to attack KRAS-mutant tumors and act synergistically with standard-of-care chemotherapy."

Highlights of AACR (Free AACR Whitepaper) Presentation – Onvansertib in KRAS-Mutated mCRC Trial

In the Phase 1b dose escalation, the 1st two dose levels (onvansertib 12 mg/m2 and 15 mg/m2) have been cleared for safety; the 3rd dose level (onvansertib 18 mg/m2) is enrolling; the maximum tolerated dose has not been reached to-date

As of the data cut-off date, clinical response was observed in 7 (88%) of the 8 evaluable patients:

3 patients had partial response (PR), 4 patients had stable disease (SD)

1 patient proceeded to have successful curative surgery

Progression-free survival (PFS) is 6.5 months to date, with 6 patients remaining on treatment

Decreases in plasma KRAS mutation level has been demonstrated to be an early marker for therapeutic response:

Onvansertib effectively targets predominant KRAS mutants associated with CRC

7 of the 8 patients had a KRAS mutation detected by ctDNA analysis at baseline (ddPCR and NGS)

Changes in KRAS mutant during cycle 1 of treatment were highly predictive of tumor regression:

5 patients had a decrease in KRAS mutant to non-detectable level in cycle 1 (28 days) and subsequent tumor regression at 8 weeks

2 patients had detectable KRAS mutant at end of cycle 1 and showed tumor growth at 8 weeks

The Phase 2 continuation trial will further assess the safety and efficacy of onvansertib at the recommended Phase 2 dose (RP2D) in combination with FOLFIRI + bevacizumab, as well as the value of KRAS liquid biopsy to predict treatment response
About the Phase 1b/2 Clinical Trial of Onvansertib in KRAS-Mutated mCRC
The ongoing trial, A Phase 1b/2 Study of Onvansertib (PCM-075) in Combination with FOLFIRI and Bevacizumab for Second‑Line Treatment of Metastatic Colorectal Cancer in Patients with a KRAS Mutation (NCT03829410) is evaluating the safety and efficacy of onvansertib in combination with standard-of-care FOLFIRI and Avastin (bevacizumab). Up to 44 patients, with a confirmed KRAS mutation, metastatic and unresectable disease, who have failed or are intolerant of treatment with FOLFOX (fluoropyrimidine and oxaliplatin) with or without Avastin (bevacizumab), will be enrolled. The trial is being conducted at two prestigious cancer centers: USC Norris Comprehensive Cancer Center and the Mayo Clinic Cancer Center.
About Onvansertib
Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported. Trovagene believes that targeting only PLK1 and having a favorable safety and tolerability profile, along
with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.
Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.

Trovagene has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410; and a Phase 2 clinical trial of onvansertib in combination with decitabine in patients with relapsed or refractory AML (NCT03303339).
Trovagene licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy, and a leader in protein kinase drug development. NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.