On April 4, 2017 Checkpoint Therapeutics, Inc. ("Checkpoint") (OTCQX: CKPT), a Fortress Biotech (NASDAQ: FBIO) company, reported that preclinical data on its third-generation epidermal growth factor receptor ("EGFR") inhibitor, CK-101, and anti-programmed cell death ligand-1 ("PD-L1") antibody, CK-301, were presented this week in poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Fortress Biotech, APR 3, 2017, View Source [SID1234518456]). The data presented strongly support the clinical development of these therapies.

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James F. Oliviero, President and Chief Executive Officer of Checkpoint, said, "These encouraging preclinical data demonstrate the potential of our EGFR inhibitor and anti-PD-L1 checkpoint antibody to be effective new treatment options for patients suffering from cancer. We look forward to advancing these drug candidates through the stages of clinical development, both as monotherapies as well as in combination with each other."

Key conclusions from the posters are as follows:

CK-101 (RX518), a Mutant-Selective Inhibitor of EGFR that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer (NSCLC)

CK-101 (also known as RX518) is a novel, irreversible, orally administered EGFR kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type EGFR. Cell proliferation assays in human cancer cell lines in vitro, and xenograft studies conducted in mouse models of NSCLC demonstrated:

CK-101 is a potent, mutant-selective inhibitor of both the activating (exon 19 deletion) and resistance mutations (L858R / T790M double mutation).

CK-101 inhibited tumor growth as a single agent in a NSCLC model with a single activating mutation (exon 19 deletion).

CK-101 showed dose-dependent inhibition of tumor growth as a single agent in a L858R / T790M double mutant NSCLC model.

CK-101 has little inhibitory potency toward wild-type EGFR (i.e., CK-101 was more than 100-fold less potent against wild-type EGFR than against L858R / T790M double mutation).

These data supported the initiation of a Phase 1/2 clinical trial in September 2016 (ClinicalTrials.gov: NCT02926768). The Phase 1 dose-escalation portion is ongoing, and Checkpoint expects to initiate the Phase 2 portion in patients with EGFR T790M mutation‐positive NSCLC cancer in the second half of 2017.

Preclinical Characterization of a Novel Fully Human IgG1 Anti-PD-L1 mAb CK-301

Based on the various assays performed, the poster concluded:
CK-301 is a high affinity PD-L1 specific fully humanized lgG1 antibody which blocks binding of PD-L1 to PD-1.

Activity of CK-301 in all assays tested was similar to anti-PD-L1’s used as active controls (surrogates of avelumab, atezolizumab or durvalumab).

Similar to the approved anti-PD-L1, avelumab, CK-301 has the potential to induce ADCC (antibody-dependent cell-mediated cytotoxicity).

A first-in-human Phase 1 study of CK-301 is planned to commence this year.

The posters are available on the Publications page within the Pipeline section of Checkpoint’s website,
www.checkpointtx.com.

On April 3, 2017 Trillium Therapeutics Inc. (Nasdaq/TSX: TRIL) a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported the following preclinical and clinical updates on its TTI-621 program (Filing, 6-K, Trillium Therapeutics, APR 3, 2017, View Source [SID1234518448]).

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AACR presentations:
Today the company presents two preclinical posters at the 110th American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, DC:

The first presentation (Abstract #2646), entitled "Intratumoral Delivery of TTI-621 (SIRPaFc), a CD47-Blocking Immunotherapeutic, Inhibits Tumor Growth and Prolongs Animal Survival in a Subcutaneous B Cell Lymphoma Model," demonstrated that TTI-621 was efficacious when injected directly into tumors in a xenograft model. In addition, intratumoral TTI-621 increased the phagocytosis of tumor cells by both M1 and M2 tumor-associated macrophages. These data support the clinical evaluation of direct tumor injections of TTI-621. A Phase 1 study of intratumorally delivered TTI-621 in patients with percutaneously accessible solid tumors and mycosis fungoides is ongoing (NCT02890368).

The second presentation (Abstract #2653), entitled "The Anti-Myeloma Activity of TTI-621 (SIRPαFc), a CD47-Blocking Immunotherapeutic, is Enhanced When Combined With a Proteasome Inhibitor," showed that TTI-621 exhibits anti-myeloma activity on its own that is further enhanced by combination with FDA-approved proteasome inhibitors, such as bortezomib and carfilzomib. These data provide a rationale to evaluate a combination cohort of TTI-621 and a proteasome inhibitor in multiple myeloma patients.

Clinical update:
The company is currently enrolling patients in the expansion phase of its ongoing Phase 1 trial of TTI-621, in patients with multiple hematologic malignancies (NCT02663518). Trillium is providing this clinical update in conjunction with the AACR (Free AACR Whitepaper) presentations.

To date, 33 evaluable patients have been enrolled into the expansion phase of the trial, with several patients demonstrating preliminary evidence of anti-tumor activity. In the AML cohort, one patient with minimal residual disease (consisting of 0.7% abnormal blasts at baseline) obtained a complete molecular remission after 4 infusions of TTI-621. A second marrow analysis at week 8 confirmed a complete molecular remission, the patient continues to tolerate weekly infusions of TTI-621 and remains in continued remission for 15+ weeks.

In the TTI-621/rituximab combination cohort, 3 of 6 patients who have had at least one interval PET/CT restaging obtained partial metabolic responses, as demonstrated by decreased tumor activity on PET/CT scans. These patients with CD20-positive, B-cell lymphoma received weekly IV infusions of TTI-621 and rituximab. Manageable infusion reactions occurred in most patients after the first infusion of TTI-621 and the combination therapy has been associated with acceptable outpatient tolerability. These responding patients remain on treatment and progression-free for 19+ (DLBCL), 18+ (transformed lymphoma), and 8+ weeks (follicular lymphoma) in continuing follow-up.

"Patients with treatment-refractory lymphoma and acute myeloid leukemia continue to represent a pronounced unmet clinical need," said Trillium’s Chief Medical Officer, Eric Sievers, MD. "We and the clinical investigators are encouraged that several of the patients treated with the TTI-621/rituximab combination obtained robust lymphoma regressions. Moreover, while anecdotal, the achievement of complete molecular remission in a patient with relapsed AML is intriguing. Taken together, we believe that the multiple clinical responses observed across varied hematologic malignancies to date is promising."

Details of these clinical responses with further follow-up will be reported at scientific symposia later this year.

On April 3, 2017 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported results from an Ohio State University-sponsored preclinical study evaluating the efficacy of non-covalent BTK inhibitor SNS-062 in chronic lymphocytic leukemia (CLL) proprietary cell lines and patient samples (Press release, Sunesis, APR 3, 2017, View Source [SID1234518447]). The study demonstrated that, unlike ibrutinib, SNS-062 inhibition of BTK signaling is unaffected by the presence of the C481S mutation and may address acquired resistance to covalent BTK inhibitors. The results are being presented today in a poster session titled "Reversal of Drug Resistance" on Monday, April 3, 2017 from 8:00 AM to 12:00 PM ET at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, D.C.

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"B-cell receptor signaling is exceptionally active in CLL and is vital for the proliferation and survival of CLL cells, making BTK inhibition an effective target. However, a subset of patients acquire resistance to ibrutinib, the current standard of care BTK inhibitor," said Amy Johnson, PhD, Associate Professor, Hematology, The Ohio State University. "A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S. In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients."

"Preclinical and healthy volunteer data continue to reveal a unique profile for SNS-062, one distinct from ibrutinib and other covalently binding BTK inhibitors," said Judy Fox, PhD, Chief Scientific Officer of Sunesis. "SNS-062 has the potential to become an important new treatment for CLL, addressing what is an increasingly well-defined and prevalent unmet patient need. With an active IND, we remain on track to dose the first patient in our planned Phase 1B/2 study in patients with advanced B-cell malignancies this quarter."

For the study, primary CLL B-cells were isolated from the whole blood of consenting patients with CLL. In these cells, SNS-062 was found to decrease surface expression of B-cell activation markers and patient CLL cell viability in a dose-dependent manner, with BTK inhibition by SNS-062 comparable to ibrutinib. Further, SNS-062 was found to inhibit BTK wild type (WT) and BTK C481S, while ibrutinib and acalabrutinib show reduced activity toward BTK C481S. SNS-062 has a unique kinase selectivity profile, affecting a limited number of kinases outside the TEC kinase family. SNS-062 was also found to diminish stromal cell protection in patient CLL cells, an important observation given the role of tumor microenvironment in this malignancy.

The poster (Poster Number 22, Abstract Number 1207, Convention Center, Halls A-C, Poster Section 6) titled "SNS-062 demonstrates efficacy in chronic lymphocytic leukemia in vitro and inhibits C481S mutated Bruton tyrosine kinase" is available on the Sunesis website at www.sunesis.com.

About SNS-062

SNS-062 is a novel, second-generation BTK inhibitor, a class of kinase inhibitors that selectively inhibits the enzyme Bruton’s tyrosine kinase (BTK). This target mediates signaling through the B-cell receptor, which is critical for adhesion, migration, proliferation and survival of normal and malignant B-lineage lymphoid cells. Unlike other drugs in its class, SNS-062 has a distinct kinase selectivity profile and binds non-covalently to the BTK enzyme. This alternate binding site potentially provides an opportunity to address the leading resistance mechanism, a mutation in the enzyme’s binding site required for covalent binding. In preclinical studies, SNS-062 demonstrated potent activity against Cys-481S mutated B-cell malignancies, and has been studied in healthy subjects in a Phase 1A, randomized, double-blind, placebo-controlled dose-ranging study to investigate the drug’s safety, pharmacokinetics, and pharmacodynamics. With the reported successful study outcome, SNS-062 is proceeding to a Phase 1B/2 study in patients with B-cell malignancies.

On April 3, 2017 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, reported the presentation of positive new data from the company’s ongoing collaboration with researchers from Memorial Sloan Kettering Cancer Center (MSK) (Press release, Peregrine Pharmaceuticals, APR 3, 2017, View Source [SID1234518444]).

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Presented preclinical study results highlighted the potential of the company’s phosphatidylserine (PS)-targeting antibodies to enhance the anti-tumor activity of adoptive T cell transfer therapy without triggering any off-target toxicities. Data were presented this morning by MSK researchers at the 2017 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which is being held April 1-5, 2017 in Washington, D.C.

For this study, a team of MSK researchers led by cancer immunotherapy thought-leaders, Taha Merghoub, Ph.D. and Jedd D. Wolchok, M.D., Ph.D., evaluated and compared the anti-tumor activity and off-target toxicities of adoptive T cell transfer therapy in combination with either PS-targeting antibodies or anti-OX40 antibodies in mice with advanced melanomas. Whereas PS-targeting and anti-OX40 demonstrated comparable tumor regression when administered in combination with transferred adoptive T cells, only the PS-targeting combination achieved these results without any off-target toxicities. By contrast, the anti-OX40 treatment combination triggered off-target inflammatory destruction of healthy tissues.

"While adoptive T cell transfer remains one of the most exciting new approaches to treating cancer, to date the toxicity associated with the treatment has limited its potential. We are encouraged that these study results showed that the combination of anti-PS and adoptive T cell treatment led to enhanced anti-tumor effect without any evidence of additional off-target side effects," said Taha Merghoub, Ph.D., co-director of the Ludwig Collaborative Laboratory at MSK. "We believe that these findings may support potential applications for this combination in solid tumors in the future."

Additional study results demonstrated that the PS-targeting antibodies decreased tumor-induced immunosuppression as evidenced by a decrease in immunosuppressive regulatory T cells (Tregs) and M2 macrophages. This finding is consistent with Peregrine’s belief that bavituximab may modulate the immunosuppressive tumor microenvironment and enhance the activity of immunotherapy agents.

"These study results provide further support for our belief that anti-PS agents such as bavituximab can play an important role as part of combination cancer treatments. This is directly tied to the agents’ ability to modulate the tumor microenvironment to combat the immunosuppression that limits the activity of CAR T and immunotherapies," said Joseph Shan, vice president of clinical and regulatory affairs at Peregrine. "Importantly, we are now also seeing evidence that this targeted modulation of the tumor microenvironment by anti-PS allows for enhanced activity of these other treatments without triggering any off-target toxicities. This is opposed to other conventional immunotherapies such as anti-OX40 with systemic mechanisms of action. We believe this advantageous tolerability profile will be a key benefit in positioning anti-PS agents for inclusion in optimal combination cancer regimens."

Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. PS-targeting antibodies have demonstrated an ability to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses. Bavituximab is believed to override PS immunosuppressive signaling by blocking the engagement of PS with its receptors and sending an alternate immune activating signal.

Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants awarded by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations. These trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination.

Additionally, Peregrine continues to advance its pre-clinical collaboration with MSK with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab’s combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.