On April 1, 2019 MaxCyte presented the corporate presentation (Press release, MaxCyte, APR 1, 2019, View Source [SID1234537621]).

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On April 1, 2019 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage company developing highly differentiated therapeutics targeting the underlying mechanisms of cancer, reported that new preclinical data for CG-806, its first-in-class, highly potent oral small molecule pan-FLT3/pan-BTK inhibitor, and APTO-253, its MYC inhibitor, are being presented in two separate posters at the 2019 AACR (Free AACR Whitepaper) Annual Meeting in Atlanta, GA (Press release, Aptose Biosciences, APR 1, 2019, View Source [SID1234534822]).

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CG-806 Poster

The poster, CG-806, a pan-FLT3 / pan-BTK inhibitor, demonstrates superior potency against cells from IDH-1 mutant and other non-favorable risk groups of AML patients, explores the activity of CG-806 on primary patient samples with acute myeloid leukemia (AML), in studies that were conducted in collaboration with the Beat AML Initiative. CG-806 demonstrated significant potency across sub-groups of AML cells, including relapsed/refractory AML and those with genetic abnormalities related to poor prognoses in AML patients. CG-806 demonstrated superior potency when compared to other FLT3 inhibitors, including midostaurin, sorafenib, sunitinib, dovitinib, quizartinib, crenolanib and gilteritinib. While patient samples with FLT3-ITD mutations were expected to have greater sensitivity to CG-806, the sensitivity of patient cells with IDH1 R132 mutations was an unexpected finding. In 28-day GLP toxicity and toxicokinetic studies, CG-806 continued to demonstrate a favorable safety profile. The poster also highlights results of combination studies with CG-806 and venetoclax, which demonstrated enhanced killing of primary cancer cells from patients with AML and B-cell cancers.

"With our IND for CG-806 just recently allowed by the FDA, we are eager to begin Phase 1 human clinical trials," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. "The Beat AML initiative has allowed us, with our research collaborators at Oregon Health & Science University (OHSU), to test the response of actual patient samples (ex vivo) to CG-806, alone and in combination, and enables us to assess its effectiveness based upon specific genetic profiles of patients. The wealth of CG-806 data continues to grow and strongly supports the clinical development of CG-806. It is our goal to improve the odds of achieving long-term disease remissions for patients."

APTO-253 Poster

The poster, Resistance to APTO-253 caused by internal deletion and alternate promoter usage of the MYC gene in Raji B cells, presents in vitro studies that further define the mechanism of action of APTO-253. A novel small molecule, APTO-253 inhibits expression of the MYC oncogene, leading to apoptosis in human-derived solid tumor and hematologic cancer cells without the myelosuppression seen with other chemotherapies. Researchers found that APTO-253 targets a G-quadruplex motif in the P1/P2 promoter region of the MYC gene and inhibits MYC gene expression to induce apoptosis, resulting in its ability to potently kill hematologic malignant cell lines and primary samples from AML and chronic lymphocytic leukemia (CLL) patients. In this study, researchers performed long-term in vitro studies to determine if and how cells might develop resistance to APTO-253. MYC driven Raji cells required three years in increasing concentrations of APTO-253 in order to adopt multiple modifications and develop high level resistance to APTO-253. These modifications include up-regulation of the ABCG2 transporter, acquisition of a more stable MYC protein lacking the conserved core sequence of MYC Box III generated by deletion of an internal region of the MYC gene exon 2, and utilization of alternate P3 promoter not inhibited by G4 binding and stabilization.

Both of the AACR (Free AACR Whitepaper) posters can be accessed here or at the publications and presentations section of Aptose’s website www.aptose.com.

About CG-806

CG-806 is an oral, first-in-class pan-FLT3/pan-BTK multi-cluster kinase inhibitor and is in a Phase 1 clinical trial for hematologic malignancies. This small molecule, in-licensed from CrystalGenomics Inc. in Seoul, South Korea, demonstrates potent inhibition of wild type and all mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), cures animals of 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 (C481S) 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/SLL, FL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. Because CG-806 targets key kinases/pathways operative in malignancies derived from the bone marrow, it is in development for B-cell cancers and AML.

About APTO-253

APTO-253 is a clinical-stage, small molecule, targeted therapeutic agent that inhibits expression of the MYC oncogene, leading to cell cycle arrest and programmed cell death (apoptosis) in human-derived solid tumor and hematologic cancer cells. Indeed, the first AML patient treated with APTO-253 at the lowest dose level demonstrated significant reductions of MYC expression in peripheral blood mononuclear cells after one 28-day cycle of drug therapy. The MYC oncogene is overexpressed in hematologic cancers, including acute myeloid leukemia (AML). Aptose researchers have reported the ability of APTO-253 to induce cell death, or apoptosis, in multiple blood cancer cell lines including AML, as well as in vitro synergy with various classes of conventional approved and investigational therapies for AML or myelodysplastic syndromes (MDS). New findings reveal that APTO-253 might also serve certain solid tumor patients with BRCA1/2 mutations, but without causing toxicity to the normal bone marrow functions.

On April 1, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported promising data from the Company’s growing bispecific and TAM (Tyro3, Axl, MerTK) receptor programs during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 1, 2019, View Source [SID1234534839]).

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"Our research and discovery efforts have yielded multiple promising candidates that address important needs in cancer immunotherapy and complement our pipeline," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "CDX-527 joins two powerful pathways in the immune system, PD-1 blockade and CD27 costimulation. The data we presented at AACR (Free AACR Whitepaper) demonstrate that this bispecific antibody candidate has greater activity than the combination of the two individual antibodies and support advancing the program into IND-enabling studies. In addition, we also presented data on our lead candidate antibodies targeting the TAM receptors, which act as checkpoints on myeloid cells. We have uncovered a unique mechanism for antibody-mediated activation of dendritic cells and macrophages and demonstrated that a surrogate MerTK mAb promotes anti-tumor immunity alone and enhances the activity of PD-1 blockade. We look forward to continuing to progress both CDX-527 and our TAM program over the course of the year," concluded Keler.

Presentation Highlights:

Poster #2392: CDX-527: A novel bispecific immune-modulating antibody targeting CD27 and PD-L1 (Vitale, et. al)

The use of bispecific antibodies provides opportunities to engage two independent pathways involved in controlling immune responses to tumors. Preclinical and clinical studies support the safety and benefit of combining PD-1 blockade with a CD27 agonist.
The bispecific CDX-527 combines a novel and potent PD-L1 antibody for blocking the PD-1 checkpoint pathway with the binding domains of a CD27 agonist antibody for CD27-mediated costimulation of T cells.
CDX-527 demonstrated potent inhibition of PD-1 signaling and T cell activation using in vitro models with reporter cell lines and human primary cell cultures.
Anti-tumor activity was tested with a surrogate bispecific molecule that binds mouse PD-L1 and human CD27 in human CD27-expressing transgenic mice. The bispecific demonstrated potent anti-tumor activity in a BCL1 lymphoma model and was significantly more effective than the combination of the CD27 and PD-L1 monoclonal antibodies (mAbs).
A pilot study in non-human primates suggests that CDX-527 demonstrates good pharmacokinetic properties and no toxicities were observed.
Based on the promising data observed to date and the PK/PD profiles, Celldex has initiated manufacturing activities and investigational new drug (IND) enabling studies to support clinical studies of CDX-527.
Poster #1555: Monoclonal antibodies targeting the TAM family of receptor tyrosine kinases (Alvarado, et al)

TAM receptors (Tyro3, Axl, MerTK) are receptor tyrosine kinases (RTKs) expressed in innate immune cells. These receptors have been gaining importance in the immunotherapy field due to their role as checkpoint molecules on macrophages, dendritic cells, and other immune cells, where they can negatively regulate anti-tumor immunity.
Celldex presented data showing that lead candidate mAbs targeting MerTK, Axl or Tyro-3 activate myeloid cells, including monocytes, macrophages and dendritic cells, enhancing pro-inflammatory cytokine release, increasing expression of costimulatory molecules and enhancing T cell activation in mixed lymphocyte reaction (MLR) assays.
Celldex demonstrated that the potent activity of the TAM-specific antibodies are dependent on a unique coupling of the TAM receptors with Fc receptors.
Celldex’s most advanced program targets MerTK, where the Company has demonstrated that antibody targeting of MerTK in mice elicits an inflammatory cytokine response similar to that observed in the human cells and in MerTK deficient mice and has anti-tumor activity when dosed alone or in combination with a PD-1 inhibitor in a colon cancer model.
These data support development of anti-TAM mAbs as therapies to activate innate immune responses with a potential for systemic dosing. The Company intends to advance potential candidates into development activities this year.

On April 1, 2019 Astellas Pharma Inc. (TSE: 4503) (President and CEO: Kenji Yasukawa, Ph.D. "Astellas") reported results from the Phase 3 ADMIRAL clinical trial comparing XOSPATA (gilteritinib) to salvage chemotherapy in adult patients with relapsed or refractory (resistant to treatment) Acute Myeloid Leukemia (AML) with a FLT3 mutation (Press release, Astellas, APR 1, 2019, View Source [SID1234534876]). The results show that patients treated with XOSPATA had significantly longer Overall Survival (OS) than those who received standard salvage chemotherapy. The data were shared today by Alexander Perl, M.D., Abramson Cancer Center, University of Pennsylvania, in a press conference at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The data will also be presented during the AACR (Free AACR Whitepaper) Clinical Trials Plenary Session (#CT184), which takes place April 2, 2019, 10:30 a.m. – 12:45 p.m. at the Georgia World Congress Center, Marcus Auditorium, Bldg A-GWCC.

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Results from the ADMIRAL trial show the median OS for patients who received XOSPATA was 9.3 months compared to 5.6 months for patients who received salvage chemotherapy (Hazard Ratio = 0.637 (95% CI 0.490, 0.830), P=0.007); one-year survival rates were 37% for patients who received XOSPATA compared to 17% for patients who received salvage chemotherapy.

The most common treatment-emergent adverse events (TEAEs) of any grade occurring in ≥10% of patients during the first 30 days of treatment with gilteritinib were anemia (33%), increased alanine aminotransferase (24%), increased aspartate aminotransferase (24%), febrile neutropenia (21%), thrombocytopenia (19%), constipation (17%), pyrexia (15%), fatigue (15%), decreased neutrophil count (14%), increased blood alkaline phosphatase (13%), nausea (13%), hypokalemia (11%), cough (11%), headache (10%), and diarrhea (10%). The most common TEAEs of any grade occurring in ≥10% of patients during the first 30 days of treatment with salvage chemotherapy were anemia (33%), febrile neutropenia (32%), nausea (30%), diarrhea (28%), hypokalemia (27%), pyrexia (26%), decreased appetite (17%), decreased white blood cell count (17%), thrombocytopenia (16%), constipation (14%), abdominal pain (14%), hyperglycemia (13%), headache (13%), stomatitis (13%), fatigue (11%), decreased neutrophil count (11%), increased aspartate aminotransferase (10%), vomiting (10%), peripheral edema (10%), and hypomagnesemia (10%).

"We are very encouraged by the findings of the ADMIRAL trial," said Alexander Perl, M.D., an associate professor of Hematology-Oncology in Penn’s Perelman School of Medicine. "Patients with relapsed/refractory FLT3 mutation-positive AML generally have a poor prognosis and short survival. Until just recently, they had few treatment options. These findings change the treatment paradigm for this patient population."

XOSPATA was approved by the U.S. Food and Drug Administration (FDA) in November 2018 for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test.[1]

XOSPATA was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and commercialize XOSPATA.

XOSPATA was approved by the Japan Ministry of Health, Labor and Welfare (MHLW) for relapsed or refractory AML with FLT3 mutations and launched as XOSPATA 40 mg Tablets in 2018.[2] In February 2019, a marketing authorization application (MAA) for the oral once-daily therapy XOSPATA for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation was accepted by the European Medicines Agency for regulatory review.[3]

Astellas is currently investigating gilteritinib in various FLT3 mutation-positive AML patient populations through several Phase 3 trials. Visit View Source to learn more about ongoing gilteritinib clinical trials.

About the ADMIRAL Trial[4]
The Phase 3 ADMIRAL trial (NCT02421939) was an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy. The primary endpoint of the trial was Overall Survival (OS). The study enrolled 371 patients with relapsed or refractory AML and positive for FLT3 mutations present in bone marrow or whole blood. Subjects were randomized in a 2:1 ratio to receive gilteritinib (120 mg)[5] or salvage chemotherapy.

About XOSPATA (gilteritinib)
XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.1

Important Safety Information

Contraindications
XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials.

Warnings and Precautions
Posterior Reversible Encephalopathy Syndrome (PRES) There have been rare reports of PRES with symptoms including seizure and altered mental status with XOSPATA. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). Of the 292 patients treated with XOSPATA in the clinical trial, 1.4% were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis There have been rare reports of pancreatitis in patients receiving XOSPATA in clinical studies. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions
The most frequent non-hematological serious adverse reactions (≥5%) reported in patients were pneumonia (19%), sepsis (13%), fever (13%), dyspnea (7%) and renal impairment (5%).

Overall, 22 of 292 patients (8%) discontinued XOSPATA treatment permanently due to an adverse reaction. The most common adverse reactions (>1%) leading to discontinuation were pneumonia (2%), sepsis (2%) and dyspnea (1%). The most common adverse reactions (≥20%) were myalgia/arthralgia (42%), transaminase increased (41%), fatigue/malaise (40%), fever (35%), non-infectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%) and vomiting (20%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (7%), cardiac failure (grouped terms) (4%), pericardial effusion (3%), pericarditis (2%), differentiation syndrome (1%), anaphylactic reaction (1%) and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities: The most common lab abnormalities (>20%) that were Grade ≥3 that occurred ≥10% were: hypophosphatemia (12%), alanine aminotransferase increased (12%), hyponatremia (12%), aspartate aminotransferase increased (10%).

Drug Interactions
Combined P-gp and Strong CYP3A Inducers: Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors: Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor: Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

Specific Populations
Lactation: Advise women not to breastfeed during treatment with XOSPATA and for 2 months after the last dose

On April 1, 2019 Candel Therapeutics (a.k.a. Advantagene, Inc.) reported the closing of a $22.5 million Series C Preferred Stock financing led by Northpond Ventures. Participating syndicate members included Sands Capital Ventures, H7 Holdings and Level One Partners. Michael P. Rubin, M.D., Ph.D., founder and CEO of Northpond Ventures, will join the company as a member of its board of directors (Press release, Candel Therapeutics, APR 1, 2019, View Source [SID1234537125]).

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"We are thrilled to join forces with the Candel team and embark on this great journey together. We have the potential to be a force for good in the world, which is what drives us," said Dr. Rubin.

"We are grateful for the financial flexibility resulting from this financing," stated Dr. Estuardo Aguilar-Cordova, Chairman and CEO of Candel Therapeutics. "The addition of Michael to our board of directors is a big win for the company and brings significant relevant expertise."

The completion of the Series C brings the total capital raised by Candel in the last year to $51.2 million. The company plans to use the proceeds to expand its operational capabilities and further accelerate its ongoing clinical development initiatives. Candel’s lead programs are based on the company’s Gene Mediated Cytotoxic Immunotherapy (GMCI) technology and include two randomized studies in prostate cancer, including a Phase 3 under an FDA approved Special Protocol Assessment. The Company also has ongoing clinical programs in glioma, lung and pancreatic cancer.

"We have the most comprehensive and promising clinical data set in the field of developing viral immunotherapies in multiple tumor indications," explained Dr. Aguilar-Cordova. "We are particularly excited about expanding our efforts for brain tumor patients as they are in desperate need of new treatment options."

Candel’s efforts in pursuit of an effective treatment for brain cancer are significant. The company has completed a Phase 2 clinical study in high grade glioma that showed promising results, including an indication of survival benefit. The launch of a combination GMCI-checkpoint inhibitor clinical study, in collaboration with Bristol-Myers Squibb and the Adult Brain Tumor Consortium, was recently announced. The Company also has an ongoing study for recurrent GBM patients with rQNestin34.5, the company’s oncolytic herpes-based platform. Additionally, the Company plans to use proceeds from this financing to launch a GMCI pivotal trial for brain cancer patients.

For more information about its clinical programs, please visit www.clinicaltrials.gov or click the following link: View Source;term=advantagene&cntry=&state=&city=&dist=