On June 27, 2018 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) accepted the company’s New Drug Application and granted Priority Review designation for glasdegib, an investigational oral smoothened (SMO) inhibitor, being evaluated for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) in combination with low-dose cytarabine (LDAC), a type of chemotherapy (Press release, Pfizer, JUN 27, 2018, View Source [SID1234527490]).

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"Patients with acute myeloid leukemia who are ineligible for intensive chemotherapy are in critical need of new treatment options to improve their overall survival," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "In an investigational Phase 2 study, glasdegib in combination with low-dose cytarabine showed a significant improvement in overall survival compared to patients who received low-dose cytarabine alone. Glasdegib is the first smoothened inhibitor to potentially offer such a benefit to patients with acute myeloid leukemia, and we are proud that our application was accepted by the FDA for Priority Review."

The FDA grants Priority Review designation to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in December 2018.

The submission is based on results from the Phase 2 BRIGHT 1003 study, a randomized, open-label, multicenter trial investigating glasdegib combined with LDAC (n=88) versus LDAC alone (n=44) in 132 patients with previously untreated AML or high-risk myelodysplastic syndrome (MDS) who were not eligible for intensive chemotherapy. Results demonstrated a significant improvement in the primary endpoint of overall survival (OS). Median OS was 8.8 months for patients treated with glasdegib plus LDAC compared with 4.9 months for patients treated with LDAC only. This difference represented a 49.9 percent reduction in the risk of death for patients treated with glasdegib plus LDAC (HR: 0.501, 95% CI: 0.334, 0.752, one-sided p-value 0.0003). The BRIGHT 1003 results were presented in 2016 at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

The most frequently (≥30% of patients) reported adverse events (AEs) in patients treated with glasdegib plus LDAC compared to LDAC alone were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%) and thrombocytopenia (30% vs 27%). The most frequently (≥15% of patients) reported serious AEs for patients treated with glasdegib plus LDAC compared to LDAC alone were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

About Glasdegib

Glasdegib is an investigational, oral, once-daily therapy that is thought to inhibit the SMO receptor, thereby disrupting the Hedgehog pathway. Abnormal Hedgehog pathway activation is thought to play a role in the development of multiple types of cancers, including solid tumors and hematologic malignancies. It has not received regulatory approval in any country.

The Phase 3 BRIGHT AML 1019 trial (NCT03416179), which is evaluating the addition of glasdegib to intensive or non-intensive chemotherapy in patients with newly diagnosed AML, began enrolling earlier this year.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for approximately 80 percent of all cases of acute leukemia.1 An estimated 19,520 people are expected to be diagnosed with AML in the U.S. in 2018.1 Despite recent advancements, only approximately one in four patients with AML survive longer than five years, and additional treatment options are needed to reduce incidence of disease progression and relapse.2,3 This is especially true for patients who are unable to receive intensive chemotherapy and are triaged to other treatments associated with poorer outcomes.

On June 28, 2018 argenx (Euronext & Nasdaq: ARGX), a clinical-stage biotechnology company developing a deep pipeline of differentiated antibody-based therapies for the treatment of severe autoimmune diseases and cancer, reported the achievement of the second of two preclinical milestones towards an investigational new drug (IND) filing for ARGX-115, triggering a further $ 10 million payment from AbbVie (Press release, argenx, JUN 28, 2018, View Source;p=RssLanding&cat=news&id=2356311 [SID1234527488]).

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In April 2016, argenx entered into a development and exclusive license option agreement with AbbVie to develop and commercialize ARGX-115. Under the terms of that agreement, argenx has been responsible for conducting and funding all ARGX-115 research and development activities up to completion of IND-enabling studies.

Over the course of the past two years, argenx has been eligible to receive two preclinical milestones of $ 10 million each. The second milestone was achieved today.

About ARGX-115
ARGX-115 employs argenx’s SIMPLE Antibody(TM) technology and binds specifically to the protein glycoprotein A repetitions predominant (GARP), which plays a key role in the regulation of production and release of active transforming growth factor beta (TGF-beta). ARGX-115 is believed to selectively limit the immunosuppressive activity of activated regulatory T-cells (Tregs), thereby stimulating the immune system to attack cancer cells. While the normal function of Tregs is to suppress certain compartments of the immune system to prevent self-directed immune responses through the release of active TGF-beta, Tregs can also prevent the immune system from recognizing and suppressing pathogenic cells including cancer cells. We believe the selective inhibition of TGF-beta release by Tregs is potentially superior to systemic inhibition of TGF-beta activity or depletion of Tregs and may give rise to therapeutic products with an improved safety profile.

ARGX-115 was discovered under argenx’s Innovative Access Program with the de Duve Institute / Université Catholique de Louvain / WELBIO and exclusively licensed under a research and option agreement in 2013.

On June 27, 2018 Kangpu Biopharmaceuticals, Ltd., a clinical-stage company based in Shanghai, China, reported that a phase I, multi-center, open-label study to evaluate the safety, tolerability, pharmacokinetics and preliminary evidence of antitumor activity of KPG-121 in combination with Enzalutamide in adult subjects with metastatic castration-resistant prostate cancer (mCRPC) has been launched in the United States (Press release, Kangpu Biopharmaceuticals, JUN 27, 2018, View Source [SID1234527486]). The study takes place at 3 medical centers in the US; part of Accelovance’s network of HERO sites dedicated to early phase research in oncology. Specifics of the study can be found on www.clinicaltrials.gov/NCT03569280.

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About KPG-121
KPG-121 is a novel generation of Lenalidomide. Compared with Lenalidomide, KPG-121 has shown enhanced immunomodulatory activities and improved anti-angiogenic properties in the preclinical studies. Results from in vitro assays and in vivo studies of mCRPC animal xenograft models demonstrated that better efficacy was observed for KPG-121 compared to Lenalidomide, when combined with Enzalutamide, Abiraterone Acetate, Apalutamide or Darolutamide. In the combination studies with Enzalutamide, KPG-121 significantly improved anti-tumor efficacy when compared to Enzalutamide alone.

On June 27, 2018 Carisma Therapeutics Inc., formerly CARMA Therapeutics, a privately-held biotechnology company focused on the development of macrophage-based immunotherapeutics, reported the close of a $53 million Series A financing to further expand its technology platform and rapidly drive its programs toward clinical development (Press release, Carisma Therapeutics, JUN 27, 2018, View Source [SID1234527485]). The financing was led by AbbVie Ventures and HealthCap and includes existing seed investors IP Group, Penn Medicine and Grazia Equity. Carisma is also proud to welcome new investors Wellington Partners, TPG Biotech, MRL Ventures Fund and Agent Capital.

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Carisma Therapeutics’ discovery and development efforts are focused on their proprietary CAR-Macrophage platform – the first technology to combine antigen recognition with the effector function of macrophages. The proposed dual mechanism of action includes the ability to directly kill targeted cells and the ability to leverage antigen-presenting cell biology to mount an adaptive immune response. Initial applications for therapeutic candidates will be in the treatment of solid tumors. Other potential applications include the disruption of protein aggregates in multiple disease states. The company anticipates initiating clinical development in 2019.

The Carisma management team is led by Steven Kelly, CEO, who brings nearly 30 years of diverse drug development and commercialization experience at a variety of biotechnology and pharmaceutical companies. The team also includes Dora Mitchell, PhD as Head of Operations and Daniel Cushing, PhD heading development. Carisma is continuing to build its team and currently recruiting a CSO and a CMO.

Founded by Saar Gill, MD, PhD, an assistant professor of Hematology-Oncology in Penn’s Abramson Cancer Center, and Michael Klichinsky, PharmD, a PhD candidate in Systems Pharmacology and Translational Therapeutics, in partnership with the UPstart Program of the Penn Center for Innovation at the University of Pennsylvania, Carisma Therapeutics raised its incubation financing and began operations last summer. The company’s founders will be joined on the Scientific Advisory Board by Drs. Carl H. June, Lisa M. Coussens, Reinhard Andreesen and S. Jane Flint.

"Carisma’s programs combine the unique effector function of macrophages with advances in CAR technology to create a revolutionary approach to adoptive cellular therapy," commented CEO, Steven Kelly. "We are thrilled about the composition of our financing syndicate, which brings varied and deep experience in cell and gene therapy to further support our research and development efforts."

The company’s Board of Directors will be comprised of Margarita Chavez, JD, Managing Director of AbbVie Ventures; Jacob Gunterberg, Partner of HealthCap; Regina Hodits, PhD, Managing Partner of Wellington Partners; Steven Kelly, CEO; Eran Nadav, PhD, Senior Advisor of TPG Biotech; Althea Stillman, PhD, Associate Director at IP Group Inc.; and Bruce Peacock, Chairman.

On June 27, 2018 Trovagene, Inc. (NASDAQ: TROV), a clinical-stage oncology therapeutics company, developing targeted therapeutics for the treatment of hematologic and solid tumor cancers, reported preliminary clinical data from the first dosing cohort showing a treatment effect with PCM-075 in combination with low-dose cytarabine (LDAC) or decitabine, as measured by decreases in leukemic cells in both peripheral blood and bone marrow in patients in its ongoing Phase 1b/2 trial in relapsed or refractory Acute Myeloid Leukemia (AML) (Press release, Trovagene, JUN 27, 2018, View Source [SID1234527483]).

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Both blood and bone marrow samples were obtained from patients with relapsed or refractory AML enrolled in the Phase 1b/2 trial prior to, and at timepoints following administration of PCM-075, in combination with cytarabine or decitabine. In the first dose level, seven patients were treated with PCM-075 at 12 mg/m2 in combination with either LDAC or decitabine. One patient was not evaluable for safety due to rapid disease progression. Among the other 6 patients, no dose-limiting toxicities (DLTs) were observed that would prohibit further escalation of the PCM-075 dosing. Three patients exhibited substantial reductions in the percentage of both circulating leukemic cells within the blood and leukemic cells within the bone marrow. Two of these three patients continued on treatment in the second cycle and further decreases in circulating leukemic cells in the blood and within the bone marrow were observed. One patient had a decrease in his bone marrow blasts from 96% to 40% at the end of cycle 2 and has continued on treatment in cycle 3. The next dose level cohort of PCM-075 at 18 mg/m2 in combination with LDAC or decitabine is currently enrolling and dosing patients.

In addition, Translational Control Tumor Protein (TCTP), which is uniquely phosphorylated by PLK1, was used to evaluate PLK1 inhibition by PCM-075. Data presented by Trovagene at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) showed that PCM-075 decreases phosphorylated TCTP (pTCTP) in AML cell lines. In these same cell lines pTCTP levels were unaffected by treatment with either LDAC or decitabine.

PLK1 inhibition in the Phase 1b/2 AML trial is being assessed in patients 3-hours following administration of PCM-075 in combination with LDAC or decitabine, when PCM-075 levels are expected to be at their peak concentration (Cmax). Significant reductions in PLK1, as measured by pTCTP levels, were observed in the circulating blood cells in four of six patients treated with PCM-075 in combination with cytarabine or decitabine. Three of these four patients also had significant reductions in circulating blast cells during the treatment cycle.

"While we are still quite early in the trial, these data points are encouraging from both a safety and efficacy standpoint," said Amer Zeidan, MBBS, MHS, Assistant Professor of Medicine, Department of Medicine, and Yale Cancer Center, Yale School of Medicine, Yale University, a leading investigator on the trial. "There were no dose limiting toxicities seen in the first cohort and treatment was generally well tolerated. We know that treatment with decitabine or low-dose cytarabine in patients with relapsed or refractory AML is rarely effective, and the rare patients who do respond usually require several cycles of therapy to do so. Seeing substantial blast reductions in blood and bone marrow achieved in several patients in the first one to two cycles at this first dose level of PCM-075, combined with significant reductions in PLK1 activity as measured by pTCTP levels, potentially suggests synergistic clinical activity with the combination therapy. We remain excited to see how our patients will do as we go to higher dose levels of PCM-075."

"In addition to the preliminary clinical data from our first dose cohort, we are encouraged by the additional pharmacodynamic data for patients in our Phase 1b/2 AML trial," said Dr. Mark Erlander, Chief Scientific Officer of Trovagene. "This is the first time we have observed a change in PLK1 status in patients during treatment with PCM-075 in combination with either LDAC or decitabine."

About the PCM-075 Phase 1b/2 Acute Myeloid Leukemia Trial

The Phase 1b/2 trial (NCT03303339) is a multi-center, open-label trial to evaluate the safety and efficacy of PCM-075 in combination with standard-of-care chemotherapy in AML patients who are ineligible for intensive induction therapy or whose disease is relapsed or refractory. In Phase 1b dose-escalation segment of the trial, the primary objective is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), using a traditional 3+3 design. In Phase 2 the MTD or RP2D will be administered to 32 patients to evaluate preliminary antitumor activity and to continue to evaluate the safety and tolerability of PCM-075 in combination with standard-of-care chemotherapy. This trial is being led by Hematologist Jorge Cortes, M.D., Deputy Department Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and Amer Zeidan, MBBS, MHS, Assistant Professor of Medicine, Department of Medicine, and Yale Cancer Center, Yale School of Medicine, Yale University, New Haven, CT. Nine clinical sites are currently activated in the U.S. and recruiting patients.

About PCM-075

PCM-075 is a highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple hematologic and solid tumor cancers. Separate studies with other PLK inhibitors have shown that inhibition of polo-like-kinases can lead to tumor cell death, including a Phase 2 study in Acute Myeloid Leukemia (AML) where response rates up to 31% were observed when used in conjunction with a standard therapy for AML (low-dose cytarabine-LDAC) versus treatment with LDAC alone with a 13.3% response rate. A Phase 1 open-label, dose escalation safety study of PCM-075 has been completed in patients with advanced metastatic solid tumor cancers and published in Investigational New Drugs. The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) in this trial was 24 mg/m2. Trovagene has an ongoing Phase 1b/2 clinical trial with PCM-075 in AML that was accepted by the National Library of Medicine (NLM) and is now publicly viewable on www.clinicaltrials.gov. The NCT number assigned by clinicaltrials.gov for this study is NCT03303339. PCM-075 has been granted Orphan Drug Designation by the FDA for the treatment of patients with AML. Trovagene is enrolling a Phase 2 trial of PCM-075 in combination with Zytiga (abiraterone acetate) and prednisone in metastatic Castration-Resistant Prostate Cancer that was accepted by the National Library of Medicine (NLM) and is now publicly viewable on www.clnincaltrials.gov. The NCT number assigned by clinicaltrials.gov for this study is NCT03414034.

PCM-075 only targets the PLK1 isoform (not PLK2 or PLK3), is orally available, has a 24-hour drug half-life with reversible on-target hematologic toxicities. Trovagene believes that targeting only PLK1 with reversible on-target activity and an improved dose/scheduling protocol can significantly improve on the long-term outcome observed in previous studies with a PLK inhibitor in AML.

PCM-075 has demonstrated synergy in preclinical studies with over 10 chemotherapeutic and targeted agents used in hematologic and solid tumor cancers, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins. Trovagene believes the combination of its targeted PLK1 inhibitor, PCM-075, with other compounds, has the potential for improved clinical efficacy in Acute Myeloid Leukemia (AML), metastatic Castration-Resistant Prostate Cancer (mCRPC), Non-Hodgkin Lymphoma (NHL), Triple Negative Breast Cancer (TNBC), as well as other hematologic and solid tumor cancers.