On October 28, 2019 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium") reported key interim findings from the pivotal Phase 3 SIERRA trial of Iomab-B, including feasibility and safety data, at 50% of total patient enrollment (Press release, Actinium Pharmaceuticals, OCT 28, 2019, View Source [SID1234549923]). The SIERRA trial (Study of Iomab-B in Elderly Relapse/Refractory Acute Myeloid Leukemia) is a 150-patient, 1:1 randomization Phase 3 pivotal trial that is studying Iomab-B (Iodine-131 apamistamab) compared to physician’s choice of salvage chemotherapy in patients age 55 and above with active, relapsed or refractory AML (Acute Myeloid Leukemia). These interim data provide information on safety and feasibility of using Iomab-B to enable a BMT (Bone Marrow Transplant), the only curative treatment option in this patient population that is not typically considered eligible for BMT.

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Key findings from the first 75 patients enrolled (50% of total enrollment) in the trial include:

– Patients enrolled in the SIERRA trial were a median age of 64 (55-76) and had active disease with a median bone marrow blast percentage at randomization of 28 percent (5-97%). All patients were intermediate or poor, adverse risk groups. Two-thirds (68%) of the patients enrolled were in the poor prognostic, adverse cytogenetic and molecular risk group.

– All patients receiving a therapeutic dose of Iomab-B (31/31) in the study arm received a bone marrow transplant and engrafted rapidly without delay in blood count recovery.

– Only 7/38 patients (18%) randomized to the control arm achieved an initial complete response (CR) and were able to proceed to a conventional bone marrow transplant.

– Of the 31 patients who failed the primary endpoint in the control arm (82% failure), 20 (64%) were considered eligible for potential rescue by treatment with Iomab-B followed by a BMT. All 20 patients (100%) who crossed over and received a therapeutic dose of Iomab-B followed by a BMT achieved engraftment without delay in blood count recovery despite high blast count burden prior to transplant (median 35%).

– 12/38 patients (32%) randomized to the control arm received targeted agents all of which were recently approved. 11/12 patients (92%) received the Bcl-2 inhibitor venetoclax with either an hypomethylating agent or low dose cytarabine. Of these, only 3/11 patients (27%) achieved a CR.

– 100-day Non-Relapse Transplant Related Mortality remains lower in the Iomab-B arm (1/31 patients or 3%) compared to patients in the control arm who received conventional transplants (2/7 or 29%). Of the 31 patients who received Iomab-B in the study arm, 30 are potentially evaluable for the primary endpoint compared to 5 in the control arm. This difference between study arm and control arm remains consistent with that reported at the interim update at 25% of enrollment.

– The SIERRA trial remains the only randomized Phase 3 clinical trial to offer BMT as an option for patients age 55 and above with active, relapsed or refractory AML.

Sergio Giralt, M.D., Chief of Adult BMT, Memorial Sloan Kettering Cancer Center; Chair, Myeloma Service, said, "The results from the first 50% of patients to be enrolled in the SIERRA trial continue to be highly encouraging, particularly Iomab-B’s ability to enable a transplant in this patient population that would otherwise be ineligible. Despite eight new therapies having been approved for patients with AML, better outcomes for patients with AML are needed, in particular for the large number of relapsed and refractory patients. Newly approved targeted agents are not curative and as seen in the SIERRA trial do not enable a high rate of potentially curative BMT."

*Footnotes for table can be found below Conference Call and Webcast information

Mark Berger, M.D., Actinium’s Chief Medical Officer, said, "We are thrilled that data from the halfway point of the SIERRA trial validate the promising interim safety and feasibility results from the first 25% of patients in this trial. It is particularly gratifying for me to see that these relapsed, refractory patients with heavy disease burden who received a therapeutic dose of Iomab-B were successfully transplanted. In addition, it is heartening that Iomab-B can be an effective pathway to transplant even when the recently approved targeted therapies unfortunately fail, as shown by our control arm and crossover data. With the first half of the trial behind us and with strong data in hand, we are focused on taking this message to hematologists and transplant physicians. We look forward to continuing to execute on our strategies to bring Iomab-B to patients as quickly as possible."

Conference Call and Webcast Information

Time and Date: 12:00 PM ET on Monday, October 28th
Registration Link: https://platform.cinchcast.com/ses/kSO55A9SLNGFoAvv1hgHpg~~
U.S./Canada Toll Free Dial-in: (855) 698-6739
Participant Dial-in: (646) 402-9440
Conference ID: 0417

A replay of the call will be available on the Investor Relations page of the Company’s website.

Table Footnotes:

Data available on 31 patients per arm
1 patient with circulating blasts and bone marrow <5% not included in median/range
No therapeutic dose (6) due to: declining KPS (3), infusion reaction (1), unfavorable biodistribution (1), post-randomization eligibility (1)
Ineligible for crossover (9) due to: hospice care/progression (4), declined/ineligible for BMT (2), died pre-crossover (3). Eligible for crossover (2), received dosimetry but not Iomab-B therapy due to declining status
Crossed-over and received therapeutic dose of Iomab-B
ANC engraftment data not available (1), platelet engraftment data not available (5)
ANC and platelet engraftment data not available (1), engraftment failure (1)
ANC engraftment data not available (2), platelet engraftment data not available (4)
1 patient at 161 days had delayed transplant due to infection and respiratory failure, received Iomab-B and BMT when stable
Data available on: Iomab-B study arm (30), CR after salvage therapy (7) and no CR after salvage crossed-over received Iomab-B and transplanted (16)
About the SIERRA Trial

The SIERRA trial (Study of Iomab-B in Elderly Relapse/Refractory Acute Myeloid Leukemia) is the only randomized Phase 3 trial that offers BMT (Bone Marrow Transplant) as an option for older patients with active, relapsed or refractory AML or acute myeloid leukemia. BMT is the only potentially curative treatment option for older patients with active relapsed or refractory AML and there is no standard of care for this indication other than salvage therapies. Iomab-B is an ARC (Antibody Radiation-Conjugate) comprised of the anti-CD45 antibody apamistamab and the radioisotope I-131 (Iodine-131). The 20 active SIERRA trial sites in the U.S. and Canada represent many of the leading bone marrow transplant centers by volume.

On October 28, 2019 ESSA Pharma Inc. (Nasdaq: EPIX; TSX-V: EPI), a pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, reported in Boston will present new preclinical data on ESSA’s lead Investigational New Drug ("IND") candidate at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, ESSA, OCT 28, 2019, View Source [SID1234549939]).

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In an oral poster presentation titled, "Treatment of castrated resistant prostate cancer, with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor", further preclinical characterization of EPI-7386 will be presented.

Abstract No.:

B117

Abstract Title:

Treatment of castrated resistant prostate cancer with EPI-7386, a second generation N-terminal domain androgen receptor inhibitor

Presenter:

Ronan Le Moigne, PhD

Date:

Monday October 28, 2019

Time:

3:00pm EST/EDT

Location:

Hall D, Hynes Convention Center, Boston, MA

On October 27, 2019 Silicon Therapeutics reported that preclinical studies on its novel, small molecule, intravenously delivered STING (stimulator of interferon genes) agonist SITX-799, demonstrating the compound produced robust and durable anti-tumor immunity and tumor regression (Press release, Silicon Therapeutics, OCT 27, 2019, View Source [SID1234552832]). Based on these and other promising studies, the company expects to begin clinical trials with SITX-799 in 2020. The data were presented at a poster session at the annual AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in Boston, MA.

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"STING is widely recognized as a very attractive but challenging immuno-oncology target because its activation requires both binding and conformational changes while maintaining the physical-chemical drug properties required for systemic exposure," said Christopher Winter, PhD, Silicon’s Chief of R&D. "The first STING agonists to reach the clinic lack the drug properties required for systemic exposure and therefore are suitable only for patients with tumors accessible to intra-tumoral injection. The preclinical SITX-799 data demonstrating potent, systemic anti-tumor activity at doses that are well tolerated, suggest the compound has promising potential for broad utility as a cancer immune-therapeutic."

"These data underscore the promise of our proprietary, physics-driven, discovery approach, which integrates physics with chemistry and biology, to develop novel therapeutics against difficult targets," said Lanny Sun, Silicon Therapeutics co-founder and CEO. "Our STING agonist program, including SITX-799, is the most advanced of several programs in our innate immune pipeline."

STING is a master regulator of type I interferons and a key mediator of innate immunity. Activation of STING provides two critical anti-tumor responses – (1) the "spark" for initiating a robust innate immune response and (2) priming and activation of a potent T cell-mediated anti-tumor adaptive response. By serving as a bridge between the two arms of the immune system, STING activation has the potential to transform the tumor microenvironment from immunologically "cold" to "hot" (inflamed), converting otherwise resistant tumors respond to checkpoint blockade as well as other T cell targeting immunotherapies.

In vivo studies presented at the conference show that a single dose of SITX-799 produced complete regression of colon cancer tumors in mice and robust induction of type I interferons. Cured mice were re-challenged with tumors 90 days after initial treatment and remained tumor free, demonstrating durable, anti-tumor immunity. No anti-tumor response to treatment was observed in mice lacking a functional immune system, demonstrating the immune-therapeutic mechanism of action. SITX-799 was shown to be well tolerated and demonstrated a favorable pharmacokinetic profile. In the poster, the company also presented in vitro data demonstrating potent, selective activity against all common human STING variants, rapid activation of the STING pathway, and induction of Type I interferon in human donor immune cells.

On October 27, 2019 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported the first data from the single agent dose-escalation arm of the Phase 1 study of AG-270 in methylthioadenosine phosphorylase (MTAP)-deleted tumors at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Agios Pharmaceuticals, OCT 27, 2019, View Source [SID1234548673]). AG-270 is an investigational, first-in-class methionine adenosyltransferase 2A (MAT2A) inhibitor.

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"The single agent arm of the Phase 1 trial for AG-270 provides the first data from a clinical study of a MAT2A inhibitor," said Rebecca Heist, M.D., Massachusetts General Hospital and an investigator in the study. "These data demonstrate that AG-270 induces reductions in the biomarkers of MAT2A inhibition, notably plasma concentrations of S-adenosylmethionine (SAM) and tumor levels of symmetrically demethylated arginine (SDMA), at well tolerated doses. These findings will help guide the dosing and schedule for the next phase of development of AG-270 in combination with taxanes."

"Inhibition of MAT2A is a unique approach to cancer treatment, based on discoveries made by Agios scientists looking for differences in metabolism between cancer cells and normal cells," said Chris Bowden, M.D., chief medical officer at Agios. "This early clinical work with AG-270 confirms that it has the desired pharmacologic effects when given as single agent, and, supported by strong pre-clinical work and rationale, we are now enrolling patients in two combination arms in homogenous patient populations to better understand AG-270’s clinical profile when combined with taxane-based regimens for non-small cell lung and pancreatic cancer. These arms will be instrumental in gathering sufficient data to determine the next steps in clinical development."

AG-270 Phase 1 Study
The Phase 1 study of AG-270 in MTAP-deleted tumors began with a single agent dose-escalation arm to establish the maximum tolerated dose of AG-270. Secondary objectives were to characterize AG-270’s safety, tolerability, pharmacokinetics and pharmacodynamics as a monotherapy. Two additional Phase 1 arms were recently initiated to explore AG-270 in combination with taxanes in second-line non-small cell lung cancer and first or second-line pancreatic cancer.

As of the August 16, 2019 data cutoff date, 39 patients had been treated in the single agent dose-escalation arm with oral AG-270 either once or twice daily, at total daily doses ranging from 50 mg to 400 mg. The study enrolled patients with a wide range of advanced and treatment-refractory solid tumors, including bile duct cancer (18%), pancreatic cancer (18%), mesothelioma (10%) and non-small cell lung cancer (10%). Nearly half of the patients enrolled had received three or more prior lines of therapy. Thirty-six patients discontinued AG-270, primarily due to disease progression.

Pharmacokinetic and Pharmacodynamic Results

Mean exposure increased in an approximately dose-proportional manner between 50 mg and 200 mg once daily.
Mean exposure was lower at 400 mg once daily than 200 mg once daily; due to this observation, a dose of 200 mg twice daily was evaluated, which increased steady-state area under the plasma concentration-time curve (AUC) by 1.9-fold relative to a dose of 200 mg once daily.
Plasma SAM concentration decreased by 65-74% across doses of 50-200 mg once daily and 200 mg twice daily.
Analysis of nine paired tumor biopsies by IHC showed decreases in levels of SDMA residues, consistent with inhibition of the methyltransferase PRMT5, downstream of MAT2A inhibition.
Safety and Efficacy Results

The most common treatment-related adverse events Grade 3 or above were reversible increases in bilirubin (10%) due to AG-270’s known ability to inhibit UGT1A1, and reversible decreases in the platelet count (8%).
Three patients (treated at 100 mg once daily, 150 mg once daily and 200 mg twice daily) developed a generalized erythematous rash. One case resolved less than 1 week after AG-270 interruption and two cases were successfully re-challenged at a lower dose.
For patients treated in the 200 mg twice daily cohort, two of six experienced reversible acute liver injury, manifested as asymptomatic Grade 3 and 4 increases in alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Outpatient treatment with oral steroids led to complete resolution. Two of six patients experienced Grade 3 and 4 thrombocytopenia.
The maximum tolerated dose was determined to be 200 mg once daily.
In this group of patients with treatment-refractory malignancies, one confirmed partial response was observed in a patient with a high-grade neuroendocrine carcinoma of the lung treated with 200 mg of AG-270 once daily. Two additional patients experienced prolonged stable disease for >6 months.
Next Steps for AG-270 Clinical Development
Patients are currently enrolling in the two combination arms of the Phase 1 study.

One arm will test AG-270 in combination with docetaxel in up to 40 patients with MTAP-deleted non-small cell lung cancer who have had no more than two prior lines of cytotoxic therapy.
The second arm will test AG-270 in combination with nab-paclitaxel and gemcitabine in up to 45 patients with MTAP-deleted pancreatic ductal adenocarcinoma who have had no more than one prior line of cytotoxic therapy.
The goal of these arms is to further characterize the safety, tolerability, PK and PD, and to detect preliminary evidence of anti-tumor activity for the combinations.

Targeting MAT2A in Cancers with MTAP Deletion
Homozygous deletion of MTAP, the gene encoding the metabolic enzyme methylthioadenosine phosphorylase, occurs in ~15% of human malignancies. MTAP deletion almost always coincides with the loss of cyclin-dependent kinase inhibitor 2A (CDKN2A), a well known negative prognostic factor in cancer. Deletion of MTAP results in the accumulation of the enzyme’s substrate, methylthioadenosine (MTA). Increased concentrations of MTA partially inhibit the activity of protein arginine methyltransferase 5 (PRMT5), while other methyltransferases are relatively unaffected. Further reduction of PRMT5 activity can be achieved through modest reductions in the concentration of its normal substrate, the methyl donor S-adenosylmethionine (SAM). Inhibition of PRMT5 activity results in a reduction in symmetrically demethylated arginine residues (SDMAs) on target proteins, many of which are involved in mRNA splicing. AG-270 is a first-in-class, oral, potent, reversible inhibitor of methionine adenosyltransferase 2A (MAT2A), the key enzyme responsible for SAM synthesis.

Investor Event and Webcast Information
Agios will host an investor event today at 6:30 p.m. ET in Boston to review the AG-270 Phase 1 dose-escalation data and pre-clinical research. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

On October 26, 2019 Adagene, Inc., a clinical stage biotech company with innovative antibody discovery and engineering technologies, reported that it is presenting its lead program at international conferences (Press release, Adagene, OCT 26, 2019, View Source [SID1234548675]).

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During the Festival of Biologics conference in Basel, Switzerland, Adagene gave a presentation on "Targeting the conserved epitopes of check points for rational single and combination immunotherapy", highlighting the unique power of Adagene’s proprietary antibody discovery technology, Dynamic Precision Library (DPL), in generating species cross-reactive antibodies to enable translational studies in immune intact animal models. The DPL system combines extensive computational design, machine learning and high throughput phage and yeast screening to generate cross-reactive antibodies targeting evolutionarily conserved epitopes with novel mechanism of actions and excellent developability.

A case study of ADG106, a species cross reactive agonist antibody which targets the conserved epitope of CD137 across human, monkey and mouse. ADG106 activates CD137 in a native ligand-like fashion, while it also blocks the reverse signaling mediated by CD137 ligand. Furthermore, ADG106 is shown to exhibit Fc-mediated strong crosslinking. ADG106 has been extensively tested for efficacy in both single and combination therapy using syngeneic mouse tumor models that are believed to be relevant preclinical models of intact immune system and highly translatable into a rational approach toward single and combination immunotherapies.

The clinical data from the ongoing phase 1, first-in-human, dose-escalation study of ADG106, will be presented in a poster session at the 2019 AACR (Free AACR Whitepaper)-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, Massachusetts. The Phase 1 study in the United States, First-In-Human study of ADG106 in subjects with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma (NCT02407990) is being conducted at NEXT Oncology (San Antonio, Texas), and consists of dose-escalation and dose-expansion phases in disease-specific cohorts.