On April 28, 2021 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune/inflammatory diseases, reported an upcoming presentation on NEON-1, the company’s Phase 1 clinical trial of ALPN-202 monotherapy at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Annual Meeting, scheduled to take place June 4-8, 2021 (Press release, Alpine Immune Sciences, APR 28, 2021, View Source [SID1234578635]).

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Details of the poster presentation are as follows:

Presentation Title:

First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies

Session Title:

Developmental Therapeutics—Immunotherapy

Date Poster Available:

Friday, June 4th

Abstract Number:

2547

The meeting presentation will update the data shown in the abstract.

Full abstracts will be available on the ASCO (Free ASCO Whitepaper) meeting website on May 19th, 2021 and a copy of the presentation will be available on June 4th on the Scientific Publications page of Alpine’s website.

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor with the potential to improve upon the efficacy of combined checkpoint inhibition while limiting significant toxicities. Preclinical studies of ALPN-202 have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. NEON-1 (NCT04186637), a Phase 1 study of ALPN-202 in patients with advanced malignancies, is currently enrolling. Alpine also plans the initiation of NEON-2, a combination study of ALPN-202 and a PD-1 inhibitor, later this year.

On April 28, 2021 Trillium Therapeutics Inc. (NASDAQ/TSX: TRIL), a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported Phase 1b/2 program priorities across seven hematologic and solid tumor indications, and governance changes with its Board of Directors (Press release, Trillium Therapeutics, APR 28, 2021, View Source [SID1234578652]).

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"We have reached a critical milestone in Trillium’s evolution," said Jan Skvarka, Trillium’s President and CEO. "We have built a robust foundation for advancing into a Phase 1b/2 program – a foundation of two highly differentiated CD47 assets with monotherapy proof-of-concept across several lymphoma indications. Our new data further solidify our position in the CD47 field as having potentially class-leading single agent activity with both TTI-622 and 621, as well as potentially best-in-class tolerability with TTI-622. Furthermore, we are particularly excited to observe substantial anti-tumor activity in the skin of our CTCL patients, which suggests that TTI-622 and 621 have the ability to exit blood circulation and penetrate skin tumors, thus underscoring the potential of both drug candidates to treat solid tumors. Finally, new translational data suggest that natural killer cell engagement plays a key role in what we believe is TTI-621’s mechanism of action, thus further differentiating TTI-621 in the CD47 field."

"We are now rapidly advancing into a Phase 1b/2 program, with multiple shots on goal – two drug candidates, seven target indications, multiple drug combinations – in patients with hematologic malignancies and solid tumors," added Ingmar Bruns, Chief Medical Officer. "Over the next twelve months, we expect to initiate studies across nine patient settings. The pipeline represents a portfolio of different risk-reward opportunities, multiple potentially accelerated regulatory paths to market, and a total addressable US patient population of over 30,000 patients in our entry settings. In parallel, we are continuing to evaluate less frequent dosing regimens than our current weekly dosing. This is supported by pharmacokinetic data, and, in the case of TTI-622, clinical experience with two CR patients who are on every three- and four-week dosing schedules."

"On a more personal note, as we are announcing governance changes, we would like to thank Bob Kirkman for his invaluable contributions over his eight-year tenure with Trillium as a Board member, including periods when he held Chair and Executive Chair roles," said Dr. Skvarka. "Bob has played a pivotal role in transitioning the CEO leadership in 2019, and positioning the company for our subsequent transformation program in 2020. Trillium would not be where it is today without Bob’s leadership, hands-on contributions and personal sacrifices. We will sorely miss Bob, and wish him all the best as he scales down his professional commitments."

TTI-622 Study Update

As of the data cutoff date of April 12, 2021, a total of 42 patients have been enrolled in the ongoing open-label Phase 1 dose escalation study of TTI-622 in patients with R/R lymphoma (NCT03530683). Patients received weekly intravenous doses between 0.05 and 18 mg/kg. All dose levels were very well-tolerated and an MTD was not reached. Adverse events (AEs) were predominantly Grade 1-2; related AEs ≥Grade 3 were neutropenia (9%), thrombocytopenia (5%) and anemia (2%). Pharmacokinetic data demonstrated dose-proportional increases in drug exposure between 8 and 18 mg/kg, and support evaluating less frequent dosing. Objective responses were achieved in 9 of 27 (33%) heavily pre-treated response-evaluable patients at dose levels ≥0.8 mg/kg, and included 2 CRs and 7 PRs. Three responses (1 CR and 2 PRs) at 12 and 18 mg/kg were obtained since the last data disclosure at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2020 Annual Meeting. All responses occurred within the first eight weeks of treatment across multiple lymphoma indications. One CR patient (0.8 mg/kg dose level) has been on study for more than 22 months and was transitioned to monthly dosing. The second CR patient (18 mg/kg) achieved a response after receiving only two doses with a 4-week dosing interval and is being maintained on every three weeks (Q3W) dosing. The study is continuing, with 3 more patients at 18 mg/kg pending response assessments as of the April 12, 2021 cutoff date.

TTI-621 Study Update

We have provided a further update on the safety data and anti-tumor activity observed in the ongoing open-label Phase 1 dose escalation study of intravenous TTI-621 in patients with R/R hematologic malignancies (NCT02663518). The study consists of four parts: (a) "Parts 1-3" in hematologic malignancies, with dosing up to 0.5 mg/kg weekly, now complete; and (b) "Part 4" in CTCL, with dosing at 0.5 mg/kg weekly and higher, currently ongoing. As of the data cutoff date of April 12, 2021, TTI-621 was well-tolerated and an MTD in Part 4 was not reached. Across Parts 1-4, the most common treatment-related AEs ≥Grade 3 were thrombocytopenia (22%), which was transient and not dose-limiting, anemia (8%), neutropenia (6%), and infusion-related reactions (4%), which occurred mostly at the first dose and were effectively managed by prophylactic treatment. Monotherapy activity was observed in CTCL (19% ORR, n=62), peripheral T-cell lymphoma (18% ORR, n=22) and diffuse large B-cell lymphoma (DLBCL) (29% ORR, n=7). Three responses (1 CR and 2 PRs) in CTCL patients treated at 1.4 and 2.0 mg/kg were obtained since the last data disclosure at ASH (Free ASH Whitepaper) 2020. Emerging translational data from patient samples suggest that NK cell activation plays a key role in the anti-tumor activity of TTI-621, in addition to inhibition of the "don’t eat me" signal and delivery of a pro-phagocytic signal. This highly differentiated proposed mode of action, together with encouraging monotherapy activity and good tolerability, prompt continued and focused further investigation of TTI-621. The study is continuing, with 3 more patients at 2.0 mg/kg pending response assessments as of the April 12, 2021 cutoff date.

Phase 1b/2 Program

Based on the strong and differentiated foundation that Trillium has built, including potentially class-leading monotherapy activity, the Company is initiating Phase 1b/2 programs with both TTI-622 and TTI-621. These programs will initially cover seven indications (four hematological cancers, three solid tumors), and study TTI-622 and TTI-621 primarily in combination with other anti-cancer agents.

Specifically, TTI-622 will be evaluated in the following settings and combination regimens:

R/R multiple myeloma, in a combination with carfilzomib + dexamethasone;
First line p53 mutant acute myeloid leukemia (AML), in a combination with azacitidine;
First line elderly or unfit p53 wild type AML patients, in a combination with azacitidine and venetoclax;
R/R DLBCL, in a combination with anti-PD-1, in an investigator-sponsored trial at Mayo Clinic;
Platinum-resistant ovarian cancer, in a combination with chemotherapy; and
A second solid tumor combination study to be announced later this year.
These studies will be initiated with 8 mg/kg weekly dosing, or potentially less frequent dosing regimens at higher doses.

The Phase 1b/2 program for TTI-622 has now been initiated with the dosing of a first multiple myeloma patient with TTI-622 in a combination with carfilzomib + dexamethasone. Both AML cohorts are open for enrollment, and we expect the first patients to be dosed this quarter.

TTI-621 will be evaluated in the following settings and combination regimens:

Second line peripheral T-cell lymphoma (PTCL), as a TTI-621 monotherapy;
R/R DLBCL, in a combination with anti-PD-1, in an investigator-sponsored trial at Mayo Clinic; and
First line leiomyosarcoma, a subtype of soft tissue sarcoma, in a combination with doxorubicin.
Initial Phase 1b/2 studies will be initiated at two dose levels (0.2 mg/kg and up to 2.0 mg/kg weekly); different levels may be chosen based on overlapping toxicities with combination agents.

In addition, bi-weekly (Q2W) and Q3W dosing schedules will be evaluated for each molecule in the ongoing monotherapy dose escalation studies.

Governance Update

Effective April 28, 2021, Scott Myers is joining the Board of Directors. Scott is an accomplished executive who brings to the Board nearly three decades of pharmaceutical and medical device industry experience. Previously, he served as CEO of AMAG Pharmaceuticals, Rainier Therapeutics, Cascadian Therapeutics, and Aerocrine AB. He currently serves on the Boards of Directors of Selecta Biosciences and Harpoon Therapeutics. We are very excited that Scott has agreed to join the Board, and look forward to benefitting from his extensive executive experience and track record of building successful biotechnology companies.

Robert Kirkman elected to retire from the Board of Directors, effective April 28, 2021. Robert has served as a director since December 2013, the Chair of the Board since March 2019, and acted as the Executive Chair from April 2019 to March 2020.

As previously announced, Tom Reynolds joined our scientific advisory board (SAB) in November 2020. Due to the resulting loss of his independent status as a Board member, Tom is now (effective April 28, 2021) retiring from the Board to focus on the SAB role, as well as to serve as a senior advisor to assist with initiation of our extensive Phase 1b/2 program and a scale-up of the clinical development organization.

Upcoming Milestones and Guidance

In 2021, Trillium expects two data updates:

TTI-622 data update from the ongoing dose escalation study in R/R lymphomas at a medical conference in 4Q 2021; and
TTI-621 data update from the ongoing dose escalation study in R/R CTCL at a medical conference in 4Q 2021.
Over approximately the next twelve months, the Company plans to initiate studies in the following indications and patient settings:

TTI-622 + azacitidine combination in p53 mutant AML patients in 2Q 2021 (enrollment open);
TTI-622 + azacitidine + venetoclax combination in elderly or unfit p53 wild type AML patients in 2Q 2021 (enrollment open);
TTI-622 + chemotherapy combination in platinum-resistant ovarian cancer patients in 2H 2021;
TTI-622 combination study in a to-be-announced solid tumor indication in 1H 2022;
TTI-622 + anti-PD-1 and TTI-621 + anti-PD-1 in DLBCL patients in 4Q 2021 to 1H 2022 (investigator-sponsored trial);
TTI-621 monotherapy study in PTCL in 3Q 2021; and
TTI-621 + doxorubicin combination in leiomyosarcoma in 3Q 2021.
As all of the above studies are open-label trials, the Company expects a robust flow of new data updates and multiple catalysts in 2022, in addition to the above mentioned updates from the continuing dose escalation studies in the fourth quarter of 2021.

As of March 31, 2021, Trillium had $276 million in cash, cash equivalents, and marketable securities, sufficient to fund operations and the above outlined clinical development priorities into 2023.

R&D Day Presentation and Webcast

The archived webcast from Trilium’s R&D Day can be found at View Source and will be available on Trillium’s website for 30 days. The R&D Day presentation can be found on our website at www.trilliumtherapeutics.com.

On April 28, 2021 Aurinia Pharmaceuticals Inc. (NASDAQ: AUPH / TSX: AUP) (the "Company") reported that it will release its first quarter 2021 financial results on Thursday, May 6, 2021, after the markets close (Press release, Aurinia Pharmaceuticals, APR 28, 2021, View Source [SID1234578673]). Aurinia’s management team will also host a conference call at 5:00 p.m. EDT to discuss the Company’s financial results and to provide a general business update.

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The conference call and webcast is scheduled for May 6, 2021 at 5:00 p.m. ET. In order to participate in the conference call, please dial +1-888-506-0062 (toll-free U.S.) or +1-973-528-0011 (international); entry code: 662377. The audio webcast can be accessed under "News/Events" through the "Investors" section of the Aurinia corporate website at www.auriniapharma.com. A replay of the webcast will also be available on Aurinia’s website approximately two hours after the live call is completed.

On April 28, 2021 BioInvent reported to make strong clinical and financial progress in Q1 2021 (Press release, BioInvent, APR 28, 2021, View Source [SID1234578699]). Positive interim results from the Phase 1/2a study of BI-1206 in B-cell non-Hodgkin’s lymphoma (NHL) are very encouraging. Our financial position was reinforced with a directed share issue, providing funding to continue the transformation of BioInvent with the expansion of our clinical programs and broadening our institutional shareholder base." – Martin Welschof, CEO BioInvent.

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Events in the quarter
PROJECT UPDATES

(R) BioInvent Phase 1/2a data suggest BI-1206 restores activity of rituximab in relapsed non-Hodgkin’s lymphoma patients.
BioInvent enrolled first patient in a Phase 1/2a trial of the first-in-class anti-TNFR2 antibody BI-1808 for the treatment of patients with solid tumors and CTCL.
BioInvent and Transgene enrolled first patient in Phase 1/2a trial of novel oncolytic virus BT-001 in solid tumors.
(R) BioInvent streamlined agreement with CRUK on anti-FcγRllB antibody, BI-1206, ahead of Phase 1/2 data. In exchange for a one-off payment of GBP 2.5 million, the revised deal simplifies and reduces BioInvent’s obligations to CRUK.
BioInvent presented proof-of-concept data on anti-FcyRIIB antibody BI-1607 at AACR (Free AACR Whitepaper) Annual Meeting 2021.
FINANCING

(R) BioInvent successfully carried out a directed share issue of approximately SEK 962 million (USD 116 million).
Events after the period

BioInvent received IND approval for Phase 1/2a trial of anti-TNFR2 antibody BI-1808.
Financial information
FIRST QUARTER 2021

Net sales SEK 6.2 (16.7) million.
Loss after tax SEK -79.8 (-32.6) million.
Loss after tax per share before and after dilution SEK -1.94 (-1.63).
Cash flow from operating activities and investment activities SEK -51.5 (-35.4) million.
Liquid funds as of March 31, 2021: SEK 1,577.1 (117.1) million.

The information was submitted for publication at 08:00 a.m. CEST on April 28, 2021.

On April 28, 2021 Provectus (OTCQB: PVCT) reported that two abstracts about data from clinical and preclinical study of investigational cancer immunotherapy PV-10 (rose bengal disodium) were accepted for the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2021 Annual Meeting, which will be held June 4-8 online (Press release, Provectus Pharmaceuticals, APR 28, 2021, View Source [SID1234578823]).

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Abstract #1:

Title: Phase I study of autolytic immunotherapy of metastatic neuroendocrine tumors using intralesional rose bengal disodium
Session Title: Poster Session: Gastrointestinal Cancer – Gastroesophageal, Pancreatic, and Hepatobiliary
Abstract number for publication: 4115
This clinical trial, a single-center study at The Queen Elizabeth Hospital (TQEH) in Adelaide, Australia that completed enrollment in 2020, is led by Tim Price, MBBS, DHlthSc (Medicine), FRACP, Head of Clinical Oncology Research and Chair of the combined Hematology and Medical Oncology Unit at TQEH and Clinical Professor in the Faculty of Medicine at the University of Adelaide.

Abstract #2:

Title: Pre-clinical research of PV-10 for in vitro anti-tumor activity in refractory and high-risk adult solid tumors
Abstract number for publication: e14544
This research on the oral administration of PV-10 for the prophylactic and/or therapeutic treatment of adult solid tumor cancers is led by Aru Narendran, MD, PhD, Professor, Departments of Pediatrics, Oncology, Biochemistry & Molecular Biology, and Physiology & Pharmacology in the Cumming School of Medicine at the University of Calgary in Calgary, Alberta, Canada.

About PV-10

Intralesional (IL) administration of PV-10 for the treatment of solid tumor cancers can yield immunogenic cell death within hours of tumor injection, and induce tumor-specific reactivity in circulating T cells within days.1,2,3 This IL PV-10-induced functional T cell response may be enhanced and boosted in combination with immune checkpoint blockade (CB).4 In CB-refractory advanced cutaneous melanoma, IL PV-10 may restore disease-specific T cell function, which may also be prognostic of clinical response. IL PV-10 has been administered to over 450 patients with cancers of the skin and of the liver. It is administered under visual, tactile or ultrasound guidance to superficial malignancies, and under CT or ultrasound guidance to tumors of the liver. Systemic administration of PV-10 is also undergoing preclinical study as prophylactic and therapeutic treatments for refractory and high-risk adult solid tumor cancers, and as a treatment for relapsed and refractory blood cancers.

About Rose Bengal Disodium

RBD is 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium, a halogenated xanthene and Provectus’ proprietary lead molecule. Provectus’ current Good Manufacturing Practices (cGMP) RBD is a proprietary pharmaceutical-grade drug substance produced by the Company’s quality-by-design (QbD) manufacturing process to exacting regulatory standards that avoids the formation of uncontrolled impurities currently present in commercial-grade rose bengal. Provectus’ RBD and cGMP RBD manufacturing process are protected by composition of matter and manufacturing patents as well as trade secrets.

An IL formulation (i.e., by direct injection) of cGMP RBD drug substance, cGMP PV-10, is being developed as an autolytic immunotherapy drug product for solid tumor cancers.

IL PV-10 is also undergoing preclinical study for relapsed and refractory pediatric solid tumor cancers, such as neuroblastoma, Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma.5,6

A topical formulation of cGMP RBD drug substance, PH-10, is being developed as a clinical-stage immuno-dermatology drug product for inflammatory dermatoses, such as atopic dermatitis and psoriasis. RBD can modulate multiple interleukin and interferon pathways and key cytokine disease drivers.7

Oral formulations of cGMP RBD are undergoing preclinical study for relapsed and refractory pediatric blood cancers, such as acute lymphocytic leukemia and acute myelomonocytic leukemia.8,9

Oral formulations of cGMP RBD are also undergoing preclinical study as prophylactic and therapeutic treatments for high-risk adult solid tumor cancers, such as head and neck, breast, pancreatic, liver, and colorectal cancers.

Different formulations of cGMP RBD are also undergoing preclinical study as potential treatments for multi-drug resistant (MDR) bacteria, such as Gram-negative bacteria.

Topical formulations of cGMP RBD are also undergoing preclinical study as potential treatments for diseases of the eye, such as infectious keratitis

Tumor Cell Lysosomes as the Seminal Cancer Drug Target

Lysosomes are the central organelles for intracellular degradation of biological materials, and nearly all types of eukaryotic cells have them. Discovered by Christian de Duve, MD in 1955, lysosomes are linked to several biological processes, including cell death and immune response. In 1959, de Duve described them as ‘suicide bags’ because their rupture causes cell death and tissue autolysis. He was awarded the Nobel Prize in 1974 for discovering and characterizing lysosomes, which are also linked to each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Building on the Discovery, Exploration, and Characterization of Lysosomes

Cancer cells, particularly advanced cancer cells, are very dependent on effective lysosomal functioning.10 Cancer progression and metastasis are associated with lysosomal compartment changes11,12, which are closely correlated (among other things) with invasive growth, angiogenesis, and drug resistance13.

RBD selectively accumulates in the lysosomes of cancer cells upon contact, disrupting the lysosomes and causing the cells to die. Provectus2,14, external collaborators5, and other researchers15,16,17 have independently shown that RBD triggers each of the three primary cell death pathways: apoptosis, autophagy, and necrosis.

Cancer Cell Autolytic Death via RBD: RBD-induced autolytic cell death, or death by self-digestion, in Hepa1-6 murine hepatocellular carcinoma (HCC) cells can be viewed in this Provectus video of the process (ethidium homodimer 1 [ED-1] stains DNA, but is excluded from intact nuclei; lysosensor green [LSG] stains intact lysosomes; the video is provided in 30-second frames, with a duration of approximately one hour). Exposure to RBD triggers the disruption of lysosomes, followed by nucleus failure and autolytic cell death. Identical responses have been shown by the Company in HTB-133 human breast carcinoma (which can be viewed in this Provectus video of the process, with a duration of approximately two hours) and H69Ar human multidrug-resistant small cell lung carcinoma. Cancer cell autolytic cell death was reproduced by research collaborators in neuroblastoma cells to show that lysosomes are disrupted upon exposure to RBD.5

Tumor Autolytic Death via RBD: RBD causes acute autolytic destruction of injected tumors (via autolytic cell death), mediating the release of danger-associated molecular pattern molecules (DAMPs) and tumor antigens; release of these signaling factors may initiate an immunologic cascade where local response by the innate immune system may facilitate systemic anti-tumor immunity by the adaptive immune system. The DAMP release-mediated adaptive immune response activates lymphocytes, including CD8+ T cells, CD4+ T cells, and NKT cells, based on clinical and preclinical experience in multiple tumor types. Mediated immune signaling pathways may include an effect on STING, which plays an important role in innate immunity.9

Orphan Drug Designations (ODDs)

ODD status has been granted to RBD by the U.S. Food and Drug Administration for metastatic melanoma in 2006, hepatocellular carcinoma in 2011, neuroblastoma in 2018, and ocular melanoma (including uveal melanoma) in 2019.

Intellectual Property

Provectus’ IP includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the process by which cGMP RBD and related halogenated xanthenes are produced, avoiding the formation of previously unknown impurities that exist in commercial-grade rose bengal in uncontrolled amounts. The requirement to control these impurities is in accordance with International Council on Harmonisation (ICH) guidelines for the manufacturing of an injectable pharmaceutical. US patent numbers are 8,530,675, 9,273,022, and 9,422,260, with expirations ranging from 2030 to 2031.

The Company’s IP also includes a family of US and international (a number of countries in Asia, Europe, and North America) patents that protect the combination of RBD and CB (e.g., anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) for the treatment of a range of solid tumor cancers. US patent numbers are 9,107,887, 9,808,524, 9,839,688, and 10,471,144, with expirations ranging from 2032 to 2035; US patent application numbers include 20200138942 (i.e., 16/678,133), which has been allowed.