On November 9, 2019 -Five Prime Therapeutics, Inc. (NASDAQ: FPRX), a clinical-stage biotechnology company focused on developing immune modulators and precision therapies for solid tumor cancers, reported initial safety data from the Phase 1 clinical trial of FPT155 in patients with advanced solid tumors in a poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 34th Annual Meeting in National Harbor, Maryland (Press release, Five Prime Therapeutics, NOV 9, 2019, View Source [SID1234550830]). The poster can be found on the Publications Page of the Five Prime Therapeutics website.

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"FPT155 is a first-in-class CD80 fusion protein with potential dual mechanisms to activate T cells," said Helen Collins, M.D., Executive Vice President and Chief Medical Officer of Five Prime Therapeutics. "Importantly, the initial safety results for FPT155 suggest that it may not cause the same safety issues seen with a prior molecule targeting CD28. This allows us to continue enrolling patients to study additional dose escalation cohorts and identify a dose for future studies."

The FPT155 data presented at SITC (Free SITC Whitepaper) included initial safety results from the Phase 1a dose escalation portion of the trial, which is designed to characterize the safety and pharmacokinetic (PK)/pharmacodynamic (PD) profile of FPT155 and identify a recommended dose for the Phase 1b portion of the trial. This included data from 15 patients with solid tumors that were treated with FPT155 at doses of 0.07 mg, 0.21 mg, 0.7 mg, 2.1 mg, 7 mg, 21 mg, and 42 mg. The key highlights from the presentation include:

FPT155 was well tolerated at all dose levels, with no dose-limiting toxicities and no grade 4 or higher adverse events.
There is no evidence of clinical or laboratory cytokine release syndrome, an adverse event associated with a prior therapy targeting CD28.
Dose escalation with FPT155 is ongoing with the study currently enrolling patients at the 70 mg dose level.
The Phase 1a/1b open-label, multicenter, dose escalation, dose exploration and dose expansion study will evaluate the safety and tolerability of FPT155 in patients with advanced solid tumors. The Phase 1a dose escalation portion of the trial will characterize the safety and PK/PD profile of FPT155 and will identify a recommended dose for the Phase 1b portion of the trial. The Phase 1b portion of the trial is intended to further characterize the safety, PK/PD profile, and preliminary efficacy of FPT155.

About FPT155

FPT155 is a first-in-class CD80 fusion protein that (i) directly engages CD28 to enhance its co-stimulatory T-cell activation activity without inducing super agonism, and (ii) blocks CTLA-4 from competing for endogenous CD80, allowing CD28 signaling to prevail in T-cell activation in the tumor microenvironment. FPT155 has also demonstrated its ability to retain anti-tumor activity independent of its engagement with CTLA-4, suggesting a differentiated mechanism of action from CTLA-4-blocking antibodies. Studies in preclinical models suggest FPT155 has the potential to be a potent T-cell co-stimulator with strong monotherapy anti-tumor activity.

On November 8, 2019 Aptevo Therapeutics Inc. (Nasdaq: APVO), a biotechnology company focused on developing novel immuno-oncology and hematology therapeutics and Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy reported that new preclinical data for ALG.APV-527 are being presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting at the National Harbor, Maryland, November 6-10, 2019.

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ALG.APV-527 is a novel immunotherapeutic candidate intended for the treatment of a variety of 5T4-positive solid tumors. It is designed to induce signaling through the co-stimulatory receptor 4-1BB (CD137), which is present on activated cytotoxic T cells and natural killer (NK) cells. Once activated, it is designed to promote potent and selective tumor-directed immune activation in the presence of the tumor associated antigen, 5T4, which is present on many different types of solid tumors.

The preclinical data presented at SITC (Free SITC Whitepaper) show that ALG.APV-527 selectively enhances T cell and NK cell responses in the presence of 5T4 in vitro and displays potent and sustained tumor suppression in vivo. The preclinical studies demonstrate that ALG.APV-527:

Enhances CD8+ T cell and NK function and proliferation preferentially over that of CD4+ T cells, upon 5T4-mediated crosslinking
In preliminary in vivo studies in a human 4-1BB knock in model, induces rejection of established murine bladder cancer cells expressing human 5T4 at doses of 20 µg in mice and induces anti-tumor immunological memory responses
Is well tolerated after repeated dosing in a GLP toxicology study above the expected human dose and displays an antibody-like half-life of up to 9.5 days
"We’re pleased that ALG.APV-527 continues to show promising preclinical results," said Jane Gross, Ph.D., Chief Scientific Officer for Aptevo. "The ability of ALG.APV-527 to induce potent anti-tumor T cell and NK cell activity suggests 4-1BB is an attractive target for designing new immuno-oncology therapeutics. Monospecific 4-1BB-directed antibodies have been challenged by dose-limiting liver toxicities. As a novel bispecific antibody ALG.APV-527 may circumvent these challenges and minimize systemic toxicity by stimulating 4-1BB function only when co-engaged with the tumor antigen, 5T4."

"The presented preclinical data strongly support a potent effect of ALG.APV-527 without compromising on safety. The data further strengthens our CTA package and we are eagerly looking forward to discuss this candidate with potential partners to take this exciting asset further into clinical development," commented Christina Furebring, Ph.D., Vice President Preclinical Development at Alligator.

The Alligator/Aptevo poster presentation, entitled "Potent Tumor-Directed T Cell Activation and Tumor Inhibition Induced by a 4-1BB x 5T4 ADAPTIR Bispecific Antibody" is being presented on Saturday, November 9, 2019 from 7:00 am – 8:30 pm ET.

About ALG.APV-527
ALG.APV-527 is a bispecific antibody (4-1BB x 5T4) intended for tumor-directed treatment of solid cancers. ALG.APV-527 was built using Aptevo’s ADAPTIR bispecific platform and combines binding domains sourced from the ALLIGATOR-GOLD human scFv library. The ALG.APV-527 bispecific antibody consists of two parts, one part activating tumor-specific T cells through the co-stimulatory receptor 4-1BB, the other part binding to the 5T4 protein displayed on the surface of tumor cells. This enables the immune-activating effect of ALG.APV-527 to be directed specifically to the tumor and not against normal tissue.

On November 8, 2019 Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, today presented new preclinical data on ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor for the treatment of advanced malignancies, at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 34th Annual Meeting (Press release, Alpine Immune Sciences, NOV 8, 2019, View Source [SID1234550761]). ALPN-202 is Alpine’s lead oncology program and remains on track to initiate a first-in-human clinical trial by the first quarter of 2020.

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ALPN-202 is designed to improve upon the safety and efficacy of existing combination checkpoint and/or costimulation therapeutic strategies. One poster presents mechanistic data supporting that ALPN-202 inhibits both the PD-L1 and CTLA-4 checkpoint pathways while also providing PD-L1-dependent CD28 costimulation, as intentionally designed. A second poster demonstrates the ability of ALPN-202 to improve significantly upon the activity of existing cancer therapeutics when given alone and/or in combination in preclinical models. In addition, crystallographic study suggests that ALPN-202 binds PD-L1 and CD28 at distinct, non-overlapping epitopes enabling its potentially unique functionality:

P793. ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, Utilizes Multiple Mechanisms to Elicit Potent Anti-Tumor Immunity Superior to Checkpoint Blockade

P467. ALPN-202, a Conditional CD28 Costimulator and Dual Checkpoint Inhibitor, Enhances the Activity of Multiple Standard of Care Modalities

Immune checkpoint inhibitors targeting the PD-1/PD-L1 and/or CTLA-4 pathways have demonstrated clinical activity in multiple cancers, but many patients still experience inadequate anti-tumor responses and/or relapse, which may be in part due to insufficient anti-tumor T cell activation and/or exhaustion. At the same time, combinations of checkpoint inhibitors and/or costimulatory agents can result in excessive immune-related toxicities. "ALPN-202 is engineered to address both of these issues by promoting T cell activity, but primarily only in a tumor-specific fashion, to produce specific, durable anti-tumor immune responses," said Stanford Peng, MD PhD, Alpine’s President and Head of Research and Development. "These data continue to encourage us regarding the potential for ALPN-202 as a new, first-in-class cancer immunotherapy. We continue to look forward to initiating our first clinical trial of ALPN-202."

The full poster presentations can be found at: View Source and View Source

About ALPN-202

ALPN-202 is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor, which has 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. We anticipate initiation of the first-in-human clinical study of ALPN-202 to begin by the first quarter of 2020.

On November 8, 2019 Zimmer Biomet Holdings, Inc. (NYSE and SIX: ZBH), a global leader in musculoskeletal healthcare, reported that it will participate in the Evercore ISI HealthCONx Conference at the Four Seasons Hotel in Boston (Press release, Zimmer Holdings, NOV 8, 2019, https://www.prnewswire.com/news-releases/zimmer-biomet-holdings-to-present-at-the-2nd-annual-evercore-isi-healthconx-conference-300954357.html [SID1234550777]). Suky Upadhyay, Executive Vice President and Chief Financial Officer and Cole Lannum, CFA, Senior Vice President Investor Relations, will present for the Company on Tuesday, December 3, 2019, at 1:15 p.m. Eastern Time.

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A live webcast of the presentation can be accessed via Zimmer Biomet’s Investor Relations website at https://investor.zimmerbiomet.com. The webcast will be archived for replay following the conference.

On November 8, 2019 Forbius, a clinical-stage protein engineering company that develops biotherapeutics to treat fibrosis and cancer,reported the first Phase 1 clinical data from its oncology development program with AVID200, in a late-breaking poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting 2019 in National Harbor, Maryland (Nov. 6-10) (Press release, Forbius, NOV 8, 2019, View Source [SID1234550745]).

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AVID200 is a first-in-class, selective inhibitor of TGF-beta 1 & 3, the main pathogenic TGF-beta isoforms. AVID200 spares TGF-beta 2 for optimal safety.

The AVID200-03 trial (NCT03834662) is an open label, multicenter, dose-escalation study of AVID200 monotherapy following a standard 3 + 3 design in patients with advanced or metastatic solid tumor malignancies and no other treatment options.

In the presentation entitled "AVID200, first-in-class TGF-beta 1 and beta 3 selective inhibitor: Results of a Phase 1 monotherapy dose escalation study in solid tumors and evidence of target engagement in patients (Abstract # P856)", Dr Timothy Yap, Associate Professor, MD Anderson Cancer Center, and a PI in the trial detailed the following:

A total of 15 patients received AVID200 at 5, 15 and 30 mg/kg once every three weeks, 4 patients remain ongoing at time of data presentation.
AVID200 achieved dose-proportional exposure and exhibited peripheral target inhibition of TGF-beta 1 & 3 over the entire dosing period at all dose levels tested.
AVID200 was well-tolerated and the maximum tolerated dose (MTD) was not reached.
No patients at either of the two higher dose levels, 15 mg/kg (550 mg/m2) and 30 mg/kg (1100 mg/m2), had any toxicities greater than Grade 2.
A single patient with appendiceal carcinoma who had a prior total colectomy and was treated in the lowest dose level cohort (5 mg/kg / 180 mg/m2), experienced grade 3 (G3) events including G3 diarrhea (worsening from G2 diarrhea at enrolment) which was characterized as the only DLT in the trial.
Several patients experienced stable disease including one patient with prolonged stable disease of more than 8 months who continues on treatment.
Ilia Tikhomirov, CEO of Forbius, commented: "With this Phase 1a dose-escalation study we have shown that selective inhibition of TGF-beta isoforms 1 & 3 via AVID200 leads to efficient blockade of the TGF-beta pathway with potentially best-in-class tolerability. We look forward to reporting additional clinical data from across the AVID200 program."

About TGF-beta 1 & 3

TGF-beta 1 & 3 are the main oncogenic TGF-beta isoforms expressed by many solid tumors. They are believed to play a major role in T-cell suppression, fibrosis and resistance to anti-PD-(L)1 therapies such as nivolumab (Opdivo) and pembrolizumab (Keytruda) (Chakravarthy, Nature Comm., 2018; Tauriello, Nature, 2018; Mariathasan, Nature, 2018).

About AVID200 and the AVID200-03 Trial (NCT03834662)

AVID200 is an isoform-selective and highly potent inhibitor of TGF-beta 1 & 3 undergoing Phase 1 clinical testing in solid tumors and fibrotic diseases. TGF-beta 1 & 3 are the principal disease-driving isoforms, while TGF-beta 2 is responsible for normal cardiac function and hematopoiesis.

AVID200’s selectivity for TGF-beta 1 & 3 was designed to achieve optimal efficacy while circumventing cardiac and other safety issues that have limited the applicability of earlier-generation, non-selective TGF-beta inhibitors. Therefore, AVID200 is positioned to be an effective and well-tolerated therapeutic in a variety of clinical settings, including in combination with anti-PD-(L)1 therapy.

AVID200-03 (NCT03834662) is an open label, multicenter, dose-escalation study to evaluate the safety, pharmacokinetics, pharmacodynamics and antitumor effects of AVID200 in patients with advanced or metastatic solid tumor malignancies.

About Forbius: Targeting TGF-beta and EGFR Pathways in Fibrosis and Cancer

Forbius is a clinical-stage protein engineering company that develops biotherapeutics to treat fibrosis and cancer. We are focused on the transforming growth factor-beta (TGF-beta) and epidermal growth factor receptor (EGFR) pathways.

Forbius’ team of TGF-beta biology experts designed a proprietary platform of TGF-beta inhibitors with best-in-class potency and selectivity against the principal disease-driving isoforms 1 & 3. This novel class of TGF-beta inhibitors has proven highly active in preclinical models of fibrosis and cancer and was well-tolerated in long-term toxicology studies. Forbius’ lead TGF-beta 1 & 3 inhibitor, AVID200, is undergoing Phase 1 clinical trials in two fibrotic indications as well as in solid tumors.

Forbius’ lead program targeting EGFR is AVID100. AVID100 is an anti-EGFR antibody-drug conjugate (ADC) with a novel tumor-selective mode of action. This program is undergoing Phase 2a clinical trials in EGFR-overexpressing solid tumors.