On December 13, 2021 Zetagen Therapeutics, Inc., a private, clinical-stage, biopharmaceutical company dedicated to driving breakthrough innovation in the treatment of metastatic bone cancers and osteologic interventions, reported it has received a two year, $2 million USD grant from the National Cancer Institute of the National Institutes of Health (NIH) (Press release, Zetagen Therapeutics, DEC 13, 2021, View Source [SID1234596966]). The grant will be used for the Phase 2 clinical and commercial development of its ZetaMet technology. ZetaMet is a synthetic, small-molecule, inductive biologic technology being developed to target and resolve metastatic bone lesions while inhibiting future tumor growth and regenerating bone.

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"This support from the NCI marks a key milestone and will facilitate the continued development of ZetaMet for the use in treating metastasis in bone," said Bryan S. Margulies, PhD,chief scientific officer of Zetagen Therapeutics. "Preclinical trials have successfully demonstrated ZetaMet’s ability to resolve existing metastatic bone lesions, inhibit pain and stimulate targeted bone regeneration. If these results hold true in the next phase of study, ZetaMet could offer an entirely new treatment for patients living with certain late-stage cancers where present therapies do not offer desired results."

ZetaMet works through a mechanism of action (MOA) which is a novel and patented molecular pathway. The small molecule, precisely-dosed, delivered to the affected area through a proprietary drug-eluting carrier, stimulates stem cells, activating cells to grow healthy bone known as "osteoblasts", and inhibits cells associated with bone degradation called "osteoclasts".

Bone metastases are common among cancer patients and occur when cells from the primary cancerous tumor relocate to the bone. When these cancers relocate, they can cause changes to the bone, damaging it in a process called osteolysis. Osteolysis can cause small holes within the bone, weakening it and increasing the risk of breakage. These holes are called "lytic lesions." Among cancers which metastasize to bone, Breast and Prostate are most prevalent, amounting to approximately 70-percent of cases.1

"We know there are hundreds of thousands of patients living with late-stage cancers which involve painful, debilitating metastatic bone lesions," said Joe C. Loy, CEO of Zetagen Therapeutics. "This recognition from the NCI further reinforces our commitment to developing breakthrough therapies that will make a tangible difference in quality of life as they battle these devastating diseases."

Earlier this year, ZetaMet received Breakthrough Device designation from the Centers for Devices and Radiological Health (CDRH) of the U.S. Food and Drug Administration (FDA). The first human clinical trial using ZetaMet in Stage 4 breast cancer patients is being targeted for early 2022.

On December 13, 2021 Precigen, Inc., a biopharmaceutical company specializing in the development of innovative gene and cell therapies to improve the lives of patients, reported that positive interim data at the 63rd ASH (Free ASH Whitepaper) Annual Meeting and Exposition (Abstract# 825) from the ongoing Phase 1/1b clinical study of PRGN-3006 UltraCAR-T in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) and higher risk myelodysplastic syndromes (MDS) (clinical trial identifier: NCT03927261) (Press release, Precigen, DEC 13, 2021, View Source [SID1234596987]). The oral presentation was delivered by David Sallman, MD, Assistant Member in the Department of Malignant Hematology at the H. Lee Moffitt Cancer Center & Research Institute (Moffitt) and a lead investigator for the PRGN-3006 clinical trial.

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PRGN-3006 UltraCAR-T is a multigenic autologous CAR-T simultaneously expressing a CAR specifically targeting CD33; membrane bound IL-15 (mbIL15) for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile. CD33 is over-expressed on AML blasts with lesser expression on normal hematopoietic stem cells. PRGN-3006 UltraCAR-T has been granted Orphan Drug Designation in patients with AML by the US Food and Drug Administration (US FDA).

The Phase 1/1b clinical study is designed to enroll in two phases, an initial dose escalation phase followed by a dose expansion phase, to evaluate safety and determine the maximum tolerated dose of PRGN-3006 delivered via intravenous (IV) infusion without lymphodepletion (Cohort 1) or with lymphodepletion (Cohort 2). The study is also evaluating in vivo persistence and anti-tumor activity of PRGN-3006.

Today’s ASH (Free ASH Whitepaper) presentation included data from 15 r/r AML patients treated in the non-lymphodepletion cohort (N=9) and the lymphodepletion cohort (N=6). Patients were heavily pre-treated with a median of 4 (range: 1 to 6) and 3 (range: 1 to 7) prior regimens in the non-lymphodepletion and the lymphodepletion cohorts, respectively. Additionally, 33% and 50% of the patients had failed prior allogeneic hematopoietic stem cell transplant (allo-HSCT) in the non-lymphodepletion and the lymphodepletion cohorts, respectively. All patients received a single infusion of PRGN-3006.

Safety Data
PRGN-3006 was well-tolerated with no dose-limiting toxicities (DLTs) and no neurotoxicity at any dose level. Overall, there was low incidence of adverse events following PRGN-3006 infusion and the most common adverse events were decreased lymphocyte count, anemia and cytokine release syndrome (CRS). More than 70% of treatment emergent adverse events (TEAEs) were either Grade 1 or 2 with only one transient Grade 3 CRS reported (Dose Level 1, Cohort 1), which resolved in less than 24 hours with tocilizumab and dexamethasone. Other cases of CRS were Grade 1 or 2 and required either no intervention or resolved following standard CRS management. No subjects experienced a significant increase in serum IL-15, demonstrating that mbIL15 remains tethered to the UltraCAR-T cells as designed and is not released.

Clinical Activity
Non-lymphodepletion Cohort
Excellent dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow was observed following a single infusion, with detection of UltraCAR-T cells in blood for more than 7 months post-infusion highlighting the ability of UltraCAR-T cells to engraft and survive even in the absence of lymphodepletion. Peak expansion was observed between days 7 and 21 in the peripheral blood (FIGURE 1).

In the non-lymphodepletion cohort at the three dose levels evaluated, 3 out of 9 (33%) patients had Stable Disease (SD), per European LeukemiaNet (ELN) criteria, persisting for more than 3 months with one patient experiencing durable SD for more than 7 months with concomitant reduction in peripheral blast levels.

Lymphodepletion Cohort
Excellent dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow was observed following a single infusion, with detection of UltraCAR-T cells in blood for more than 3 months post-infusion. Peak expansion was observed between days 14 and 21 in the peripheral blood with higher peak expansion (> 10 fold) observed in the lymphodepletion cohort (FIGURE 2) at the same dose level.

An ORR of 50% (3 out of 6) was reported in the lymphodepletion cohort in patients treated at the two lowest dose levels. This included an ORR of 33% (1 out of 3) at Dose Level 1 and 67% (2 out of 3) at Dose Level 2 as summarized in TABLE 1. One responder (Dose Level 1) subsequently received allo-HSCT with ongoing survival greater than 1 year.

TABLE 1: Summary Objective Response Data for the Lymphodepletion Cohort

Dose Level
(DL)

AML Subtype

Dose Received

Age

Sex

Prior
Regimens*

Safety**

Objective Response***

DL 1

Persistent AML

8.7 x 106

60

F

2 prior:

CLAG and HiDAC

No incidence
of CRS,
neurotoxicity
or DLT

CRh at Day 84

DL 2

Extramedullary AML

28 x 106

53

M

7 prior: intensive chemo,
vidasia, venetoclax, FLAG,
anti-IDH1, allo-HSCT

No incidence
of CRS,
neurotoxicity
or DLT

PR#

AML

20 x 106

61

F

4 prior:

vyxeos, HMA+venetoclax,
allo-HSCT

CRS Grade 1,
with SAE skin
rash,
(possible
GVHD)

CRi at Day 28

CRh at Day 60

*CLAG=cladribine, cytarabine, and granulocyte-stimulating factor; HiDAC=high-dose cytarabine; FLAG=fludarabine, cytarabine and filgrastim; anti-IDH1=isocitrate dehydrogenases 1 inhibitor; HMA=hypomethylating agents (HMA); allo-HSCT= allogeneic hematopoietic stem cell transplant
**SAE=small ubiquitin-like modifier activating enzyme; GVHD=graft versus host disease
***Per ELN criteria; Complete Response with incomplete hematologic recovery (CRi); Complete response with hematologic recovery (CRh)
#Per RECIST v1.1; PR=partial response

Analysis of peripheral blood samples post PRGN-3006 infusion showed gene expression changes consistent with improvement in the immune compartment function for anti-tumor effect in responders. There was an increase in cytotoxicity, costimulatory signaling, and lymphoid compartment and decreased apoptosis pathway scores in the lymphodepletion cohort on Days 14 and 28 post PRGN-3006 treatment compared to baseline.

The study is anticipated to progress to the multicenter expansion phase with the plan to evaluate the potential of repeated dosing of PRGN-3006.

"The interim data for PRGN-3006 showed excellent, dose-dependent expansion and persistence of PRGN-3006 in peripheral blood and bone marrow following a single infusion, with detection of UltraCAR-T cells in blood more than 3 months post-infusion in the non-lymphodepletion and lymphodepletion cohorts," said David A. Sallman, MD, of Moffitt and lead investigator for the PRGN-3006 clinical study. "An ORR of 50% in patients treated at the two lowest dose levels in the lymphodepletion cohort is highly encouraging and the specifics of the responding patients suggest the potential for PRGN-3006 as a bridge to allo-HSCT, which is a very important potential treatment pathway for these patients."

"We are excited by these interim data, which clearly highlight the extraordinary potential and flexibility of the UltraCAR-T platform to deliver precision medicine to patients at any time, at any place and as many times as needed," said Helen Sabzevari, PhD, President and CEO of Precigen. "Based on the favorable safety profile and excellent expansion observed for both the lymphodepletion and the non-lymphodepletion cohorts, we believe UltraCAR-T cells have the potential to improve outcomes for cancer patients."

On December 13, 2021 Immatics N.V. (NASDAQ: IMTX, "Immatics"), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, and Bristol Myers Squibb (NYSE: BMY), reported that they have entered into a license, development and commercialization agreement (the "agreement") for Immatics’ TCR Bispecific candidate, IMA401 (Press release, FierceBiotech, DEC 13, 2021, View Source [SID1234597041]).

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Under the terms of the agreement, Immatics will receive an upfront payment of $150 million as well as up to $770 million in development, regulatory and commercial milestone payments, in addition to tiered double-digit royalty payments on net sales of IMA401. Immatics retains the options to co-fund U.S. development in exchange for enhanced U.S. royalty payments and/or to co-promote IMA401 in the US.

IMA401 is the most advanced product candidate in Immatics’ TCR Bispecifics pipeline, called TCER (T Cell Engaging Receptors), in which one binding region targets MAGEA4/8, a highly prevalent antigen in multiple solid tumors, and the other region engages and activates T cells. In preclinical proof-of-concept studies, IMA401 has shown anti-tumor activity with complete remissions in various in vivo tumor models including patient-derived xenograft models. The agreement outlines a development plan under which both companies will collaborate to advance the program through clinical development.

In November 2021, Immatics filed a Clinical Trial Application (CTA)1 with Paul-Ehrlich-Institute (PEI), the German federal regulatory authority, for the development of IMA401. The clinical trial, which is planned to commence in the first half of 2022, will enroll patients across various solid tumor types.

"At Immatics, we are committed to our goal of delivering meaningful clinical benefits to cancer patients, and based on the promising preclinical data, we see remarkable potential for our TCER platform" said Carsten Reinhardt, M.D., Ph.D., Chief Development Officer at Immatics. "We are delighted to extend our existing collaboration with Bristol Myers Squibb to the IMA401 program and view this as an important validation of the therapeutic potential of our TCER approach. Bristol Myers Squibb’s global clinical development and commercialization capabilities in oncology make them the ideal partner for the further development of IMA401."

"We are pleased to expand our collaboration with Immatics to now include IMA401," said Teri Foy, Senior Vice President, Research and Early Development, Immuno-Oncology and Cell Therapy at Bristol Myers Squibb. "TCERs are an important, emerging modality for solid tumors with the potential for cell therapy-like efficacy in an off-the-shelf platform offering potentially broader patient access. We look forward to advancing IMA401 into the clinic to further assess its potential as an innovative medicine to help patients prevail over serious diseases."

Immatics entered a strategic collaboration in 2019 with Celgene Corporation, a wholly owned subsidiary of Bristol-Myers Squibb Company, to develop novel adoptive cell therapies. This new collaboration to develop Immatics’ Bispecific candidate TCER IMA401 complements ongoing cell therapy activities – both therapeutic modalities built on Immatics’ capabilities to identify novel targets and develop high-affinity, target-specific TCRs. The terms of the current agreement regarding Immatics’ TCER IMA401 program exclude any MAGEA4/8 targets for cell therapy. The agreement is subject to customary clearance by antitrust regulators.

1 Clinical Trial Application – the European equivalent of an Investigational New Drug (IND) application

About IMA401
IMA401 is Immatics’ half-life extended TCER molecule that targets an HLA-A*02-presented (human leukocyte antigen) peptide derived from two different cancer-associated proteins, melanoma-associated antigen 4 and/or 8 ("MAGEA4/8"). MAGEA4/8 is highly prevalent in several solid tumor types including squamous non-small-cell lung carcinoma, head and neck squamous cell carcinoma, bladder, uterine, esophageal and ovarian carcinomas, as well as melanoma, sarcoma subtypes and other solid cancer types.

About TCER
Immatics’ TCER molecules are antibody-like "off-the-shelf" biologics that leverage the body’s immune system by redirecting and activating T cells towards cancer cells expressing a specific tumor target. To do so, the proprietary biologics are engineered to have two binding regions. The first region contains an affinity- and stability-improved TCR that binds specifically to the cancer target on the cell surface presented by an HLA molecule. The second region is derived from an antibody domain that recruits endogenous T cells to the tumor to become activated. The design of the TCER molecules enables the activation of any T cell in the body to attack the tumor, regardless of the T cells’ intrinsic specificity. In addition, the TCER molecule has a Fc-part conferring stability, half-life extension and enhanced manufacturability.

On December 13, 2021 Rottapharm Biotech reported that dosing the first patient in the Phase 1/2 study of CR6086 in combination with Agenus’ balstilimab (anti-PD-1) in advanced colorectal cancer at the National Cancer Institute (Istituto Nazionale dei Tumori) – Milan (Italy) (Press release, Rottapharm Biotech, DEC 13, 2021, View Source [SID1234597093]).

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Patients with colorectal cancers have limited treatment options, as most do not respond to PD-1 therapy or other immunotherapy regimens studied to date. Colorectal cancers represent one of the three most common cancers diagnosed, and the second leading cause of deaths across all cancer types globally. More than 80% of colorectal cancers are classified as mismatch repair-proficient (pMMR) and microsatellite stable (MSS) colorectal cancer (CRC), which correlates with low tumor mutation burden and poor immune cell infiltration within the tumor microenvironment ("cold tumors"). These patients generally do not benefit from PD-1 therapy alone and combination strategies with other immune-modulating therapies are necessary to address immune suppression in the tumor microenvironment and improve sensitivity to PD-1 therapy.

The involvement of prostaglandin E2 (PGE2) in cancerogenesis has been known for decades. There is now growing evidence about the role of PGE2, via its EP4 receptor on different immune cells, as a key effector for the impaired immune response within the tumor microenvironment and the potential for an EP4 receptor antagonist to turn the tumor microenvironment into an immune-responsive ("hot") tissue.

Rottapharm Biotech is developing CR6086, a potent and selective small molecule antagonist of EP4. EP4 signaling broadly suppresses immune activity in the tumor microenvironment, contributing to treatment resistance and tumor progression. CR6086 is designed to increase the activity and infiltration of several different immune cell types – including T cells, natural killer cells, and dendritic cells – while blocking the immune suppressive role of PGE2 in the tumor microenvironment. Preclinical evidence suggests that CR6086 may work in combination with PD-1 therapy to promote durable, anti-tumor immune responses. CR6086 is a potential best-in-class EP4 receptor antagonist, based on its pharmacokinetics and pharmacodynamic profile, and has demonstrated a strong safety profile in >250 subjects treated to date.

Balstilimab is a monoclonal antibody developed by Agenus Inc., belonging to the immune checkpoint inhibitor class, and is an inhibitor of programmed cell death 1 (PD-1) protein. It has been evaluated in >400 patients to date and has demonstrated strong clinical activity and an excellent safety profile in several tumor types, including cervical cancer (results published in Gynecologic Oncology this year).

The Phase 1/2 clinical study aims at evaluating the safety and efficacy of CR6086 combined with balstilimab in patients with advanced pMMR/MSS metastatic CRC (mCRC). The primary endpoints are safety, tolerability, and preliminary efficacy, as determined by disease control rate. The secondary endpoints include objective response rate, duration of response, progression-free survival, and overall survival.

Rottapharm Biotech’s clinical collaboration with Agenus offers a promising new combination therapy for patients with advanced pMMR/MSS mCRC where there is a high unmet need, and for a further range of potential applications in other immunotherapy-resistant tumors.

On December 13, 2021 Keros Therapeutics, Inc. ("Keros") (Nasdaq: KROS), a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel treatments for patients suffering from hematological and musculoskeletal disorders with high unmet medical need, reported it has entered into a licensing agreement with Hansoh (Shanghai) Healthtech Company Limited ("Hansoh"), a subsidiary of Hansoh Pharmaceutical Group Company Limited ("Hansoh Pharma"), a leading R&D driven biopharmaceutical company in China (Press release, Keros Therapeutics, DEC 13, 2021, View Source [SID1234597182]). Under the terms of the agreement, Hansoh will obtain an exclusive license from Keros to develop, manufacture and commercialize KER-050 within the territories of mainland China, Hong Kong, and Macau.

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"We look forward to working with Hansoh in China, to unlock the potential of KER-050 for patients in China," said Jasbir S. Seehra, Ph.D., President and Chief Executive Officer of Keros. "This agreement enables us to strategically expand our program, subsidized by non-dilutive capital, while also gaining access to one of the largest pharmaceutical markets globally."

Yuan Sun, Executive Director of Hansoh Pharma, added, "We are excited to partner with Keros, a leader in understanding the role of the Transforming Growth Factor-Beta family of proteins. We believe in the potential of KER-050 as a treatment for diseases associated with ineffective hematopoiesis, such as myelodysplastic syndromes and other hematologic disorders, and we believe that our extensive clinical development and commercialization experience in China can help to bring this differentiated product candidate to benefit patients across China."

Under the terms of the agreement, Hansoh is responsible for the development, regulatory approval and commercialization of KER-050 in mainland China, Hong Kong, and Macau. Keros will receive a $20 million upfront payment and will also be eligible to receive up to $170.5 million in development and commercial milestones, plus tiered royalties on net product sales ranging from the low double digit to high teens.

About KER-050

Keros’ lead protein therapeutic product candidate, KER-050, is an engineered ligand trap comprised of a modified ligand-binding domain of the Transforming Growth Factor-Beta receptor known as activin receptor type IIA that is fused to the portion of the human antibody known as the Fc domain. KER-050 is being developed for the treatment of low blood cell counts, or cytopenias, including anemia and thrombocytopenia, in patients with myelodysplastic syndromes, or MDS, and in patients with myelofibrosis.