On December 13, 2021 Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (NYSE: LLY), and Foghorn Therapeutics Inc. (Nasdaq: FHTX), reported a strategic collaboration to create novel oncology medicines by applying Foghorn’s proprietary Gene Traffic Control platform (Press release, Eli Lilly, DEC 13, 2021, View Source [SID1234596918]). The collaboration includes a co-development and co-commercialization agreement for Foghorn’s selective BRM oncology program and an additional undisclosed oncology target. In addition, the collaboration includes three additional discovery programs using Foghorn’s proprietary Gene Traffic Control platform.

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Under the terms of the agreement, Foghorn will receive upfront consideration of $300 million in cash for the collaboration agreement and an equity investment by Lilly of $80 million in Foghorn common shares at a price of $20 per share.

"Oncogenic mutations in BRG1 impact a large population of cancer patients and we believe are best addressed therapeutically with a highly selective BRM inhibitor, though designing such a drug is a difficult chemistry challenge. We’ve been very impressed by the progress the Foghorn team has made against this product profile and are excited to work with this highly talented team," said Jacob Van Naarden, CEO of Loxo Oncology at Lilly and president, Lilly Oncology. "Foghorn has a differentiated platform and we look forward to the prospect of leveraging it to discover multiple new drugs against similarly challenging targets with strong biologic rationale."

"We are excited to be collaborating with the Loxo Oncology at Lilly team to use our platform and utilize Foghorn’s powerful precision biology-first approach to create medicines targeting genetic dependencies within the chromatin regulatory system," said Foghorn CEO Adrian Gottschalk. "This collaboration enables an acceleration and expansion of our pipeline and significantly strengthens our balance sheet as we strive to bring new medicines to patients and their families."

Terms of Collaboration
For the BRM-selective program and the additional undisclosed target program, Foghorn will lead discovery and early research activities, while Lilly will lead development and commercialization activities with participation from Foghorn in operational activities and cost sharing. Foghorn and Lilly will share 50/50 in the U.S. economics, and Foghorn is eligible to receive royalties on ex-U.S. sales starting in the low double-digit range and escalating into the twenties based on revenue levels.

For the additional discovery programs, Foghorn will lead discovery and early research activities. Foghorn may receive up to a total of $1.3 billion in potential development and commercialization milestones. Additionally, Foghorn will have an option to participate in a percentage of the U.S. economics and is eligible to receive tiered royalties from the mid-single digit to low-double digit range on sales outside the U.S. that may be exercised after the successful completion of the dose-finding toxicity studies.

The terms of the transaction have cleared the required waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (HSR Act).

This transaction will be reflected in Lilly’s reported results and financial guidance according to Generally Accepted Accounting Principles (GAAP). There will be no change to Lilly’s 2021 non-GAAP earnings per share guidance as a result of this transaction.

About BRM-Selective Program
Data suggest there are over 30 different cancers with brahma-related gene-1 (BRG1) mutations accounting for approximately 5% of all tumors with up to 10% of non-small cell lung cancer tumors, with minimal overlap with other driver mutations. The BRM-selective program is being developed to address BRG1 mutated cancers utilizing two distinct approaches including protein degradation and enzymatic inhibition.

About Foghorn Proprietary Gene Traffic Control Platform
Foghorn’s proprietary Gene Traffic Control platform is a powerful tool for understanding and modulating the chromatin regulatory system. The chromatin regulatory system regulates gene expression by directing the movement of molecules that turn genes on and off. Disease dependencies associated with the chromatin regulatory system are estimated to impact over 2.5 million cancer patients across the U.S., Europe and Japan. This system is further implicated in neurological, autoimmune, and other serious diseases. Foghorn is pursuing multiple treatments for breakdowns in this system and is the only company with the ability to study and target the chromatin regulatory system at scale, in context, and in an integrated way.

On December 13, 2021 Novo Nordisk reported that initiated a share repurchase programme in accordance with Article 5 of Regulation No 596/2014 of the European Parliament and Council of 16 April 2014 (MAR) and the Commission Delegated Regulation (EU) 2016/1052 of 8 March 2016 (the "Safe Harbour Rules") (Press release, Novo Nordisk, DEC 13, 2021, View Source [SID1234596934]). This programme is part of the overall share repurchase programme of up to DKK 20 billion to be executed during a 12- month period beginning 3 February 2021.

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Under the programme initiated 5 November 2021, Novo Nordisk will repurchase B shares for an amount up to DKK 3.7 billion in the period from 11 November 2021 to 1 February 2022.

Since the announcement 6 December 2021, the following transactions have been made:

The details for each transaction made under the share repurchase programme are published on novonordisk.com.

With the transactions stated above, Novo Nordisk owns a total of 30,415,276 B shares of DKK 0.20 as treasury shares, corresponding to 1.3% of the share capital. The total amount of A and B shares in the company is 2,310,000,000 including treasury shares.

Novo Nordisk expects to repurchase B shares for an amount up to DKK 20 billion during a 12- month period beginning 3 February 2021. As of 10 December 2021, Novo Nordisk has since 3 February 2021 repurchased a total of 31,661,725 B shares at an average share price of DKK 565.96 per B share equal to a transaction value of DKK 17,919,256,493.

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.