On May 2, 2023 2seventy bio, Inc. (Nasdaq: TSVT), a leading immuno-oncology cell therapy company, reported the presentation of five abstracts, including one late-breaking oral presentation, at this year’s American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) Annual Meeting, taking place in Los Angeles, California from May 16-20, 2023 (Press release, 2seventy bio, MAY 2, 2023, View Source [SID1234630820]).

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The late-breaking abstract featuring early findings from the ongoing Phase 1 PLAT-08 trial in collaboration with Seattle Children’s Therapeutics, evaluating SC-DARIC33 in pediatric and young patients with relapsed/refractory AML, will be presented on Friday, May 19. SC-DARIC33 is an investigational CD33-targeted chimeric antigen receptor (CAR) T cell therapy that utilizes 2seventy bio’s proprietary Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T cell platform, a regulatable CAR T cell technology. A second oral presentation will feature preclinical data on enhanced anti-AML potency of DARIC33 by coupling it with iSynPro-IL-15, an encoded IL-15 expression module driven by an antigen-regulated synthetic promoter that will be presented on Thursday, May 18.

"At 2seventy bio, we are focused on utilizing our advanced scientific toolkit to develop innovative cell therapies with the goal of achieving tumor control and elimination across hematologic cancers and solid tumors," said Philip Gregory, D.Phil., chief scientific officer, 2seventy bio. "Our data at ASGCT (Free ASGCT Whitepaper) demonstrate continued progress in deepening our next-generation cell therapy product engine and pipeline, particularly early findings for DARIC33 that continue to reinforce its potential as a new T cell therapy approach in AML, CBLB gene edited CAR T cell therapy advancements with bbT369, and our potency enhanced MAGE-A4 TCR program in solid tumors. We are also revealing, for the first time, our novel receptor architecture called RESET, which is designed to blend both the sensitivity of TCRs with the ease of tumor antigen targeting through CARs, all within a drug-regulated CAR T platform."

Key data presentations include:

Details of 2seventy bio Presentations at ASGCT (Free ASGCT Whitepaper) Annual Meeting
Late-breaking Oral Presentation [#3092]: First in human studies show activation of SC-DARIC33, a rapamycin-regulated anti-CD33 CAR T cell therapy, in patients with AML
Presenting Author: Jacob Appelbaum, M.D., Ph.D., Hematologist, Fred Hutch Cancer Center & Acting Instructor, Hematology, Univ. of Washington
Date/Time: Friday, May 19, 2023, 11:30 – 11:45am PT

Oral Presentation [#148]: Enhanced anti-AML potency of DARIC33 by iSynPro-IL-15*: an IL-15 expression module driven by a tightly regulated synthetic promoter activated by antigen receptor signaling
Presenting Author: Jacob Appelbaum, M.D., Ph.D., Hematologist, Fred Hutch Cancer Center & Acting Instructor, Hematology, Univ. of Washington
Date/Time: Thursday, May 18, 2023, 2:30 – 2:45pm PT

Poster Presentation [#585]: bbT369, a clinical-stage dual-targeted and CBLB gene edited autologous CAR T product for non-Hodgkin Lymphoma, shows edit driven enhanced activity in preclinical in vitro and in vivo models
Presenting Author: Michael Certo, 2seventy bio
Date/Time: Wednesday, May 17, 2023, 12:00 – 2:00pm PT

Poster Presentation [#612]: Novel TGFb switch receptor drives robust MAGE-A4 TCR anti-tumor activity with a favorable safety profile
Presenting Author: Esteban Carrizosa, 2seventy bio
Date/Time: Wednesday, May 17, 2023, 12:00 – 2:00pm PT

Poster Presentation [#608]: RESET: a novel TCR coupled antigen receptor displaying superior targeting sensitivity and pharmacologically controlled anti-tumor activity
Presenting Author: Jardin Leleux, 2seventy bio
Date/Time: Wednesday, May 17, 2023, 12:00 – 2:00pm PT

About SC-DARIC33

2seventy bio is collaborating with Seattle Children’s Therapeutics to rapidly accelerate development of potential new therapies for patients with acute myeloid leukemia (AML). This research collaboration is investigating potential solutions to two challenges in treating AML: disease heterogeneity and toxicity due to shared expression of targets between tumor and normal tissue.

SC-DARIC33 is an investigational, pharmacologically controlled CD33-targeted autologous T cell product that utilizes 2seventy bio’s proprietary Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T cell platform, a regulatable CAR T cell technology. DARIC T cells are intended to be switched from "OFF" to "ON" in the presence of rapamycin, such that while in the "ON" state the T cell is poised to be activated upon encounter with its target antigen.

PLAT-08, the Phase 1 study of SC-DARIC33 in relapsed/refractory pediatric AML, led by Seattle Children’s Therapeutics, couples 2seventy bio’s DARIC T cell platform with Seattle Children’s world-class bench-to-bedside expertise in oncology cell therapies. This study is a first-in-human investigation of the DARIC T cell platform and is open for enrollment at Seattle Children’s. For more information visit: clinicaltrials.gov using identifier NCT05105152.

SC-DARIC33 is not approved for any indication in any geography.

About bbT369

bbT369 is an investigational dual-targeting CAR T cell therapy with a gene edit for patients with relapsed and/or refractory B-NHL.

bbT369 has three layers of innovation, purposely designed to address the potential mechanisms of anti-CD19 CAR T cell therapy failure: dual targeting (CD79a/CD20), split co-stimulation signaling technology, and a gene edit to remove the function of CBLB.

In December 2021, the FDA cleared the Investigational New Drug (IND) application for bbT369. The clinical development program for bbT369 includes the Phase 1/2 CRC-403 study (NCT05169489). Safety and potential efficacy of bbT369 in patients with specific subtypes of relapsed and/or refractory B-NHL will be assessed, including patients who relapsed after CD19 CAR T cell therapy as well as patients who are CAR-naïve.

bbT369 is not approved for any indication in any geography.

About the MAGE-A4 Program

MAGE-A4 is a member of the MAGE family of cancer-testis antigens expressed in a number of solid tumor types. Our program employs a highly potent TCR discovered in our MediGene collaboration that recognizes HLA-presented MAGE-A4 peptides and further enhances the potency of these re-directed T cells using our CTBR12 TGF-beta "flip" receptor technology — which converts the immunosuppressive effects of TGF-beta into an activation signal for the T cells. Regeneron and 2seventy bio are co-developing the program under their collaboration entered into in 2018.

On May 2, 2023 Medigene AG (Medigene, FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported that it has partnered with Helmholtz Munich to acquire the exclusive, worldwide rights to the CD40L-CD28 costimulatory switch receptor adding to the portfolio of technologies within Medigene’s end-to-end platform (Press release, MediGene, MAY 2, 2023, View Source [SID1234630792]).

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"The CD40L-CD28 costimulatory switch receptor expands our suite of "Product Enhancement" technologies within our platform and joins our existing PD1-41BB costimulatory switch receptor as a technology that has the potential to further enhance the anti-tumor activity of our TCR-T cells and improve their ability to overcome the immunosuppressive solid tumor microenvironment." said Prof. Dolores Schendel, Chief Scientific Officer.

"We believe that the beneficial effects of the CD40L-CD28 costimulatory switch receptor may be separate or even complementary to those of our existing technologies. We look forward to generating and sharing the data for this in due course.

On May 1, 2023 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported the United States Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to ERAS-801 for the treatment of adult patients with glioblastoma (GBM) with epidermal growth factor receptor (EGFR) gene alterations (Press release, Erasca, MAY 1, 2023, View Source [SID1234639356]). ERAS-801 is an orally bioavailable, small molecule EGFR inhibitor that exhibited substantial central nervous system (CNS) penetration in animal studies.

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FTD is designed to help drugs reach patients faster by facilitating the development and expediting the review of drugs with the potential to fill an unmet medical need by treating a serious or life-threatening condition. Programs that receive FTD benefit from early and frequent interactions with the FDA during the clinical development process and, if relevant criteria are met, the FDA may consider reviewing portions of a marketing application before the sponsor submits the complete application.

"Receiving FTD from the FDA underscores the serious unmet medical need in patients with GBM and reinforces the promise that ERAS-801 may offer as a differentiated treatment option," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "GBM is an aggressive malignancy with high rates of relapse and a five-year survival rate below 10%. While over half of GBM cases are driven by EGFR alterations and/or amplifications, there are no approved EGFR inhibitors for the treatment of GBM due to the lack of sufficient brain penetration to treat primary brain tumors as well as lack of activity against EGFR alterations observed in GBM, such as EGFRvIII. To help overcome these limitations, ERAS-801 was specifically designed to have high CNS penetration and broad activity against both oncogenic and wildtype EGFR. We look forward to working closely with the FDA to expedite clinical development of ERAS-801 for these patients and anticipate reporting initial monotherapy data from the Phase 1 THUNDERBBOLT-1 trial in recurrent GBM (rGBM) in the second half of 2023."

ERAS-801 was designed and developed by a renowned team of cancer researchers—Michael Jung, Ph.D., Timothy Cloughesy, M.D., and David Nathanson, Ph.D.

About ERAS-801
ERAS-801 is a highly potent, selective, reversible, and orally available small molecule EGFR inhibitor with significantly enhanced CNS penetration. In animal models, ERAS-801 had a brain-to-plasma partition coefficient, Kp, of 3.7 and a corresponding unbound partition coefficient, Kp,uu, of 1.2, which was up to four times higher than approved EGFR inhibitors, suggesting that approximately 100% of the free drug in plasma is able to cross the blood-brain barrier (BBB). At clinically relevant exposures across 30 patient-derived GBM models that are intended to represent the heterogeneity of GBM, ERAS-801 demonstrated a survival benefit in 13 out of 14 (93%) EGFR mutant and/or amplified models and had statistically significantly higher brain penetrance and prolonged survival compared to approved EGFR tyrosine kinase inhibitors, including osimertinib, lapatinib, and erlotinib. ERAS-801 is currently being evaluated as a monotherapy in THUNDERBBOLT-1, an ongoing Phase 1 trial in patients with rGBM.

About THUNDERBBOLT-1
THUNDERBBOLT-1 is evaluating the safety, tolerability, and preliminary efficacy of ERAS-801 as a monotherapy in patients with rGBM. The dose escalation portion will determine the recommended dose, which will then be used during the dose expansion portion to further evaluate the efficacy and safety of ERAS-801. Future sub-studies of THUNDERBBOLT-1 may potentially explore ERAS-801 in combination with other agents and in broader patient types. Initial Phase 1 data from THUNDERBBOLT-1 are anticipated in the second half of 2023.

On May 1, 2023 Apple Tree Partners (ATP), a leader in life sciences venture capital, reported the launch of Initial Therapeutics, a biotechnology company created to make medicines that block notoriously difficult-to-drug protein targets with a new mode of action: selective termination of protein synthesis (STOPS) (Press release, Initial Therapeutics, MAY 1, 2023, View Source [SID1234632243]). Initial developed its proprietary STOPS platform to discover new therapeutics based on the recently demonstrated scientific premise that translation of a specific protein can be selectively interrupted at the moment in which its linear sequence is first produced in the exit tunnel of the ribosome.

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Initial was created by ATP with $75 million in Series A funding and co-founders Jamie H.D. Cate, Ph.D., Professor of Chemistry, Biochemistry, Biophysics, and Structural Biology at the University of California (UC) Berkeley; Brian Paegel, Ph.D., Professor of Pharmaceutical Sciences, Chemistry, and Biomedical Engineering at UC Irvine; and Kevan Shokat, Ph.D., Professor of Cellular and Molecular Pharmacology at UC San Francisco (UCSF) and Chemistry at UC Berkeley.

"Initial grew out of conversations between Jamie, Kevan, Brian, and me about work we had each been doing in these intersecting areas of protein synthesis kinetics, ribosome profiling, rapid chemistry, etc., and how we could collaborate to build something new to expand on the idea of selectively modulating protein translation, which we all saw as potentially transformative," said Spiros Liras, Ph.D., founding CEO of Initial Therapeutics and a venture partner at ATP. "The resulting combination of unmatched expertise and technologies brought by our founders grants Initial unique abilities to prosecute this new approach, and we are very excited about its promise to fight certain cancers and other serious illnesses."

Groundbreaking structural biology work from the Cate Lab has revealed how protein synthesis can be affected selectively in any phase of translation by interactions of small molecules with a complex that includes the ribosome and the nascent peptide chain of a target protein. Within Initial, this work has been industrialized with custom ribosomal assays scaled to ultra-large library screening using miniaturized microfluidics technology from the Paegel Lab.

"We started Initial Therapeutics to go after therapeutically important proteins that no one has been able to target successfully. I’m thrilled to see the amazing progress the Initial team has made on that front, with profound implications for the treatment of life-threatening diseases," Dr. Cate said.

Initial designs small molecule therapeutics to modulate the cellular synthesis of known, wellvalidated, high-value targets. Unlike interventions that work with mature proteins, such as targeted protein stabilization and protein degradation, Initial’s strategy circumvents the need to accommodate the cellular activity of the fully formed protein or to structurally solve for docking. Moreover, preventing protein synthesis may stave off aggregate formations and other diseaserelated molecular pathologies that are difficult to reverse, and in that regard Initial’s approach may offer therapeutic benefit. "Where other drug modalities involve recognition of the three-dimensional shape of the protein, Initial’s modality recognizes the primary linear sequence. I see that as a game-changer," said Dr. Shokat. "Some proteins don’t have ligandable pockets, but a linear sequence, that’s in everything. Initial’s bespoke platform allows us to go into the ribosome, the machinery of mRNA translation, in a selective way that has never before been technically possible." "When the therapeutic approach doesn’t concern mature proteins, the rules of drug discovery change and the universe of what is ‘druggable’ expands significantly," Dr. Paegel said.

On May 1, 2023, Century Therapeutics, Inc. (the "Company") reported a voluntary prepayment of all outstanding principal, accrued and unpaid interest, fees, costs and expenses, equal to $10.6 million in the aggregate (the "Payoff Amount"), under the Loan and Security Agreement (as amended, the "Loan Agreement"), dated as of September 14, 2020 between the Company and Hercules Capital, Inc. ("Hercules") (Filing, 8-K, Century Therapeutics, MAY 1, 2023, View Source [SID1234631085]). The Payoff Amount includes a prepayment charge of $100,000 equal to 1.0% of the outstanding principal, and an exit fee of $395,000. Upon receipt by Hercules of the Payoff Amount on May 1, 2023, all obligations, covenants, debts and liabilities of the Company under the Loan Agreement were satisfied and discharged in full, and the Loan Agreement and all other documents entered into in connection with the Loan Agreement were terminated.

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The Loan Agreement provided for a term loan with aggregate maximum borrowings of up to $30.0 million (the "Term Loan"). Under the Loan Agreement, the Company borrowed $10.0 million. The Term Loan bore interest at a variable annual rate equal to the greater of either (i) the sum of (a) 6.30% plus (b) the prime rate (as reported in the Wall Street Journal on the last business day of the month that immediately precedes the month in which the interest will accrue) or (ii) 9.55%. Interest-only payments on the borrowings under the Loan Agreement were due through May 1, 2023. After the interest-only payment period, borrowings under the Loan Agreement were due in equal monthly payments of principal and accrued interest until the maturity date of April 1, 2024.