On April 25, 2025, United Therapeutics Corporation (the "Company") entered into a Credit Agreement (the "Credit Agreement") with the lenders referred to therein and Wells Fargo Bank, National Association ("Wells Fargo"), as administrative agent and as a swingline lender (Filing, 8-K, United Therapeutics, APR 25, 2025, View Source [SID1234652250]). The Credit Agreement provides for an unsecured, revolving credit facility of up to $2.5 billion (which facility may, subject to obtaining commitments from existing or new lenders for such increase and subject to other condition, be increased by up to $750 million in the aggregate). The facility matures five years after the closing date of the Credit Agreement, subject to an ability of the lenders thereunder, or certain of the lenders thereunder, to elect to extend the maturity date of their commitments by one year following a request for such extension by the Company in accordance with the terms of the Credit Agreement, up to a maximum of two such extensions.

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As of April 25, 2025, there are no subsidiaries of the Company required to be a guarantor and guarantee the Company’s obligations under the Credit Agreement. From time to time, one or more subsidiaries of the Company may be required to guarantee the Company’s obligations under the Credit Agreement.

At the Company’s option, the loan will bear interest at either an adjusted Term SOFR rate or a fluctuating base rate, in each case, plus an applicable margin that is determined on a quarterly basis based on the Company’s consolidated total leverage ratio (as calculated in accordance with the Credit Agreement).

The proceeds of borrowings under the Credit Agreement are available to refinance certain existing indebtedness of the Company and its subsidiaries and/or for working capital and other general corporate purposes. Upon closing of the Credit Agreement on April 25, 2025, the Company borrowed $200.0 million under the Credit Agreement, and used the funds to repay outstanding indebtedness under the 2022 Credit Agreement discussed under Item 1.02 below.

The Credit Agreement also contains customary affirmative and negative covenants that, among other things, limit the ability of the Company and its subsidiaries to (a) in the case of subsidiaries that are not guarantors of the credit facility, incur indebtedness; (b) grant liens; (c) solely with respect to credit parties under the credit facility, enter into a merger, consolidation or amalgamation; (d) liquidate, wind up or dissolve; or (e) sell all or substantially all of the property, business or assets of the Company and its subsidiaries taken as a whole. In addition, as of the last day of each fiscal quarter, the Company must not permit a consolidated ratio of total indebtedness to EBITDA to be greater than 3.50 to 1.00 (which ratio may, upon consummation of (i) certain qualifying acquisitions, be increased to 4.00 to 1.00 for four fiscal quarters following such acquisition and (ii) certain qualifying inbound licensing transactions, be increased to 4.00 to 1.00 for the first two fiscal quarters following such inbound licensing transaction and 3.75 to 1.00 for the next two fiscal quarters following such inbound licensing transaction) and its consolidated interest coverage ratio to be less than 3.00 to 1.00, in each case calculated in accordance with the Credit Agreement.

The Credit Agreement contains customary events of default, including a change of control. Upon the occurrence and continuation of an event of default, all amounts due under the Credit Agreement and the other loan documents become (in the case of a bankruptcy event), or may become (in the case of all other events of default and at the option of the lenders), immediately due and payable.

The foregoing summary is qualified in its entirety by reference to the copy of the Credit Agreement attached hereto as Exhibit 10.1.

On April 25, 2025 FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, reported new plixorafenib results from the Phase 1/2a clinical trial that demonstrate that circulating tumor DNA (ctDNA) accurately detects BRAF mutations in tumor biopsies and change in variant allele frequency (VAF) of BRAF mutation in ctDNA may be a surrogate marker for monitoring disease (Press release, Fore Biotherapeutics, APR 25, 2025, View Source [SID1234652143]). The data is being presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, taking place April 25-30 in Chicago.

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"Plixorafenib was designed to inhibit mutated oncogenic BRAF V600, without causing paradoxical MAPK pathway activation, and also confers dimer–breaking properties and activity against non-V600 BRAF alterations," said Rona Yaeger, M.D., Gastrointestinal Medical Oncologist and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center. "The data from this clinical study, demonstrating molecular response and durable clinical responses (including when given without a MEK inhibitor) and the absence of emergent MAPK pathway alterations on treatment, further support the unique mechanism of action and the potential to benefit patients with BRAF-altered malignancies."

"These results are important because they show additional evidence of the strong clinical activity of plixorafenib, in both BRAF V600 mutations and BRAF fusions," said Stacie Peacock Shepherd, M.D., Ph.D., Chief Medical Officer of Fore. "In addition, this analysis also demonstrated high concordance of ctDNA BRAF mutations with biopsy tissue and changes in ctDNA corresponded closely to tumor size across tumor types; thus, liquid biopsies with widely used next-generation sequencing methodologies may provide a straightforward approach to identify appropriate patients for plixorafenib treatment, monitor disease status, and response. We are excited to share this data, along with the study design for our ongoing registrational FORTE study in BRAF altered advanced solid tumors, as we develop plixorafenib to help patients with BRAF driven tumors and generate further data to inform treatment."

The ctDNA results are from over 70 plixorafenib-treated patients and were an exploratory endpoint from a previously completed Phase 1/2a study. Utilizing next-generation sequencing (NGS), the plasma ctDNA results demonstrated high concordance with tissue biopsy at baseline across tumor types and mutations. Declines of V600 VAF% were observed in 85% of study participants after one cycle of plixorafenib treatment. Declines of class 2 and class 3 BRAF alterations in ctDNA were also observed. In participants with available paired tumor biopsies, decreases in pERK validated ctDNA results and demonstrated the suppression of the MAPK pathway at clinically relevant exposures. In addition, participants with V600E-mutated advanced solid tumors, early changes in V600E VAF% may predict response to plixorafenib, as responders had larger decreases in VAF% from baseline to cycle 2. In longitudinal samples, changes in ctDNA corresponded to tumor size across tumor types, suggesting that ctDNA may be a surrogate marker for monitoring disease. Compared to acquired mutations driving resistance to early generation BRAF inhibitors, no new mutations in MAPK pathway genes were found following plixorafenib treatment, supporting the dimer–breaker property and novel mechanism of action of plixorafenib from the early generation BRAF inhibitors. In participants without response, co-occurrent drivers at baseline included RAS, MAPK-associated or NF1 mutation, including melanoma patients who all received prior MAPKi therapies.

Also being presented at AACR (Free AACR Whitepaper) 2025 is a trial in progress poster showcasing the global FORTE master protocol with a basket design, including three monotherapy sub-protocols in patients with BRAF fusions, rare BRAF V600-mutated tumors, and BRAF V600 primary recurrent central nervous system tumors. An interim analysis is planned for each of the monotherapy baskets during 2025. A fourth, exploratory sub-protocol will assess preliminary activity of plixorafenib in BRAF V600-mutated select solid tumors. Alongside primary and key secondary endpoints of overall response rate, duration of response, safety, progression-free survival, overall survival, and pharmacokinetics, key exploratory endpoint of each of the four sub-protocols is a longitudinal ctDNA assessment.

Poster Presentation Details:

Title: Circulating tumor DNA analysis of patients with BRAF-mutated advanced unresectable solid tumors treated with plixorafenib (FORE8394/PLX8394) in Phase 1/2a study
Poster Session: Liquid Biopsy Circulating Nucleic Acids 1
Date and Time: Monday, April 28, 2025, 2:00 – 5:00 p.m. CT
Abstract Number: 3248
Presenter: Jessica C. Jang, Fore Biotherapeutics

Title: FORTE: A phase 2 master protocol assessing plixorafenib for BRAF-altered cancers
Poster Session: Late Breaking and Clinical Trials – Phase II and Phase III Clinical Trials in Progress
Date and Time: Tuesday, April 29, 2025, 2:00 – 5:00 p.m. CT
Abstract Number: CT247
Presenter: Macarena I. de la Fuente, M.D., Sylvester Comprehensive Cancer Center

On April 25, 2025 Rgenta Therapeutics, a clinical-stage biotechnology company pioneering the development of a new class of oral small molecules targeting RNA and RNA regulation for oncology and neurological disorders, reported that preclinical data from its lead program, RGT-61159 were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2025 Annual Meeting, which is being held from April 25-30, 2025, in Chicago, IL (Press release, Rgenta Therapeutics, APR 25, 2025, View Source [SID1234652159]). The data demonstrate robust anti-tumor activity of RGT-61159 in several cell-derived xenograft (CDX) models of AML and synergistic benefit when combined with standard of care for AML highlighting the potential of RGT-61159 to treat a broad AML patient population.

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"The data presented at the AACR (Free AACR Whitepaper) meeting highlight the ability of RGT-61159 to reduce levels of both MYB RNA transcripts and correspondingly MYB protein in a dose dependent fashion, which translates to potent killing activity in cells that overexpress MYB," said Travis Wager, Ph.D. co-founder and chief scientific officer. "Importantly, we see robust antitumor activity with RGT-61159 across a range of AML models that carry genetic alterations that are common in patients with AML highlighting its potential to treat a broad AML patient population."

"Using RGT-61159, which specifically acts at the RNA level, we are able to address MYB which has been shown to function as an oncogenic driver in a variety of cancers including AML, colorectal cancer (CRC) and adenoid cystic carcinoma (ACC), and until now, has been a difficult target to drug," said Simon Xi, Ph.D., cofounder and chief executive officer of Rgenta. "Our ongoing Phase 1a/b clinical trial of RGT- 61159 in patients with relapsed or refractory ACC or CRC is advancing well and we look forward to broadening that program and initiating a new Phase 1/2 study of RGT-61159 in adults with AML/high risk myelodysplastic syndromes the second half of 2025."

In a poster titled RGT-61159, Best-in-class Oral Small Molecule Inhibitor of MYB via Selective RNA Splicing Alteration, Synergistic Anti-Tumor Activity When Combined with Standards of Care in Leukemia Disease Models Harboring AML Common Genetic Lesions, data were presented highlighting the close correlation between the elimination of MYB RNA and protein by RGT-61159 and its potent killing activity against leukemia and lymphoma cancer cell lines that over express MYB, demonstrating on-target therapeutic activity of this potent, orally available small molecule. RGT-61159 also inhibited AML cell proliferation and downregulated the expression of master oncogenes controlled by MYB, including MYC, BCL2, FLT3 and IDH1. Data from several CDX models of AML with genetic alterations seen commonly in AML, demonstrated the robust anti-tumor activity of tolerated doses of RGT-61159 and synergistic activity both in vitro and in vivo when administered in combination with agents used in AML standard of care.

About RGT-61159
RGT-61159 is an orally available small molecule designed to specifically modulate splicing of the transcription factor MYB resulting in the inhibition of the oncogenic MYB protein and potential cell death of the cancer cells that overexpress the MYB protein. MYB acts as a master regulator of cell proliferation, self-renewal, and differentiation processes and its aberrant expression has been demonstrated in multiple forms of human cancer including adenoid cystic carcinoma (ACC), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), colorectal cancer (CRC), small cell lung cancer (SCLC) and breast cancer. Rgenta is evaluating RGT-61159 in an ongoing multi-center, open-label Phase 1a/b clinical trial in patients with advanced relapsed or refractory ACC or CRC. The Phase 1a/b study is designed to evaluate safety, tolerability, pharmacokinetics, target engagement and clinical efficacy of RGT-61159 in patients with ACC or CRC. Additional information about the Phase 1a/b clinical trial can be accessed at ClinicalTrials.gov (NCT06462183).

On April 25, 2025 Tempus AI, Inc. (NASDAQ: TEM), a technology company leading the adoption of AI to advance precision medicine and patient care, reported that 18 abstracts, including one oral presentation, have been accepted for presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025, on April 25 – 30 in Chicago (Press release, Tempus, APR 25, 2025, View Source [SID1234652176]). Tempus researchers will showcase scientific and clinical research that highlight the transformative impact of AI on oncology treatment and patient outcomes.

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"Tempus is proud to showcase a comprehensive collection of scientific research this year, highlighting the impact of our multimodal dataset and AI-enabled diagnostic solutions on cancer research," said Kate Sasser, PhD, Chief Scientific Officer at Tempus. "AACR stands as a leading forum for cancer research, and we look forward to presenting our findings alongside our collaborators in Tempus’ home city of Chicago."

Research highlights include:

Oral Presentation: Investigating the clinical landscape and biological impact of SF3B1 hotspot mutations in breast cancer
Date/Time: April 27, 2025; 4:40 PM – 4:45 PM CT
Location: To be announced

Overview: This study examines the implications of SF3B1 hotspot mutations in breast cancer, focusing on genetic profile, survival outcomes, and biological impacts, by analyzing de-identified data from Tempus’ multimodal real-world database consisting of 420 breast cancer patients with SF3B1 mutations. Innovative genome editing in isogenic breast cell lines revealed that SF3B1 mutations negatively impact cell growth and tumor development. The findings support the utility of SF3B1 mutations as potential therapeutic targets and underscore the importance of understanding their role in cancer biology, with ongoing research aimed at uncovering the mechanisms behind hotspot-specific effects.
Poster Presentation: Genetic and clinical landscape of NUTM1 structural variants
Date/Time: April 28, 2025; 2:00 PM – 5:00 PM CT
Location: Section 34
Overview: Within Tempus’ multimodal real-world database, researchers identified 59 patients with a primary diagnosis of NUT carcinoma—an aggressive cancer—81% of whom had a confirmed NUTM1 fusion. Notably, there were 106 additional patients who had a NUTM1 fusion without a corresponding initial NUT carcinoma diagnosis, suggesting a potentially significant underdiagnosis rate. The study found a variety of fusion gene partners, with certain cancer types showing enrichment of specific fusions. With a median overall survival of just over 5 months, the findings suggest that certain cancer types with a high enrichment of NUTM1 fusions may benefit from universal next-generation sequencing to ensure accurate diagnosis and potentially improve outcomes for patients with high-risk cancer types.
Poster Presentation: A longitudinal, circulating tumor molecular response biomarker as a predictor of clinical outcomes in a real-world cohort of patients with advanced solid tumors treated with tyrosine kinase inhibitors
Date/Time: April 29, 2025; 9:00 AM – 12:00 PM CT

Location: Section 45

Overview: In a study analyzing advanced cancer patients, researchers evaluated the prognostic value of changes in circulating tumor DNA tumor fraction (ctDNA TF) during tyrosine kinase inhibitor (TKi) therapy. The study, which consisted of 109 patients from Tempus’ multimodal real-world database, found that molecular responders had significantly longer real-world overall survival (rwOS) than molecular non-responders across various cancer types. The findings suggest that ctDNA TF may serve as a biomarker to predict molecular response to TKi therapy, potentially guiding treatment decisions and improving patient outcomes in a real-world setting.
Collaborator-led Poster Presentation: Enhancing TCR-T with a Fas-based switch receptor boosts T cell engraftment, persistence, and anti-tumor activity in models of hard-to-treat PRAME solid tumor indications
Date/Time: April 29, 2025; 9:00 AM – 12:00 PM CT

Location: Section 39

Overview: T-knife Therapeutics is developing a FAS-based switch receptor (FAS-TNFR) to target PRAME-positive solid tumors, designed to enhance T cell activity and overcome the hostile tumor microenvironment. Utilizing Tempus multi-modal data, T-Knife analyzed a large database of tumor samples to identify the inhibitory ligands most frequently found in PRAME-expressing indications and to understand in depth the pattern of expression of PRAME and inhibitory ligands in different patient populations. These insights provided by Tempus were crucial for T-knife to select the optimal switch receptor from their armoring toolbox and determine appropriate target populations for their upcoming clinical trials (Figures 1A, 2D, and 3A-C present Tempus-driven data and insights).

On April 25, 2025 Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "the Company") reported the financial results for fiscal year 2024 ending March 31, 2025 (FY2024) (Press release, Astellas, APR 25, 2025, View Source [SID1234653926]).

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