On March 18, 2024 bluebird bio, Inc. (NASDAQ: BLUE) ("bluebird bio" or the "Company") reported that it has entered into a $175 million five-year, term loan facility with Hercules Capital, Inc. (NYSE: HTGC) ("Hercules") (Press release, bluebird bio, MAR 18, 2024, View Source [SID1234641229]). The transaction strengthens the Company’s balance sheet as it executes on the commercial launches for its three FDA approved gene therapies – LYFGENIA for sickle cell disease, ZYNTEGLO for beta-thalassemia and SKYSONA for cerebral adrenoleukodystrophy.

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The term loan facility provides for up to $175 million of term loans in aggregate, available in four tranches. Upon closing of the transaction, the first tranche of $75 million was drawn. Under the terms of the agreement, bluebird will be eligible to draw two additional tranches of $25 million each, subject to the achievement of commercial milestones. Based on launch trajectory and current business plans, and assuming three tranches totaling $125 million are executed, the transaction is expected to extend bluebird’s cash runway through the first quarter of 2026. A fourth tranche of up to $50 million may be available at the sole discretion of Hercules. During the first three years of the five-year term, the Company will be responsible for paying only the interest on any amounts borrowed; any outstanding balance as of April 1, 2027 will be amortized over the remaining life of the loan.

"Since establishing bluebird as an independent gene therapy company in 2021, we have been focused on diligently deploying our capital and strengthening our balance sheet to further our mission," said Chris Krawtschuk, chief financial officer, bluebird bio. "This financing underscores the value bluebird offers as a standalone gene therapy leader and meaningfully extends our runway, bolstering our ability to bring transformative treatments to patients and their families."

"Hercules is excited to partner with bluebird as they launch LYFGENIA and bring this transformational therapy to patients living with sickle cell disease," said Michael Dutra, Managing Director and Senior Investment Officer at Hercules Capital. "We are proud to support bluebird’s mission of developing and commercializing treatments for severe genetic diseases. This financing should help support the availability of their novel gene therapies for patients," added John Miotti, Principal at Hercules Capital.

Additional details of the loan agreement will be filed with the Securities and Exchange Commission on a Current Report on Form 8-K.

J. Wood Capital Advisors acted as sole financial advisor to the Company. Latham & Watkins LLP served as legal counsel to bluebird and DLA Piper served as legal counsel to Hercules.

On March 18, 2024 Alpine Immune Sciences, Inc. (NASDAQ: ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for autoimmune and inflammatory diseases, reported full year 2023 financial results and company highlights for the fourth quarter ended December 31, 2023 (Press release, Alpine Immune Sciences, MAR 18, 2024, View Source [SID1234641228]).

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"2023 was a transformational year for Alpine, with initial IgA nephropathy (IgAN) data presented at the American Society of Nephrology Kidney Week 2023 suggesting a best-in-class profile for povetacicept, our next-generation dual BAFF/APRIL inhibitor. With our encouraging data set in IgAN, convenient once monthly dosing regimen, and strong balance sheet, we are rapidly advancing development of povetacicept as a potentially meaningful new therapeutic option for patients living with IgAN, systemic lupus erythematosus (SLE), and multiple other autoantibody-related diseases," said Mitchell H. Gold, MD, Executive Chairman and Chief Executive Officer of Alpine.

Dr. Gold continued, "Looking ahead, Alpine is well positioned for a year of meaningful catalysts, with multiple updates for povetacicept in IgAN and other indications, and the planned initiation of RAINIER, a pivotal phase 3 study of povetacicept in IgAN, and DENALI, a phase 2 study of povetacicept in SLE. In addition to updates on our clinical studies, we look forward to sharing translational data that further supports the best-in-class potential of povetacicept in multiple inflammatory diseases."
Fourth Quarter 2023 Corporate Updates
Povetacicept (ALPN-303)
•First clinical data in IgAN demonstrate that povetacicept 80 mg administered once every four-weeks (Q4W) reduced proteinuria (as assessed by urine protein to creatinine ratio, UPCR) by greater than 50% and was associated with stable renal function (as assessed by estimated glomerular filtration rate, eGFR) at six months. In addition, povetacicept was well tolerated during subcutaneous administration, with no instances of IgG < 3 g/L, and no severe infections (2023 American Society of Nephrology Kidney Week).
•In a model of murine experimental autoimmune myasthenia gravis, povetacicept improved disease activity, with clinical scores superior to treatment with either the FcRn inhibitor efgartigimod or an anti-CD20 depleting antibody (2023 American Association of Neuromuscular & Electrodiagnostic Medicine Annual Meeting).
•New translational data from povetacicept in systemic lupus erythematosus demonstrate that povetacicept, as compared to single BAFF or APRIL pathway inhibitors, more potently downregulates genes associated with activation in B cells and significantly reduces multiple disease parameters in a mouse model of lupus, more effectively than WT TACI-Fc or conventional B cell depletion (2023 American College of Rheumatology Convergence).
•Throughout 2023, the Company presented multiple oral and poster presentations on povetacicept at scientific conferences.
Corporate Updates
•The Company plans to present additional data on povetacicept in IgA nephropathy, including follow up data from the 80 mg Q4W and initial data from the IgAN 240 mg Q4W dose cohorts, during a Late Breaking Abstract session at the World Congress of Nephrology 2024 on Monday, April 15th at 4:45 PM ET.
•The Company plans to present new preclinical data on povetacicept, demonstrating its greater distribution to disease-related end organs compared with WT TACI-Ig, at the 14th European Lupus Meeting. These findings correlate with povetacicept’s improved efficacy in multiple preclinical disease models.

•The Company intends to initiate RAINIER, a pivotal phase 3 study of povetacicept in IgA nephropathy and DENALI, a phase 2 study of povetacicept in systemic lupus erythematosus in the second half of 2024, pending regulatory agreement.
•The Company plans to share initial data from RUBY-4 in autoimmune cytopenias in the first half of 2024 at a relevant scientific congress.
•The Company amended its option and license agreement on acazicolcept with AbbVie, stopping enrollment in the phase 2 study in systemic lupus erythematosus (Synergy), and facilitating early assessment of data.
•The Company ended the year with $368.2 million in cash and investments as of December 31, 2023, which the Company anticipates should be sufficient to fund its planned operations into 2026.
2023 Financial Results
Cash Position and Runway: As of December 31, 2023, Alpine’s cash and investments totaled $368.2 million compared to $273.4 million as of December 31, 2022. The Company anticipates its current cash and investments are sufficient to fund planned operations into 2026.
Collaboration Revenue: For the year ended December 31, 2023, collaboration revenue was $58.9 million compared to $30.1 million for the same period in 2022. The increase in collaboration revenue relates primarily to a $24.9 million increase in AbbVie revenue, of which $20.4 million relates to a cumulative catch-up adjustment resulting from the completion of enrollment in Synergy per the amendment with AbbVie, and a $4.5 million increase in Amgen revenue, driven primarily by the expiration of Amgen’s option to select a third Research Program. These increases were partially offset by a $0.6 million decrease in Adaptimmune revenue as we completed our final deliverables under the agreement in June 2023.
Research and Development Expense: For the year ended December 31, 2023, research and development expense, inclusive of non-cash expenses, were $80.9 million compared to $70.2 million for the same period in 2022. The increase of $10.7 million was driven by an $8.2 million increase in povetacicept costs, primarily related to higher clinical trial costs, process development, and manufacturing, a $1.3 million increase in acazicolcept costs, due primarily to process development and manufacturing costs, and a $7.7 million increase in personnel costs.
General and Administrative Expenses: For the year ended December 31, 2023, general and administrative expenses, inclusive of non-cash expenses, were $22.2 million compared to $18.0 million for the same period in 2022. The increase of $4.3 million was primarily attributable to increases in personnel costs and professional services.
Net Loss: Net loss for the year ended December 31, 2023, was $32.2 million compared to $57.8 million for the same period in 2022.

On March 17, 2024 Infinitopes reported the company collaborating with the leading mass spectrometry technology company Bruker to develop a world leading immunopeptidomic based antigen discovery platform (Press release, Infinitopes, MAR 17, 2024, View Source [SID1234648454]). In a recent poster, Infinitopes showcase their state-of-the-art sample preparation capabilities in synergy with the latest high-sensitivity mass spectrometry technology from Bruker. Building on Inifinitopes’ proprietary antigen purification strategy Bruker optimise the performance of their new timsTOF Ultra mass spectrometer providing a highly sensitive platform for antigen discovery. Bruker fine-tuned their instrument parameters to enable identification of thousands of peptide antigens from just 1 million melanoma cells. This development paves the way for cancer antigen discovery directly from patient biopsies, overcoming a critical unmet need for target discovery in the field of immuno-oncology. Dr. Rob Parker, Lead Scientist Discovery Immunomics of Infinitopes, commented:

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"We are excited to see our R&D capabilities drastically expanded through our unique collaboration with Bruker. Bruker’s commitment toward ultra-sensitive discovery immunopeptidomics will accelerate Infinitopes growth and provide unique benefit to our existing and future and partners, with our enhanced R&D output positioning Infinitopes as a leading force in cancer antigen discovery".

On March 17, 2024 Aadi Bioscience, Inc. (NASDAQ: AADI), a commercial-stage precision oncology company focused on developing and commercializing therapies for cancers with alterations in the mTOR pathway, reported patients in the AMPECT trial whose malignant perivascular epithelioid cell tumor (PEComa) had gynecologic origins experienced efficacy and safety consistent with the overall study population (Press release, Aadi Bioscience, MAR 17, 2024, View Source [SID1234641218]). The AMPECT trial formed the basis for the FDA approval of the company’s nab-sirolimus, FYARRO, for advanced malignant PEComa regardless of mutational status. This new subgroup analysis will be presented during an oral plenary at the Society of Gynecologic Oncology (SGO) Annual Meeting in San Diego, CA on March 17, 2024.

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"In AMPECT, advanced malignant PEComa tumors originating from uterine, ovarian, pelvic or retroperitoneal sites had a response to nab-sirolimus consistent with that of the full study population, including overall response rate, onset and duration of tumor response," said Thomas J. Herzog, MD, Deputy Director, University of Cincinnati Cancer Center. "Malignant PEComa tumors of gynecologic or retroperitoneal origin accounted for more than half of the evaluable patients enrolled, offering important insights into this population and reinforcing the need for awareness and understanding of this rare but aggressive cancer among the gynecologic oncologist community."

Oral plenary presentation details and study highlights include:

Title: "Response to Treatment with nab-Sirolimus in Patients with Perivascular Epithelioid Cell Sarcoma (PEComa) of Gynecologic or Retroperitoneal Origin: Subgroup Analysis from AMPECT"
Presenting Author: Thomas J. Herzog, MD
Session Title: Focused Plenary V: Rare Care: Updates in Uncommon Cancers
Location: Ballroom 20CD
Date/Time: Sunday, March 17, 2024 – 1:45 PM to 2:45 PM

Of the 31 patients enrolled in AMPECT, 16 had malignant PEComas originating from uterine, ovarian, pelvic or retroperitoneal sites
Overall response rate to nab-sirolimus for the subgroup was 37.5% (6/16), consistent with the overall AMPECT population
Subgroup responses were rapid and durable, with 1.4 months median time to response and 36.2 months median duration of response
Safety profile of the subgroup was manageable and consistent with the overall AMPECT population
Additional data presented at SGO further highlight nab-sirolimus as a potential approach for mTOR-driven gynecologic cancers. These presentations include a real-world study characterizing TSC1 and TSC2 inactivating alterations in patients with advanced gynecologic cancers; trial-in-progress updates for the ongoing, tumor agnostic, registration-intended PRECISION1 trial; and a Phase 2 study of nab-sirolimus in combination with letrozole for advanced or recurrent endometrioid-type endometrial cancer (EEC).

"Overactivation of the mTOR pathway has been implicated in gynecological cancers," said Loretta Itri, MD, Chief Medical Officer at Aadi. "nab-Sirolimus is a nanoparticle albumin-bound (nab) mTOR inhibitor under investigation in TSC1- and TSC2-mutated tumors as well as other mTOR-driven tumors. We are diligently continuing to explore the potential of nab-sirolimus for this patient community in need of new therapies."

Poster presentation details and highlights include:

Title: "Analysis of inactivating TSC1 and TSC2 alterations in a real-world patient population with advanced gynecological cancers in the Foundation Medicine genomic database"
Presenting Author: Lauren E. Dockery, MD, MS
Session Title: Poster Session 1
Location: Exhibit Hall (Hall GH)
Poster Number: 1176
Date/Time: Sunday, March 17, 2024 – 1:15 PM to 2:45 PM

Registration-directed PRECISION1 study is enrolling patients with solid tumors harboring TSC1 and/or TSC2 inactivating alterations
In a large real-world database of patients with advanced cancer, 1,342 (2.4%) of the 54,911 patients with gynecological cancers harbored at least one inactivating alteration in TSC1 or TSC2
TSC1 and/or TSC2 inactivating alterations were present in 3.6% of endometrial cancers, 2.0% of ovarian cancers and 1.5% of cervical cancers
Title: "nab-Sirolimus Plus Letrozole in Advanced or Recurrent Endometrioid Endometrial Cancer: A Phase 2, Open-Label, Single-Arm, Prospective, Multi-Center Study"
Presenting Author: Lauren E. Dockery, MD, MS
Session Title: Poster Session 2
Location: Exhibit Hall (Hall GH)
Poster Number: 2127
Date/Time: Monday, March 18, 2024 – 11:45 AM to 12:45 PM

This ongoing phase 2, open-label, single-arm, multicenter study is evaluating nab-sirolimus in combination with letrozole for the treatment of patients with advanced or recurrent EEC
Prior clinical studies with mTOR inhibitors and endocrine therapy have yielded promising results in EEC
Title: "nab-Sirolimus for Malignant Solid Tumors Harboring Pathogenic Inactivating Alterations in TSC1 and TSC2 in a Phase 2, Multicenter, Open-Label Tumor-Agnostic Trial: PRECISION 1"
Presenting Author: Debra L. Richardson, MD
Session Title: Poster Session 2
Location: Exhibit Hall (Hall GH)
Poster Number: 2126
Date/Time: Monday, March 18, 2024 – 11:45 AM to 12:45 PM

TSC1 and/or TSC2 inactivating alterations have been observed in patients with gynecological cancers with a frequency of up to 5.0% in endometrial cancer, 2.2% in ovarian cancer and 1.5% in cervical cancer

On March 16, 2024 Labcorp (NYSE: LH), a global leader of innovative and comprehensive laboratory services, reported the results from two studies at the 2024 SGO Annual Meeting on Women’s Cancer (Press release, LabCorp, MAR 16, 2024, View Source [SID1234641217]). The studies demonstrate the value of biomarker testing in closing testing gaps and guiding targeted therapies for patients with epithelial ovarian cancer (EOC).

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With the rapid rate at which cancer biomarkers are being identified and new targeted therapies become available, comprehensive testing approaches are becoming even more critical as corresponding treatment guidelines evolve. Labcorp researchers conducted two studies to generate further evidence of the value of comprehensive genomic profiling to drive guideline-compliant testing that enables increased patient access to targeted therapies for improved outcomes.

Combination of BRCA testing with HRD Testing Needed to Inform Benefit of PARP Inhibitor Therapy
In one such study, conducted in partnership with Illumina, a leader in next-generation sequencing technologies, 1,093 patients diagnosed with EOC were evaluated to assess real-world clinical practice patterns for ordering BRCA and Homologous Recombination Deficiency (HRD) testing. When combined, the results of BRCA and HRD testing can determine which patients are most likely to benefit from treatment with poly-ADP ribose polymerase (PARP) inhibitors. For patients who test negative for BRCA1 and BRCA2, testing for HRD can help determine the degree of benefit from a PARP inhibitor.1

PARP inhibitors have transformed the standard of care, especially for women with germline or deleterious somatic mutations in BRCA1 or BRCA2.2 However, at least 40% of patients do not respond to PARP inhibitors, and if treated with PARP inhibitors, may experience longer treatment durations and potentially serious side effects,3 as well as increased overall costs. Treatment guidelines for PARP inhibitors emphasize the importance of diagnostic testing and individualized patient assessments.1

Within the study population, 84% of patients underwent evaluation for BRCA mutations or HRD testing; however, less than 50% of patients underwent HRD testing. Researchers then evaluated PARP inhibitor utilization and evaluated the time to treatment discontinuation (TTD) among patients with germline/somatic BRCA mutations, tumors with HRD, and those that were homologous recombination proficient (HRP). Patients with BRCA mutations4 or HRD[5] tend to do well on PARP inhibitors, so testing for each can help identify patients who may be most appropriate for PARP inhibitor maintenance.

Consistent with prior prospective clinical trials, researchers reported that the median TTD of first-line PARP inhibitor maintenance therapy was the longest for patients with germline or somatic BRCA mutations or HRD tumors. Among the study groups, 77% of the patients with a germline BRCA mutation, 65.1% of patients with a somatic BRCA mutation, and 42.7% of those with HRD and BRCA wild-type continued PARP inhibitor therapy at 18 months, compared to 29% of patients in the HRP/BRCA wild-type group.

"This research emphasizes the power of comprehensive biomarker testing in advancing the treatment of ovarian cancer. By closing critical diagnostic gaps through precision testing, we are not just improving patient care but also propelling science and healthcare forward," said Shakti Ramkissoon, M.D., Ph.D., vice president, head of oncology at Labcorp. "These findings affirm that access to advanced technology, in collaboration with partners with a shared commitment to the most current care models, is the cornerstone of developing innovative diagnostic tools. These new assays can offer more patients with access to effective, biomarker-guided therapies, ultimately leading to better prognoses and opening doors to new possibilities in gynecologic oncology."

The studies are among the growing body of evidence highlighting the value of biomarker testing for EOC, specifically in real-world settings. High-grade serous epithelial ovarian cancer (HGSOC) is the deadliest of all gynecological cancers, with 70% of patients having a cancer recurrence within two to three years and almost 50% dying from the disease after five years of diagnosis.

"This research highlights the need for additional healthcare provider education on comprehensive genomic approaches and the clinical utility of guideline-driven testing to improve patient care in ovarian cancer," said Pratheesh Sathyan, head of oncology for Americas region in medical affairs at Illumina.

High Folate-receptor Alpha (FOLR1/FRα) Expression Seen in Primary EOC Tumors
In another study, Labcorp researchers evaluated real-world testing practice patterns for Folate-receptor Alpha (FRα) on primary tumors versus metastatic tumors to guide targeted therapy for patients with platinum-resistant EOC. FRα is an actionable biomarker in ovarian cancer and is overexpressed in up to 90% of EOC patients.6 Patients with platinum-resistant EOC whose tumors highly express FRα may be eligible for treatment with Mirvetuximab soravtansine (MIRV), the only currently available targeted therapy that improves overall survival for patients with platinum-resistant EOC.

Researchers performed a retrospective analysis of tumor samples from 432 patients with EOC undergoing standard-of-care testing via the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay (developed by Roche). Of the tumor samples analyzed, 291 were from metastatic tumors, and 133 were from primary tumors. Researchers reported that 36.2% of patients had tumors that highly expressed FRα. In a critical study finding, tumor samples from primary sites were associated with higher rates of FRα positivity than those from metastatic sites.

"This study demonstrates not only the important role that FOLR1 testing can play in developing treatment strategies, but how it can help guide clinicians on the appropriate tumor sites to test to acquire the best information for that treatment guidance," said Ramkissoon.