On March 11, 2024 Mustang Bio, Inc. ("Mustang" or the "Company") (Nasdaq: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for difficult-to-treat cancers and rare genetic diseases, reported financial results and recent corporate highlights for the full-year ended December 31, 2023 (Press release, Mustang Bio, MAR 11, 2024, View Source [SID1234641016]).

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"2023 was an exciting year for Mustang filled with many highlights, including compelling interim data from Mustang’s multicenter Phase 1/2 clinical trial of MB-106 presented at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, which builds upon the stellar data presented earlier in the year from the MB-106 Phase 1/2 single institution clinical trial conducted at Fred Hutch. In both the multicenter Phase 1/2 trial and the single institution Phase 1/2 trial, the observed deepening and durability of responses are very gratifying. We believe the CAR T-cell persistence of up to 3 years in the original single institution trial at Fred Hutch and up to 1 year in the current Mustang-sponsored multicenter trial are important potential contributors to the deepening and durability of responses," said Manuel Litchman, M.D., President and Chief Executive Officer of Mustang. "We plan to move ahead with the first ever registrational CAR-T trial focused on relapsed or refractory Waldenstrom macroglobulinemia ("WM"), a subtype of indolent lymphoma with no FDA-approved therapy or standard of care in the third-line setting and no FDA-approved CAR-T for any line of therapy. We expect to treat the first patient in the second half of 2024, which could enable topline results in the second half of 2026. In order to facilitate interactions with the FDA throughout this process, we anticipate requesting Regenerative Medicine Advanced Therapy (‘RMAT’) designation for indolent lymphoma – which includes WM – from the FDA in the first half of 2024. Advantages of the RMAT designation include all the benefits of the Fast Track and Breakthrough Therapy Designation programs, including early interactions with FDA."

Dr. Litchman continued, "Additionally, we are evaluating the potential to initiate a first-ever Phase 1 multicenter clinical trial at City of Hope ("COH") and the University of Alabama at Birmingham ("UAB") to assess the safety, tolerability and efficacy of MB-109, a novel combination of MB-101 (IL13Rα2-targeted CAR T-cell therapy) and MB-108 (HSV-1 oncolytic virus) in adult patients with recurrent GBM and high-grade astrocytomas that express IL13Rα2 on the surface of the tumor cells. The combination leverages MB-108 to reshape the tumor microenvironment ("TME") and make cold tumors "hot," which could potentially enhance the clinical effect of MB-101 CAR T-cell therapy. As per a recent publication in Nature Medicine, two patients treated solely with MB-101 who had high levels of intratumoral CD3+ T-cells pre-therapy (i.e., "hot" tumors) achieved complete responses lasting 7.5 and 66+ months, respectively. Also noteworthy is our continued work with the Mayo Clinic to progress our exclusively licensed novel in vivo CAR-T technology platform, for which we anticipate an upcoming publication of proof-of-concept research in a murine tumor model in 2024."

Financial Results:

· As of December 31, 2023, Mustang’s cash and cash equivalents and restricted cash totaled $7.0 million, compared to $76.7 million as of December 31, 2022, a decrease of $69.7 million year-over-year. In 2023 Mustang made a $30.4 million payment to terminate existing debt. Mustang continues to evaluate opportunities to reduce its cash utilization while focusing on its top priority development programs.

· Research and development expenses were $40.5 million for the year ended December 31, 2023, compared to $62.5 million for 2022. Non-cash, stock-based compensation expenses included in research and development were $0.1 million for the year ended December 31, 2023, compared to $1.6 million for 2022.

· Mustang recorded a gain on the sale of property and equipment of $1.5 million, in connection with the sale of assets to uBriGene.

· General and administrative expenses were $9.7 million for the year ended December 31, 2023, compared to $12.2 million for 2022. Non-cash, stock-based compensation expenses included in general and administrative expenses were $0.4 million for the year ended December 31, 2023, compared to $0.7 million for 2022.

· Net loss attributable to common stockholders was $51.6 million, or $6.00 per share, for the year ended December 31, 2023, compared to a net loss attributable to common stockholders of $77.5 million, or $10.09 per share, for 2022.

2023 and Recent Corporate Highlights:

General Corporate:

· In July 2023, Mustang announced that it amended its previously announced asset purchase agreement with uBriGene (Boston) Biosciences Inc. ("uBriGene") and closed the transaction. Per the terms of the amended asset purchase agreement, at closing, uBriGene acquired all of Mustang’s assets primarily relating to the manufacturing and production of cell and gene therapies at Mustang’s manufacturing facility in Worcester, Massachusetts, for upfront consideration of $6 million in cash. An additional $5 million contingent payment will be payable to Mustang upon (i) Mustang raising $10 million in gross proceeds from equity raises following the closing of the transaction and (ii) completion of the assignment of Mustang’s lease to uBriGene, which remains subject to landlord’s approval, within two years of the closing. Unless and until the lease is transferred to uBriGene, Mustang will retain its facility lease and facility personnel and will continue to occupy the leasehold premises and manufacture there its lead product candidate, MB-106. Clearance for assignment of Mustang’s lease to uBriGene remains under review by the U.S. Committee on Foreign Investment in the United States ("CFIUS"), and Mustang and uBriGene are continuing discussions with CFIUS regarding the nature and extent of national security risk posed by the assignment.

· In October 2023, Mustang completed a registered direct offering priced at-the-market for approximately $4.4 million in gross proceeds.

MB-106 (CD20-targeted CAR T-cell therapy):

· Mustang’s lead clinical candidate is MB-106, a CD20-targeted, autologous CAR T-cell therapy to treat a wide range of hematologic malignancies, including WM and follicular lymphoma ("FL"). MB-106 continues to demonstrate a favorable safety and efficacy profile in both the Fred Hutch single institution and Mustang multicenter Phase 1/2 clinical trials.

· In December 2023, Mustang announced initial data from its ongoing multicenter, open-label, non-randomized Phase 1/2 clinical trial evaluating the safety and efficacy of MB-106 CAR T-cell therapy at the 2023 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. Initial data show that all patients responded clinically to treatment with MB-106 (n=9), with a 100% overall response rate for patients with FL and WM. 100% of patients with FL (n=5) had a complete response; 1 very good partial response and 2 partial responses were observed in WM patients (n=3); and the hairy cell leukemia variant ("HCL-v") patient experienced stable disease, with prolonged, ongoing independence from blood transfusions. Complete responses were observed in patients previously treated with CD19-targeted CAR T-cell therapy. MB-106 demonstrated a tolerable safety profile in patients with indolent NHL, with no occurrence of cytokine release syndrome ("CRS") above grade 1, and no immune effector cell-associated neurotoxicity syndrome ("ICANS") of any grade, despite not using prophylactic tocilizumab or dexamethasone. Outpatient administration was allowed and found to be feasible. MB-106 CAR T-cell expansion and persistence in patients was demonstrated.

· The FDA granted Orphan Drug Designation to MB-106 for the treatment of WM, and results from this arm of the multicenter trial are expected to support an accelerated Phase 2 registration strategy for WM, with the first pivotal Phase 2 patient with WM to be treated potentially in 2024.

· Mazyar Shadman, M.D., M.P.H., Study Chair, Associate Professor and physician at Fred Hutch and University of Washington, also presented data from the ongoing Fred Hutch Phase 1/2 clinical trial specific to two B-cell non-Hodgkin lymphoma cohorts, FL and WM. In the FL data cohort (n=20), an overall response rate ("ORR") of 95% was seen, of which 80% of patients experienced a complete response and 15% had a partial response. The complete response patients include a patient who was previously treated with a CD19-directed CAR T-cell therapy. Of the six patients who experienced cytokine release syndrome ("CRS"), only one had Grade 2, while the remaining five had Grade 1. Ten patients continue to experience complete response for more than 10 months, four patients have experienced complete response for more than two years (all ongoing), and the first patient enrolled has sustained complete response for more than 3 years. In the WM cohort (n=6), all of whom had received prior Bruton tyrosine kinase inhibitor, two patients experienced complete response, one of whom continues to be in complete response at more than 22 months; 1 patient experienced a very good partial response; and 1 patient experienced a partial response. No patients experienced CRS or ICANS greater than Grade 2. None of the six patients with WM has needed to start new therapy for their disease.

MB-109 (IL13Rα2-targeted CAR T-cells + HSV-1 oncolytic virus for recurrent glioblastoma):

· In October 2023, Mustang announced that the FDA accepted the Company’s IND to initiate a Phase 1 open label, multicenter clinical trial to assess the safety, tolerability and efficacy of MB-109, a novel combination of MB-101 (IL13Rα2-targeted CAR T-cell therapy) and MB-108 (HSV-1 oncolytic virus), for the treatment of recurrent GBM and high-grade astrocytoma. Mustang is evaluating plans to initiate the clinical trial and request orphan drug designation for GBM, subject to resource allocation, in 2024.

· As previously reported, preclinical data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2022 supported this combination therapy to optimize results to treat recurrent GBM. The combination leverages MB-108 to make cold tumors "hot," thereby potentially improving the efficacy of MB-101 CAR T-cell therapy.

· In March 2024, data from the Phase 1 trial evaluating MB-101 IL13Rα2-targeted CAR T-cells in high-grade glioma were published in Nature Medicine. MB-101 was well tolerated and 50% of patients achieved stable disease or better, with two partial responses and two complete responses in high grade glioma patients. The two patients who achieved complete response both had high levels of intratumoral CD3+ T-cells pre-therapy (i.e., "hot" tumors), and their responses lasted 7.5 and 66+ months, respectively. In the cohort with dual intratumoral (ICT)/ intraventricular (ICV) delivery and an optimized manufacturing process there was a ~70% improvement in median overall survival (10.2 months) compared to the expected survival rate of six months in this patient population.

In Vivo CAR-T Technology Platform:

· Mustang continues to collaborate with the Mayo Clinic to progress our exclusively licensed novel in vivo CAR-T technology platform that may be able to transform the administration of CAR-T therapies and has the potential to be used as an off-the-shelf therapy. Mustang anticipates the publication of proof-of-concept research in a murine tumor model in 2024.

MB-117 and MB-217 Lentiviral Gene Therapies for X-Linked Severe Combined Immunodeficiency (XSCID):

· In 2024, the first patients are expected to be treated in both new investigator-sponsored trials for newborns diagnosed with XSCID and for previously transplanted patients with XSCID. These trials with MB-117 and MB-217, respectively, are planned by our partners and will test a modified version of the current lentiviral vector.

On March 11, 2024 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported the completion of the acquisition of Harpoon Therapeutics, Inc. (Nasdaq: HARP) (Press release, Merck & Co, MAR 11, 2024, View Source [SID1234641015]). Harpoon is now a wholly-owned subsidiary of Merck, and Harpoon’s common stock will no longer be publicly traded or listed on the Nasdaq Stock Market.

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"We continue to augment and diversify our oncology pipeline with innovative approaches to help people with cancer worldwide," said Dr. Dean Y. Li, president, Merck Research Laboratories. "We are pleased to welcome our Harpoon colleagues to Merck and look forward to working together to advance a novel portfolio of T-cell engagers, including MK-6070."

Harpoon’s lead candidate, MK-6070 (formerly known as HPN328), is a T-cell engager targeting delta-like ligand 3 (DLL3), an inhibitory canonical Notch ligand that is expressed at high levels in small cell lung cancer (SCLC) and neuroendocrine tumors. The safety, tolerability and pharmacokinetics of MK-6070 is currently being evaluated as monotherapy in a Phase 1/2 clinical trial (NCT04471727) in certain patients with advanced cancers associated with expression of DLL3. The study is also evaluating MK-6070 in combination with atezolizumab in certain patients with SCLC. In March 2022, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to MK-6070 for the treatment of SCLC.

Additional pipeline candidates include HPN217, a T-cell engager targeting B-cell maturation antigen (BCMA), currently in Phase 1 clinical development for the treatment of patients with relapsed/refractory multiple myeloma, and several preclinical stage candidates, including HPN601, a conditionally activated targeting epithelial cell adhesion molecule (EpCAM) for the treatment of certain patients with EpCAM expressing tumors.

Transaction details
Under the terms of the merger agreement, Merck, through a subsidiary, has acquired all outstanding shares of Harpoon. As previously disclosed, this transaction is being accounted for as an asset acquisition. Merck is recording a non-tax deductible charge to R&D expense of approximately $650 million. The impact of the transaction on expected full-year non-GAAP EPS is approximately $0.26 per share, which was included in Merck’s full-year 2024 financial outlook issued on February 1, 2024.

On March 11, 2024 Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX), reported financial results for the three months ended December 31, 2023 and provided an update on key corporate milestones (Press release, Lexicon Pharmaceuticals, MAR 11, 2024, View Source [SID1234641013]).

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"2023 was a pivotal year for Lexicon," said Lonnel Coats, Lexicon’s chief executive officer. "We launched INPEFA within weeks of receiving U.S. FDA approval with a broad label for heart failure, while in parallel continuing the advancement of our innovative research and development pipeline."

"In the fourth quarter, we saw continued progress on the launch of INPEFA and began to see increased prescriber demand and important formulary wins, which we expect to accelerate in the first half of 2024. We advanced LX9211 into late-stage development for diabetic peripheral neuropathic pain (DPNP), with the potential to become the first new, non-opioid drug approved for neuropathic pain in over two decades."

"We are preparing for Phase 3 development of sotagliflozin in hypertrophic cardiomyopathy (HCM), an area of high unmet need with very few treatments in development. And following recent feedback from FDA, we are preparing to resubmit our New Drug Application (NDA) for sotagliflozin as an adjunct to insulin therapy in patients with type 1 diabetes and chronic kidney disease. Our research and development engine also continues to produce, and we are conducting preclinical development on an oral small molecule compound for obesity and weight management. With these opportunities and the support from shareholders in our recent successful financing, Lexicon is well positioned for growth and expansion in 2024 and beyond."

Fourth Quarter Highlights

INPEFA (sotagliflozin)

Launch Progress

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INPEFA was placed on the formularies of multiple important Medicare and commercial plans during the fourth quarter, including Express Scripts’ Premier Access and Premier Performance national formularies for Medicare patients and Basic and High Performance formularies for commercially insured patients.

Publications and Data

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On October 4, Craig Granowitz, M.D., Ph.D., Lexicon’s senior vice president and chief medical officer, conducted an oral presentation entitled Temporal shift in heart failure medications prescribed to hospitalised patients with and without diabetes in a large US integrated health system at the 59th Annual Meeting of European Association for the Study of Diabetes (EASD) in Hamburg, Germany and online.

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On October 8, Michael J. Davies, Ph.D., Lexicon’s executive director of clinical development, presented a new analysis of clinical trial data for sotagliflozin entitled Sotagliflozin Reduces the Risk of Cardiovascular Events In Patients With Left Ventricular Hypertrophy Without Hypertension: A Post Hoc Analysis From SCORED at the Heart Failure Society of America (HFSA) Annual Scientific Meeting in Cleveland, Ohio.

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On November 12, 2023, Lexicon had a significant presence and conducted multiple presentations related to INPEFA at the American Heart Association Scientific Sessions 2023, including one oral presentation highlighting the early clinical benefit of INPEFA for heart failure and atherosclerotic events and another focusing on cost-effectiveness metrics associated with the use of INPEFA.

LX9211

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In December, patient enrollment began in the PROGRESS Phase 2b dose optimization study and is progressing well. The PROGRESS study marks initiation of the late-stage development program for AAK1 inhibitor LX9211, with potential to become the first new, non-opioid drug therapy approved in neuropathic pain in more than 20 years. Topline data from the PROGRESS study is anticipated in 2Q 2025.

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Data relating to LX9211 were shared at various global congresses during the fourth quarter, including the 33rd Annual Meeting of the Diabetic Neuropathy Study Group (NeuroDiab), held September 28-October 1 in Thessaloniki, Greece; the 59th Annual Meeting of the European Association for the Study of Diabetes (EASD), held October 2-6 in Hamburg, Germany and online; the 17th Annual Pain Therapeutics Summit (Arrowhead Conference), held October 19-20 in San Diego, California; and the 2nd World Brain Disorders and Neuroscience Summit (BDNS), held November 9-11 in Singapore and online.

Additional Pipeline Opportunities

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Preparations are underway for Phase 3 development of sotagliflozin in HCM.

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Following recent feedback from FDA, preparations are underway to resubmit Lexicon’s NDA for sotagliflozin as an adjunct to insulin therapy in patients with type 1 diabetes and chronic kidney disease.

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As part of Lexicon’s ongoing discovery efforts, the company is advancing preclinical development of a novel oral compound for obesity and weight management.

Fourth Quarter 2023 Financial Highlights

Unless otherwise stated, all comparisons are for the fourth quarter and full year of 2023 compared to the fourth quarter and full year of 2022.

Revenues: Revenues for the fourth quarter and full year of 2023 were $0.7 million and $1.2 million, respectively, primarily from the commercialization of INPEFA.

Research and Development (R&D) Expenses: Research and development expenses for the fourth quarter of 2023 increased to $14.8 million from $14.0 million for the corresponding period in 2022. Full-year research and development expenses increased to $58.9 million in 2023 from $52.8 million for the corresponding period in 2022, primarily due to higher manufacturing costs, partially offset by lower professional and consulting fees related to the prior year NDA resubmission for heart failure.

Selling, General and Administrative (SG&A) Expenses: Selling, general and administrative expenses for the fourth quarter of 2023 increased to $32.6 million from $16.3 million in 2022 and for the full-year 2023 increased to $114.0 million from $48.1 million in 2022. The increase in 2023 is primarily due to the significant investment in the commercial launch of INPEFA, including higher salaries and benefits of the new sales force and other increased headcount, higher travel, and higher marketing costs.

Net Loss: Net loss for the fourth quarter of 2023 was $48.2 million, or $0.20 per share, as compared to a net loss of $30.5 million, or $0.16 per share, in the corresponding period in 2022. For the fourth quarters of 2023 and 2022, net loss included non-cash, stock-based compensation expense of $3.2 million and $3.3 million, respectively. Net loss for the full year was $175.6 million, or $0.79 per share, in 2023 as compared to a net loss of $101.9 million, or $0.62 per share, in the corresponding period in 2022. For the full years of 2023 and 2022, net loss included non-cash, stock-based compensation expense of $14.3 million and $11.5 million, respectively.

Cash and Investments: As of December 31, 2023, Lexicon had $170.0 million in cash and investments, as compared to $138.4 million as of December 31, 2022.

Lexicon 2024 Investor Day – April 22, 2024

In lieu of a year-end earnings conference call, Lexicon plans to hold an Investor Day on April 22, 2024. The event will be webcast live on Lexicon’s website at www.lexpharma.com/events. The agenda will include a business and regulatory update, with participation from multiple physician experts in the areas of cardiometabolic disorders, HCM, type 1 diabetes and diabetic peripheral neuropathic pain.

For Lexicon’s latest investor presentation, please visit View Source

Planned Participation in Upcoming Investor Conferences:

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Leerink Partners Global Biopharma Conference March 12

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Needham 23rd Annual Virtual Healthcare Conference on April 8-11

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Piper Sandler Virtual Cardiovascular Day on April 10

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Piper Sandler Spring Biopharma Symposium on April 16-17

These events will be webcast live on Lexicon’s website at www.lexpharma.com/events

About INPEFA (sotagliflozin)

Discovered using Lexicon’s unique approach to gene science, INPEFA (sotagliflozin) is an oral inhibitor of two proteins responsible for glucose regulation known as sodium-glucose cotransporter types 2 and 1 (SGLT2 and SGLT1). SGLT2 is responsible for glucose and sodium reabsorption by the kidney and SGLT1 is responsible for glucose and sodium absorption in the gastrointestinal tract. Sotagliflozin has been studied in multiple patient populations encompassing heart failure, diabetes, and chronic kidney disease in clinical studies involving approximately 20,000 patients.

INDICATION

INPEFA is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with:

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heart failure or

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type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors

IMPORTANT SAFETY INFORMATION

Dosing: Assess renal function and volume status and, if necessary, correct volume depletion prior to initiation of INPEFA. INPEFA dosing for patients with decompensated heart failure may begin when patients are hemodynamically stable, including when hospitalized or immediately upon discharge.

Contraindications: INPEFA is contraindicated in patients with hypersensitivity to INPEFA or any of its components.

Ketoacidosis: INPEFA increases the risk of ketoacidosis in patients with type 1 diabetes mellitus (T1DM). Type 2 diabetes Mellitus (T2DM) and pancreatic disorders are also risk factors. The risk of ketoacidosis may be greater with higher doses. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes using sodium glucose transporter 2 (SGLT2) inhibitors. Before initiating INPEFA, assess risk factors for ketoacidosis. Consider ketone monitoring in patients with T1DM and consider ketone monitoring in others at risk for ketoacidosis and educate patients on the signs/symptoms of ketoacidosis. Patients receiving INPEFA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. INPEFA is not indicated for glycemic control. Assess patients who present with signs and symptoms of metabolic acidosis or ketoacidosis, regardless of blood glucose level. If suspected, discontinue INPEFA, evaluate, and treat promptly. Monitor patients for resolution of ketoacidosis before restarting INPEFA.

Volume Depletion: INPEFA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR < 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INPEFA in patients with one or more of these characteristics, assess volume status and renal function, and monitor for signs and symptoms of hypotension during therapy.

Urosepsis and Pyelonephritis: Treatment with SGLT2 inhibitors, including INPEFA, increases the risk for urinary tract infections. Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly.

Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INPEFA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used with INPEFA.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of Fournier’s Gangrene, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors. Assess patients who present with pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INPEFA, closely monitor patient signs and symptoms, and provide appropriate alternative therapy for heart failure.

Genital Mycotic Infections: INPEFA increases the risk of genital mycotic infections. Monitor and treat as appropriate.

Urinary Glucose Test and 1,5-anhydroglucitol (1,5-AG) Assay: these are not reliable for patients taking SGLT2 inhibitors. Use alternative testing methods to monitor glucose levels.

Common Adverse Reactions: the most commonly reported adverse reactions (incidence ≥ 5%) were urinary tract infection, volume depletion, diarrhea, and hypoglycemia.

Drug Interactions:

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Digoxin: Monitor patients appropriately as there is an increase in the exposure of digoxin when coadministered with INPEFA 400 mg.

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Uridine 5’-diphospho-glucuronosyltransferase (UGT) Inducer: The coadministration of rifampicin, an inducer of UGTs, with sotagliflozin resulted in a decrease in the exposure of sotagliflozin.

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Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INPEFA initiation and with dosage changes.

Use in Specific Populations:

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Pregnancy and Lactation: INPEFA is not recommended during the second and third trimesters of pregnancy, nor while breastfeeding.

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Geriatric Use: No INPEFA dosage change is recommended based on age. No overall differences in efficacy were detected between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be at increased risk for volume depletion adverse reactions, including hypotension.

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Renal Impairment: INPEFA was evaluated in patients with chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m2) and in patients with heart failure with eGFR < 60 mL/min/1.73 m2. The safety profile of INPEFA across eGFR subgroups in these studies was consistent with the known safety profile. There was an increase in volume-related adverse events (e.g., hypotension, dizziness) in patients with eGFR < 30 mL/min/1.73m2 relative to the overall safety population. Efficacy and safety studies with INPEFA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. After starting therapy in the studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m2 or were initiated on chronic dialysis.

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Hepatic Impairment: INPEFA is not recommended in patients with moderate or severe hepatic impairment.

On March 11, 2024 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a leader in the field of conditionally activated, localized biologics, reported full year 2023 financial results and provided a business update (Press release, CytomX Therapeutics, MAR 11, 2024, View Source [SID1234641012]).

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"2023 was a year of sustained execution across our pipeline, highlighted by the continued progress of CX-904 in Phase 1 dose escalation and the parallel advancement of CX-2051 and CX-801 through successful IND enabling activities towards clinical initiation in the first half of 2024," said Sean McCarthy, D.Phil., chief executive officer and chairman of CytomX. "We entered 2024 with a robust therapeutic pipeline based upon more than a decade of innovation with the PROBODY platform. Our lead programs leverage validated oncology targets, potent effector mechanisms and tailored masking approaches. Our strategy is to address large oncology markets and major unmet needs to make a meaningful difference for patients, building on the strong company foundation we have laid with our comprehensive progress to date."

McCarthy added, "Importantly, while advancing key programs throughout 2023, we maintained a consistently strong financial position through disciplined capital allocation and financing that included a strategic equity investment from our largest shareholder, BVF Partners, and ongoing funding from major collaborations."

Fourth Quarter Business Highlights and Recent Developments

Pipeline

CX-904, PROBODY T-cell-engager (TCE) targeted to EGFRxCD3 progressing in Phase 1, with dose escalation data anticipated in second half of 2024.

CX-904 is a conditionally activated PROBODY T-cell engager designed to target the epidermal growth factor receptor (EGFR) on cancer cells and the CD3 receptor on T cells within the tumor microenvironment. CX-904 is partnered with Amgen in a global co-development alliance and is being evaluated in an ongoing Phase 1 study in unselected patients with advanced solid tumors that are considered to have EGFR expression. Backfilling of certain dose escalation cohorts has been initiated and dose ranging continues.

Initial Phase 1a dose escalation data is anticipated in the second half of 2024. The Phase 1a data is expected to focus primarily on identification of safe and tolerable doses and schedules and will include an evaluation of indicators of clinical activity, including pharmacokinetic-pharmacodynamic (PK-PD) data and assessment of anti-tumor activity.
The CX-904 Phase 1a data will inform a potential decision during 2024 to initiate Phase 1b expansion cohorts in specific EGFR positive tumor types. The decision to potentially initiate Phase 1b expansion cohorts will be taken in conjunction with Amgen.
CX-2051, an EpCAM-directed PROBODY antibody drug conjugate advancing to Phase 1 in the 1st half of 2024.

EpCAM is a high potential oncology target that is highly expressed across many indications including colorectal, gastric, endometrial, and ovarian cancers. EpCAM has been clinically validated by locally administered, previously approved cancer therapies. However, efforts to generate systemically administered anti-EpCAM therapeutics have, to date, been unsuccessful due to toxicities in certain epithelial tissues, notably in the gastrointestinal tract. As a conditionally activated ADC, CX-2051 is tailored to optimize the therapeutic index for EpCAM-expressing epithelial cancers. The cytotoxic payload utilized in CX-2051 is a derivative of camptothecin, a topoisomerase-1 inhibitor, a class of drug that has shown potent clinical anti-cancer activity in the ADC context for multiple targets and cancer types. CX-2051 has demonstrated a wide predicted therapeutic index in multiple preclinical models, constituting an opportunity for broad clinical use in large patient populations.

In January 2024, CytomX announced that the Investigational New Drug (IND) application for CX-2051 was allowed to proceed by the U.S. Food and Drug Administration (FDA).
The Phase 1 dose escalation of CX-2051 in patients with solid tumors generally known to express EpCAM, including CRC, will be initiated in the first half of 2024. The Phase 1 dose escalation study will follow a Bayesian Optimal Interval (BOIN) design and is intended to demonstrate initial clinical proof of concept to inform a potential decision to move into dose expansion in 2025.
CX-801, a dually-masked PROBODY interferon-alpha 2b advancing to Phase 1 in the 1st half of 2024.

Interferon-alpha 2b is an immunotherapeutic cytokine that has demonstrated clinical activity and gained regulatory approval previously in multiple cancer types, including locally advanced or metastatic melanoma, renal cancer and bladder cancer. IFNα2b provides a potentially superior approach to activating anti-tumor immune responses compared to other cytokines but its clinical benefit has been hindered by severe dose-limiting toxicity. CX-801 is an optimized, dually masked, conditionally activated version of IFNα2b, with an expanded therapeutic index that has the potential to become a cornerstone of combination therapy for a wide range of tumor types.

In January 2024, CytomX announced the Investigational New Drug (IND) application for CX-801 was allowed to proceed by the U.S. Food and Drug Administration (FDA).
CX-801 is anticipated to initiate Phase 1 dose escalation in patients with solid tumors including melanoma, renal, and head and neck squamous cell carcinoma in the first half of 2024. The Phase 1 dose escalation will utilize a BOIN design to evaluate safety and signs of clinical activity for CX-801 monotherapy and for CX-801 in combination with immune checkpoint inhibition.
Focus of Bristol Myers Squibb (BMS) research collaboration evolves to ongoing research programs, including multiple T-cell engagers. The anti-CTLA-4 PROBODY BMS-986288 will not be further advanced following a recent BMS internal portfolio review.

CytomX’s research collaboration with Bristol Myers Squibb originated in 2014 and includes multiple PROBODY therapeutic programs.

Following a corporate portfolio prioritization process, Bristol Myers Squibb (BMS) notified CytomX on March 6th, 2024 that it does not intend to continue the development of BMS-986288 beyond the current Phase 2 study.
CytomX’s ongoing research collaboration with Bristol Myers Squibb includes multiple preclinical programs, including T-cell engagers.
CytomX continues to make progress in R&D partnerships.

CytomX has multiple active research and development partnerships and more than 10 ongoing research programs with major biotechnology and pharmaceutical companies (Amgen, Astellas, Bristol Myers Squibb, Moderna and Regeneron). Throughout 2023, CytomX made substantial progress across all research partnerships including the commencement of programs under its new alliances with Regeneron and Moderna. CytomX has a consistent track record of forming new strategic research and development alliances and achieving preclinical research and clinical milestones. Partnering is expected to remain an important part of the Company’s strategy.

2024 Priorities and Key Milestones:

CX-904 (EGFRxCD3): Continued enrollment into Phase 1a dose escalation with initial data expected in the second half of 2024. These data are expected to inform a potential 2024 decision, to be taken with Amgen, to initiate Phase 1b expansion cohorts in specific EGFR positive tumor types.
CX-2051 (EpCAM): Initiation of Phase 1 dose escalation in solid tumors with known EpCAM expression, including locally advanced/metastatic colorectal cancer as a priority indication, is expected in the first half of 2024.
CX-801 (IFNα2b): Initiation of Phase 1 dose escalation in solid tumors including melanoma, renal, and head and neck squamous cell carcinoma is expected in the first half of 2024.
Collaborations: Continuation of drug discovery and development activities with Bristol Myers Squibb, Amgen, Astellas, Regeneron, and Moderna with potential pre-clinical and clinical milestones possible in 2024 and beyond.
Full Year and Q4 2023 Financial Results

Cash, cash equivalents and investments totaled $174.5 million as of December 31, 2023, compared to $193.7 million as of December 31, 2022. The cash balance as of December 31, 2023, included cash inflows during 2023 of a $35.0 million upfront payment received in January 2023 as a result of the collaboration with Moderna, a $5.0 million clinical candidate milestone from Astellas in February of 2023 and approximately $30.0 million of proceeds from the financing transaction with BVF Partners L.P. in July of 2023.

Total revenue was $101.2 million for the year ended December 31, 2023, compared to $53.2 million in 2022. The increase in revenue was driven primarily by a higher percentage of completion for research programs in the Bristol Myers Squibb collaboration and the recent collaborations with Regeneron and Moderna. Revenue in the fourth quarter of 2023 was $26.6 million compared to $20.1 million in the corresponding period in 2022.

In 2023, CytomX remained focused on controlling costs and efficiently allocating capital towards its lead pipeline programs. Total operating expense in 2023 was $107.7 million compared to $154.5 million in 2022, a reduction of $46.8 million. The operating expense reduction was driven by the Company’s workforce reduction in 2022, strategic pipeline prioritization, and primarily allocating early phase research efforts towards partnered programs. Operating expenses in the fourth quarter of 2023 were $27.2 million compared to $29.6 million in the corresponding period in 2022.

Research and development expenses decreased by $34.0 million during the year ended December 31, 2023, to $77.7 million compared to $111.6 million in 2022. The reduction in research and development expenses was primarily due to a decrease in personnel related expenses, as well as winding down of laboratory contract services and clinical study activities related to the CX-2009 and CX-2029 programs, partially offset by an increase in laboratory contract services related to IND-enabling activities for CX-2051 and CX-801 programs. Research and development expenses in the fourth quarter of 2023 were $19.4 million compared to $19.6 million in the corresponding period in 2022.

General and administrative expenses decreased by $12.8 million during the year ended December 31, 2023, to $30.0 million, compared to $42.8 million for the corresponding period in 2022. The reduction in general and administrative expenses was primarily due to a decrease in personnel related expenses as a result of the workforce reduction in 2022, reduced external vendor services, and lower occupancy costs as a result of a partial sublease of the Company’s headquarters. General and administrative expenses in the fourth quarter of 2023 were $7.8 million compared to $10.1 million in the corresponding period in 2022.

Conference Call & Webcast
CytomX management will host a conference call and simultaneous webcast today at 5 p.m. EDT (2 p.m. PDT) to discuss the financial results and provide a business update. Participants may access the live webcast of the conference call from the Events and Presentations page of CytomX’s website at View Source Participants may register for the conference call here and are advised to do so at least 10 minutes prior to joining the call. An archived replay of the webcast will be available on the company’s website.

On March 11, 2024 Caribou Biosciences, Inc. (Nasdaq: CRBU), a leading clinical-stage CRISPR genome-editing biopharmaceutical company, reported financial results for the fourth quarter and full year 2023 and reviewed recent pipeline progress (Press release, Caribou Biosciences, MAR 11, 2024, View Source [SID1234641011]).

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"Following our execution in 2023, we enter 2024 with momentum advancing three clinical-stage off-the-shelf CAR-T cell therapy programs for patients with hematologic malignancies while we plan for two clinical data releases this year," said Rachel Haurwitz, PhD, Caribou’s president and chief executive officer. "For our lead program, CB-010, we plan to present initial dose expansion data and the RP2D in the second quarter of 2024. For our second program, CB-011, we continue to enroll patients in the CaMMouflage trial and plan to report initial dose escalation data by year-end 2024. For our third program, CB-012, we are thrilled to have recently dosed the first patient in the AMpLify trial. Our team is focused on clinical execution to inform two clinical datasets this year as part of our mission of bringing transformative therapies to patients with devastating diseases."

Clinical highlights

CB-010, a clinical-stage allogeneic anti-CD19 CAR-T cell therapy for B cell non-Hodgkin lymphoma
•Caribou has dosed the 30th patient in the dose expansion portion of the ongoing ANTLER Phase 1 clinical trial (View Source) in second-line relapsed or refractory large B cell lymphoma (r/r LBCL) patients. Previously, 16 patients were dosed in the dose escalation portion of ANTLER. The company will continue enrolling additional second-line r/r LBCL patients in ANTLER to collect additional clinical data.
•In December 2023, Caribou shared regulatory feedback (View Source) from the U.S. Food and Drug Administration (FDA) following a Type B clinical meeting. The company received the FDA’s input on a Phase 3 randomized pivotal trial for CB-010 in second-line r/r LBCL, stating that Caribou’s proposed comparator arm of platinum-based immunochemotherapy followed by high dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) is acceptable.
•As previously reported, CB-010 demonstrated encouraging data (View Source) from the dose escalation portion of the ANTLER Phase 1 clinical trial (View Source) in 16 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). Dose escalation data showed CB-010 has the potential to rival the efficacy and safety profile of approved autologous CAR-T cell therapies.

•To Caribou’s knowledge, CB-010 is the first anti-CD19 allogeneic CAR-T cell therapy to be evaluated in the second-line LBCL setting, and it was granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, and Orphan Drug designations by the FDA for specific indications in 2022.
CB-011, a clinical-stage allogeneic anti-BCMA CAR-T cell therapy for multiple myeloma
•Caribou is enrolling patients with relapsed or refractory multiple myeloma (r/r MM) in the dose escalation portion of the ongoing CaMMouflage Phase 1 clinical trial (View Source). Patients are currently being enrolled at dose level 3 (450×106 CAR-T cells).
•Preclinical data for CB-011 were published in Cancer Immunology Research (View Source) in February 2024. The manuscript is available on Caribou’s website under Scientific Publications (View Source).
CB-012, a clinical-stage allogeneic anti-CLL-1 CAR-T cell therapy for acute myeloid leukemia
•The first patient has been dosed in the AMpLify Phase 1 clinical trial (View Source?term=cb-012&" target="_blank" title="View Source?term=cb-012&" rel="nofollow">View Source;rank=1&tab=table), which is evaluating CB-012 in patients with relapsed or refractory acute myeloid leukemia (r/r AML). Additional site activation is underway.
•Preclinical data for CB-012 highlighting the investigational new drug (IND)-enabling studies will be presented as a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024, held April 5-10, 2024 in San Diego.
CB-020, a preclinical allogeneic anti-ROR1 CAR-NK cell therapy
•As part of a regular portfolio prioritization process, Caribou has paused the development of CB-020, a preclinical allogeneic anti-ROR1 CAR-NK cell therapy. Caribou continues to develop its CAR-NK cell therapy platform as these therapies may have potential for the treatment of multiple diseases.

2024 anticipated milestones
•CB-010: In Q2 2024, Caribou plans to present initial dose expansion data, the recommended Phase 2 dose (RP2D), and emerging translational data from the ANTLER Phase 1 clinical trial, as well as an updated timeline for the pivotal Phase 3 trial initiation.
•CB-011: Caribou plans to present initial dose escalation data from the CaMMouflage Phase 1 clinical trial by year-end 2024.
•CB-012: Caribou plans to provide updates on dose escalation as the AMpLify Phase 1 clinical trial in r/r AML advances.

Fourth Quarter and Full Year 2022 Financial Results
Cash, cash equivalents, and marketable securities: Caribou had $372.4 million in cash, cash equivalents, and marketable securities as of December 31, 2023, compared to $317.0 million as of December 31, 2022. The 2023 amount includes the approximately $134.4 million in net proceeds from the Company’s underwritten public offering in July and August 2023 and the $25.0 million equity investment (View Source) in June 2023 from Pfizer. Caribou expectsthese cash, cash equivalents, and marketable securities will be sufficient to fund its current operating plan into Q1 2026.

Licensing and collaboration revenue: Revenue from Caribou’s licensing and collaboration agreements was $3.6 million for the three months ended December 31, 2023 and $34.5 million for the full year 2023, compared to $3.7 million and $13.9 million, respectively, for the same periods 2022. The increase for the year ended December 31, 2023 was primarily due to $24.8 million in revenue recognized under the now-terminated AbbVie Collaboration and License Agreement, including $20.8 million of deferred revenue recognized upon termination of this agreement as previously disclosed, which was the remaining deferred revenue balance from AbbVie’s $30 million upfront payment in February 2021.
R&D expenses: Research and development expenses were $31.3 million for the three months ended December 31, 2023 and $112.1 million for full year 2023, compared to $25.7 million and $82.2 million respectively, for the same periods in 2022. The increase for the year ended December 31, 2023 was primarily due to costs to advance pipeline programs, including the CB-010 ANTLER, CB-011 CaMMouflage, and CB-012 AMpLify Phase 1 clinical trials; personnel-related expenses, including stock-based compensation, due to headcount increases; and facilities and other allocated expenses.

G&A expenses: General and administrative expenses were $9.7 million for the three months ended December 31, 2023 and $38.5 million for the full year 2023, compared to $8.5 million and $38.0 million, respectively, for the same periods in 2022. The increase for the year ended December 31, 2023 was primarily due to personnel-related expenses, including stock-based compensation, due to headcount increases, and other facilities and allocated expenses. These increases were partially offset by decreases in insurance and other service-related expenses, and patent prosecution and maintenance costs.
Net loss: Caribou reported a net loss of $34.5 million for the three months ended December 31, 2023 and $102.1 million for the full year 2023, compared to a net loss of 27.0 million and $99.4 million, respectively, for the same periods in 2022.

About CB-010
CB-010 is the lead product candidate from Caribou’s allogeneic CAR-T cell therapy platform and is being evaluated in patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). In the ongoing ANTLER Phase 1 trial, Caribou is enrolling second-line patients with large B cell lymphoma (LBCL) comprised of different subtypes of aggressive r/r B-NHL (DLBCL NOS, PMBCL, HGBL, tFL, and tMZL). CB-010 is an allogeneic anti-CD19 CAR-T cell therapy engineered using Cas9 CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology. To Caribou’s knowledge, CB-010 is the first allogeneic CAR-T cell therapy in the clinic with a PD-1 knockout, a genome-editing strategy designed to improve antitumor activity by limiting premature CAR-T cell exhaustion. To Caribou’s knowledge, CB-010 is the first anti-CD19 allogeneic CAR-T cell therapy to be evaluated in the second-line LBCL setting and it has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, and Orphan Drug designations by the FDA for specific indications. Additional information on the ANTLER trial (NCT04637763) can be found at clinicaltrials.gov (View Source).

About CB-011
CB-011 is a product candidate from Caribou’s allogeneic CAR-T cell therapy platform and is being evaluated in patients with relapsed or refractory multiple myeloma (r/r MM) in the CaMMouflage Phase 1 trial. CB-011 is an allogeneic anti-BCMA CAR-T cell therapy engineered using Cas12a chRDNA genome-editing technology. To Caribou’s knowledge, CB-011 is the first allogeneic CAR-T cell therapy in the clinic that is engineered to improve antitumor activity through an immune cloaking strategy with a B2M knockout and insertion of a B2M–HLA-E fusion protein to blunt immune-mediated rejection. CB-011 has been granted Fast Track and orphan drug designations by the FDA. Additional information on the CaMMouflage trial (NCT05722418) can be found at clinicaltrials.gov (View Source).

About CB-012
CB-012 is a product candidate from Caribou’s allogeneic CAR-T cell therapy platform and is being evaluated in the AMpLify Phase 1 clinical trial in patients with relapsed or refractory acute myeloid leukemia (r/r AML). CB-012 is an anti-CLL-1 CAR-T cell therapy engineered with five genome edits, enabled by Caribou’s patented next-generation CRISPR technology platform, which uses Cas12a chRDNA genome editing to significantly improve the specificity of genome edits. To Caribou’s knowledge, CB-012 is the first allogeneic CAR-T cell therapy with both checkpoint disruption, through a PD-1 knockout, and immune cloaking, through a B2M knockout and B2M–HLA-E fusion protein insertion; both armoring strategies are designed to improve antitumor activity. Caribou has exclusively in-licensed from Memorial Sloan Kettering Cancer Center (MSKCC) in the field of allogeneic CLL-1-targeted cell therapy a panel of fully human scFvs targeting CLL-1, from which the company has selected an appropriate scFv for the generation of the company’s CAR. Additional information on the AMpLify trial (NCT06128044) can be found at clinicaltrials.gov (View Source).