On November 2, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported that three abstracts detailing results from the completed Phase 3 SIERRA trial of Iomab-B in patients age 55 and above with active relapsed or refractory acute myeloid leukemia (r/r AML) have been accepted for presentation at the 65th Annual American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper) being held in San Diego on December 9-12, 2023 (Press release, Actinium Pharmaceuticals, NOV 2, 2023, View Source [SID1234636821]). Outcomes of patients with a TP53 gene mutation enrolled in the SIERRA trial have been accepted for an oral presentation and results detailed in the abstract include the following:

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Median Overall Survival (OS) of TP53 positive patients receiving Iomab-B and a bone marrow transplant (BMT) was 5.49 months compared to 1.66 months in patients who did not receive Iomab-B
Iomab-B produced a statistically significant improvement in median OS in TP53 positive patients with a hazard ratio of 0.23 and p-value of 0.0002
Median OS of 6.37 months in TP53 negative patients receiving Iomab-B and 5.72 months for TP53 positive patients demonstrating Iomab-B’s mutation agnostic mechanism and ability to overcome TP53 gene mutations
24% of patients (37/153) enrolled on the SIERRA trial had a TP53 mutation, with 17 being randomized to the Iomab-B arm and 20 randomized to the control arm
Dr. Avinash Desai, Actinium’s Chief Medical Officer, commented, "We are very excited by these results which show a statistically significant and greater than three-times increase in median OS in TP53 positive patients receiving Iomab-B. These results further support Iomab-B’s differentiated profile and ability to improve outcomes for the most difficult to treat r/r AML patients. A TP53 gene mutation is arguably the most unfavorable risk factor leading to the worst patient outcomes as it is associated with inherent resistance to available therapies, short duration of responses and the lowest survival rates. Despite being a common mutation found in approximately 10-15% of all AML cases and up to 25% of patients over age 60, there are no approved therapies that target TP53. For patients with high-risk AML, particularly those with r/r disease and a TP53 mutation, BMT is associated with the best treatment outcomes and is the only potentially curative therapeutic option. Iomab-B’s ability to facilitate a BMT in this patient population continues to demonstrate a strong clinical benefit as supported by these results and we look forward to presenting the full TP53 analysis at ASH (Free ASH Whitepaper) in early December."

Detailed results will be presented in an oral presentation on December 10, 2023, as follows:

Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Novel Conditioning Regimens for Myeloid Malignancies
Session Date: Sunday, December 10, 2023
Session Time: 9:30 AM – 11:00 AM Pacific Time
Presentation Time: 9:30 AM
Room: Marriott Marquis San Diego Marina, Pacific Ballroom Salons 18-19

Publication Number: 469
Title: 131I-Apamistamab-Led Allogeneic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients with TP53 Mutated R/R AML
Submission ID: 182177

Sandesh Seth, Actinium’s Chairman and CEO, added, "This oral presentation at ASH (Free ASH Whitepaper) represents the eighth oral presentation from the SIERRA results in 2023. Through these presentations, we have built strong recognition for Iomab-B’s unique clinical profile and utility in this disease with high unmet medical need amongst key medical and scientific communities comprised of BMT physicians, hematologists, nuclear medicine physicians, nurses and transplant coordinators. These additional data in TP53 positive patients further supports the potential of targeted radiotherapy in heterogenous, difficult-to-treat blood cancers given its mutation-agnostic mechanism of action. Further, we believe the broad expression of CD45 enables development of Iomab-B across various blood cancers, as well as cell and gene therapy with our next-generation conditioning agent, Iomab-ACT, allowing Actinium to address a significant patient need."

Additional SIERRA data will be presented in two poster presentations as follows:

Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster I
Session Date: Saturday, December 9, 2023
Presentation Time: 5:30 PM – 7:30 PM Pacific Time
Location: San Diego Convention Center, Halls G-H

Publication Number: 2159
Title: 131I-Apamistamab Effectively Achieved Durable Responses in Patients with R/R AML Irrespective of the Presence of Multiple High-Risk Factors

Session Name: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster II
Session Date: Sunday, December 10, 2023
Presentation Time: 6:00 PM – 8:00 PM Pacific Time
Location: San Diego Convention Center, Halls G-H

Publication Number: 3529
Title: High-Dose Targeted Radiation with 131I-Apamistamab Prior to HCT Demonstrated a Dose-Response for Durable Complete Remission in Patients with R/R AML

Financial results and business update

On November 2, 2023, Actinium reported financial results for the third quarter 2023 and provided a business update. For additional information, refer to the Company’s Form 10-Q for the third quarter 2023 filed with the SEC on November 2, 2023, which should be read in addition to this press release.

Cash and cash equivalents: The Company reported cash and cash equivalents of approximately $82.9 million as of September 30, 2023, and maintains its prior cash runway guidance through year-end 2025 based on its current operating plan.

Research and Development Expense, net of reimbursements: Research and development expenses of $11.6 million for the third quarter of 2023 increased $4.8 million from $6.8 million for the same period in 2022. Higher research and development expenses were primarily due to increased CMC activity related to BLA-enabling work for Iomab-B. Once complete, CMC expenses are expected to decrease in 2024 as we expect to use final drug product material produced to support the BLA filing and to supply initial Iomab-B commercialization. Additionally, compensation expense increased $1.1 million as a result of higher headcount necessary to support BLA-enabling CMC activity.

General and Administrative Expense: General and administrative expenses of $2.7 million for the third quarter 2023 decreased by $0.4 million from $3.1 million for the same period in 2022. Lower professional and consulting fees of $0.5 million, lower legal fees of $0.1 million and lower non-cash equity compensation of $0.1 million were partially offset by increased compensation of $0.3 million as a result of higher headcount.

Other Income: Other income is comprised of net interest income in both reporting periods. The amount for the third quarter 2023 of $1.1 million increased from $0.3 million for the same period in 2022 due to a higher average interest rate.

Net Loss: Net loss of $13.3 million for the third quarter 2023 increased by $3.8 million from $9.5 million for the same period in 2022 primarily due to higher research and development expenses, primarily due to increased CMC BLA-enabling activity and CMC headcount that was partially offset by lower general and administrative expenses and higher other income.

Actinium also provided an update on its regulatory activity pertaining to its planned Biologics License Application (BLA) for Iomab-B as well as the planned marketing authorization application (MAA) to the European Medicines Agency (EMA) that will be completed by Immedica Pharma AB (Immedica), Actinium’s European, Middle East and North Africa commercial partner for Iomab-B. The Company has been meeting with the FDA regarding its BLA strategies, and has received positive feedback regarding the Chemistry, Manufacturing and Controls (CMC) package for Iomab-B. As a continuation of its regulatory interactions with the FDA, the Company will request a meeting prior to completion of the CMC package to further discuss the clinical and non-clinical modules that will determine the finalization and timing of its planned BLA filing. As a result of the CMC meeting, as well as updated project timelines necessitated by the now complete facility modifications at one of its third-party manufacturers, the Company is progressing with completion of CMC activities and believes it is on track to complete the CMC modules and be in a position to submit a BLA filing in the first half of 2024. The Early Access Program for Iomab-B is also anticipated to start post completion of these activities. Actinium is also simultaneously working with Immedica to support its planned MAA filing for Iomab-B. Europe represents a large commercial market opportunity with approximately twice as many transplants performed in Europe compared to the U.S.

About Iomab-B and the Pivotal Phase 3 SIERRA Trial

Iomab-B is a first-in-class targeted radiotherapy intended to improve patient access to potentially curative BMT by simultaneously and rapidly depleting blood cancer, immune and bone marrow stem cells that uniquely express CD45. Multiple studies have demonstrated increased survival in patients receiving BMT, however, an overwhelming majority of patients with blood cancers do not receive BMT as current approaches do not produce a remission, which is needed to advance to BMT, or are too toxic. Studied in over 400 patients, prior studies with Iomab-B have demonstrated nearly universal access to BMT, increased survival and tolerability in multiple clinical trials including the recently completed pivotal Phase 3 SIERRA trial in patients with active (leukemic blasts >5%), relapsed or refractory acute myeloid leukemia (r/r AML) age 55 and above.

Iomab-B met the primary endpoint of durable Complete Remission (dCR) of 6 months after initial remission post-BMT in the pivotal Phase 3 SIERRA trial with high statistical significance (p<0.0001). Iomab-B produced a 75% post-BMT CR rate (44/59 patients), which is 12-times greater than the post-BMT rate of 6.3% (4/64 patients) in the control arm. Patients receiving Iomab-B had a 78% lower probability of an event, defined as not achieving a CR/CRp, crossover, not receiving a BMT, relapse or death, with a Hazard Ratio of 0.22 (p<0.0001). Iomab-B doubled 1-year overall survival with 26.1% compared to 13.1% in the control arm for patients who did not crossover as well as median overall survival with 6.4 months vs 3.2 months. Overall survival statistics are confounded by the crossover arm. Crossover patients had a 35.8% 1-year overall survival rate. Due to its targeted nature, Iomab-B was well tolerated with four times lower rates of sepsis compared to the control arm (6.1% vs. 28.6%) and lower rates of BMT associated adverse events including febrile neutropenia, mucositis and graft versus host disease (GVHD). Actinium intends to submit a Biologics License Application (BLA) seeking approval for Iomab-B in 2024 to address patients age 55+ with r/r AML who cannot access BMT with currently available therapies. Iomab-B has been granted Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) and has patent protection into 2037.

The pivotal Phase 3 SIERRA (Study of Iomab-B in Elderly relapsed or refractory AML) is a 153-patient, randomized, multi-center clinical trial, studying Iomab-B compared to the control arm of physician’s choice of salvage therapy. Control arm options included chemotherapies like cytarabine and daunorubicin and targeted agents such as a Bcl-2 inhibitor (Venetoclax), FLT3 inhibitors and IDH 1/2 inhibitors. The SIERRA control arm reflects real-world treatment of r/r AML patients with over 20 agents used alone or in combination as no standard of care exists for this patient population. The SIERRA trial enrolled patients at 24 leading transplant centers in the United States and Canada that perform over 30% of AML BMTs.

Developed at the Fred Hutchinson Cancer Research Center, a pioneer in the field of BMT, Iomab-B is supported by data in six disease indications including leukemias, lymphomas and multiple myeloma, which afflict over 100,000 patients annually. Actinium intends to pursue additional indications for Iomab-B beyond AML. Actinium also intends to pursue international regulatory approvals independently and through partnerships. In April 2022, Actinium licensed the European, Middle East and North African commercial rights for Iomab-B to Immedica Pharma AB, a fully-fledged independent pharmaceutical company headquartered in Sweden. In exchange, Actinium received an upfront payment of $35 million USD with the potential for an additional $417 million USD in regulatory and sales milestones and mid-twenty percent royalties. Europe represents a commercial opportunity approximately double the size of the United States by number of patients with AML receiving BMT. Iomab-B has been granted Orphan Drug Designation by the European Medicines Agency (EMA) and has received positive Scientific Advice from the Committee for Medicinal Products for Human Use (CHMP) of the EMA indicating that the Phase 3 SIERRA trial design, primary endpoint and planned statistical analysis are acceptable as the basis for a Marketing Authorization Application.

On November 2, 2023 Autolus Therapeutics plc (Nasdaq: AUTL), a clinical-stage biopharmaceutical company developing next-generation programmed T cell therapies, reported the online publication of four abstracts submitted to the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, to be held December 9 to 12, 2023 (Press release, Autolus, NOV 2, 2023, View Source [SID1234636820]).

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"We look forward to presenting data from a number of our clinical trials at ASH (Free ASH Whitepaper) this year, with obe-cel continuing to show a potentially best-in-class profile across several indications," said Dr. Christian Itin, Chief Executive Officer of Autolus. "Importantly, ahead of our expected BLA filing later this year, we will be presenting safety, efficacy and longer follow up data of obe-cel in relapsed/refractory B-ALL from the FELIX phase Ib and the pivotal phase II study, a pooled analysis from the ALLCAR19 and FELIX Phase Ib studies and the ALLCAR19 extension study, as well as data demonstrating the robustness of obe-cel’s manufacturing process. Additionally, we will be presenting the first AUTO8 clinical data from the MCARTY Phase I study in multiple myeloma."

Oral Presentations:

Title: Obecabtagene Autoleucel (obe-cel, AUTO1) for Relapsed/Refractory Adult B-cell Acute Lymphoblastic Leukemia (R/R B-ALL): Pooled Analysis of the Ongoing FELIX Phase Ib/II Study
Session Title: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Expanding Disease Targets for CAR-T Cell Therapies
Session date and time: Saturday, December 9, 2023, 3:15 PM PT
Session room: San Diego Convention Center, Room 6B
Publication Number: 222
Presenting Author: Dr. Claire Roddie, MD, PhD, FRCPath, Associate Professor Haematology and Honorary Consultant Haematologist, Cancer Institute, University College London (UCL)

Summary:
Obe-cel is an autologous chimeric antigen receptor (CAR) T cell product with a novel CD19 binding domain conferring a fast antigen off-rate designed for an improved benefit risk ratio.
In this session, pooled analysis of data from all patients treated to date in the FELIX study will be presented, with an extended follow up. Data continued to demonstrate high rates of CR/CRi and a favorable safety profile. Additionally, subgroup analysis data suggests better outcomes in patients with low leukemia burden at screening/lymphodepletion, with higher rates of deep MRD negative complete remission and no Gr ≥3 CRS and one Gr ≥3 ICANS.

Title: Development of a Phase I Study Evaluating the Activity of Modular CAR T for Multiple Myeloma (MCARTY) Targeting BCMA and CD19 for Improved Persistence
Session Title: 703. Cellular Immunotherapies: Basic and Translational: Cellular Immunotherapy: Preclinical and Translational Insights
Date and time: Saturday, December 9, 2023, 4:15 PM PT
Session room: San Diego Convention Center, Room 6A
Publication Number: 350
Presenting Author: Dr. Lydia Lee, Consultant Haematologist & Senior Clinical Research Fellow, University College London, Research Department of Haematology (UCLH)

Summary:
AUTO8 is a dual targeting autologous CAR T therapy targeting BCMA and CD19 using two independently expressed CARs for multiple myeloma. In the MCARTY study, we demonstrate dual CD19/BCMA targeting, alongside feasibility of clinical grade manufacture by double-transduction. Clinical responses were seen in 6 of 6 evaluable patients.
Poster Presentations:

Title: Long-Term Efficacy and Safety of Obecabtagene Autoleucel (obe-cel) in Adult Patients (pts) with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia ([R/R B-ALL]; Pooled Analysis from ALLCAR19 and FELIX Phase Ib Studies) or Other B-cell Malignancies (ALLCAR19 Extension Study)
Session Title: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster I
Session date and time: Saturday, December 9, 2023, 5:30 PM – 7:30 PM PT
Session room: San Diego Convention Center, Halls G-H
Publication Number: 2114
Presenting Author: Dr. Claire Roddie, MD, PhD, FRCPath, Associate Professor Haematology and Honorary Consultant Haematologist, Cancer Institute, University College London (UCL)

Summary:
The clinical activity of obe-cel has been explored in adults with R/R B-ALL in a Phase I study (ALLCAR19), and a Phase Ib/II study (FELIX). Additionally, obe-cel has been tested in patients with R/R B-cell chronic lymphocytic leukemia (B-CLL) and R/R B-cell non-Hodgkin lymphoma (B-NHL).
Data from the pooled analysis of r/r ALL patients treated with obe-cel in the ALLCAR19 and FELIX Ib studies demonstrate that after a median follow up of >3 years approximately 30% of patients remain in remission without subsequent transplant. In the CLL and NHL cohorts of the ALLCAR19 study and with >2 years follow up, the studies show durable responses and a low incidence of serious infections. In summary, obe-cel shows durable remissions in a range of B-cell malignancies with an excellent and consistent safety profile.

Title: Delivery of Obecabtagene Autoleucel (obe-cel, AUTO1) for the FELIX Pivotal Study Demonstrating Robust Cell Processing, Robust Release Testing, and Reliable Logistics, Together with Readiness for Sustainable Patient (pt) Care
Session Title: 711. Cell Collection and Processing: Poster III
Session date and time: Monday, December 11, 2023, 6:00 PM – 8:00 PM PT
Session room: San Diego Convention Center, Halls G-H
Publication Number: 4892
Presenting Author: Michael Merges VP, Process Development, Autolus

Summary:
The FELIX study successfully demonstrated the robust operability of obe-cel manufacturing, QC and logistics processes, meeting target V2C (time from leukapheresis to quality release) and V2D (time from leukapheresis to delivery of product to the hospital). All apheresis starting material was successfully processed despite the multitude of constraints posed by the COVID-19 pandemic. Further optimization and improvements made during the study increased reliability, consistency and precision of the manufacturing process, and supported the development of a new obe-cel manufacturing facility with greater production capacity that aims to achieve a ≥95% manufacturing success rate with ≤15-day V2C times.
Abstracts can be viewed via the ASH (Free ASH Whitepaper) abstract portal

On November 2, 2023 Moderna, Inc. (NASDAQ:MRNA) reported financial results and provided business updates for the third quarter of 2023 (Press release, Moderna Therapeutics, NOV 2, 2023, View Source/news/news-details/2023/Moderna-Reports-Third-Quarter-2023-Financial-Results-and-Provides-Business-Updates–" target="_blank" title="View Source/news/news-details/2023/Moderna-Reports-Third-Quarter-2023-Financial-Results-and-Provides-Business-Updates–" rel="nofollow">View Source;/default.aspx [SID1234636819]).

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"Through this quarter, we demonstrated our ability to increase share in the U.S. market, and we now expect this year’s vaccination rate to be similar to last fall," said Stéphane Bancel, Chief Executive Officer of Moderna. "In the third quarter, we significantly resized our manufacturing infrastructure to make our COVID-19 franchise profitable for 2024 and beyond. We are preparing to launch multiple products through 2025, including our RSV vaccine. We expect to return to sales growth in 2025 and, through disciplined investment, to break even in 2026."

Recent progress includes:

2023 Commercial Updates

COVID-19: The Company reported $1.8 billion in Spikevax (COVID-19 vaccine) sales in the third quarter of 2023, which includes $0.9 billion of U.S. sales and $0.8 billion of international sales. This leads to $3.9 billion in vaccine sales for the year through the third quarter. The Company believes that the U.S. market for fall 2023 will be at least 50 million doses, supporting total 2023 Spikevax sales of at least $6 billion. The U.S. fall 2023 vaccinations administered in retail pharmacies to date are tracking similarly to the 2022 fall season, despite a later launch. Spikevax is available in all leading pharmacies and points of care and continues to gain market share. With 45% cumulative market share1 as of the most recently available date in October, Moderna’s market share in the fall 2023 season is tracking ahead of its cumulative market share of 36% during the fall 2022 U.S. vaccination season.

The Company continues to focus on public health efforts to increase vaccination rates globally. In the United States, the Company has undertaken significant marketing and awareness campaigns, working closely with vaccinators and others to drive a robust vaccination season, including by activating the medical community, supporting and re-engaging customers (including those who deferred updated vaccination due to recent infections) and amplifying the voices of credible influencers.

RSV: The Company continues to expect the launch of its RSV vaccine in 2024 with a potential best-in-class profile. Moderna has submitted marketing authorization applications globally for mRNA-1345, a vaccine for the prevention of RSV-associated lower respiratory tract disease (RSV-LRTD) and acute respiratory disease (ARD) in adults aged 60 years or older. The Company filed for a Biologics License Application (BLA) with the FDA and used a Priority Review Voucher (PRV) to accelerate review.

The regulatory applications are based on positive data from the pivotal ConquerRSV study, a randomized, double-blind, placebo-controlled study of approximately 37,000 adults, 60 years or older. The trial met both its primary efficacy endpoints, with a vaccine efficacy (VE) of 83.7% (95.88% CI: 66.1%, 92.2%; p<0.0001) against RSV-LRTD as defined by two or more symptoms, and a VE of 82.4% (96.36% CI: 34.8%, 95.3%; p=0.0078) against RSV-LRTD defined by three or more symptoms. mRNA vaccine technology has a well-established safety and tolerability profile, with over 1 billion COVID-19 doses administered. Most solicited adverse reactions were mild to moderate, and no cases of Guillain-Barre Syndrome (GBS) have been reported with mRNA-1345 in the Phase 3 RSV trial. In addition to older adults, mRNA-1345 is being investigated in a fully enrolled, ongoing Phase 1 trial in pediatric populations.

Moderna is preparing for the marketing launch of mRNA-1345 and believes its U.S. COVID-19 market share to date demonstrates the Company’s ability to compete in the commercial market. The Company is encouraged by early indications of strong consumer awareness and demand in the RSV market. Moderna believes that clinical data for its RSV vaccine supports a best-in-class profile and that its ready-to-use pre-filled syringes (PFS) offer another competitive differentiator over currently licensed products, which require multiple preparatory steps by pharmacists and clinicians. Feedback from clinicians and customers in the COVID-19 market, where Moderna has a similar presentation, validates the benefits of PFS administration. The Company’s pre-launch activities at this time are largely focused on scientific exchanges and public health engagements.

Third Quarter 2023 Financial Results

Revenue: Total revenue for the third quarter of 2023 was $1.8 billion, compared to $3.4 billion in the same period in 2022, mainly due to a decrease in sales of the Company’s COVID-19 vaccine. Net product sales for the third quarter of 2023 were $1.8 billion, a decrease of 44% compared to the same period in 2022, primarily driven by lower sales volume and partially offset by a higher average selling price.

Cost of Sales: Cost of sales for the third quarter of 2023 was $2.2 billion. Moderna has made substantial progress during the quarter in resizing its COVID-19 manufacturing footprint to accelerate gross margin expansion toward its longer-term target of 75-80%. In addition to $0.4 billion in unit driven manufacturing, distribution cost and royalties, the remaining $1.9 billion includes the following charges: $1.3 billion for inventory write-downs related to excess and obsolete COVID-19 product, contract manufacturing wind-down cost of $0.5 billion, and cancellation fees of $0.1 billion. $1.4 billion of these charges were primarily driven by resizing efforts in the third quarter, with an additional $0.2 billion expected in the fourth quarter of 2023.

Research and Development Expenses: Research and development expenses for the third quarter of 2023 increased by 41% to $1.2 billion, in comparison to the same quarter of 2022. The growth in spending was mainly due to an increase in clinical trial-related expenses, largely driven by increased clinical development activities, particularly with respect to the Company’s respiratory and oncology programs.

Selling, General and Administrative Expenses: Selling, general and administrative expenses for the third quarter of 2023 increased by 59% to $442 million, in comparison to the third quarter of 2022. The growth in spending was primarily due to increased personnel-related cost and outside services spend, driven by the build-out of our commercial activities and medical affairs in particular to support the launch of the U.S. commercial market.

Income Taxes: Income taxes for the third quarter of 2023 were $1.7 billion, which is primarily driven by a $1.7 billion non-cash charge related to a valuation allowance on deferred tax assets. This valuation allowance does not impact cash flows, future returns or the Company’s ability to utilize deferred tax assets in future periods.

Net Income (Loss): Net loss was $3.6 billion for the third quarter of 2023, compared to net income of $1.0 billion for the third quarter of 2022, primarily driven by mostly non-cash charges of $3.1 billion related to resizing and tax allowances.

Earnings (Loss) Per Share: Diluted loss per share was $9.53 for the third quarter of 2023, compared to diluted earnings per share of $2.53 for the third quarter of 2022.

Cash, Cash Equivalents and Investments: Cash, cash equivalents and investments were $12.8 billion as of September 30, 2023, down from $14.6 billion as of June 30, 2023, driven by the operating loss in the quarter.

2023 Financial Framework

Product Sales: The Company now expects product sales of at least $6 billion for 2023. The largest remaining variable to sales for the year relates to U.S. vaccination rates, and the estimate assumes trends consistent with the fall 2022 period.

Cost of Sales: The Company now expects cost of sales to be approximately $5 billion for the year, inclusive of charges of approximately $1.6 billion across the third and fourth quarters related to proactive resizing of the Company’s manufacturing footprint. Before the resizing charges of $1.6 billion, costs of sales would be at the lower end of previous guidance range of $3.5 billion to $4 billion.

Respiratory Cost of Sales Framework: The Company’s manufacturing resizing is expected to drive more predictable cost of sales going forward. Write-downs/charges are expected to be less than 10% of sales in 2024 and beyond (74% year to date). Moderna’s resized footprint is now better positioned to scale with volume. At a $4 billion sales level, the Company expects cost of sales of approximately 35%, reducing to approximately 30% at $6 billion of sales and 20-25% at higher sales levels.

Research and Development (R&D) and Selling, General and Administrative (SG&A): The Company now expects full-year 2023 expenses of approximately $6.3 billion (previously $6 billion), with approximately $4.8 billion in R&D (previously $4.5 billion).

Income Taxes: The Company now anticipates a full-year tax expense of approximately $0.8 billion to $1.0 billion, driven by an increase in valuation allowance on deferred tax assets (previously a benefit of ~$0.7-1.0 billion). This valuation allowance does not impact cash flows, future returns or the Company’s ability to utilize deferred tax assets in future periods.

Capital Expenditures: The Company expects capital expenditures for 2023 of approximately $0.9 billion (previously $1.0 billion).

Moderna Operating Principles

The Company expects its COVID-19 franchise to be profitable in its anticipated sales scenarios for 2024 and beyond. While Moderna plans to continue to invest in its business to drive an unparalleled opportunity for organic sales growth, the Company will be disciplined and will adjust its investments in R&D and SG&A based on its sales performance. Moderna expects to break even in 2026 through product launches and disciplined investments. The Company’s current balance sheet is sufficient to fund its planned investments without raising additional equity.

Early Thoughts on 2024 and 2025 Sales

Moderna is projecting approximately $4 billion in sales in 2024, mostly in the second half of the year, primarily due to COVID-19 vaccine global sales and the launch of its RSV vaccine. In 2025, the Company expects to return to organic sales growth. The Company is projecting cost of sales as a percentage of sales to be approximately 35% in 2024, which is expected to improve with sales increasing in 2025. R&D expenses are expected to be approximately $4.5 billion in 2024 and flat to down in 2025. SG&A expenses are expected to be approximately $1.3 billion in 2024 and flat to down in 2025. Taxes are expected to be negligible in both 2024 and 2025. The Company expects capital expenditures to be approximately $0.9 billion in 2024 and materially lower in 2025, following the completion of manufacturing sites in Australia, Canada and the United Kingdom. Moderna expects to break even in 2026. The Company expects an ending cash balance of approximately $9 billion in 2024 and in the range of $6 billion to $7 billion in 2025.

Clinical Updates

Moderna’s mRNA platform is positioned to continue to deliver significant impact with our mRNA medicines. The Company is anticipating up to 15 launches in the next five years and provided a comprehensive overview of its pipeline and clinical programs at R&D Day in September. Moderna currently has therapeutics in development across four therapeutic areas, with a total of 43 development programs. Other notable updates are provided below.

Respiratory : Moderna has advanced three respiratory disease programs to positive Phase 3 data (COVID-19, RSV, Influenza).

Moderna also recently announced positive interim results from the Phase 1/2 trial of mRNA-1083, an investigational combination vaccine against seasonal influenza and COVID-19. Moderna’s investigational combination vaccines are designed to deliver value to individuals, providers and healthcare systems through higher compliance, easier administration and greater convenience.

The ongoing Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT05827926) is a randomized, observer blind study evaluating the safety and immunogenicity of mRNA-1083 compared to a standard dose influenza vaccine, Fluarix, in adults 50-64 years of age and against an enhanced influenza vaccine, Fluzone HD, in adults 65-79 years of age. For both age groups, mRNA-1083 was compared against Spikevax booster.

The Company also recently announced that it has initiated a Phase 3 trial of mRNA-1083 in 2023 and is targeting initial regulatory approval for the combination vaccine in 2025. The Phase 3 study will evaluate the immunogenicity, safety, and reactogenicity of mRNA‐1083 as compared with active control, co‐administered licensed influenza and SAR‐CoV‐2 vaccines in 8,000 healthy adults 50 years of age or older.

mRNA‐1083 has the potential to efficiently reduce the overall burden of acute viral respiratory diseases by providing simultaneous protection against influenza and SARS‐CoV‐2 viruses in a single injection. mRNA‐1083 offers greater convenience and has the potential to lead to increased compliance with vaccine recommendations. This approach could benefit public health by synergistically increasing coverage rates against influenza and SARS‐CoV‐2 viruses.

Latent: The pivotal Phase 3 study of Moderna’s CMV vaccine candidate (mRNA-1647), known as CMVictory, is fully enrolled including an adolescent cohort. The trial evaluates the efficacy, safety and immunogenicity of mRNA-1647 in the prevention of primary infection in women of childbearing age.

INT: In April 2023, Moderna and Merck reported the results from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial evaluating mRNA-4157 (V940), an investigational individualized neoantigen therapy (INT), in combination with KEYTRUDA, Merck’s anti-PD-1 therapy, in patients with resected high-risk melanoma (stage III/IV). In the overall intention-to-treat population, adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) and reduced the risk of recurrence or death by 44% (HR=0.56 [95% CI, 0.309-1.017]; one-sided p value=0.0266) compared with KEYTRUDA alone. In June, the Company announced a statistically significant and clinically meaningful improvement in distant metastasis-free survival from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial. mRNA-4157-P201/KEYNOTE-942 is the first randomized trial to demonstrate improvement in recurrence-free survival and distant metastasis-free survival with an individualized neoantigen therapy approach. The Company expects to provide additional data from the Phase 2 study in the fourth quarter of 2023.

Merck and Moderna announced the initiation of a pivotal Phase 3 study (V940-001) to evaluate the safety and efficacy of mRNA-4157 (V940) in combination with KEYTRUDA in people with resected high-risk (Stage IIB-IV) melanoma compared to KEYTRUDA alone. The primary endpoint of the study is recurrence-free survival, and secondary endpoints include distant metastasis-free survival, overall survival and safety. That trial is underway globally.

The Companies will also imminently commence a Phase 3 trial in non-small cell lung cancer (NSCLC) in patients with resected stage II-IIIB NSCLC who have received adjuvant chemotherapy, with no recurrence. The primary endpoint is disease free survival compared to pembrolizumab. Secondary endpoints are overall survival, distant metastasis-free survival, and safety. The trial is expected to enroll approximately 868 patients.

Moderna and Merck plan to expand the INT development program to additional tumor types.

Moderna is scaling manufacturing to support clinical development and commercial markets. The Company is also currently building a manufacturing site in Marlborough, MA as a commercial INT manufacturing facility.

Corporate Updates

Moderna announced strategic partnerships with Immatics and CARsgen
Moderna announced positive clinical results across cancer, rare disease and infectious disease at its 8th annual R&D Day
Company Accolades:

Moderna was ranked as one of the top employers in the global biopharmaceutical industry by Science and Science Careers’ 2023 Top Employers Survey (ninth consecutive year on the list)
Moderna was named to the Boston Business Journal’s annual list of the Most Charitable Companies in Massachusetts (first year on the list)
Moderna was recognized as a top-scoring company on the Disability: IN’s Disability Equality Index (second consecutive year on the list)
Key 2023 Investor and Analyst Event Dates

Digital Day: November 8
ESG Day: December 7
Investor Call and Webcast Information

Moderna will host a live conference call and webcast at 8:00 a.m. ET on November 2, 2023. To access the live conference call via telephone, please register at the link below. Once registered, dial-in numbers and a unique pin number will be provided. A live webcast of the call will also be available under "Events and Presentations" in the Investors section of the Moderna website.

Telephone: https://register.vevent.com/register/BI9ee4891809624391a5618bb9e2ca440f
Webcast: View Source
The archived webcast will be available on Moderna’s website approximately two hours after the conference call and will be available for one year following the call.

On November 2, 2023 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported a poster presentation on the initial Phase 1b clinical data for ORIC-533 in patients with relapsed/refractory multiple myeloma at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting to be held December 9-12, 2023, in San Diego, CA (Press release, ORIC Pharmaceuticals, NOV 2, 2023, View Source [SID1234636816]).

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Details of the ASH (Free ASH Whitepaper) poster presentation are as follows:

Title: Preliminary Results of the Oral CD73 Inhibitor, ORIC-533, in
Relapsed/Refractory Multiple Myeloma (RRMM)
Abstract #: 4761
Session Name: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster III
Session Date: Monday, December 11, 2023
Presentation Time: 6:00 PM – 8:00 PM PT
Location: San Diego Convention Center, Halls G-H

Abstract Highlights

ORIC-533 is a highly potent and selective, orally bioavailable, small molecule inhibitor of CD73, currently being evaluated in an ongoing Phase 1b dose escalation study to determine its safety, tolerability, and pharmacokinetics and selection of the recommended Phase 2 dose in patients with relapsed/refractory multiple myeloma. The study included a heavily pretreated patient population where all patients were triple-class refractory, 88% were penta-refractory, and 59% also received prior anti-BCMA/CD3 bispecific therapy or anti-BCMA CAR-T therapy. ORIC-533 was well tolerated with the vast majority of treatment-related adverse events (TRAEs) Grade 1 or 2 in severity and with no dose limiting toxicities, no Grade ≥ 4 TRAEs, and no treatment-related serious adverse events. ORIC-533 demonstrated good bioavailability and a plasma half-life of ~24 hours. Strong inhibition of soluble CD73 enzymatic activity was seen across all dose levels. Preliminary evidence of enhanced CD8+ T-cell activation was seen at the highest dose levels tested in both the peripheral blood and bone marrow, and early evidence of single agent clinical activity was observed. Overall, ORIC-533 demonstrated an acceptable safety profile and preliminary evidence of immune activation in this heavily pretreated patient population.

Full abstracts are available for online viewing via the ASH (Free ASH Whitepaper) Annual Meeting website at Hematology.org.

About ORIC-533

ORIC-533 is a highly potent, orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy and immunotherapy-based treatment regimens. ORIC-533 has demonstrated greater potency in preclinical studies compared to an antibody approach, as well as other small molecule inhibitors of CD73 and adenosine receptor antagonists. Preclinical data demonstrated that ORIC-533 binds CD73 with high affinity and effectively blocks adenosine-driven immunosuppression in a high AMP environment, reflective of AMP levels observed in tumors. In preclinical studies, nanomolar concentrations of ORIC-533 efficiently rescued cytotoxic T-cell function in the presence of high AMP concentrations, as well as in ex vivo bone marrow aspirates from relapsed or refractory multiple myeloma patients.

On November 2, 2023 Kura Oncology, Inc. (NASDAQ: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, and Mirati Therapeutics, Inc. (NASDAQ: MRTX), a commercial-stage targeted oncology company, reported a clinical collaboration and supply agreement to evaluate the combination of KO-2806, a next-generation farnesyl transferase inhibitor (FTI), and adagrasib, a highly selective KRASG12C inhibitor, in patients with KRASG12C-mutated non-small cell lung cancer (NSCLC) (Press release, Kura Oncology, NOV 2, 2023, View Source [SID1234636815]).

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"Recent findings suggest that combining KO-2806 with adagrasib can drive tumor regressions and enhance both duration and depth of antitumor response in preclinical models of KRASG12C-mutated NSCLC," said Stephen Dale, M.D., Chief Medical Officer of Kura Oncology. "This collaboration highlights the potential to address the urgent need for more durable and effective treatment options for patients with advanced solid tumors, and we look forward to collaborating with Mirati, an established leader in targeted oncology."

"We are pleased to collaborate with Kura Oncology on this clinical study of KO-2806 with adagrasib. Preclinical work demonstrates the ability of adagrasib, in combination with a FTI, to improve patient outcomes," said Alan Sandler, M.D., Chief Medical Officer, Mirati Therapeutics. "This collaboration exemplifies the potential combinability of adagrasib as a key differentiation from other KRASG12C inhibitors."

Under the terms of the agreement, Kura will sponsor the Phase 1 study of KO-2806 and adagrasib in patients with KRASG12C-mutated NSCLC. Mirati will supply Kura with adagrasib for the study.

About KO-2806

KO-2806 is a next-generation inhibitor of farnesyl transferase designed to improve upon potency, pharmacokinetic and physicochemical properties of earlier FTI drug candidates. Earlier this year, Kura received FDA clearance of its Investigational New Drug application for KO-2806. In addition to KRASG12C NSCLC, KO-2806 has demonstrated encouraging preclinical activity in clear cell renal cell carcinoma (ccRCC). The Company recently dosed the first patients in a Phase 1 dose-escalation trial of KO-2806 (FIT-001). Concurrent with dose escalation as a monotherapy, Kura also plans to evaluate KO-2806 in dose-escalation combination cohorts with other targeted therapies in advanced solid tumors, including adagrasib in KRASG12C-mutated NSCLC and a tyrosine kinase inhibitor in ccRCC.

About Adagrasib

Adagrasib is being evaluated as monotherapy and in combination with other anti-cancer therapies in patients with advanced KRASG12C-mutated solid tumors, including NSCLC, colorectal cancer, and pancreatic cancer. For more information, visit Mirati.com/science.

KRAZATI (adagrasib) U.S. Indication

KRAZATI is indicated for the treatment of adult patients with KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). For Prescribing Information, visit Mirati.com/KRAZATI_USPI.

KRAZATI (adagrasib) Important Safety Information

WARNINGS AND PRECAUTIONS

Gastrointestinal Adverse Reactions

In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal obstruction in 1.6%, including 1.4% grade 3 or 4, gastrointestinal bleeding in 0.5% of patients, including 0.5% grade 3, and colitis in 0.3%, including 0.3% grade 3. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of KRAZATI in 0.3%
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity
QTc Interval Prolongation

KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (eg, torsades de pointes) or sudden death
In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥501 ms, and 11% of patients had an increase from baseline of QTc >60 msec. KRAZATI causes concentration-dependent increases in the QTc interval
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are taking medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI, depending on severity
Hepatotoxicity

KRAZATI can cause hepatotoxicity
In the pooled safety population, hepatotoxicity occurred in 37%, and 7% were grade 3 or 4. A total of 32% of patients who received KRAZATI had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were grade 3 and 0.5% were grade 4. Increased ALT/AST leading to dose interruption or reduction occurred in 11% of patients. KRAZATI was discontinued due to increased ALT/AST in 0.5% of patients
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to the start of KRAZATI, and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity
Interstitial Lung Disease /Pneumonitis

KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population, ILD/pneumonitis occurred in 4.1% of patients, 1.4% were grade 3 or 4, and 1 case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). KRAZATI was discontinued due to ILD/pneumonitis in 0.8% of patients
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (eg, dyspnea, cough, fever). Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified
Adverse Reactions

The most common adverse reactions (≥25%) are nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite
Females and Males of Reproductive Potential

Infertility: Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential
Please see Full Prescribing Information.