On January 5, 2024 ProfoundBio, a clinical-stage biotechnology company developing novel antibody-drug conjugate (ADC) therapeutics for cancer, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for rinatabart sesutecan (Rina-S; PRO1184), a folate receptor alpha (FRα) targeted ADC, for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer (Press release, ProfoundBio, JAN 5, 2024, View Source [SID1234639028]). Fast Track designation is intended to facilitate the development and expedited review of drugs with demonstrated potential to improve over available therapy for serious conditions with unmet medical need.

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"Our receipt of Fast Track designation from the FDA underscores our belief in the tremendous promise of Rina-S as a potential best-in-class FRα ADC to address the significant need for improved treatment options for advanced ovarian cancer," said Naomi Hunder, Chief Medical Officer of ProfoundBio. "FRα is a highly prevalent antigen in ovarian cancer and Rina-S has shown encouraging antitumor activity and tolerability in our Phase 1 dose escalation study in ovarian and endometrial cancer patients across the full spectrum of FRα expression. We look forward to working closely with the FDA as we progress further clinical development and registrational studies for Rina-S."

About Rinatabart Sesutecan (Rina-S, PRO1184)
Rina-S is a folate receptor-alpha (FRα) targeted ADC being developed as a novel treatment option for patients with ovarian and endometrial cancer, and potentially other FRα-expressing cancers. Rina-S is comprised of a FRα-directed antibody conjugated to sesutecan, ProfoundBio’s novel, proprietary hydrophilic exatecan-based linker-drug, at a homogeneous drug-to-antibody ratio (DAR) of 8. Exatecan is a highly potent, membrane permeable topoisomerase-1 inhibitor with strong bystander effect. Sesutecan is a highly hydrophilic, stable, cleavable linker designed to mask the hydrophobicity of conjugated exatecan on the ADC, enabling high DAR and efficient delivery of the exatecan payload to tumors while maintaining favorable physicochemical and pharmacokinetic properties of the ADC.

Status of PRO1184-001 Phase 1/2 Study (NCT05579366)
PRO1184-001 is a Phase 1/2 study of rinatabart sesutecan to evaluate the safety, tolerability, PK, and antitumor activity of PRO1184 in patients with selected locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma. The study consists of two parts, Part A: Dose Escalation and Part B: Dose Expansion. Initial results from Part A were reported in November 2023, demonstrating encouraging antitumor activity at well tolerated doses in heavily pretreated ovarian and endometrial cancer patients unselected for FRα expression. Part B is currently enrolling patients at multiple sites in the U.S. and China.

On January 5, 2024 Akeso (9926.HK) reported that the China National Medical Products Administration (NMPA) has accepted the supplemental new drug application (sNDA) of cadonilimab (开坦尼, PD-1/CTLA-4 bispecific antibody, AK104) in combination with capecitabine plus oxaliplatin (XELOX) for first-line treatment of unresectable locally advanced, recurrent or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (Press release, Akeso Biopharma, JAN 5, 2024, View Source [SID1234639027]).

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This will be the second indication for which cadonilimab has received approval in China, following its use as a monotherapy treatment for recurrent or metastatic cervical cancer.

The sNDA acceptance was based on the results from the AK104-302 trial, representing the first Phase III clinical study of a PD-1/CTLA-4 bispecific antibody combined with chemotherapy for first-line treatment of gastric cancer. In November 2023, AK104-302 trial achieved its primary endpoint by demonstrating a statistically significant overall survival (OS) improvement.

Cadonilimab combined with chemotherapy significantly reduced the risk of death in all-comer patients, including those with PD-L1 CPS≥5 and PD-L1 CPS < 5. The hazard ratios (HRs) for OS among patients with different PD-L1 status were superior to the disclosed PD-1 plus chemotherapy combination treatments. The combination of cadonilimab and chemotherapy also demonstrated superior OS in patients with PD-L1 CPS < 5 as well as PD-L1 negative.

"In the real world, approximately 60% of patients exhibit low PD-L1 expression, which further underscores the need for more effective treatment options," said Professor Ji Jiafu from the Peking University Cancer Hospital. "There is a significant need to enhance overall effectiveness, particularly among patients with low PD-L1 expression. The combination of cadonilimab therapy for first-line treatment of advanced gastric cancer has shown a high tumor objective remission rate, significantly improve the overall survival of the entire population with advanced gastric cancer while reducing the risk of death. We are eagerly awaiting the earliest approval of this indication and the positive impact it will have on patients’ lives."

"The combination therapy of cadonilimab demonstrates differentiated efficacy advantages compared to commonly used immunotherapy approaches in clinical practice," said Professor Lin Shen from the Peking University Cancer Hospital. "It brings significant benefits to all-comer patients regardless of PD-L1 expression, and even demonstrated strong anti-tumor effects in patients with low PD-L1 expression or negative status. This addresses the limitations of current single-target immunotherapy in clinical settings, effectively showcasing the synergistic mechanism of ‘PD-1+CTLA-4’ dual immune therapy. It is expected to overcome the shortcomings of current immune treatment strategies for advanced gastric cancer and represents a potentially superior immunotherapeutic approach for this condition."

"We would like to express our sincere gratitude to all the investigators, participants, and patients who actively participated in the clinical trial," said Dr. Yu Xia, Founder, Chairwoman, President, and CEO of Akeso. "The groundbreaking bispecific IO therapy from cadonilimab will soon bring significant benefits to approximately 500,000 gastric cancer patients in China, underscoring the immense clinical and market value of cadonilimab as the first PD-1/CTLA-4 bispecific antibody. Since its approval for cervical cancer treatment in 2022, cadonilimab has garnered recognition from both clinicians and patients due to its remarkable efficacy and safety. We eagerly anticipate the approval of its new indication for gastric cancer, as it will revolutionize the clinical treatment approach for advanced gastric cancer and introduce a new era of immunotherapy options for patients."

About AK104-302 trial

AK104-302 is a Phase III randomized, double-blind, multi-center clinical trial evaluating the use of cadonilimab ( the world’s first approved PD-1/CTLA-4 bispecific antibody) in combination with XELOX as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This study aims to assess the efficacy of cadonilimab plus XELOX compared to placebo plus XELOX in the intent-to-treat (ITT) population. The AK104-302 trial represents the first Phase III clinical study of a PD-1/CTLA-4 bispecific antibody combined with chemotherapy for first-line treatment of gastric cancer. Approximately 60% of patients in the ITT population had a PD-L1 CPS＜5, a proportion comparable to real-world scenarios.

About Cadonilimab

Cadonilimab is a first-in-class bispecific antibody that targets both PD-1 and CTLA-4 developed by Akeso. In Jun 2022, the China National Medical Products Administration (NMPA) approved cadonilimab for recurrent or metastatic cervical cancer. Cadonilimab has been included and recommended in multiple clinical guidelines such as CSCO. Cadonilimab has been engaged in more than 60 ongoing clinical trials including investigator-initiated studies.

Currently, a Phase III study of cadonilimab for first-line treatment of gastric cancer has met its endpoint of PFS. A Phase III study of cadonilimab has also met one of its primary endpoints of PFS for first-line treatment of recurrent/metastatic cervical cancer (R/M CC).

On January 5, 2024 Illumina Inc. (NASDAQ: ILMN), a global leader in DNA sequencing and array-based technologies, reported that it has signed an agreement with Janssen Research & Development, LLC (Janssen) (Press release, Illumina, JAN 5, 2024, View Source [SID1234639026]). This collaboration will be the first relating to the development of Illumina’s novel molecular residual disease (MRD) assay, a whole-genome sequencing (WGS) multi-cancer research solution that detects circulating tumor DNA (ctDNA) to better understand the persistence or recurrence of disease following clinical intervention.

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In oncology, MRD testing is increasingly being used as a prognostic indicator of disease recurrence after treatment by helping clinicians assess the effectiveness of a patient’s current course of clinical intervention and guide their decisions about precision therapy. MRD testing for solid tumors shows promise for improving the standard of care where current disease-monitoring tools fall short in accurately identifying patients’ response to treatment.

"This collaboration reflects the value of our unique MRD technology and the promise of Illumina’s whole-genome approach in oncology," said Joydeep Goswami, chief strategy and corporate development officer and chief financial officer of Illumina. "Working together with pharma partners like Janssen, we aim to deliver a sensitive, accurate, and easily accessible whole-genome sequencing MRD assay to advance clinical research in oncology."

The Illumina WGS MRD assay, which is currently in development, will detect ctDNA for MRD assessment in research settings that evaluate samples from patients previously diagnosed with cancer across multiple solid tumor indications. In contrast with existing MRD solutions with complex workflows, Illumina plans to develop a research solution that will provide a cost-effective, highly sensitive, and automated workflow, with the potential to achieve a turnaround time of five to seven days.

Illumina intends to collaborate with other leaders in pharma to help further develop and expand the utility of its WGS MRD assay.

On January 5, 2024 Orion Corporation ("Orion") and MSD (known as Merck & Co., Inc., Rahway, N.J., USA in the United States and Canada) reported to have initiated two pivotal Phase 3 clinical trials evaluating ODM-208/MK5684, an investigational CYP11A1 inhibitor, in combination with hormone replacement therapy (HRT), for the treatment of certain patients with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Orion, JAN 5, 2024, View Source [SID1234639025]). Patients are now enrolling in the trials, named OMAHA1 (NCT06136624) and OMAHA2a (NCT06136650).

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"The start of our co-development Phase 3 program with MSD provides exciting opportunities to evaluate the potential of ODM-208/MK5684 as a novel treatment of mCRPC, both in front-line and late-line patients, including those with and without androgen receptor ligand binding domain (AR LBD) mutations," said Professor Outi Vaarala, Senior Vice President, Innovative Medicines and Research and Development, Orion. "Our ultimate aim is to bring innovative medicines to all patients with unmet need, and we look forward to the beginning of these studies with our partner, MSD."

"By inhibiting CYP11A1 enzyme activity, we believe ODM-208/MK5684 represents a compelling approach to suppress the production of steroid hormones, a key driver of prostate cancer," said Dr. Scot Ebbinghaus, Vice President, global clinical development, MSD Research Laboratories. "The initiation of these two Phase 3 trials of ODM-208/MK5684 in different stages of mCRPC, in collaboration with Orion, demonstrates our continued commitment to exploring innovative new approaches and pathways to treat this complex disease."

OMAHA1 is a randomized, open-label Phase 3 trial evaluating ODM-208/MK5684 in combination with HRT for the treatment of patients with later-line mCRPC who have failed one prior new hormonal agent (NHA) and one or two prior taxane-based chemotherapies compared to an alternative NHA (abiraterone or enzalutamide). The trial will enroll an estimated 1,200 patients around the world. The primary endpoints are overall survival (OS) and radiographic progression-free survival (rPFS) by AR LBD mutation status. Secondary endpoints include time to first subsequent therapy (TFST), objective response rate (ORR) and duration of response (DOR).

OMAHA2a is a randomized, open-label Phase 3 trial evaluating ODM-208/MK5684 in combination with HRT for the treatment of patients with front-line mCRPC who have failed one prior NHA compared to physician’s choice of NHA (abiraterone or enzalutamide). The trial will enroll an estimated 1,500 patients around the world. The primary endpoints are OS and rPFS by AR LBD mutation status. Secondary endpoints include TFST, ORR and DOR.

About ODM-208/MK-5684

ODM-208/MK5684 is an oral, non-steroidal and selective inhibitor of the CYP11A1 enzyme discovered and developed by Orion and is being investigated for the treatment of hormone-dependent cancers, such as prostate cancer. By inhibiting CYP11A1 enzyme activity, ODM-208/MK5684 is designed to suppress the production of all steroid hormones and their precursors that may activate the androgen receptor signaling pathway.

About metastatic castration-resistant prostate cancer

Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body, despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20% of patients with prostate cancer are estimated to develop castration-resistant prostate cancer (CRPC) within five years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. mCRPC is associated with a significant mortality rate.

On January 5, 2024 BioCryst Pharmaceuticals, Inc. (Nasdaq: BCRX) reported preliminary, unaudited ORLADEYO (berotralstat) net revenue for the fourth quarter and full year 2023 (Press release, BioCryst Pharmaceuticals, JAN 5, 2024, View Source [SID1234639024]). The company also provided guidance for full year 2024 ORLADEYO net revenue, full year 2024 operating expenses, expected peak ORLADEYO sales and an accelerated path to profitability.

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"After three years on the market, ORLADEYO continues on a steady growth trajectory to achieve $1 billion at peak. This commercial success, alongside our proven discovery platform that is producing additional first-in-class or best-in-class molecules, uniquely positions BioCryst to achieve financial independence from the capital markets and accelerate our path to profitability," said Jon Stonehouse, president and chief executive officer of BioCryst.

The company also announced that, if its ongoing proof-of-concept trial produces best-in-class data, it plans to out-license late-stage development and commercialization of BCX10013, its potential once-daily, oral Factor D inhibitor, to a partner that can drive the speed and breadth of investment required to accelerate BCX10013 for patients across multiple complement-mediated diseases and maximize the commercial potential of the program. As a result, the company has reduced the size of its R&D organization and accelerated its timeline to profitability.

Preliminary Fourth Quarter and Full Year 2023 ORLADEYO Revenue and 2024 ORLADEYO Outlook
Preliminary, unaudited ORLADEYO net revenue in the fourth quarter of 2023 was $89.9 million (+27 percent y-o-y). Preliminary, unaudited ORLADEYO net revenue for full year 2023 was $325 million (+29 percent y-o-y).

The company expects full year 2024 global net ORLADEYO revenue to be between $380 million and $400 million. The general pattern of revenue throughout 2024 is expected to be similar to past years, with the seasonal impact of prescription reauthorizations and the potential impact of the Inflation Reduction Act in the first quarter driving a quarter-over-quarter revenue decline in the first quarter, followed by a strong return to growth in the second quarter.

"ORLADEYO growth remained strong in the fourth quarter of 2023 as hereditary angioedema patients gain the excellent attack control they expect. Comparing U.S. patient trends year over year (y-o-y), we had more new patient prescriptions and a lower average rate of monthly discontinuations in 2023 compared to 2022. U.S. performance combined with continued global expansion keep ORLADEYO on track for $1 billion in peak sales," said Charlie Gayer, chief commercial officer of BioCryst.

Operating Expense and Profitability Outlook
The company expects full year 2024 operating expenses to be between $365 million and $375 million, flat to expected full year 2023 operating expenses. The company now expects that R&D expenses in 2024 will be reduced by $20 million versus 2023. This represents a $45 million to $55 million reduction from the 2024 R&D expense guidance it provided at its R&D Day in November 2023, and reflects both the R&D restructuring and the postponement of previously planned capital expenditures at its Discovery Center in Alabama. SG&A expenses are expected to increase by $20 million in 2024, primarily to support the continued U.S. and global growth of ORLADEYO to $1 billion in peak sales.

This operating expense outlook does not reflect non-cash stock compensation expense, or one-time expenses related to the reduction of 59 jobs (10 percent of total organization) in the first quarter of 2024.

Based on the company’s disciplined approach to capital allocation, and the revenue expected from ORLADEYO, the company expects to achieve a full-year operating profit in 2024 (not including non-cash stock compensation), be approaching quarterly positive earnings per share (EPS) and positive cash flow in the second half of 2025 (not including non-cash stock compensation), and be profitable on an EPS basis, with positive cash flow, for full year 2026. The company expects it can achieve these financial milestones without raising additional funds and does not intend to draw the additional $150 million of debt available to it from Pharmakon.

Presentation Tuesday at 42nd Annual J.P. Morgan Healthcare Conference
On Tuesday, January 9, 2024 at 6:00 p.m. ET, the company will present at the 42nd Annual J.P. Morgan Healthcare Conference in San Francisco. Links to a live audio webcast and replay of the presentation may be accessed in the Investors section of BioCryst’s website at https://www.biocryst.com/.