On March 14, 2024 Bristol Myers Squibb (NYSE: BMY) reported the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor (Press release, Bristol-Myers Squibb, MAR 14, 2024, View Source [SID1234641184]). This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). In R/R CLL or SLL, Breyanzi is delivered through a treatment process which culminates in a one-time infusion* with a single dose containing 90 to 110 x 106 CAR-positive viable T cells. Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi regarding Cytokine Release Syndrome (CRS), Neurologic Toxicities, and Secondary Hematological Malignancies.

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"CAR T cell therapies represent a transformative treatment option for patients with certain types of blood cancers," said Bryan Campbell, senior vice president, Head of Commercial, Cell Therapy, Bristol Myers Squibb. "For years, attempts to bring other CAR T cell therapies to patients with relapsed or refractory CLL or SLL met challenges and found little success. With the approval of Breyanzi as the first CAR T for relapsed or refractory CLL or SLL, we are now able to offer these patients a personalized option, while further expanding access across the broadest array of B-cell malignancies, to address this critical unmet need."

CLL and SLL are among the most common types of B-cell lymphoma. Treatments for people living with CLL or SLL primarily consist of targeted therapies including BTK- and BCL-2 inhibitors. However, patients often experience relapse or become refractory following early-line treatment with these therapies and there is no established standard of care for patients with double-class exposed CLL or SLL. After relapsing or becoming refractory to these therapies, patients have few options and poor outcomes, including lack of durable complete responses.

The Phase 1/2 open-label, single-arm TRANSCEND CLL 004 study was the first pivotal multicenter trial to evaluate a CAR T cell therapy in patients with relapsed or refractory CLL or SLL. The CR rate associated with Breyanzi treatment was 20% (95% CI: 11.1-31.8). Among patients who achieved a CR, median duration of response was not reached (95% CI: 15 months-NR) at the time of data cutoff. Among all responders (ORR = 45%; 95% CI: 32.3-57.5), median duration of response was 35.3 months (95% CI: 12.4-NR). High rates of minimal residual disease (MRD) negative status were observed across patients treated with Breyanzi who achieved a CR, with an MRD-negativity rate of 100% in the blood (95% CI: 75.3-100) and 92.3% in the bone marrow (95% CI: 64-99.8).

"CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses, something that has historically been associated with improved long-term outcomes," said Tanya Siddiqi, M.D., lead investigator and Associate Professor, Division of Lymphoma, City of Hope National Medical Center. "The FDA approval of liso-cel in relapsed or refractory CLL and SLL after treatment with prior BTKi and BCL2i is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission."

Among 89 patients in the study treated with Breyanzi, occurrences of cytokine release syndrome (CRS) and neurologic events (NEs) were mostly low grade. Any grade CRS occurred in 83% of patients, with Grade 3 CRS occurring in 9% of patients. No Grade 4/5 CRS events were reported. Any grade NEs were reported in 46% of patients, with Grade 3 NEs reported in 20% of patients and one case of Grade 4 NE reported. No Grade 5 NEs were reported.

"For people struggling with relapsed or refractory CLL or SLL, current treatment choices are limited," said Dr. Brian Koffman, physician, CLL patient and cofounder, executive vice president and chief medical officer of CLL Society. "The approval of Breyanzi as the first CAR T cell therapy available for relapsed or refractory CLL or SLL brings new hope to these patients with the potential for durable responses after a single CAR T infusion. We are grateful to the patients and their families who enter the trials and to all the researchers involved in making possible this important new treatment option in CLL and SLL."

Bristol Myers Squibb offers various programs and resources to address the needs of patients and caregivers, and provides support that allows for access to therapies, including Breyanzi. Bristol Myers Squibb also supports the patient and physician treatment experience by providing Cell Therapy 360, a digital service platform, which optimizes access to relevant information, manufacturing updates, and patient and caregiver support.

About TRANSCEND CLL 004

TRANSCEND CLL 004 (NCT03331198) is a Phase 1/2 open-label, single-arm, multicenter study evaluating Breyanzi in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The Phase 1 dose escalation portion of the study assessed the safety and recommended dose for the subsequent Phase 2 expansion cohort. The Phase 2 portion of the study is evaluating Breyanzi at the recommended dose from the Phase 1 monotherapy arm. The primary endpoint of the Phase 2 portion of the study is complete response rate, including complete remission with incomplete bone marrow recovery, based on independent review committee according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines.

About CLL and SLL

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults. In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes, and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets. Small lymphocytic lymphoma (SLL) also affects the lymphocytes, with cancer cells found mostly in the lymph nodes. While there are several treatments available for CLL and SLL, there is a need for additional effective therapies as there is no standard of care for relapsed or refractory CLL or SLL after prior therapy with targeted agents, such as Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors. Patients with relapsed or refractory disease have limited treatment options and generally experience shorter periods of response with each subsequent treatment.

About Breyanzi

Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is made from a patient’s own T cells, which are collected and genetically reengineered to become CAR T cells that are then delivered via infusion as a one-time treatment.

Breyanzi is approved in the U.S., Japan and Europe for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland, and Canada for relapsed and refractory LBCL after two or more lines of systemic therapy. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in other types of lymphoma. For more information, visit clinicaltrials.gov.

* Treatment process includes leukapheresis, manufacturing, administration, and adverse event monitoring.

Indication

BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
relapsed or refractory disease after two or more lines of systemic therapy.
Limitations of Use: BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma.

adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.
This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Important Safety Information

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome

Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Among patients receiving BREYANZI for LBCL (N=418), CRS occurred in 46% (190/418), including ≥ Grade 3 CRS in 3.1% of patients. In patients receiving BREYANZI after two or more lines of therapy for LBCL, CRS occurred in 46% (122/268), including ≥ Grade 3 CRS in 4.1% of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 98% with a median duration of 5 days (range: 1 to 17 days). In patients receiving BREYANZI after one line of therapy for LBCL, CRS occurred in 45% (68/150), including Grade 3 CRS in 1.3% of patients. The median time to onset was 4 days (range: 1 to 63 days). CRS resolved in all patients with a median duration of 4 days (range: 1 to 16 days).

Among patients receiving BREYANZI for CLL/SLL, CRS occurred in 83% (74/89), including Grade 3 CRS in 9% of patients. The median time to onset was 4 days (range: 1 to 18 days). CRS resolved in 97% with a median duration of 6 days (range: 2 to 37 days).

The most common manifestations of CRS (≥ 10% in LBCL or CLL/SLL) included fever (94% LBCL; 97% CLL/SLL), hypotension (42% LBCL; 46% CLL/SLL), tachycardia (28% LBCL), chills (23% LBCL; 43% CLL/SLL), hypoxia (16% LBCL; 35% CLL/SLL), sinus tachycardia (22% CLL/SLL), and headache (12% LBCL; 18% CLL/SLL).

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Of the patients who received BREYANZI for LBCL (n=418) and CLL/SLL (n=89), 23% (LBCL) and 64% (CLL/SLL) received tocilizumab and/or a corticosteroid for CRS, including 10% (LBCL) and 33% (CLL/SLL) who received tocilizumab only and 2.2% (LBCL) and 2.2% (CLL/SLL) who received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.

In patients receiving BREYANZI after two or more lines of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 35% (95/268), including ≥ Grade 3 cases in 12% of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of neurotoxicity was 8 days (range: 1 to 46 days). Neurologic toxicities resolved in 85% of patients with a median duration of 12 days (range: 1 to 87 days). In patients receiving BREYANZI after one line of therapy for LBCL, CAR T cell-associated neurologic toxicities occurred in 27% (41/150) of patients, including Grade 3 cases in 7% of patients. The median time to onset of neurologic toxicity was 8 days (range: 1 to 63 days). The median duration of neurologic toxicity was 6 days (range: 1 to 119 days). In all patients combined receiving BREYANZI for LBCL, CAR T cell-associated neurologic toxicities occurred in 33% (136/418), including ≥ Grade 3 cases in 10% of patients. The median time to onset was 8 days (range: 1 to 63), with 87% of cases developing by 16 days. Neurologic toxicities resolved in 85% of patients with a median duration of 11 days (range: 1 to 119 days). Of patients developing neurotoxicity, 77% (105/136) also developed CRS.

In patients receiving BREYANZI for CLL/SLL, CAR T cell-associated neurologic toxicities occurred in 46% (41/89), including Grade 3 cases in 20% of patients and a single Grade 4 case. The median time to onset of neurotoxicity was 7 days (range: 1 to 21 days), with 95% of cases developing by 16 days. Neurologic toxicities resolved in 85% with a median duration of 7 days (range: 1 to 83 days). Of patients developing neurotoxicity, 95% (39/41) also developed CRS.

The most common neurologic toxicities (≥ 5% in LBCL or CLL) included encephalopathy (20% LBCL; 36% CLL/SLL), tremor (13% LBCL; 14% CLL/SLL), aphasia (8% LBCL; 8% CLL/SLL), headache (6% LBCL; 9% CLL/SLL), dizziness (6% LBCL), and delirium (5% LBCL; 12% CLL/SLL).

CRS and Neurologic Toxicities Monitoring

Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Further information is available at www.BreyanziREMS.com, or contact Bristol-Myers Squibb at 1-866-340-7332.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In patients receiving BREYANZI, infections of any grade occurred in 36% (LBCL) and 35% (CLL/SLL), with Grade 3 or higher infections occurring in 12% (LBCL) and 16% (CLL/SLL) of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7% (LBCL) and 10% (CLL/SLL), bacterial infections in 4.3% (LBCL) and 2.2% (CLL/SLL), viral infections in 1.9% (LBCL) and 1.1% (CLL/SLL), and fungal infections in 0.5% (LBCL) and 2.2% (CLL/SLL).

Febrile neutropenia developed after BREYANZI infusion in 8% (LBCL) and 12% (CLL/SLL) of patients. Febrile neutropenia may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. In patients who received BREYANZI, 15 of 16 LBCL patients, and all 9 CLL/SLL patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 36% (LBCL) and 45% (CLL/SLL) of patients, and included thrombocytopenia in 28% (LBCL) and 23% (CLL/SLL), neutropenia in 21% (LBCL) and 35% (CLL/SLL), and anemia in 6% (LBCL) and 12% (CLL/SLL). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In patients receiving BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 11% (LBCL) and 14% (CLL/SLL) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 28% (LBCL) and 37% (CLL/SLL) of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1- 888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.

Adverse Reactions

The most common nonlaboratory adverse reactions (incidence ≥ 30%) in:

LBCL are fever, cytokine release syndrome, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities (≥ 30%) include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.
CLL/SLL are cytokine release syndrome, encephalopathy, fatigue, musculoskeletal pain, nausea, and diarrhea. The most common Grade 3-4 laboratory abnormalities (≥ 30%) in CLL/SLL include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease.
Please see full Prescribing Information, including Boxed WARNINGS and Medication Guide.

On March 14, 2024 Prelude Corporation (PreludeDx), a leader in precision diagnostics, reported data from an analysis of over 700 early-stage invasive breast cancer patients for AidaBreast – a novel biosignature that predicts 10-year recurrence rate and radiation therapy (RT) benefit – at the 41st Annual Miami Breast Cancer Conference (MBCC) (Press release, PreludeDx, MAR 14, 2024, View Source [SID1234641183]).

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Building on the clinical adoption of the company’s initial test offering, DCISionRT, which predicts radiation benefit for patients with ductal carcinoma in situ (DCIS), AidaBreast will provide personalized testing to the larger Stage I and IIA breast cancer market. AidaBreast is powered by a multi-omic platform utilizing proteomic and genomic analyses, and offers a unique, differentiated approach to determine individual patient risk profiles. The first test in the AidaBreast portfolio will be for the assessment of radiation therapy benefit.

"We are very encouraged by the predictive data presented at the Miami Breast Cancer Conference. We look forward to the launch of AidaBreast to initially assist with radiation treatment decisions, and soon after to help answer additional therapeutic questions, so that we can significantly increase our clinical impact in the broader breast cancer market," said Dan Forche, President and CEO of PreludeDx. "Our focus remains on delivering precision diagnostics to enhance shared decision-making between physicians and their patients."

The poster entitled, ‘A Novel Biosignature for Early-Stage Invasive Breast Cancer to Predict Radiotherapy Benefit and Assess Recurrence Risk for Patients Treated with Breast-Conserving Surgery’, demonstrates the potential of the assay to predict radiation benefit in over 700 patients diagnosed with hormone receptor-positive, HER2-negative, Stage I, IIA, node negative, no evidence of metastasis breast cancer who underwent breast conserving surgery (BCS) with or without RT. The biosignature identified clinically meaningful risk groups with differential RT benefit associated with 10-year recurrence rate. The identified low-risk group had a recurrence rate of 1% with or without RT. The elevated risk group had a recurrence rate of 20% without RT and 13% with RT. The residual risk group had a recurrence rate of 30% with or without RT.

"While tests for predicting the benefit of chemotherapy and endocrine therapy currently exist for early-stage breast cancer patients, AidaBreast addresses the gap for assessing radiation therapy benefit," said Chirag Shah, MD, radiation oncologist at Cleveland Clinic, co-director of the comprehensive breast cancer program, and director of breast radiation oncology. "The test fills a long-needed void in providing better tools which can optimize shared treatment decision-making based on each patient’s unique biology."

PreludeDx Additional Poster Presentations at MBCC 2024:

A Comparative Analysis of Changes in Treatment Recommendation for Black and White Patients with Ductal Carcinoma in Situ Using a 7-Gene Predictive Biosignature: Analysis of the PREDICT Study

Limitations in the Application of Clinicopathologic Factors Alone in Predicting Radiation Benefit for Women with Low-Risk DCIS after Breast Conserving Surgery: The Impact of a 7-Gene Biosignature Based on 10-year Ipsilateral Breast Recurrence (IBR) Rates

About DCISionRT for Breast DCIS

DCISionRT is the only risk assessment test for patients with ductal carcinoma in situ (DCIS) that predicts radiation therapy benefit. Patients with DCIS have cancerous cells lining the milk ducts of the breast, but they have not spread into surrounding breast tissue. In the US, over 60,000 women are newly diagnosed with DCIS each year. DCISionRT, developed by PreludeDx on technology licensed from the University of California San Francisco, and built on research that began with funding from the National Cancer Institute, enables physicians to better understand the biology of DCIS. DCISionRT combines the latest innovations in molecular biology with risk-based assessment scores to assess a woman’s individual tumor biology along with other pathologic risk factors and provide a personalized recurrence risk. The test provides a Decision Score that identifies a woman’s risk as low or elevated. Unlike other risk assessment tools, the DCISionRT test combines protein expression from seven biomarkers and four clinicopathologic factors, using a non-linear algorithm to account for multiple interactions between individual factors in order to better interpret complex biological information. DCISionRT’s intelligent reporting provides a woman’s recurrence risk after breast conserving surgery alone and with the addition of radiation therapy. In turn, this new information may help patients and their physicians to make more informed treatment decisions.

On March 14, 2024 I-Mab (the "Company") (NASDAQ: IMAB), a U.S.-based, global biotech company, exclusively focused on the development and potential commercialization of highly differentiated immunotherapies for the treatment of cancer, reported financial results for the full year ended December 31, 2023, and highlighted recent business updates (Press release, I-Mab Biopharma, MAR 14, 2024, View Source [SID1234641182]).

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"2023 was a transitional year for I-Mab and we were pleased to report encouraging clinical results in our two lead global assets in oncology, uliledlimab and givastomig. As we prepare for the closing of the strategic divestiture, we look forward to providing investors with a road map to value creation and believe that our differentiated clinical assets, uliledlimab, givastomig, and ragistomig will achieve critical milestones and trial initiations this year," said Raj Kannan, Director and Chief Executive Officer of I-Mab.

Pipeline Overview and Upcoming Milestones:

Uliledlimab: Phase 2, with a focus on non-small cell lung cancer (NSCLC)

Uliledlimab is designed to target CD73 and promote stronger activation of the patient’s immune system against cancer cells. Uliledlimab is potentially differentiated from other products in development due to its non-competitive binding with adenosine monophosphate and the potential for complete inhibition of CD73’s immune dampening function. Encouraging results from a Phase 2 study of uliledlimab in combination with toripalimab, presented at the American Society for Clinical Oncology (ASCO 2023) in patients with advanced NSCLC, provided compelling support for further development of uliledlimab. In particular, the subset of patients with both high CD73 expression and PD-L1 TPS>1% showed an impressive 63% overall response rate. Additionally, enrollment of patients with treatment resistant ovarian cancer has been completed, and ongoing efforts will be streamlined to focus on expediting NSCLC development.

Upon the receipt of the investigational new drug (IND) approval, the Company plans to initiate the triplet study for uliledlimab in combination with chemotherapy and checkpoint inhibitors in newly diagnosed patients with advanced NSCLC in the second half of 2024.
Givastomig (Claudin 18.2 x 4-1BB bispecific antibody): Phase 1b, with a focus on gastric cancer and esophageal adenocarcinoma

Givastomig was designed as a bispecific antibody to target Claudin 18.2-positive tumor cells, with conditional activation of pro-immune 4-1BB in the tumor microenvironment. Phase 1 monotherapy data presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) (ESMO 2023) showed encouraging objective responses in patients with gastric cancer and esophageal adenocarcinoma whose tumors progressed or recurred after prior standard treatments, including those with low levels of Claudin 18.2 expression. This program is being jointly developed with ABL Bio. I-Mab owns 50% of the global rights of givastomig.

The enrollment of patients from the U.S. and China with newly diagnosed (frontline treatment) gastric and esophageal cancer in combination with chemotherapy and a checkpoint inhibitor began in the first quarter of 2024.
Ragistomig (PD-L1 x 4-1BB bispecific antibody): Phase 1 dose escalation, with a focus on solid tumors

Ragistomig was designed as a bispecific antibody to address PD-L1 resistant tumors, differentiated by the conditional activation of 4-1BB’s pro-immune stimulation when it binds to its PD-L1 target. Early observations reported by our development partner, ABL Bio, showed promising objective responses in patients with various solid tumors whose tumors progressed or recurred after prior standard treatments, including in patients with relapsed or refractory cancer after prior PD-L1 inhibitors. These early signs of efficacy are encouraging, and enrollment in the Phase 1 study continues. This program is being jointly developed with ABL Bio. I-Mab owns 50% of the global rights of ragistomig (TJ-L14B/ABL503).

Top-line Phase 1 dose escalation and dose expansion results are expected to be presented at a major medical conference in the first half of 2024.
Impact of Strategic Transaction on Pipeline

The agreement to divest assets and business operations in China, previously announced in a press release on February 7, 2024, is expected to be completed by the end of March 2024. Upon the closing of the transaction, the Greater China rights for assets including eftansomatropin alfa, felzartamab, uliledlimab, and givastomig will be transferred to I-Mab Biopharma (Hangzhou) Co., Ltd., an unconsolidated affiliate (the "Hangzhou Company"). I-Mab will no longer bear future development costs of these divested assets in China and may receive an aggregate consideration of the RMB equivalent of up to US$80 million, contingent on the Hangzhou Company group’s achievement of certain future regulatory and sales-based milestone events relating to these divested assets in China. The transaction, if closed, will also extinguish existing repurchase obligations owed by a wholly-owned subsidiary of the Company in the amount of approximately US$183 million.

As a result of the closing of the transaction, the Company will cease consolidation of the divested entities, assets, and businesses as well as their corresponding financial results. The Company’s financial condition and results of operations will be materially affected and the Company’s historical results will not be indicative of future financial condition or results of operations.

Full-Year 2023 Financial Results

Cash Position

As of December 31, 2023, the Company had cash, cash equivalents, and short-term investments of RMB2.3 billion (US$321.8 million), compared with RMB3.5 billion as of December 31, 2022.

Share Buyback

In August 2023, the Board of Directors of the Company authorized a new share repurchase program under which the Company may repurchase up to US$40 million of American Depository Shares ("ADSs"), each ten ADSs representing 23 ordinary shares of the Company, or ordinary shares in aggregate over a 12-month period. During the period ended December 31, 2023, the Company repurchased US$8.6 million of its ADSs, equating to 4,633,386 ADSs or 10,656,794 ordinary shares. As of December 31, 2023, the Company had issued and outstanding ordinary shares of 185,613,662, representing the equivalent of 80,701,592 ADSs assuming the conversion of all ordinary shares into ADSs.

Net Revenues

Total net revenues for the full year of 2023 were RMB27.6 million (US$3.9 million), compared with RMB-221.6 million (US$-32.1 million) for the full year of 2022. Total net revenues in 2023 consisted of revenues recognized in connection with the strategic collaboration with AbbVie Inc. (AbbVie) and revenues generated from the supply of investigational products to AbbVie and Human Immunology Biosciences, Inc. The negative figure for net revenue in 2022 was primarily due to a one-time, non-cash accounting treatment of US$-48.0 million (equivalent to RMB-314.2 million) recorded in the second half of 2022 following the amendment to the original license and collaboration agreement with AbbVie in August 2022. This amendment led to a reduced probability of achieving a key milestone that was included in the consideration of revenue recognition in prior years.

Research & Development Expenses

Research and development expenses for the full year of 2023 were RMB810.6 million (US$114.2 million), compared with RMB904.9 million (US$131.2 million) for the full year of 2022. The decrease was primarily due to reduced payroll expenses related to headcount optimization as a result of asset prioritization and reduced share-based compensation expenses. Share-based compensation expense was RMB66.8 million (US$9.4 million) for the full year of 2023, compared with RMB117.9 million (US$17.1 million) for the full year of 2022.

Administrative Expenses

Administrative expenses for the full year of 2023 were RMB453.0 million (US$63.8 million), compared with RMB815.8 million (US$118.3 million) for the full year of 2022. The decrease was primarily due to reduced payroll expenses related to decreased headcount as a result of resource optimization and reduced share-based compensation expenses for management personnel, reduced expenses for professional services, and reduced legal expenses in relation to the disputes with Tracon Pharmaceuticals, Inc. of RMB95.5 million (US$13.5 million). Share-based compensation expense was RMB126.2 million (US$17.8 million) for the full year of 2023, compared with RMB239.3 million (US$34.7 million) for the full year of 2022.

Other Expenses, Net

Net other expenses for the full year of 2023 were RMB38.1 million (US$5.4 million), compared with RMB126.6 million (US$18.4 million) for the full year of 2022. The change was primarily driven by unrealized exchange rate losses due to the significant fluctuation in the exchange rate of the Renminbi against the U.S. dollar in 2022.

Equity in Loss of Affiliates

Equity in loss of affiliates for the full year of 2023 was RMB80.0 million (US$11.3 million), compared with RMB437.5 million (US$63.4 million) for the full year of 2022. The loss was mainly recognized in relation to the operating loss of the Company’s investee, I-Mab Biopharma (Hangzhou) Co., Ltd.

Impairment of Goodwill

For the full year of 2023, the Company recognized an impairment of goodwill of RMB162.6 million (US$22.9 million). The goodwill impairment resulted from the Company’s annual impairment analysis, and reflects the continued disconnect between I-Mab’s anticipated future performance and present uncertainty reflected in its market valuation.

Net Loss

Net loss for the full year of 2023 was RMB1,465.7 million (US$206.4 million), compared with RMB2,507.3 million (US$363.5 million) for the year 2022. Net loss per share attributable to ordinary shareholders for the full year of 2023 was RMB7.19 (US$1.01), compared with RMB13.21 (US$1.92) for the full year of 2022. Net loss per ADS attributable to ordinary shareholders for the full year of 2023 was RMB16.54 (US$2.33), compared with RMB30.38 (US$4.41) for the full year of 2022.

On March 14, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported financial results for the three months and full year ended December 31, 2023, and highlighted recent progress (Press release, Verastem, MAR 14, 2024, View Source [SID1234641181]).

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"In 2023, we made significant progress toward expanding the opportunities for avutometinib combination therapies across RAS/MAPK driven cancers and I am extremely proud of the team’s accomplishments," said Dan Paterson, president and chief executive officer of Verastem Oncology. "2024 is expected to be a pivotal year with the planned NDA submission for our avutometinib and defactinib combination in recurrent LGSOC, and multiple clinical data readouts across our programs including initial data from the RAMP 205 trial in metastatic pancreatic cancer and data from the combination with G12C inhibitors in NSCLC. We look forward to continuing to deliver results across our programs."

Fourth Quarter 2023 and Recent Highlights

Avutometinib and Defactinib Combination in Low-Grade Serous Ovarian Cancer (LGSOC)

Initiated international confirmatory Phase 3 RAMP 301 trial evaluating the avutometinib and defactinib combination versus standard of care chemotherapy or hormonal therapy for the treatment of recurrent LGSOC in December 2023 to support potential full approval.
Reported results of a planned subgroup analysis of Part A of the Phase 2 RAMP 201 trial evaluating avutometinib and defactinib combination in recurrent LGSOC, which demonstrated promising efficacy in patients regardless of number and class of prior therapies including after poor response to prior therapy at the Annual Global Meeting of the International Gynecologic Cancer Society meeting in November 2023.
Launched patient and healthcare professional programs, including Let’s Talk About LGSOC, to support clinicians in the diagnosis and management of LGSOC and provide information and resources to patients.
Received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) in March 2024 for avutometinib alone or in combination with defactinib for the treatment of all patients with recurrent LGSOC.
Verastem anticipates the following milestones for avutometinib and defactinib combination in LGSOC in 2024:

On track to submit a rolling New Drug Application (NDA) for Accelerated Approval for the avutometinib and defactinib combination in LGSOC in H1 2024. Preparations for a potential U.S. commercial launch in 2025 are ongoing and plans to initiate discussions with European and Japanese regulatory authorities to address patient needs outside the U.S. continue to advance.
Plan to announce updated topline data from RAMP 201 trial in LGSOC in H1 2024.
Avutometinib in Combination with KRAS G12C Inhibitors in Non-Small Cell Lung Cancer (NSCLC)

Received Fast Track designation from the FDA for avutometinib, in combination with Amgen’s G12C inhibitor, LUMAKRAS (sotorasib), for the treatment of patients with KRAS G12C-mutant metastatic NSCLC who have received at least one prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor, in January 2024.
Presented initial results from Phase 1/2 RAMP 203 trial evaluating the efficacy and safety of avutometinib and sotorasib in patients with KRAS G12C-mutant NSCLC who have or have not been previously treated with a KRAS G12C inhibitor at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in October 2023. The confirmed objective rate of response (ORR) was 25% with responses observed in both KRAS G12C inhibitor resistant and naïve patients, and a recommended Phase 2 dose was selected.
Added defactinib to RAMP 203 trial of avutometinib with sotorasib based on stronger tumor regressions in KRAS G12C-mutant NSCLC preclinical models when FAKi is added along with G12Ci + avutometinib.
Verastem anticipates the following milestones for avutometinib in combination with KRAS G12C inhibitors in 2024:

Data updates from patients with KRAS G12C-mutant NSCLC in the Phase 1/2 RAMP 203 trial evaluating avutometinib and sotorasib and the Phase 1/2 RAMP 204 trial evaluating avutometinib and adagrasib are planned for mid-2024.
Avutometinib and Defactinib Combination in Frontline Metastatic Pancreatic Cancer

Plan to present initial safety and efficacy results from RAMP 205 trial of avutometinib and defactinib in combination with current standard of care gemcitabine and nab-paclitaxel in frontline metastatic pancreatic cancer in H1 2024.
GFH375 (VS-7375): Oral KRAS G12D (ON/OFF) Inhibitor

Completed investigational new drug (IND)-enabling studies for oral KRAS G12D (ON/OFF) inhibitor GFH375 (VS-7375), the lead program in the collaboration with GenFleet Therapeutics ("GenFleet").
GenFleet is expected to submit an IND application for GFH375 (VS-7375) in China in H1 2024 with plans to begin a Phase 1 trial in H2 2024. Discovery/lead optimization continues for second and third programs.
Upcoming Presentations

Verastem previously announced the acceptance of multiple abstracts for presentation at upcoming medical conferences:

Multiple abstracts were selected for oral and poster presentations at the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer on March 16-18 in San Diego. These presentations will include a late-breaking oral presentation on a planned subgroup analysis of Part A of the Phase 2 RAMP 201 trial of avutometinib and defactinib combination of heavily pretreated patients with LGSOC and a plenary oral presentation of preclinical efficacy data of avutometinib in combination with a FAK inhibitor in recurrent LGSOC as well as a trials-in-progress poster about the Phase 3 RAMP 301 trial. See press release here.
Five preclinical data abstracts were accepted for poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 on April 5-10 in San Diego. These presentations will highlight anti-tumor efficacy data of GFH375 (VS-7375), data on RAF/MEK clamp avutometinib and FAK inhibition in pancreatic ductal adenocarcinoma models supporting the ongoing RAMP 205 trial, and avutometinib and a FAK inhibitor combination in cutaneous melanoma models to overcome resistance to BRAF and MEK inhibitors, resistance to immunotherapy, and brain metastasis. See press release here.
Corporate Updates

Strengthened the executive leadership team with appointments of Mike Crowther to Chief Commercial and Business Strategy Officer and the promotion of Dan Calkins to Chief Financial Officer in October 2023.
Fourth Quarter 2023 Financial Results

Verastem Oncology ended the fourth quarter of 2023 with cash, cash equivalents and investments of $137.1 million.

Total operating expenses for the three months ended December 31, 2023 (the "2023 Quarter") were $31.1 million, compared to $16.8 million for the three months ended December 31, 2022 (the "2022 Quarter").

Research & development expenses for the 2023 Quarter were $22.5 million, compared to $10.7 million for the 2022 Quarter. The increase of $11.8 million, or 110.3%, primarily resulted from increased contract research organization costs, increased drug substance and drug product costs, and increased personnel costs, including non-cash stock compensation.

Selling, general & administrative expenses for the 2023 Quarter were $8.6 million, compared to $6.1 million for the 2022 Quarter. The increase of $2.5 million, or 41.0%, was primarily related to increased personnel costs, including non-cash stock compensation, increased consulting and professional fees, and additional costs in anticipation of a potential launch of avutometinib and defactinib in LGSOC.

Net loss for the 2023 Quarter was $27.4 million, or $1.02 per share (basic and diluted), compared to a net loss of $16.8 million, or $0.99 per share (basic and diluted, each as adjusted for the Company’s reverse stock split), for the 2022 Quarter.

For the 2023 Quarter, non-GAAP adjusted net loss was $29.6 million, or $1.10 per share (diluted), compared to non-GAAP adjusted net loss of $15.4 million, or $0.90 per share (diluted, as adjusted for the Company’s reverse stock split), for the 2022 Quarter. Please refer to the GAAP to Non-GAAP Reconciliation attached to this press release.

Full-Year 2023 Financial Results

Total operating expenses for the year ended December 31, 2023 (the "2023 Period") were $92.1 million, compared to $75.5 million for the year ended December 31, 222 (the "2022 Period").

Research & development expenses for the 2023 Period were $61.4 million, compared to $50.6 million for the 2022 Period. The increase of $10.8 million, or 21.3%, was primarily related to increases in contract research organization costs, the $2.0 million upfront payment made to GenFleet pursuant to the collaboration and option agreement, and increased personnel costs, including non-cash stock compensation.

Selling, general & administrative expenses for the 2023 Period were $30.7 million, compared to $25.0 million for the 2022 Period. The increase of $5.7 million, or 22.8%, was primarily related to increased personnel costs, including non-cash stock compensation, additional costs in anticipation of a potential launch of avutometinib and defactinib in LGSOC, and increased consulting and professional fees.

Net loss for the 2023 Period was $87.4 million, or $3.96 per share (basic and diluted, each as adjusted for the Company’s reverse stock split), compared to $73.8 million, or $4.57 per share (basic and diluted, each as adjusted for the Company’s reverse stock split) for the 2022 Period.

For the 2023 Period, non-GAAP adjusted net loss was $85.2 million, or $3.86 per share (diluted, as adjusted for the Company’s reverse stock split), compared to non-GAAP adjusted net loss of $67.4 million, or $4.18 per share (diluted, as adjusted for the Company’s reverse stock split), for the 2022 Period. Please refer to the GAAP to non-GAAP Reconciliation attached to this press release.

Use of Non-GAAP Financial Measures

To supplement Verastem Oncology’s condensed consolidated financial statements, which are prepared and presented in accordance with generally accepted accounting principles in the United States (GAAP), the Company uses the following non-GAAP financial measures in this press release: non-GAAP adjusted net loss and non-GAAP net loss per share. These non-GAAP financial measures exclude certain amounts or expenses from the corresponding financial measures determined in accordance with GAAP. Management believes this non-GAAP information is useful for investors, taken in conjunction with the Company’s GAAP financial statements, because it provides greater transparency and period-over- period comparability with respect to the Company’s operating performance and can enhance investors’ ability to identify operating trends in the Company’s business. Management uses these measures, among other factors, to assess and analyze operational results and trends and to make financial and operational decisions. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of the Company’s operating results as reported under GAAP, not in isolation or as a substitute for, or superior to, financial information prepared and presented in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. The determination of the amounts that are excluded from non-GAAP financial measures is a matter of management judgment and depends upon, among other factors, the nature of the underlying expense or income amounts. Reconciliations between these non-GAAP financial measures and the most comparable GAAP financial measures for the three months and year ended December 31, 2023 and 2022 are included in the tables accompanying this press release after the unaudited condensed consolidated financial statements.

About the Avutometinib and Defactinib Combination

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors. The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for the combination of Verastem Oncology’s investigational RAF/MEK clamp avutometinib, with defactinib, a selective FAK inhibitor, for the treatment of all patients with recurrent LGSOC regardless of KRAS status after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.

Verastem Oncology is currently conducting clinical trials with its RAF/MEK clamp avutometinib in RAS/MAPK driven tumors as part of its (Raf And Mek Program). RAMP 301 (NCT06072781) is a Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent LGSOC. RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and enrollment has been completed in each of the dose optimization and expansion phases and the low-dose evaluation.

Verastem Oncology has established clinical collaborations with Amgen and Mirati to evaluate LUMAKRAS (sotorasib) in combination with avutometinib and defactinib and KRAZATI (adagrasib) in combination with avutometinib in KRAS G12C mutant NSCLC as part of the RAMP 203 (NCT05074810) and RAMP 204 (NCT05375994) trials, respectively. Supported by the "Therapeutic Accelerator Award" received from PanCAN, Verastem Oncology is conducting RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer.

About GFH375 (VS-7375)

GFH375 (VS-7375) is a potential best-in-class, potent and selective oral KRAS G12D (ON/OFF) inhibitor, identified as the lead program from the Verastem Oncology discovery and development collaboration with GenFleet Therapeutics. GenFleet plans to submit an IND in China for GFH375 (VS-7375) in the first half of 2024, and upon approval GenFleet is expected to initiate a Phase 1 trial in China in the second half of 2024. The collaboration includes three discovery programs, the first being the KRAS G12D inhibitor, and will provide Verastem Oncology with exclusive options to obtain licenses to each of the three compounds in the collaboration after successful completion of pre-determined milestones in Phase 1 trials. The licenses would give Verastem Oncology development and commercialization rights outside of the GenFleet territories of mainland China, Hong Kong, Macau, and Taiwan.

On March 14, 2024 Molecular Partners AG (SIX: MOLN; NASDAQ: MOLN), a clinical-stage biotech company developing a new class of custom-built protein drugs known as DARPin therapeutics, reported its corporate highlights and audited financial results for the full year 2023 (Press release, Molecular Partners, MAR 14, 2024, View Source [SID1234641180]).

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"2023 was a year of successful innovation and execution on our strategy, focusing on novel mechanisms that we believe only DARPin therapies can deliver. The encouraging new clinical and preclinical data across our portfolio illustrate the versatility and differentiated promise of DARPin therapies and our long-term leadership in this field," said Patrick Amstutz, Ph.D. Molecular Partners’ Chief Executive Officer. "In 2024, we look forward to presenting further clinical data from our lead oncology program MP0533, and translating our significant progress across the Radio-DARPin Therapy and Switch-DARPin platforms into initiation of IND-enabling studies."

Research & Development

MP0533
In December 2023, the Company presented positive initial data from the first four dosing cohorts of its ongoing Phase 1/2a trial of MP0533 at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. Results from the first 11 patients treated with MP0533 indicated an acceptable safety profile as of the data cut-off across all four dosing regimens (DRs), with no dose-limiting toxicities observed. Two responders were observed at the time of presentation, including a patient achieving a complete response (CR) in DR 4 and another patient with morphological leukemia-free state (MLFS) in DR 3. These responses are particularly notable for having occurred at dose levels below those predicted as therapeutically active.

MP0533 is a novel tetra-specific T cell-engaging DARPin, which simultaneously targets the antigens CD33, CD123, and CD70 on AML cells as well as the immune activator CD3 on T cells. AML cells display higher co-expression at least two of these target antigens as compared with healthy cells. MP0533 binds with increasing avidity as the number of its target antigens present increases, dramatically favoring binding to AML cells over healthy cells. This unique avidity-driven mode of action is designed to enable T cell-mediated killing of AML cells while preserving a therapeutic window that minimizes damage to healthy cells.

The Phase 1/2a study is on track with dosing in DR 6 currently ongoing. The Company expects to present data from further cohorts receiving MP0533 in H1 2024. Based on current safety and tolerability data from the ongoing study, and based on discussion with treating investigators and key opinion leaders, a protocol amendment is being filed to expand enrollment to additional higher dose cohorts of MP0533 beyond the initially planned highest cohort (DR 7). The goal of the additional higher doses will be to explore the full potential efficacy of MP0533. The Company expects to enroll patients in the added higher cohorts seamlessly in H2 2024.

Switch-DARPin Platform
In 2023, the Company introduced the Switch-DARPin platform and presented data evidencing its mechanism-of-action. The Switch-DARPin platform represents a further evolution of the Company’s capabilities to deliver multispecific candidates to address different disease needs. The Switch-DARPin platform provides a logic-gated "on/off" function (the "Switch") to multispecific DARPin candidates leading to activation only in the presence of defined antigens. The objective is conditional activation of a targeted immune response.

In January 2024, the first program from the Switch-DARPin platform was introduced at the 42nd Annual J.P. Morgan Healthcare Conference, namely a cKIT x CD16a x CD47 multispecific Switch-DARPin candidate designed as next-generation targeted conditioning regimen for hematopoietic stem cell transplantation (HSCT) in AML and other diseases benefiting from HSCT such as genetic diseases. The cKIT x CD16a x CD47 Switch-DARPin program is designed to induce exhaustive killing of stem cells to increase long-term disease control post HSCT for AML patients, including those with a poor cytogenetic risk profile, and those currently not eligible for standard high-intensity conditioning. Our intent is to extend the access to potentially curative HSCT for more patients with AML and beyond.

The target-by-target rationale for this program’s design is:

cKIT is critical for stem cell maintenance and renewal and thus expressed on both hematopoietic and leukemic stem cells.
The CD16a DARPin engages NK cells and macrophages to selectively kill cKIT-positive cells.
The Switch-DARPin will block the CD47 "don’t eat me" signal only when the molecule binds on cKIT-positive cells, leveraging the power of CD47 inhibition without its associated toxicity to healthy cells.
The Company expects to present initial pre-clinical data from the first Switch-DARPin program cKIT x CD16a x CD47 in H1 2024 and to run preclinical proof-of-concept studies in H2 2024, which should provide strong translational efficacy data.

Radio-DARPin Therapy (RDT) Platform
In September 2023, Molecular Partners presented preclinical data from its RDT platform at the 36th Annual Meeting of the European Association of Nuclear Medicine (EANM) demonstrating a substantially increased tumor uptake of RDT candidates through an adjustment of systemic half-life, achieved by binding to the human serum albumin protein. These results expand on preclinical data that were previously reported at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting in 2023 and highlight that surface engineering of the DARPin backbone into a "Stealth" DARPin can lead to marked reduction of RDT candidate reabsorption by kidneys, addressing a key challenge for protein-based radionuclide delivery vectors. At the 42nd Annual J.P. Morgan Healthcare Conference in January 2024, Molecular Partners presented data showing the reduction of kidney absorption through novel engineered Stealth DARPins as well as enhanced tumor uptake via half-life engineering for several targets. Achieving improved tumor uptake and reduced kidney reabsorption has enabled the expansion of the RDT pipeline and strategy for the RDT portfolio.

Furthermore, in January 2024, Molecular Partners and Orano Med entered a strategic collaboration to co-develop 212Pb-based RDTs for patients with solid tumors. The deal combines the power of DARPins, as a highly differentiated modality for tumor-targeted delivery of radioisotopes, with Orano Med’s leading capabilities in Targeted Alpha Therapy and supply to further advance the RDT platform and expand Molecular Partners’ RDT portfolio.

The tumor-associated protein Delta-like ligand 3 (DLL3) was selected as the target of the Company’s lead RDT program to be advanced into IND-enabling studies in H1 2024. Expression of DLL3 is low in healthy tissue but significantly increased in certain tumor types, providing an opportunity for selective targeting through the high affinity and specificity offered by DARPins. The initiation of clinical studies and first-in-human data are expected in 2025 through co-development with Orano Med. Molecular Partners also expects to nominate additional targets and RDT candidates in 2024.

In addition to the above updates, Molecular Partners continued to progress its RDT portfolio of projects in partnership with Novartis.

MP0317
In November 2023, the Company presented additional positive dose-escalation data from its Phase 1 study of MP0317 in patients with advanced solid tumors at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper). These data from 46 patients corroborated earlier reported findings of MP0317-induced CD40 activation and related remodeling of the tumor microenvironment (TME). At the time of the presentation, MP0317 monotherapy continued to display a favorable safety profile across all dosing cohorts up to the highest planned dose.

MP0317 enables tumor-localized immune activation through simultaneously targeting the immunostimulatory protein CD40 and fibroblast activation protein (FAP). FAP is expressed in high amounts around tumors. Through this proposed mechanism of action, MP0317 is designed to activate immune cells specifically within the tumor microenvironment, potentially delivering greater efficacy with fewer side effects compared to systemic CD40-targeting therapies.

The Company expects to report the full dataset from the Phase 1 study dose-escalation in H1 2024.

Corporate Governance & Leadership Highlights

Dr. Philippe Legenne, M.D., MBA, MHS, assumed responsibilities as acting Chief Medical Officer in August 2023.

Dr. Legenne joined Molecular Partners in early 2020. Over this time, he has led the clinical development strategy and execution across the Molecular Partners portfolio. Prior to joining Molecular Partners, Philippe held positions of increasing responsibility at JNJ, GSK, and Novartis, both in the United States and Europe. In his most recent role prior to Molecular Partners, Philippe led the EU medical organization for the oncology portfolio at Amgen. He received his medical degree from the Université de Lille (France), an MBA from ESSEC Business School (Paris) and a Master’s degree in health economics from Université Paris Dauphine-PSL.​

Update to Class Action Lawsuit

On February 29, 2024 a putative class action complaint against the Company, its directors, and certain of its executive officers was dismissed in the Company’s favor, and the case has been ordered closed. The original case was filed on July 12, 2022 in the U.S. District Court for the Southern District of New York.

2023 Financial Highlights

In the financial year 2023, Molecular Partners recognized total revenues and other income of CHF 7.0 million (2022: CHF 189.6 million) and incurred total expenses of CHF 68.1 million (2022: CHF 73.0 million). This led to an operating loss of CHF 61.1 million for 2023 (2022: Operating profit of CHF 116.6 million). The net financial loss recorded in 2023 was CHF 0.9 million, compared to a net financial gain of CHF 1.2 million in 2022. This resulted in a 2023 net loss of CHF 62.0 million (2022: Net profit of CHF 117.8 million).

The net cash used in operating activities in 2023 was CHF 59.0 million (2022: Net cash from operating activities CHF 118.6 million). Including short-term time deposits, the cash and cash equivalents position decreased by CHF 62.2 million as compared to year-end 2022, to CHF 186.9 million as of December 31, 2023 (December 31, 2022: CHF 249.1 million). Total shareholders’ equity stood at CHF 176.4 million as of December 31, 2023, a decrease of CHF 58.8 million (December 31, 2022: CHF 235.2 million).

The Company’s cash position and short-term time deposits were CHF 186.9 million as per December 31, 2023, and continue to provide the Company with financial flexibility and a forecasted cash runway well into 2026.

The Company’s balance sheet remained debt-free in 2023. As of December 31, 2023, the Company employed 167.5 FTE (full-time equivalents), down 4% year-on-year. About 83% of the employees are employed in R&D-related functions.

Key figures as of December 31, 2023

Key Financials (CHF million, except per share, FTE data) FY 2023 FY 2022 Change
Total revenues and other income 7.0 189.6 (182.6 )
R&D expenses (48.7 ) (50.7 ) 2.0
SG&A expenses (19.4 ) (22.3 ) 2.9
Operating result (68.1 ) (73.0 ) 4.9
Net finance result (61.1 ) 116.6 (177.7 )
Net result (0.9 ) 1.2 (2.1 )
Basic net result per share (in CHF) (1.89 ) 3.63 (5.52 )
Diluted net result per share (in CHF) (1.89 ) 3.54 (5.43 )
Net cash (used in) from operating activities (59.0 ) 118.6 (177.6 )
Cash & cash equivalents (incl. short-term time deposits) 186.9 249.1 (62.2 )
Total shareholders’ equity 176.4 235.2 (58.8 )
Number of total FTE 167.5 175.3 -7.8

Financial outlook 2024
For the full year 2024, at constant exchange rates, the Company expects total operating expenses of CHF 70-80 million, of which around CHF 8 million will be non-cash effective costs for share-based payments, IFRS pension accounting and depreciation.

Documentation

This press release, the Company’s Annual Report on Form 20-F for the year ended December 31, 2023 to be filed with the U.S. Securities and Exchange Commission (SEC), and the Company’s annual report 2023 will be made available through www.molecularpartners.com under the investor section after 9.00 pm CET (4.00 pm EST) on March 14, 2024.

Full Year 2023 Conference Call & Audio Webcast

Molecular Partners will hold a conference call and audio webcast on March 15, 1.00 pm CET (8.00 am EST).
To register for the full year 2023 conference call, please dial the following numbers approximately 10 minutes before the start of the presentation:

Participant Dial In (Toll Free): 1-866-652-5200
Participant International Dial In: 1-412-317-6060
Switzerland Toll Free: 0800-246787

Participants in the conference call will have the opportunity to ask questions after the presentation.

Audio webcast

The full year 2023 results will be webcast live and will be made available on the Company’s website under the investor section. The replay will be available for 90 days following the presentation.