davoceticept (ALPN-202) / Vertex - LARVOL DELTA

Correction: Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2). (PubMed, J Immunother Cancer) - No abstract available

Combination therapy • Journal • Metastases • Monotherapy • P1 data • Oncology • Solid Tumor

Case report of fatal immune-mediated myocarditis following treatment with davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual PD-L1/CTLA-4 checkpoint inhibitor, in combination with pembrolizumab. (PubMed, J Immunother Cancer) - P1 | "Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383)."

Checkpoint inhibition • Combination therapy • Journal • Cardiovascular • Choroidal Melanomas • Colorectal Cancer • Gastrointestinal Cancer • Inflammation • Melanoma • Ocular Melanoma • Oncology • Solid Tumor • CD80

Phase I studies of davoceticept (ALPN-202), a PD-L1-dependent CD28 co-stimulator and dual PD-L1/CTLA-4 inhibitor, as monotherapy and in combination with pembrolizumab in advanced solid tumors (NEON-1 and NEON-2). (PubMed, J Immunother Cancer) - P1 | "Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated."

Combination therapy • IO biomarker • Journal • Metastases • Monotherapy • P1 data • Cardiovascular • Choroidal Melanomas • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Genito-urinary Cancer • Melanoma • Ocular Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • CD80 • CTLA4

NEON-2: ALPN-202 With PD-1 Inhibition in Advanced Malignancies (clinicaltrials.gov) - P1 | N=29 | Terminated | Sponsor: Alpine Immune Sciences, Inc. | Trial completion date: Dec 2024 ➔ Feb 2023 | Active, not recruiting ➔ Terminated; Sponsor decision

Metastases • Trial completion date • Trial termination • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • PD-L1

NEON-1: An Open-label Study of ALPN-202 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1 | N=62 | Terminated | Sponsor: Alpine Immune Sciences, Inc. | Trial completion date: Dec 2024 ➔ Feb 2023 | Active, not recruiting ➔ Terminated; Sponsor decision

Metastases • Trial completion date • Trial termination • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • PD-L1

Interim dose escalation of davoceticept, a conditional CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in advanced malignancies (NEON-2) (SITC 2022) - P1 | "Of 14 evaluable subjects, 1 confirmed partial response has been observed in a nivolumab-experienced subject with clear cell RCC. Trial Registration NCT04920383 Ethics Approval This study received ethics approval from the WCG IRB (Sarah Cannon; ID 20211877), Salus IRB (START Texas; ID START2021.28, START Midwest; ID STMW2021.18), and Mass General Brigham IRB (Massachusetts General Hospital; ID 2021P002079). All study subjects provided their informed consent to participate in this study."

Checkpoint inhibition • Combination therapy • IO biomarker • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Oncology • Peritoneal Cancer • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • CD80

Development of a clinical ex vivo assay for the assessment of therapeutic CD28 costimulatory pathway engagement (SITC 2021) - P1 | "This assay has been successfully employed to monitor controlled CD28 costimulation by the CD28 agonist therapeutic candidate ALPN-202, helping to establish a PK/PD relationship that is consistent with preclinical data. More broadly, this type of cell-based, ex vivo TDC assay could be adapted to assess costimulatory receptor engagement, particularly target-dependent costimulation, for other therapeutic agonists in clinical development."

Preclinical • Oncology • IL2

Monotherapy dose escalation of davoceticept (ALPN-202), a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1) (AACR 2022) - P1 | "First-in-human dose escalation with davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity in a largely treatment-refractory, non-immunogenic tumor population. These findings suggest a potential additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and demonstrate further rationale for combination development. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned."

Checkpoint inhibition • Monotherapy • Colorectal Cancer • Cutaneous Melanoma • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • ICOS

IMMUNE CHECKPOINT INHIBITOR-INDUCED MYOCARDITIS: A RARE ENTITY WITH POTENTIAL FOR RAPID DECOMPENSATION (ACC-WCC 2023) - "Her medical history included metastatic choroidal melanoma and new hypothyroidism; she recently began a phase I clinical trial with pembrolizumab and a novel dual ICI, davoceticept. Be aware of myocarditis as a serious illness with the increase of ICI use in cancer therapy."

Checkpoint inhibition • IO biomarker • Cardiomyopathy • Cardiovascular • Choroidal Melanomas • CNS Disorders • Depression • Endocrine Disorders • Immune Modulation • Inflammation • Melanoma • Metabolic Disorders • Ocular Melanoma • Oncology • Psychiatry • Renal Disease • Solid Tumor

NEON-1: An Open-label Study of ALPN-202 in Subjects With Advanced Malignancies (clinicaltrials.gov) - P1 | N=62 | Active, not recruiting | Sponsor: Alpine Immune Sciences, Inc. | Recruiting ➔ Active, not recruiting | N=102 ➔ 62 | Trial primary completion date: Dec 2024 ➔ Dec 2022

Enrollment change • Enrollment closed • Trial primary completion date • Hematological Malignancies • Lymphoma • Melanoma • Oncology • Renal Cell Carcinoma • Solid Tumor • PD-L1

Davoceticept (ALPN-202), a PD-L1-dependent CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in patients with advanced malignancies (NEON-2). (ASCO 2022) - P1 | "The 0.1 mg/kg cohorts have been completed without DLT. Enrollment to the 0.3 mg/kg cohorts began in September 2021."

Checkpoint inhibition • Clinical • Combination therapy • IO biomarker • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Oncology • Solid Tumor • CD28 • CD86 • PD-L1

Dose escalation of davoceticept, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies (NEON-1). (ASCO 2022) - P1 | "Davoceticept was well tolerated at doses capable of engaging CD28 costimulation in vivo, with early signs of activity and peripheral immune activation in a largely treatment-refractory, non-immunogenic tumor population. These findings support an additive benefit of combining CD28 agonism with checkpoint inhibition and identify biologically active dose regimens of davoceticept for subsequent single agent development, and provide further rationale for combination study. Expansion cohorts, including cutaneous melanoma and PD-L1-positive cancers, are planned, and a combination study with pembrolizumab has initiated (NCT04920383)."

Checkpoint inhibition • Cutaneous Melanoma • Gastrointestinal Disorder • Hematological Malignancies • Immune Modulation • Inflammation • Lymphoma • Melanoma • Oncology • Solid Tumor • ICOS

A Study of ALPN-202, a PD-L1-dependent CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in patients with advanced malignancies (SITC 2021) - P1 | "This study is being conducted in collaboration with Merck & Co., Inc., Kenilworth, NJ, USA. Trial Registration NCT04920383"

Checkpoint inhibition • Clinical • Combination therapy • IO biomarker • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor • CD86 • PD-L1

NEON-2: ALPN-202 With PD-1 Inhibition in Advanced Malignancies (clinicaltrials.gov) - P1 | N=29 | Active, not recruiting | Sponsor: Alpine Immune Sciences, Inc. | Recruiting ➔ Active, not recruiting | N=323 ➔ 29 | Trial primary completion date: Aug 2024 ➔ Dec 2022

Enrollment change • Enrollment closed • Trial primary completion date • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • PD-L1

"$ALPN ALPN-202 studies scrapped after 2 patient deaths. Ongoing CD28-activating trials incl $REGN & $SNY" (@JacobPlieth)

Clinical

Alpine Immune Sciences Terminates Enrollment of Davoceticept Clinical Studies (NEON-1 and NEON-2) (Businesswire) - "Alpine Immune Sciences, Inc...announced that the Company has voluntarily terminated enrollment in both clinical studies involving davoceticept (ALPN-202), an investigational CD28 costimulator and dual checkpoint inhibitor, including the NEON-1 study of davoceticept as monotherapy and the NEON-2 study of davoceticept in combination with pembrolizumab....The decision to terminate enrollment in the davoceticept studies was made in the interest of patient safety after the Company was notified of a second death in the NEON-2 study, attributed to cardiogenic shock. The participant, who had metastatic colorectal cancer previously treated with colectomy and multiple prior systemic chemotherapies, had received a single dose each of davoceticept and pembrolizumab. NEON-2 had previously been subject to a partial clinical hold due to a death attributed to cardiogenic shock. The Company is conducting an ongoing, comprehensive assessment of all NEON study participants."

Trial status • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor

"$ALPN Alpine Immune Sciences Terminates Enrollment of Davoceticept Clinical Studies (NEON-1 and NEON-2) https://t.co/yiZJ7G2N9J" (@stock_titan)

Clinical

Alpine Immune Sciences to Highlight Clinical Updates on Autoimmune and Immuno-Oncology Programs at Inaugural R&D Day (Businesswire) - "Alpine Immune Sciences, Inc...announced clinical updates from two wholly owned programs, ALPN-303 and davoceticept....'ALPN-303 is particularly exciting because it may be the first truly dual inhibitor of both BAFF and APRIL-a clinically validated target space for complex diseases like lupus,' said Dr. Vibeke Strand. 'This early human data suggest that ALPN-303 is in fact more potent and should be able to be more conveniently administered than existing candidates like the wild-type TACIs, which have already shown proof-of-concept in these diseases. Together with ALPN-303’s excellent initial tolerability, these findings strongly encourage further clinical development, and I look forward to continuing to work with this team and seeing the results of the planned studies.'"

Media quote

Alpine Immune Sciences to Highlight Clinical Updates on Autoimmune and Immuno-Oncology Programs at Inaugural R&D Day (Businesswire) - P1 | N=323 | NEON-2 (NCT04920383) | Sponsor: Alpine Immune Sciences, Inc. | "Preliminary analyses of the ongoing dose escalation in NEON-2, the study of davoceticept in combination with pembrolizumab, show encouraging outcomes. These include evidence of tumor reduction in two subjects: a 37.8% reduction in prostate-specific antigen (PSA; 622.9 to 387.7 ng/mL) in a subject with castrate-resistant prostate cancer, and a 25.5% tumor volume reduction in a subject with poorly differentiated renal cell carcinoma (RCC) with prior primary resistance to pembrolizumab and axitinib....Across both the NEON-1 davoceticept monotherapy and NEON-2 studies, 2/5 (40%) and 3/5 (60%) of subjects have achieved a confirmed partial response or stable disease, respectively. Dose escalation in NEON-2 is ongoing. In NEON-1, expansion cohorts in RCC, melanoma, and PD-L1-positive tumors are also ongoing."

P1 data • Trial status • Genito-urinary Cancer • Kidney Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Urothelial Cancer

"$ALPN Alpine Immune Sciences Announces R&D Day to Provide Clinical Updates on Wholly-Owned Programs ALPN-303 and Davoceticept https://t.co/ASGJ7JDTor" (@stock_titan)

Clinical

Alpine Immune Sciences Provides Corporate Update and Reports Second Quarter 2022 Financial Results (Businesswire) - "FDA removed the partial clinical hold on the NEON-2 trial of davoceticept in combination with pembrolizumab after review of the Company’s Complete Response, which included a comprehensive review of the davoceticept safety database, as well as a revised investigator brochure and study protocol. Preliminary data from the NEON-2 combination trial is anticipated in the second half of 2022."

P1 data • Oncology • Solid Tumor

NEON-2: ALPN-202 With PD-1 Inhibition in Advanced Malignancies (clinicaltrials.gov) - P1 | N=323 | Recruiting | Sponsor: Alpine Immune Sciences, Inc. | Active, not recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • PD-L1

Alpine Immune Sciences Announces Presentations at the 2022 EULAR and ASCO Annual Meetings (BioSpace) - "Alpine Immune Sciences Inc...announced the acceptance of abstracts for presentation at the 2022 European Congress of Rheumatology (EULAR) Annual Congress in Copenhagen, Denmark to be held June 1–4, 2022 and the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago to be held June 3-7, 2022...Updated data from the dose escalation portion of NEON-1, a phase 1 study of davoceticept as monotherapy, and a trials in progress poster of NEON-2, a phase 1 combination study of davoceticept and pembrolizumab, will be presented at poster presentations..."

P1 data • Oncology • Solid Tumor

Alpine Immune Sciences Announces FDA Removes Partial Clinical Hold on NEON-2 Clinical Trial of Davoceticept (ALPN-202) in Combination with Pembrolizumab (Businesswire) - "Alpine Immune Sciences, Inc...announced that the U.S. Food and Drug Administration (FDA) has removed the partial clinical hold placed on its NEON-2 trial evaluating davoceticept (ALPN-202), a first-in-class conditional CD28 costimulator and dual checkpoint inhibitor, in combination with pembrolizumab in adults with advanced malignancies. The FDA removed the hold after review of the Company’s Complete Response, which included a comprehensive review of the davoceticept safety database, as well as a revised investigator brochure and study protocol."

FDA event • Oncology • Solid Tumor

AACR 2022: Davoceticept (ALPN-202) Monotherapy Reduces Tumors, Supports Multiple Expansion Cohorts (Businesswire) - P1 | N=102 | NEON-1 (NCT04186637) | "Despite a highly heterogeneous, heavily pretreated, advanced solid tumor population – the majority classically considered to be unresponsive to immunotherapy – 11 (23%) of 48 evaluable participants demonstrated tumor volume reduction; 26 (54%) achieved clinical benefit as defined as a best response of stable disease or better; Three (6%) remained on treatment beyond 6 months."

P1 data • Hematological Malignancies • Lymphoma • Oncology • Solid Tumor