NNC0385-0434 / Novo Nordisk - LARVOL DELTA

Meta-Analysis of Oral PCSK9 Inhibitors for Hypercholesterolemia in Adults: A Systematic Review and GRADE Assessment. (PubMed, Cardiol Rev) - "Five trials (n = 4232) evaluating AZD0780, NNC0385-0434, MK-0616, and enlicitide were included. No significant differences were observed in discontinuation due to adverse events, any adverse events, serious adverse events, or treatment-related adverse events. Oral PCSK9 inhibitors provide substantial short-term reductions in atherogenic lipoproteins without an apparent excess of short-term adverse events; longer-term cardiovascular outcome trials are needed."

Journal • Retrospective data • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOB

Efficacy and Safety of Oral PCSK9 Inhibitors: Insights from a Meta-analysis of RCTS. (PubMed, Eur J Prev Cardiol) - "Oral PCSK9 inhibitors demonstrate potent LDL-C-lowering efficacy, comparable to parenteral PCSK9i, with favourable effects on other atherogenic lipids and a reassuring short-term safety profile."

Journal • Retrospective data • Dyslipidemia • Metabolic Disorders • APOB

New frontiers in the treatment of hypercholesterolaemia: oral inhibition of PCSK9. (PubMed, Eur Heart J Suppl) - "Agents in advanced development include enlicitide (MK-0616) and laroprovstat (AZD0780), while DC371739, NNC0385-0434 (development currently suspended), and CVI-LM001 should also be considered...AZD0780 demonstrates dose-dependent reductions in LDL-C (up to 50%) and potential synergism with rosuvastatin, whereas NNC0385-0434-despite documenting significant decreases in LDL-C and Lp(a)-has been discontinued. DC371739 (a dual PCSK9/ANGPTL3 inhibitor) and CVI-LM001 (a transcriptional modulator) may represent additional therapeutic perspectives. Overall, oral PCSK9 inhibitors show consistent efficacy and favourable safety profiles, positioning them as next-generation lipid-lowering therapies, pending cardiovascular outcome data from ongoing studies."

Journal • Cardiovascular • Dyslipidemia • Heterozygous Familial Hypercholesterolemia • ANGPTL3 • APOB

Safety and efficacy of oral PCSK9 inhibitors in hypercholesterolemia: A systematic review and network meta-analysis. (PubMed, Endocr Pract) - "Limited short-term data suggest that oral PCSK9i are reasonably safe and effective, reducing LDL-C and improving other lipids. Longer, larger RCTs are required to confirm safety, efficacy, and cardiovascular benefits before broader use."

Journal • Retrospective data • Cardiovascular • Dyslipidemia • Metabolic Disorders • APOB

Lipid-Lowering Efficacy and Safety of Oral Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: A Systematic Review and Meta-Analysis. (PubMed, Adv Ther) - "Oral PCSK9 inhibitors demonstrate lipid-lowering efficacy and safety comparable to that of currently approved injectable PCSK9 therapies. These findings support their potential as a convenient and effective alternative, although current evidence remains limited to early-phase studies."

Clinical • Journal • Retrospective data • Dyslipidemia • APOB

Oral PCSK9 Inhibitors for Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Trials (AHA 2025) - "MK-0616 achieved the greatest LDL-C reduction (–53.69%; 95% CI, –61.05% to –46.34%), followed by NNC0385-0434 (–46.23%; 95% CI, –63.15% to –29.31%) and AZD0780 (–38.18%; 95% CI, –45.06% to –31.29%). Oral PCSK9 inhibitors significantly reduced LDL-C, lipoprotein(a), apolipoprotein B, and total cholesterol compared to placebo, with no significant reduction in triglycerides. Among the agents studied, MK-0616 demonstrated the greatest overall LDL-C lowering effect."

Retrospective data • Review • Dyslipidemia • Metabolic Disorders • APOB

Emerging oral therapeutic strategies for inhibiting PCSK9. (PubMed, Atheroscler Plus) - "Subcutaneous administration of monoclonal antibodies (evolocumab and alirocumab) every 2 or 4 weeks determined a 60 % reduction of LDL cholesterol levels, while the GalNac-siRNA anti PCSK9 (inclisiran) provided an effective lipid lowering activity (-50 %) after an initial subcutaneous dose, repeated after 3 months and followed by a maintenance dose every 6 months. These problems could be overcome by the development of small chemical molecules anti PCSK9 as oral therapy for controlling hypercholesterolemia. In the present review, we summarized the pharmacological properties of oral anti PCSK9 molecules that are currently under clinical development (DC371739, CVI-LM001, and AZD0780), including the mimetic peptides enlicitide decanoate (MK-0616) and NNC0385-0434."

Journal • Review • Cardiovascular • Dyslipidemia • Metabolic Disorders

PCSK9 inhibition with orally administered NNC0385-0434 in hypercholesterolaemia: a randomised, double-blind, placebo-controlled and active-controlled phase 2 trial. (PubMed, Lancet Diabetes Endocrinol) - P2 | "This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations."

Journal • P2 data • Atherosclerosis • Cardiovascular • Dyslipidemia • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Novel Coronavirus Disease

A Research Study Looking at New Protein-based Tablets in Healthy Male Participants (clinicaltrials.gov) - P1 | N=384 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study Looking at New Protein-based Tablets in Healthy Male Participants (clinicaltrials.gov) - P1 | N=384 | Recruiting | Sponsor: Novo Nordisk A/S | Trial primary completion date: Nov 2022 ➔ Feb 2023

Trial primary completion date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study Looking at New Protein-based Tablets in Healthy Men - Oral Formulation II (clinicaltrials.gov) - P1 | N=152 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion

A Research Study Looking at New Protein-based Tablets in Healthy Male Participants (clinicaltrials.gov) - P1 | N=384 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Nov 2022 ➔ Apr 2023

Trial completion date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study Looking Into Levels of the Medicine NNC0385-0434 in the Body and How Well it is Tolerated in Participants With Impaired Kidney Function Compared to Participants With Normal Kidney Function (clinicaltrials.gov) - P1 | N=60 | Terminated | Sponsor: Novo Nordisk A/S | Trial completion date: Dec 2022 ➔ Aug 2022 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2022 ➔ Aug 2022; Business decision

Trial completion date • Trial primary completion date • Trial termination • Chronic Kidney Disease • Nephrology • Renal Disease

A Research Study Looking Into Levels of the Medicine NNC0385-0434 in the Body and How Well it is Tolerated in Participants With Impaired Kidney Function Compared to Participants With Normal Kidney Function (clinicaltrials.gov) - P1 | N=60 | Recruiting | Sponsor: Novo Nordisk A/S | Trial completion date: Sep 2022 ➔ Dec 2022 | Trial primary completion date: Jul 2022 ➔ Dec 2022

Trial completion date • Trial primary completion date • Chronic Kidney Disease • Nephrology • Renal Disease

A Research Study Looking at How NNC0385-0434 Tablets Work to Lower Blood Cholesterol in People With Heart Disease or a High Risk of Heart Disease (clinicaltrials.gov) - P2 | N=255 | Completed | Sponsor: Novo Nordisk A/S | Active, not recruiting ➔ Completed

Trial completion • Atherosclerosis • Cardiovascular • Dyslipidemia • Heart Failure

A Research Study Looking at the Effect of Food Intake on How the Medicine NN0385-0434 Behaves in the Body of Healthy Participants (clinicaltrials.gov) - P1 | N=73 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Atherosclerosis • Cardiovascular • Dyslipidemia

A Research Study Looking at New Protein-based Tablets in Healthy Men - Oral Formulation II (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: Novo Nordisk A/S | Not yet recruiting ➔ Recruiting

Enrollment open

A Research Study Looking at New Protein-based Tablets in Healthy Men - Oral Formulation II (clinicaltrials.gov) - P1 | N=150 | Not yet recruiting | Sponsor: Novo Nordisk A/S

New P1 trial

A Research Study Looking at How NNC0385-0434 Tablets Work to Lower Blood Cholesterol in People With Heart Disease or a High Risk of Heart Disease (clinicaltrials.gov) - P2 | N=255 | Active, not recruiting | Sponsor: Novo Nordisk A/S | Recruiting ➔ Active, not recruiting

Enrollment closed • Atherosclerosis • Cardiovascular • Dyslipidemia • Heart Failure

A Research Study Looking at How the Medicine NNC0385-0434 Works in the Body of Healthy Japanese Men (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Novo Nordisk A/S | Recruiting ➔ Completed

Trial completion • Atherosclerosis • Cardiovascular • Dyslipidemia

A Research Study Looking at the Effect of Food Intake on How the Medicine NN0385-0434 Behaves in the Body of Healthy Participants (clinicaltrials.gov) - P1; N=72; Recruiting; Sponsor: Novo Nordisk A/S; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Atherosclerosis • Cardiovascular • Dyslipidemia

A Research Study Looking Into Levels of the Medicine NNC0385-0434 in the Body and How Well it is Tolerated in Participants With Impaired Kidney Function Compared to Participants With Normal Kidney Function (clinicaltrials.gov) - P1; N=60; Recruiting; Sponsor: Novo Nordisk A/S; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Chronic Kidney Disease • Nephrology • Renal Disease

A Research Study Looking at New Protein-based Tablets in Healthy Male Participants (clinicaltrials.gov) - P1; N=384; Recruiting; Sponsor: Novo Nordisk A/S

Clinical • New P1 trial • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Research Study Looking Into Levels of the Medicine NNC0385-0434 in the Body and How Well it is Tolerated in Participants With Impaired Kidney Function Compared to Participants With Normal Kidney Function (clinicaltrials.gov) - P1; N=60; Not yet recruiting; Sponsor: Novo Nordisk A/S

Clinical • New P1 trial • Chronic Kidney Disease • Nephrology • Renal Disease

A Research Study Looking at the Effect of Food Intake on How the Medicine NN0385-0434 Behaves in the Body of Healthy Participants (clinicaltrials.gov) - P1; N=72; Not yet recruiting; Sponsor: Novo Nordisk A/S

Clinical • New P1 trial • Atherosclerosis • Cardiovascular • Dyslipidemia