zifcasiran (ARO-HIF2) / Arrowhead - LARVOL DELTA

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: Arrowhead Pharmaceuticals | Phase classification: P1b ➔ P1

Phase classification • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma. (PubMed, Clin Cancer Res) - "ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC)...Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner."

Journal • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Fatigue • Genito-urinary Cancer • Oncology • Pain • Pulmonary Disease • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma (Clin Cancer Res) - P1b | N=26 | NCT04169711 | Sponsor: Arrowhead Pharmaceuticals | "Twenty-six subjects received ARO-HIF2....Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia."

P1 data • Clear Cell Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

Targeting HIF2a with siRNA: From preclinical models to the clinic (AACR 2022) - P1b | "Referring herein to both first- and second-generation (ARO-HIF2) siRNA drugs, siHIF2 is specifically taken up by human ccRCC tumors transplanted in mice, where it depletes HIF2a inhibiting target gene expression and tumor growth...siHIF2 has activity against both wild-type and drug-resistant mutant HIF2a and is expected to be active in patients progressing on PT2977 (belzutifan), a PT2399-related drug recently approved by the FDA. To our knowledge, this is the first example of functional inactivation of an oncoprotein with a tumor-directed siRNA in humans. In summary, these studies provide unique insight into HIF2a (the only known core dependency in ccRCC), illustrate how it can be effectively inhibited by an siRNA drug, and establish a paradigm for the development of tumor directed siRNA-based therapeutics."

Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • VHL

Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). (ASCO-GU 2022) - No abstract available

Clinical • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Renal Cell Carcinoma • EPAS1

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b | N=26 | Completed | Sponsor: Arrowhead Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b | N=26 | Active, not recruiting | Sponsor: Arrowhead Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=50 ➔ 26 | Trial completion date: Mar 2022 ➔ Jul 2022

Enrollment change • Enrollment closed • Trial completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

ARO-HIF2 Lowers HIF2α Expression and Demonstrates Favorable Safety Profile in Clear Cell RCC (OncLive) - P1 | N=50 | NCT04169711 | "This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2α expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2,' lead study author James Brugarolas, MD, PhD...wrote in a poster on the findings."

Media quote • P1 data

Arrowhead Pharmaceuticals to Participate in Upcoming April 2022 Conferences (Businesswire) - "Arrowhead Pharmaceuticals Inc...announced that it is scheduled to participate in the following upcoming events:...American Association for Cancer Research Annual Meeting 2022 (AACR) – April 8-13, 2022; DIA/FDA's Oligonucleotide-based Therapeutics Conference (Oligo22) – April 25-27, 2022"

P1 data • Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

Arrowhead Presents New Clinical Data on ARO-HIF2 at ASCO GU 2022 (Businesswire) - P1b | N=50 | NCT04169711 | Sponsor: Arrowhead Pharmaceuticals | "Key results from AROHIF21001 as of December 1, 2021 data cut...Among patients with evaluable biopsy, 9/14 showed reductions in HIF2α protein; Disease control rate (complete response + partial response + stable disease) was 39% (10 of 26) across all cohorts; ARO-HIF2 was generally well-tolerated in patients. Anemia and hypoxia, frequently reported on-target adverse events (AEs) with small molecule HIF2α inhibitors, were reported in 12% of patients"

P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

Arrowhead Announces Positive Interim Results from Phase 1b Study of ARO-HIF2 for Treatment of Clear Cell Renal Cell Carcinoma (Businesswire) - P1b, N=50; NCT04169711; Sponsor: Arrowhead Pharmaceuticals; "Arrowhead Pharmaceuticals Inc...announced positive interim results from the first two cohorts of AROHIF21001, a Phase 1b dose-finding clinical study of ARO-HIF2, the company’s investigational RNA interference (RNAi) therapeutic being developed as a treatment for patients with clear cell renal cell carcinoma...Arrowhead is currently enrolling the third planned patient cohort of AROHIF21001 and the company intends to present additional data at an appropriate medical congress...The study has progressed to a dose of 1050 mg weekly (cohort 3); In cohort 2, one subject had a partial response with approximately 65% tumor shrinkage and 5 had a best response of stable disease"

P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma

"Some context for today's $ARWR ARO-HIF2 data https://t.co/wJ8EMgwE9C $MRK" (@JacobPlieth)

"Yes sir, going to wake the pharma industry big time, $ARWR is going to cause a reawakening of RNAi, ARO-Hif2 cancer, ARO- ENaC for cystic fibrosis and ARO-HSD for NASH." (@SauveRod)

Cystic Fibrosis • Fibrosis • Genetic Disorders • Hepatology • Immunology • Non-alcoholic Steatohepatitis • Oncology • Pulmonary Disease • Respiratory Diseases

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b; N=50; Recruiting; Sponsor: Arrowhead Pharmaceuticals; N=30 ➔ 50

Clinical • Enrollment change • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b; N=30; Recruiting; Sponsor: Arrowhead Pharmaceuticals; N=18 ➔ 30

Clinical • Enrollment change • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Arrowhead Pharmaceuticals Initiates Phase 1b Study of ARO-HIF2 for Treatment of Clear Cell Renal Cell Carcinoma (Businesswire) - "Arrowhead Pharmaceuticals Inc…announced that it has dosed the first patient in AROHIF21001, a Phase 1b dose-finding clinical study of ARO-HIF2, the company’s investigational RNA interference (RNAi) therapeutic being developed as a treatment for patients with clear cell renal cell carcinoma (ccRCC)…'Most patients with ccRCC, one of the most common forms of kidney cancer, have an inactivated mutation in the Von Hippel-Lindau gene rendering them unable to degrade HIF-2α, which leads to an increase in activity during tumor hypoxia and promotes tumor growth'...AROHIF21001 (NCT04169711) is a Phase 1b dose-finding clinical study in up to 18 patients with advanced ccRCC to evaluate the safety of ARO-HIF2 and to determine the recommended Phase 2 dose."

Enrollment open • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b; N=18; Recruiting; Sponsor: Arrowhead Pharmaceuticals; N=40 ➔ 18

Enrollment change • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b; N=40; Recruiting; Sponsor: Arrowhead Pharmaceuticals; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b; N=40; Not yet recruiting; Sponsor: Arrowhead Pharmaceuticals; Initiation date: Feb 2020 ➔ May 2020

Clinical • Trial initiation date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Arrowhead Pharmaceuticals files IND for phase 1b study of ARO-HIF2 for treatment of clear cell renal cell carcinoma (Businesswire) - "Arrowhead Pharmaceuticals In...announced that it has submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for a Phase 1b adaptive dose-finding clinical study of ARO-HIF2....Pending regulatory review, the company intends to initiate AROHIF21001 (NCT04169711), a Phase 1b adaptive design dose-finding clinical study in patients with advanced ccRCC to evaluate the safety of ARO-HIF2 and to determine the recommended Phase 2 dose."

IND • New P1 trial

Phase update (clinicaltrials.gov) - Preclinical ➔ P1, Oncology, RCC

Phase shift

Study of ARO-HIF2 in Patients With Advanced Clear Cell Renal Cell Carcinoma (clinicaltrials.gov) - P1b; N=40; Not yet recruiting; Sponsor: Arrowhead Pharmaceuticals

New P1 trial