Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced positive interim results from 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). The data presented provide initial proof of target engagement based on reductions in hypoxia inducible factor-2 alpha (HIF2α) expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2. The data are being presented by James Brugarolas, M.D., Ph.D, Professor at University of Texas Southwestern Medical Center and investigator in the study, in a poster presentation at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), being held February 17-19, 2022, in San Francisco, CA and online.

Presentation Details:

Title: Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001)

Authors: James Brugarolas, et al.

Session: Poster Session C: Renal Cell Cancer; Adrenal, Penile, Urethral, and Testicular Cancers

Abstract Number: 339

Poster Number: F9

Key results from AROHIF21001 as of December 1, 2021 data cut:

Pharmacodynamics and Efficacy

• Tumoral expression of HIF2α protein was assessed via immunohistochemistry
  • Among patients with evaluable biopsy, 9/14 showed reductions in HIF2α protein
  • Responders in Cohort 1 (225 mg, n=3), Cohort 2 (525 mg, n=4), and Cohort 3 (1050 mg, n=2) achieved mean reductions of HIF2α protein of -45%, -57%, and -80%, respectively
• Tumoral expression of HIF2α messenger RNA (mRNA) was assessed by quantitative polymerase chain reaction (qPCR)
  • Among patients with evaluable biopsy, 9/9 showed reductions in HIF2α mRNA
  • Cohort 1, Cohort 2, and Cohort 3 achieved mean reductions of HIF2α mRNA of -38%, -28%, and -44%, respectively
• Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST)
  • Disease control rate (complete response + partial response + stable disease) was 39% (10 of 26) across all cohorts
  • Objective response (complete response + partial response) was 8% (2 of 26), with one patient in Cohort 2 and one patient in Cohort 3 achieving a partial response

Safety

• 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
• Five serious AEs in 5 patients were reported by investigators as possibly drug related, including myocarditis (in a patient with a history of TKI induced cardiomyopathy), demyelinating neuropathy (in a patient with autoimmune sequelae due to checkpoint inhibitors), chronic inflammatory demyelinating polyradiculoneuropathy (in a patient with distant history of checkpoint inhibitor use), hypoxia (in a patient with a pulmonary infiltrate), and acute hypoxemic respiratory failure (in a patient with progressive lung metastatic disease)

A copy of the presentation materials with full data may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.

AROHIF21001 (NCT04169711) is a Phase 1b dose-finding clinical study in patients with advanced ccRCC to evaluate the safety of ARO-HIF2 and to determine the recommended Phase 2 dose. Secondary objectives include the assessment of pharmacokinetics and preliminary efficacy, based on Response Evaluation Criteria in Solid Tumors (RECIST). Exploratory objectives for AROHIF21001 are post-dose tumoral expression of HIF genes in response to treatment with ARO-HIF2, change in Karnofsky Performance Status (KPS), correlation of tumor response based on RECIST with tumor HIF2α gene expression and tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, evaluation of serum biomarkers of ARO-HIF2 activity, correlation of RCC-related gene expression to ARO-HIF2 activity, and evaluation of plasma and urine metabolites.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.

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Source: Arrowhead Pharmaceuticals, Inc.

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