ARROWHEAD PHARMACEUTICALS, INC. Initial Results from a Phase 1 Study Using ARO-HIF2 to Silence HIF2-alpha in Patients with Advanced ccRCC (AROHIF21001)
James Brugarolas1, Katy E. Beckermann2, Brian I. Rini 2, Nicholas J. Vogelzang3, Elaine T. Lam4, James Hamilton5, Thomas Schluep5, Min Yi5, So Wong5, Erick Gamelin6, Nizar M. Tannir7
1 UT Southwestern Medical Center, Dallas, TX; 2 Vanderbilt University Medical Center, Nashville, TN; 3 Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 4 University of Colorado Cancer Center, Aurora, CO; 5 Arrowhead Pharmaceuticals, Pasadena, CA; 6 Gamelin Biopharma Consulting, Thousand Oaks, CA; 7 MD Anderson Cancer Center, Houston, TX.
Abstract 339 Clinicaltrials.gov identifier: NCT04169711
INTRODUCTION
- Hypoxia inducible factor-2 alpha (HIF2a) is a transcription factor and key tumorigenic driver of clear cell renal cell carcinoma (ccRCC). Normally, HIF2a is expressed at low levels and targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein.
- VHL inactivation, the causative event of ccRCC, induces tumorigenesis through uncontrolled accumulation of HIF2a and constitutive expression of downstream target genes implicated in cell survival, cell proliferation and angiogenesis.
- ARO-HIF2is a synthetic double-stranded RNAi trigger with an alpha-v beta3 targeting ligand, designed to silence HIF2a expression.
AIM
The aim of the ongoing Phase1 study AROHIF21001 is to evaluate the safety, tolerability, and recommended phase 2 dose based on preliminary efficacy and pharmacodynamic effects of ARO-HIF2 in patients (pts) with advanced ccRCC.
METHODS
Figure 1: AROHIF21001 Study Design
28-day DLT window
Screen Cohort 1: 225hmg, weekly
DRC Meeting | ||
W2 |
28-day DLT window
Screen Cohort 2: 525hmg, weekly
W2 | DRC Meeting |
RESULTS
Table 1: Baseline Characteristics
ARO-HIF2 | ARO-HIF2 | ARO-HIF2 | Total | |
Mean (min, max) | 225 mg | 525 mg | 1050 mg | |
(N=26) | ||||
(N=7) | (N=10) | (N=9) | ||
Age (years) | 68.4 (55, 75) | 69.5 (63, 87) | 57.7 (44, 74) | 65.1 (44, 87) |
Male (%) | 6 (86) | 7 (70) | 7 (78) | 20 (77) |
Weight (kg) | 81 (67, 104) | 82 (49, 113) | 86 (57, 124) | 83 (49, 124) |
BMI (kg/cm2) | 26 (21, 32) | 26 (17, 33) | 28 (20, 37) | 27 (17, 37) |
IMDC Criteria, n (%) | ||||
Good Risk | 1 (14.3) | 4 (40.0) | 1 (11.1) | 6 (23.1) |
Intermedate Risk | 5 (71.4) | 5 (50.0) | 4 (44.4) | 14 (53.8) |
Poor Risk | 1 (14.3) | 1 (10.0) | 2 (22.2) | 4 (15.4) |
ECOG, n (%) | ||||
0 | 4 (57.1) | 4 (40.0) | 3 (33.3) | 11 (42.3) |
1 | 3 (42.9) | 6 (60.0) | 6 (66.7) | 15 (57.7) |
>1 | -- | -- | -- | -- |
Prior lines of | ||||
therapy, n (%) | ||||
1 | -- | -- | -- | -- |
2 | 2 (28.6) | 3 (30.0) | 3 (33.3) | 8 (30.8) |
3 | 2 (28.6) | 4 (40.0) | 2 (22.2) | 8 (30.8) |
4 | 1 (14.3) | 1 (10.0) | 1 (11.1) | 3 (11.5) |
≥5 | 2 (28.6) | 2 (20.0) | 3 (33.3) | 7 (26.9) |
Prior Therapy, n (%) | ||||
Anti-VEGF | 7 (100) | 10 (100) | 9 (100) | 26 (100) |
Checkpoint | 7 (100) | 10 (100) | 9 (100) | 26 (100) |
Inhibitor | ||||
VHL mutation | ||||
status, n (%) | ** | ** | ||
Frame shift | 2 (28.6) | 1 (10.0) | 3 (17.6) | |
Missense | 1 (14.3) | 4 (40.0)* | 5 (29.4) | |
In frame deletion | -- | 1 (10.0) | 1 (5.9) | |
No variant | 2 (28.6) | -- | 2 (11.8) | |
Not available | 2 (28.6) | 4 (40.0) | 6 (35.3) |
* One pt additionally had a stop codon gain ** Cohort 3 sequencing data not available as of cutoff date
Table 2: Summary of Pharmacodynamics and Efficacy
Median / Mean change | ARO-HIF2 | ARO-HIF2 | ARO-HIF2 | Total | |
(min, max, n) | 225 mg (N=7) | 525 mg (N=10) | 1050 mg (N=9) | (N=26) | |
Hif2a mRNA by qPCR | -46%(-22,-47, 3) | -27%(-19,-39, 4) | -44%(-28,-59, 2) | -30%(-19,-59, 9) | |
All evaluable (median) | |||||
All reductions (mean) | -38%(-22,-47, 3) | -28%(-19,-39, 4) | -44%(-28,-59, 2) | -35%(-19,-59, 9) | |
HIF2a protein by IHC | |||||
All evaluable (median) | -26% (500*, -82, 4) | -47% (0, -90, 5) | 0% (1700**, | -26% (1700**, -98, | |
-98, 5) | 14) | ||||
All reductions (mean) | -45%(-26,-82, 3) | -57%(-9,-90, 4) | -80%(-63,-98, 2) | -58%(-9,-98, 9) | |
Best Response by RECIST, | |||||
n (%) | |||||
Complete response (CR) | -- | -- | -- | -- | |
Partial response (PR) | -- | 1 (10.0) | 1 (11.1) | 2 | (7.7) |
Stable disease (SD) | 1 (14.3) | 6 (60.0) | 1 (11.1) | 8 (30.8) | |
Progressive disease (PD) | 5 (71.4) | 2 (20.0) | 6 (66.7) | 13 | (50.0) |
Not evaluable (NE) | -- | -- | 1 (11.1) | 1 | (3.8) |
Missing | 1 (14.3) | 1 (10.0) | -- | 2 | (7.7) |
Objective Response | 0 (0) | 1 (10.0) | 1 (11.1) | 2 | (7.7) |
(CR+PR), n (%) | |||||
Disease control rate | 1 (14.3) | 7 (70.0) | 2 (22.2) | 10 | (38.5) |
(CR+PR+SD***), n (%) | |||||
- One pt with no VHL variant detected had a very low baseline H score of 1 that increased to 5 at week 2 (+500%). ** One pt had a very low baseline H score of 5 that increased to 85 at week 2 (+1700%, genotyping not available). IHC H score represents overall staining with a maximum score of 300 (100% of cells at intensity 3, 0% at intensity 0, 1, and 2). *** SD for 2 months or more.
Table 3: Summary of Safety and Adverse Events
ARO-HIF2 | ARO-HIF2ARO-HIF2 | Total | |||
525 mg | 1050 mg | ||||
225 mg (N=7) | (N=26) | ||||
Subject Incidence, n (%) | (N=10) | (N=9) | |||
Treatment-emergent AEs* (TEAEs) | 7 (100) | 10 (100) | 8 (88.9) | 25 | (96.2) |
TEAEs by severity | |||||
Grade 1 or 2 | 5 (71.4) | 6 (60.0) | 4 (44.4) | 15 | (57.7) |
Grade 3 | 1 (14.3) | 3 (30.0) | 4 (44.4) | 8 (30.8) | |
Grade 4 | -- | 1 (10.0) | -- | 1 | (3.8) |
Grade 5 | 1 (14.3) | -- | -- | 1 | (3.8) |
RESULTS
Figure 3: Tumor tissue distribution of ARO-HIF2
Representative images of tumor tissue distribution of ARO-HIF2 (magenta puncta) visualized by miRNAscope.
Safety
- ARO-HIF2was generally well-tolerated in patients. Anemia and hypoxia, frequently reported on-target AEs with small molecule HIF2a inhibitors, were reported in 12% of patients.
- Five SAEs in 5 pts were reported by investigators as possibly drug related including myocarditis (in a pt with a history of TKI induced cardiomyopathy), demyelinating neuropathy (in a pt with autoimmune sequelae due to checkpoint inhibitors), chronic inflammatory demyelinating polyradiculoneuropathy (in a pt with distant history of checkpoint inhibitor use), hypoxia (in a pt with a pulmonary infiltrate), and acute hypoxemic respiratory failure (in a pt with progressive lung metastatic disease).
Pharmacodynamics and Efficacy:
• Among patients with evaluable biopsy 9/9 showed reductions in |
HIF2a mRNA by qPCR and 9/14 showed reductions in HIF2a |
protein by IHC. |
• Disease control rate was 39% across all cohorts and two subjects |
biopsy collection
Screen Cohort 3: 1050h mg, weekly
W2
Figure 2: Summary of Treatment Duration with Tumor Response
Treatment-related TEAEs | 5 (71.4) | 7 (70.0) | 5 (55.6) | 17 (65.4) |
Treatment-emergent SAE | 2 (28.6) | 4 (40.0) | 3 (33.3) | 9 (34.6) |
experienced a partial response. |
- ARO-HIF2was administered IV weekly
- Patients with advanced ccRCC (ECOG ≤ 1), with progressive disease on prior anti-VEGF and checkpoint inhibitor therapy
- Tumor biopsy performed at baseline and at 2 weeks
- Patients were assessed weekly for safety and every 8 weeks for tumor response by RECIST.
- Assessments: Safety, pK, changes in tumor HIF2a mRNA by qPCR and HIF2a protein by IHC, VHL mutation status, and RECIST. Minimum sufficient biopsy tumor cell content for qPCR and IHC evaluations were 40% and 5%, respectively.
- Data Cut: 1 December 2021
- PR measured at week 8 after discontinuation due to AE
TEAEs leading to treatment discontinuation | 1 (14.3) | -- | -- | 1 (3.8) |
TEAEs in >4 subjects by descending | ||||
Frequency of PT | 5 (71.4) | 5 (50.0) | 3 (33.3) | 13 (50.0) |
Fatigue | ||||
Dizziness | 1 (14.3) | 4 (40.0) | 2 (22.2) | 7 (26.9) |
Dyspnea | 1 (14.3) | 2 (20.0) | 4 (44.4) | 7 (26.9) |
Nausea | 1 (14.3) | 3 (30.0) | 2 (22.2) | 6 (23.1) |
Abdominal pain (abdominal pain lower, | 1 (14.3) | 2 (20.0) | 3 (33.3) | 6 (23.1) |
abdominal discomfort, abdominal distention, | ||||
abdominal pain, abdominal pain upper) | ||||
Neuropathy (Peripheral sensory neuropathy, | -- | 4 (40.0) | 1 (11.1) | 5 (19.2) |
neuropathy peripheral, demyelinating neuropathy) | ||||
Constipation | -- | 2 (20.0) | 3 (33.3) | 5 (19.2) |
*TEAE is defined as any adverse events after the first dose of ARO-HIF2 and up to 30 days after the last dose or at the time that subsequent anti- cancer therapy begins, whichever is earlier.
CONCLUSIONS
HIF2a is a clinically validated driver of ccRCC which can be targeted with a RNAi therapeutic. This ongoing Phase 1 study provides initial proof of target engagement based on reductions in HIF2a expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2.
ACKNOWLEDGEMENTS
The study sponsors would like to acknowledge the help and participation of all patients who agreed to take part in this study, as well as the work and dedication of the staff at the clinical sites.
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Arrowhead Pharmaceuticals Inc. published this content on 17 February 2022 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 17 February 2022 14:07:02 UTC.
