Ron Peck, MD, Chief Medical Officer of Arvinas speaks about Arvinas Releases Interim Clinical Data Further Demonstrating the Powerful Potential of PROTAC® Protein Degraders ARV-471 and ARV-110.
NEW HAVEN, Conn., 14 December 2020-Clinical-stage Arvinas, Inc. (Nasdaq: ARVN),
The biopharmaceutical company that uses its PROTAC® Discovery Engine to build a new class of drugs focused on targeted protein degradation today revealed clinical program updates for its PROTAC® protein degraders ARV-471 and ARV-110. Interim Phase 1 results for ARV-471 indicate the potential for best-in-class protection and tolerability, degradation of the estrogen receptor (ER) higher than previously recorded for the current standard of care agent (fulvestrant), and robust efficacy signals in highly pretreated patients with locally advanced or metastatic ER-positive/HER2 negative (ER+/HER2-) breast cancer. The success
Signals include one confirmed partial response (PR) Response Assessment Criteria in Solid Tumors (RECIST), two additional unconfirmed PR patients, and a 42 percent clinical benefit rate (CBR). For ARV-110, additional evidence of anti-tumor activity and patient benefit has been given by the ongoing dose-escalation portion of the Phase 1/2 trial in men with metastatic castration-resistant prostate cancer (mCRPC), including a prostate-specific antigen reduction of more than 50 percent (PSA50) rate of 40 percent in a molecularly specified patient population. A Phase 2 dose expansion was initiated by Arvinas to explore a two-pronged development strategy, including the potential for accelerated molecularly defined approval,
In less-heavily pretreated mCRPC patients with fewer late-line patients and wider development
Tumor resistance mechanisms are androgen receptor (AR)-independent.
ARV-471 and ARV-110 have both been well-tolerated, and the maximum tolerated dose has not been reached, and Phase 1 dose-escalation studies for both programs continue. The Phase 1b combination trial of ARV-471 and Ibrance® (palbociclib) is scheduled to commence in December 2020 and the Phase 2 extension cohort of ARV-471 is scheduled to commence in the first half of 2021.
Clinical ARV-471 Update
In Phase 1 clinical trial, 21 adult patients with locally advanced or metastatic ER+/HER2-breast cancer completed at least one treatment period with ARV-471 (orally, once daily) as of the data cut-off date of November 11, 2020. 100% of these patients were previously treated with a 4/6 inhibitor of cyclin-dependent kinase (CDK), 71% of patients were previously treated with fulvestrant, and 23% were pretreated with investigational selective estrogen receptor degraders (SERDs). Patients had a median of five previous treatments combined.
Prior treatment with CDK4/6 inhibitors predicts high ER-independence of the tumor in metastatic breast cancer, making ER-targeting therapies ineffective. However, as evaluated by RECIST, one patient in the ARV-471 trial had a confirmed PR with a 51 percent reduction in the target lesion size. Two additional patients had unconfirmed PRs, and with >50 percent target lesion shrinkage, one additional patient showed stable disease. Twelve patients had ample follow-up to be included for assessment of CBR. CBR (CBR identified as PRs + complete responses + stable illness at 6 months) was achieved by five of 12 patients (42 percent).
Fulvestrant was previously given to three of these five patients and two investigational SERDs were used to treat another.
At all dose levels, as of the data cut-off date, ARV-471 has been well tolerated. The most widespread
Grade 1-2 treatment-related adverse events included nausea (24%), arthralgia (19%), fatigue (19%), and
Appetite reduced (14 percent ). None of these caused ARV-471 to be discontinued or dose-reduced. No
Grade 3 treatment-related patients reported 4 adverse effects and no dose-limiting toxicities (DLTs) were reported. The maximum tolerated dose (MTD) was not achieved and the increase of the dose has proceeded.
ARV-471 plasma doses were dose-proportional up to and including 360 mg once daily orally and greatly surpassed Arvinas’ expected efficacy thresholds based on preclinical studies. ARV-471’s approximate half-life is 28 hours, supporting a once-daily administration schedule. A study of five paired tumor biopsies at doses of up to 120 mg offers convincing evidence of an ARV-471 mechanism that has shown up to 90 percent (average 62 percent) of ER degradation at those doses, while dose escalation continues.
A potential best-in-class ER targeting therapy is confirmed by the combined profile of ARV-471, including efficacy indications in a highly refractory population, an excellent tolerability profile, and high levels of ER degradation.
It is planned that the Phase 2 dose expansion of ARV-471 will begin in the first half of 2021. In December 2020, Arvinas also plans to initiate a Step 1b expansion of the cohort of ARV-471 in combination with Ibrance® (palbociclib). The safety and tolerability of ARV-471 in combination with palbociclib will be tested in this trial and a recommended combination dose will be identified. In the second half of 2021, Arvinas plans to launch two additional trials of ARV-471: a combination trial of ARV-471 and another targeted therapy for 2L/3L metastatic breast cancer, and an opportunity research window for adjuvant breast cancer. The combined results from these studies will inform the global development strategy of Arvinas and drive forward towards the goal of being the leading endocrine therapy for ER+/HER2-breast cancer for ARV-471.
Medical Update ARV-110
ARV-110 continues to show promising activity in a very late-line population in Phase 1 clinical trial in men with mCRPC, with PSA reductions of >50 percent observed at doses greater than 280 mg, the last recorded cohort.
At dose-escalation, ARV-110 exposures increased in proportion to and at 420 mg oral daily doses, respectively.
In enzalutamide-resistant preclinical models of prostate cancer, dosing exposures in almost all patients exceeded the threshold associated with ARV-110 tumor responses. Exposure changes are correlated with an increased occurrence of decreases in PSA.
In Phase 1 dose-escalation analysis, 76 percent of patients had undergone prior chemotherapy treatment and 82 percent had received both abiraterone and enzalutamide previously. The patients had a median of five previous treatment lines. In nonmetastatic and metastatic castrate-resistant prostate cancer, multiple therapy lines are associated with a decreased response to AR-directed therapies and an increase in tumor heterogeneity, even in genetic mutations, which decreases the tumor’s AR signaling axis dependence. Genetic profiling of patient tumors in the trial has led to valuable insights into the ARV-110
Patient population Step 1, especially with regard to genetic variability. In the study, 84 percent of patients have non-AR gene mutations and will not be expected to respond as such. Moreover, it was found that the rates of particular AR mutations were higher than reported in publications that characterized the prevalence of AR mutations in mCRPC males.
Despite the highly heterogeneous existence of Phase 1 patient population, Arvinas has identified a molecularly established, late-line population with a particularly strong response to ARV-110. Two out of five patients (40%) with T878 or H875 AR mutations had PSA reductions of >50%, including one patient with RECIST-confirmed PR and an 80% reduction in tumor size.
Furthermore, two out of 15 wild-type AR patients (13 percent) have had PSA reductions of >50 percent, representing >50 percent.
In a larger patient group, operation. In the entire community of patients with exposures above the Arvinas minimum threshold expected to be successful in preclinical studies, four out of 28 (14 percent) had > 50 percent PSA reductions. In such late-line patients, these PSA50 concentrations are greater than would be anticipated from approved AR-directed therapies. Specifically, in mCRPC patients with less previous therapies than the patients in the ARV-110 study, PSA50 response rates from standard-of-care AR-directed therapies normally decrease to 8-15%.
In a molecularly specified population (T878/H875) and in wild-type patients, the dual signals of ARV-110 activity endorse Arvinas’ two-pronged ARV-110 development strategy and indicate a robust potential to address unmet needs in mCRPC patients.
In both T878/H875 and wild-type patients, a regular dose of 420 mg was selected as a Phase 2 expansion dose based on pharmacokinetics, safety profile, and activity signals. T878/H875 patients will be enriched in the subgroup during the ARDENT phase 2 expansion to ensure adequate patient numbers to support the potential for accelerated approval in this population. For less-pretreated patients (i.e., without prior chemotherapy and with only one previous second-generation AR-directed therapy, such as enzalutamide or abiraterone), a different subgroup would be enriched to ensure adequate numbers of patients whose tumors are predicted to be more AR-dependent, less genetically complex, and more ARV-110 sensitive.
In October 2020, the ARDENT Phase 2 expansion (N = ~100) began to record, and Arvinas expects to
Provide interim study results in the second half of the year 2021. Arvinas also plans to launch at least one Phase 1b combination trial with standard-of-care prostate cancer treatment in 2021 and to provide full Phase 1 dose-escalation results.
Expected Milestones 2020/2021
471-ARV
Initiation of a Phase 1b trial with Ibrance® (palbociclib) in combination (December 2020)
Initiation of an extension of Phase 2 doses (1H21)
"¢ Completion of the dose-escalation process 1 (1H21)
"¢ Safety evidence from the Phase 1b trial in conjunction with Ibrance® (palbociclib) (2H21)
Initiation of a chance sample window for adjuvant breast cancer (2H21)
Initiation of a 2L/3L metastatic combination trial of ARV-471 and another targeted therapy
Breast Cancer Cancer (2H21)
With ARV-110
"¢ Completion of the dose-escalation process 1 (1H21)
"¢ Interim data from the extension of the Passionate Phase 2 dose at 420 mg (2H21)
Initiation of combination trial(s) with treatment requirements (2021)
Additional clinical milestones
First-in-human start for ARV-766, an AR degrader from ARV-110 with a different profile (1H21)