On February 27, 2024 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported financial results for the fourth quarter and full year ended December 31, 2023, and provided a corporate update (Press release, Arvinas, FEB 27, 2024, View Source [SID1234640506]).

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"Our focused execution in 2023 enabled us to progress multiple trials across our entire portfolio and we are well-positioned for a catalyst rich year ahead, including completing our first Phase 3 trial," said John Houston, Ph.D., president and chief executive officer at Arvinas. "Our collaboration with Pfizer remains strong and we are on track to report topline data from our first Phase 3 clinical trial with vepdegestrant, the only PROTAC ER degrader in clinical development for patients with ER+/HER2- breast cancer. If successful, assuming regulatory approval, we have the opportunity to address an area of high unmet need and offer patients a new oral treatment option in the second-line metastatic breast cancer setting. And with the recent Phase 1 initiation with our LRRK2 PROTAC degrader – our first neuroscience program – we continue making significant progress with our novel PROTAC technology."

Recent Developments and Fourth Quarter Business Highlights

Vepdegestrant (ARV-471)

Received U.S. Food and Drug Administration Fast Track designation for the investigation of vepdegestrant for monotherapy in the treatment of adults with estrogen receptor (ER) positive/human growth epidermal growth factor 2 (HER2) negative (ER+/HER2-) locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.
Presented interim results (data cutoff: June 6, 2023) from the Phase 1b vepdegestrant and palbociclib (IBRANCE) combination cohort at the 2023 San Antonio Breast Cancer Symposium (SABCS), which demonstrated encouraging clinical activity in heavily pre-treated patients with locally advanced or metastatic ER+/HER2- breast cancer with a median of four lines of therapy across disease settings.
A clinical benefit rate (CBR, defined as the rate of confirmed complete response, partial response, or stable disease ≥ 24 weeks) of 63% (95% CI: 47.5–76.8), or 29/46 patients; at the recommended Phase 3 dose of 200 mg (n=21), the CBR was 67% (95% CI: 43.0 – 85.4), or 14/21 patients.
An objective response rate (ORR) in evaluable patients with measurable disease at baseline (n=31) of 42% (95% CI: 24.5–60.9), or 13/31 patients; at the RP3D of 200 mg (n=15), the ORR was 53% (95% CI: 26.6 – 78.7); the median duration of response was 10.2 months.
Median progression free survival (PFS) of 11.1 months (95% CI: 8.2 – NE); 22 of 46 patients across all doses had progression events by time of data cutoff.
Median PFS of 11.1 and 11.0 months in patients with ESR1 wild-type and ESR1 mutant tumors, respectively.
The safety profile of vepdegestrant plus palbociclib was manageable. The primary toxicity was neutropenia, which was managed with palbociclib dose modifications (reductions and/or interruptions) per protocol. There was no febrile neutropenia and 3 of 46 patients discontinued due to neutropenia.
Initiated Phase 1b/2 with vepdegestrant plus Pfizer’s novel CDK4 inhibitor (PF-07220060) (TACTIVE-K: ClinicalTrials.gov Identifier: NCT06206837).
Initiated an additional arm of the Phase 1b/2 combination umbrella trial with the CDK7 inhibitor samuraciclib (TACTIVE-U: ClinicalTrials.gov Identifiers: NCT05548127, NCT05573555, and NCT06125522).
Completed enrollment in the TACTIVE-N Phase 2 trial of vepdegestrant as a monotherapy in the neoadjuvant setting in patients with ER+/HER2- localized breast cancer (ClinicalTrials.gov Identifier: NCT05549505).
Completed enrollment in the TACTIVE-E Phase 1 trial of vepdegestrant in combination with everolimus for the treatment of advanced or metastatic ER+/HER2- breast cancer (ClinicalTrials.gov Identifier: NCT05501769).
Androgen Receptor PROTAC degraders

Presented data from the Phase 1/2 clinical trial with bavdegalutamide (ARV-110) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress showing a median radiographic progression free survival (rPFS) of 11.1 months in patients with AR 878/875 tumor mutations, demonstrating the strong potential for a PROTAC AR degrader in prostate cancer.
Manageable tolerability profile with no grade >4 treatment-related adverse events (TRAEs).
Selected our second generation PROTAC AR degrader, ARV-766, as the lead program in prostate cancer and prioritized the initiation of a Phase 3 trial with ARV-766 in metastatic castrate resistant prostate cancer (mCRPC).
New interim data from Phase 1/2 trial with ARV-766 showed a broader efficacy profile and superior tolerability versus bavdegalutamide in the clinical setting, with a potentially differentiated profile against other AR-directed therapies.
Completed enrollment in the bavdegalutamide Phase 1b combination trial with abiraterone.
Pipeline

Received authorization from the European Medicines Agency to initiate clinical trials with the Company’s new PROTAC degrader, ARV-102, designed to target the LRRK2 protein.
Initiated first-in-human Phase 1 clinical trial in healthy volunteers with LRRK2 targeting PROTAC ARV-102.
Received clearance from the U.S. Food and Drug Administration to initiate clinical trials with the Company’s PROTAC degrader, ARV-393, designed to target the BCL6 protein.
Corporate

Completed oversubscribed $350 million private placement co-led by EcoR1 Capital and RTW Investments LP, with participation by new and existing investors.
Announced the resignation of Chief Financial Officer and Treasurer, Sean Cassidy, effective February 29, 2024.
Announced the appointment of Randy Teel, Ph.D., Arvinas’ current senior vice president of corporate and business development, to the role of interim chief financial officer and treasurer.
The Arvinas Board of Directors has launched a formal search process to identify Mr. Cassidy’s permanent replacement.
Appointed Jared Freedberg, J.D., as general counsel.
Entered into a new collaboration with Pfizer to identify novel chemical matter for E3 ligases leveraging Pfizer’s proprietary compound libraries and Arvinas’ ligase ligand expertise.
Anticipated Upcoming Milestones and Expectations
Vepdegestrant (ARV-471)
As part of Arvinas’ global collaboration with Pfizer, the companies plan to:

Complete enrollment of the VERITAC-2 Phase 3 monotherapy trial (ClinicalTrials.gov Identifier: NCT05654623) in patients with metastatic breast cancer (2H 2024).
Continue enrollment in the study lead-in for the VERITAC-3 Phase 3 trial of vepdegestrant and palbociclib as a first-line treatment in patients with ER+/HER2- locally advanced or metastatic breast cancer.
Continue enrollment of the ongoing Phase 1b/2 clinical trial with vepdegestrant plus Pfizer’s novel CDK4 inhibitor (PF-07220060) (TACTIVE-K: ClinicalTrials.gov Identifier: NCT06206837).
Continue enrollment of the ongoing Phase 1b combination umbrella trial evaluating combinations of vepdegestrant with abemaciclib, ribociclib, or samuraciclib (TACTIVE-U: ClinicalTrials.gov Identifiers: NCTC05548127, NCTC05573555, and NCT06125522).
Initiate discussion with regulatory authorities on a second-line Phase 3 trial of vepdegestrant in combination with palbociclib and potentially other CDK4/6 inhibitors, and a new first-line Phase 3 trial of vepdegestrant plus Pfizer’s novel CDK4 inhibitor (PF-07220060).
ARV-766

Continue enrollment of Phase 2 dose expansion study with ARV-766, with progression free survival data anticipated in mid-2024.
Continue enrollment of Phase 1b/2 dose escalation trial with ARV-766 in combination with abiraterone in patients who have not previously received novel hormonal agents.
Initiate discussions with regulatory authorities for a planned Phase 3 clinical trial with ARV-766 in mCRPC (2Q 2024).
Pipeline

Continue enrollment in Phase 1 clinical trial in healthy volunteers with LRRK2 targeting PROTAC ARV-102 (2024)
Initiate first-in-human Phase 1 clinical trial in B-cell lymphomas with BCL6 targeting PROTAC ARV-393 (1H 2024)
Financial Guidance
Based on its current operating plan, Arvinas believes its cash, cash equivalents, restricted cash and marketable securities as of December 31, 2023, is sufficient to fund planned operating expenses and capital expenditure requirements into 2027.

Full Year and Fourth Quarter Financial Results

Cash, Cash Equivalents and Marketable Securities Position: As of December 31, 2023, cash, cash equivalents, restricted cash and marketable securities were $1,266.5 million, as compared with $1,210.8 million as of December 31, 2022. The increase in cash, cash equivalents, restricted cash and marketable securities of $55.7 million for the year was primarily related to net proceeds from our private placement and ATM offerings of $370.2 million, unrealized gains on marketable securities of $16.1 million and proceeds from the exercise of stock options and issuance of ESPP shares of $4.5 million, offset by cash used in operations of $331.3 million (net of $2.5 million received from two collaborators), purchases of lab equipment and leasehold improvements of $2.9 million and losses on the sale of securities of $0.9 million.

Research and Development Expenses: Research and development expenses were $379.7 million and $95.2 million for the year and quarter ended December 31, 2023, as compared with $315.0 million and $98.3 million for the year and quarter ended December 31, 2022. The increase in research and development expenses of $64.7 million for the year was primarily due to an increase in expenses associated with our platform and exploratory programs of $1.1 million, our AR program (which includes ARV-766 and bavdegalutamide (ARV-110)) of $22.0 million and our ER program of $41.6 million, which includes the cost sharing of vepdegestrant (ARV-471) under the Vepdegestrant (ARV-471) Collaboration Agreement. The decrease in research and development expenses of $3.1 million for the quarter was primarily due to a decrease in expenses associated with our platform and exploratory programs of $19.4 million, offset by increases in our AR program of $5.7 million and our ER program of $10.6 million.

General and Administrative Expenses: General and administrative expenses were $100.3 million and $27.0 million for the year and quarter ended December 31, 2023, as compared with $79.6 million and $15.1 million for the year and quarter ended December 31, 2022. The increase in general and administrative expenses of $20.7 million for the year was primarily due to an increase in personnel and infrastructure related costs of $11.5 million, an increase in professional fees of $6.3 million and increases related to establishing our commercial operations of $3.5 million, offset in part by reduced insurance costs of $1.0 million. The increase in general and administrative expenses of $11.9 million for the quarter was primarily due to an increase in personnel and infrastructure related costs of $8.4 million, an increase in professional fees of $1.8 million and increases related to establishing our commercial operations of $1.7 million.

Revenues: Revenue was $78.5 million and $(43.1) million for the year and quarter ended December 31, 2023 as compared with $131.4 million and $38.0 million for the year and quarter ended December 31, 2022. Revenue is related to the Vepdegestrant (ARV-471) Collaboration Agreement, the collaboration and license agreement with Bayer, the collaboration and license agreement with Pfizer, the amended and restated option, license and collaboration agreement with Genentech and revenue related to our Oerth Bio joint venture. The decrease of $52.9 million for the year was primarily due to adjustments to revenue from changes in contract estimates related to our Pfizer ARV-471 Collaboration Agreement, Pfizer Research Collaboration Agreement and Bayer Collaboration Agreement, net of current year revenues, totaling $39.7 million, a decrease of $8.1 million in previously constrained deferred revenue recognized in 2023 related to our Oerth Bio joint venture and a decrease in revenue recognized from our Genentech License Agreement of $5.1 million. The decrease of $81.1 million for the quarter was primarily due to an adjustment to revenue from a change in contract estimate related to our Pfizer ARV-471 Collaboration Agreement.

About bavdegalutamide (ARV-110) and ARV-766
Bavdegalutamide (ARV-110) and ARV-766 are investigational orally bioavailable PROTAC protein degraders designed to selectively target and degrade the androgen receptor (AR). Bavdegalutamide and ARV-766 are being developed as potential treatments for men with prostate cancer. Preclinically, both investigational agents have demonstrated activity in models of wild type tumors in addition to tumors with AR mutation or amplification, both common mechanisms of resistance to currently available AR-targeted therapies.

About vepdegestrant (ARV-471)
Vepdegestrant is an investigational, orally bioavailable PROTAC protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with early and locally advanced or metastatic ER positive/human epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-) breast cancer. Use of vepdegestrant in the ongoing and planned clinical trials will continue to monitor and evaluate patient safety and anti-tumor activity.

In preclinical studies, vepdegestrant demonstrated up to 97% ER degradation in tumor cells, induced tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed increased anti-tumor activity when compared to a standard of care agent, fulvestrant, both as a single agent and in combination with a CDK4/6 inhibitor. In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will equally share worldwide development costs, commercialization expenses, and profits.