UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): October 23, 2019
Arvinas, Inc.
(Exact name of registrant as specified in its charter)
| Delaware | 001-38672 | 47-2566120 | ||
| (State or other jurisdiction of incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) | ||
| 5 Science Park 395 Winchester Ave. New Haven, Connecticut |
06511 | |||
| (Address of principal executive offices) | (Zip Code) | |||
Registrant’s telephone number, including area code: (203) 535-1456
Not applicable
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
| ☐ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| ☐ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ☐ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ☐ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading Symbol(s) |
Name of each exchange on which registered | ||
| Common stock, par value $0.001 per share | ARVN | The Nasdaq Stock Market LLC |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company ☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒
| Item 8.01 | Other Events |
On October 23, 2019, Arvinas, Inc. (the “Company”) issued a press release announcing a platform update that includes initial safety, tolerability and pharmacokinetic data from its ongoing Phase 1 clinical trial of ARV-110 in patients with metastatic castration-resistant prostate cancer (mCRPC) and its ongoing Phase 1 clinical trial of ARV-471 in patients with locally advanced or metastatic estrogen receptor positive (ER+) / human epidermal growth factor receptor-2 negative (HER2-) breast cancer. A copy of this press release is attached hereto as Exhibit 99.1 and is incorporated herein by reference.
The Company will present the initial data from the Phase 1 clinical trials at the 2nd Targeted Protein Degradation Summit on October 23, 2019. The presentation containing the initial data from the Phase 1 clinical trials is attached hereto as Exhibit 99.2 and is incorporated by reference herein.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits.
| 99.1 | Press Release, dated October 23, 2019. | |
| 99.2 | Company presentation, dated October 23, 2019. | |
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| ARVINAS, INC. | ||||||
| Date: October 23, 2019 | By: | /s/ Sean Cassidy | ||||
| Sean Cassidy | ||||||
| Chief Financial Officer | ||||||
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Exhibit 99.1
Arvinas Presents a Platform Update, Including Initial Data from the First Two Clinical Trials of PROTAC® Targeted Protein Degraders
-Data from initial cohorts suggest that Arvinas’ PROTAC® platform has the potential to create safe and well-tolerated orally bioavailable drugs for the treatment of certain cancers
-Conference call to be held at 8:30 AM ET today
NEW HAVEN, CT, October 23, 2019 – Arvinas, Inc., (Nasdaq: ARVN), a biotechnology company creating a new class of drugs based on targeted protein degradation, today announced a platform data update that includes initial safety, tolerability, and pharmacokinetic data from the company’s ongoing Phase 1 clinical trials of ARV-110 and ARV-471. The data, which show dose-proportional exposures of ARV-110 and that both ARV-110 and ARV-471 have been well tolerated, will be presented by Ian Taylor, Ph.D., Chief Scientific Officer at Arvinas, at the 2nd Targeted Protein Degradation Summit in Boston, MA. Dr. Taylor’s presentation will be available on Arvinas’ website this morning.
“This is the first look at clinical data from our PROTAC® platform and is an exciting milestone for both Arvinas and for the field of targeted protein degradation. We are seeing a favorable overall safety profile for both clinical programs to date, and dose-proportional exposures of ARV-110,” said John Houston, Ph.D., Chief Executive Officer at Arvinas. “We are encouraged by these initial results as we work to create well tolerated therapies to treat serious diseases.”
Phase 1 Study Designs and Clinical Data
Both ARV-110 and ARV-471 are being evaluated in Phase 1, open-label, dose-escalation clinical trials designed to assess safety, tolerability, and pharmacokinetics (PK).
The ARV-110 clinical trial is of 28 to 36 patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on at least two prior systemic therapies. The ARV-471 clinical trial is of 24 to 36 patients with estrogen receptor positive (ER+) / human epidermal growth factor receptor-2 negative (HER2-) locally advanced or metastatic breast cancer who have received prior hormonal therapy and chemotherapy.
Both ARV-110 and ARV-471 are oral therapies dosed once per day.
The presentation today will show that Arvinas’ PROTAC® protein degraders have been well tolerated by patients at the doses tested to date. The initial data for ARV-110 are from the first three dose-escalation cohorts (35 mg, 3 patients; 70 mg, 4 patients; and 140 mg, 3 patients), while the initial data presented for ARV-471 are from three patients enrolled in the first dose cohort (30 mg). Both ARV-110 (35, 70, and 140 mg) and ARV-471 (30 mg) were well tolerated, with no dose-limiting toxicities (DLTs) and no grade 2, 3, or 4 related adverse events observed.
The presentation today will also show dose proportionality for ARV-110 and that exposures of both ARV-110 and ARV-471 have reached levels associated with tumor growth inhibition in preclinical studies. For both programs and at each dose level tested to date, PK data were evaluated at days 1 and 15 following initial dosing. The third (140 mg) cohort of ARV-110 and the first (30 mg) cohort of ARV-471 reached average plasma exposures and average maximum concentrations that were above the lower ends of the ranges that were associated with tumor growth inhibition in preclinical studies. In addition, increases in exposure and average maximum concentration of ARV-110 were dose-proportional across all three doses tested to date.
For the next cohorts of each of ARV-110 and ARV-471, the dose is being increased by 100% (to 280 mg for ARV-110, and to 60 mg for ARV-471). Aside from continuing to investigate safety and PK, the Phase 1 clinical trial of ARV-110 will also evaluate biochemical and clinical activity by assessing prostate specific antigen (PSA) levels and RECIST response in patients with baseline measurable disease, androgen receptor (AR) degradation, and other exploratory biomarkers. The Phase 1 clinical trial of ARV-471 will continue to evaluate safety and PK, as well as evaluate estrogen receptor (ER) degradation, RECIST response in patients with baseline measurable disease, and other exploratory biomarkers.
Arvinas expects to next share clinical data from the Phase 1 dose escalation trial of ARV-110 in the first half of 2020 and from the Phase 1 dose escalation trial of ARV-471 in the second half of 2020.
Conference Call:
The company will host a conference call and webcast at 8:30 AM ET today to discuss these initial data. Participants are invited to listen by dialing (844) 467-7654 (domestic) or (602) 563-8497 (international) five minutes prior to the start of the call and providing the passcode access code 9096099. A listen-only webcast of the conference call can also be accessed through the “Investors” tab on the Arvinas website, www.arvinas.com, and a replay will be available for six weeks following the call.
About Arvinas:
Arvinas is a clinical-stage biopharmaceutical company dedicated to improving the lives of patients suffering from debilitating and life-threatening diseases through the discovery, development, and commercialization of therapies that degrade disease-causing proteins. Arvinas uses its proprietary technology platform to engineer proteolysis targeting chimeras, or PROTAC® targeted protein degraders, that are designed to harness the body’s own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins. The company has two clinical-stage programs: ARV-110 for the treatment of patients with metastatic castrate-resistant prostate cancer; and ARV-471 for the treatment of patients with ER+/HER2- locally advanced or metastatic breast cancer. For more information, visit www.arvinas.com.
About ARV-110
ARV-110 is an orally-bioavailable PROTAC® protein degrader designed to selectively target and degrade the androgen receptor (AR). ARV-110 is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer (mCRPC). Arvinas’ Phase 1 trial of ARV-110 will assess its safety, tolerability, and pharmacokinetics, and will also include measures of anti-tumor activity and pharmacodynamic readouts as secondary endpoints.
ARV-110 has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.
About ARV-471
ARV-471 is a PROTAC® protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of women with metastatic breast cancer. Arvinas’ Phase 1 trial of ARV-471 will assess its safety, tolerability, and pharmacokinetics, and will also include measures of anti-tumor activity and pharmacodynamic readouts as secondary endpoints.
In preclinical studies, ARV-471 demonstrated near-complete ER degradation in tumor cells, induced robust tumor shrinkage when dosed as a single agent in multiple ER-driven xenograft models, and showed superior anti-tumor activity as a single agent and in combination with a CDK4/6 inhibitor when compared to a standard of care agent, fulvestrant (as a single agent and in combination with a CDK4/6 inhibitor).
Forward-Looking Statements
This press release contains forward-looking statements that involve substantial risks and uncertainties, including statements regarding the development and regulatory status of our product candidates, such as statements with respect to our lead product candidates, ARV-110 and ARV-471, and the timing of clinical trials and data from those trials for our product candidates, and our discovery programs that may lead to our development of additional product candidates, the potential utility of our technology and advantages and therapeutic potential of our product candidates, and the sufficiency of our cash resources. All statements, other than statements of historical facts, contained in this press release, including statements regarding our strategy, future operations, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make as a result of various risks and uncertainties, including but not limited to: whether we will be able to successfully conduct Phase 1 clinical trials for ARV-110 and ARV-471, complete other clinical trials for our product candidates, and receive results from our clinical trials, on our expected timelines, or at all, whether our cash resources will be sufficient to fund our foreseeable and unforeseeable operating expenses and capital expenditure requirements on our expected timeline and other important factors discussed in the “Risk Factors” sections contained in our quarterly and annual reports on file with the Securities and Exchange Commission. The forward-looking statements contained in this press release reflect our current views with respect to future events, and we assume no obligation to update any forward-looking statements except as required by applicable law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this release.
Contacts for Arvinas
Investor Relations
Will O’Connor, Stern Investor Relations
ir@arvinas.com
Media
Cory Tromblee, ScientPR
pr@arvinas.com
Moving PROTAC® Protein Degraders from the Laboratory to the Clinic IAN TAYLOR, PHD 2nd Annual Targeted Protein Degradation Summit OCTOBER 2019 Exhibit 99.2
Safe Harbor and Forward-Looking Statements This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the development and regulatory status of our product candidates, such as statements with respect to our lead product candidates, ARV-110 and ARV-471, and the timing of clinical trials and data from those trials for our product candidates, and our discovery programs that may lead to our development of additional product candidates, the potential utility of our technology and therapeutic potential of our product candidates, the potential commercialization of any of our product candidates, and the sufficiency of our cash resources. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make as a result of various risks and uncertainties, including but not limited to: whether we will be able to successfully conduct Phase 1 clinical trials for ARV-110 and ARV-471, complete other clinical trials for our product candidates, and receive results from our clinical trials on our expected timelines, or at all, whether our cash resources will be sufficient to fund our foreseeable and unforeseeable operating expenses and capital expenditure requirements on our expected timeline and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, discussed in the “Risk Factors” section of the Company’s quarterly and annual reports on file with the Securities and Exchange Commission. The forward-looking statements contained in this presentation reflect our current views as of the date of this presentation with respect to future events, and we assume no obligation to update any forward-looking statements except as required by applicable law. The Arvinas name and logo are our trademarks. We also own the service mark and the registered U.S. trademark for PROTAC®. The trademarks, trade names and service marks appearing in this presentation are the property of their respective owners. We have omitted the ® and ™ designations, as applicable, for the trademarks named in this presentation.
Arvinas: Company Overview PIPELINE ARV-110 - Metastatic castration-resistant prostate cancer; Phase 1 initiated 1Q19, and received “Fast Track” designation from FDA in May 2019 ARV-471 - Estrogen receptor-positive / HER2-negative locally advanced or metastatic breast cancer; Phase 1 initiated 3Q19 Brain-penetrant PROTAC® programs targeting tauopathies and a-synucleinopathies OUTSTANDING TEAM Strong leadership team with unparalleled protein degrader development experience World-class board and advisors, including scientific founder Craig Crews (Yale) HISTORY Founded July 2013; New Haven, CT ~125 employees September 2018 IPO COLLABORATORS Exclusive worldwide license to PROTAC® degrader technology with Yale University Strategic, discovery-stage partnerships with Pfizer, Genentech and Bayer Partnerships across broad set of therapeutic areas and a JV for agricultural applications
High Potential PROTAC® Pipeline, Focused on Cancer and Neurology1 1 Pipeline as of October 23, 2019 Programs [Target] Discovery Lead Optimization IND Enabling Phase 1 Arvinas Owned Oncology Metastatic Castration-resistant Prostrate Cancer ü ü ü Locally Advanced or Metastatic ER+ / HER2- Breast Cancer ü Additional Oncology Indications ü Neurology Tauopathies ü Synucleinopathies ü Additional Neurology Indications ü ARV-110 [Androgen Receptor] Next Generation Degrader [Androgen Receptor] AR Variant Degrader [AR-V7] ARV-471 [Estrogen Receptor] e.g., CRC, NSCLC [Various Undisclosed] e.g., PSP2 [Tau] e.g., MSA3, Parkinson’s [a-synuclein] Various [Undisclosed] 2 PSP, progressive supranuclear palsy 3 MSA, multiple systems atrophy
The “Tenets of PROTAC® Degraders” Areas where the PROTAC® mechanism of action may be particularly well-suited TENETS OF PROTAC® Degraders
Two Big Questions of the PROTAC® Platform As It Moves From Laboratory to the Clinic TWO BIG QUESTIONS
Asking the Two Big Questions of ARV-110: Androgen Receptor PROTAC®
Androgen Receptor (AR) Activity Drives Prostate Cancer Current agents work by decreasing androgen levels (abiraterone) or blocking androgen binding to AR (enzalutamide) 15-25% of patients never respond to abiraterone or enzalutamide (intrinsic resistance) Resistance mechanisms to abiraterone and enzalutamide include: AR gene amplification (40-60% of patients) AR gene enhancer amplification (>70% of patients) AR point mutations (~15% of patients) Intra-tumoral androgen production PROTAC® Degrader ARV-110 Highly selective degrader of AR; DC50 = 1 nM In preclinical models, overcomes resistance mechanisms to enzalutamide and abiraterone Not brain penetrant First-in-class AR degrader being tested in men with metastatic castration-resistant prostate cancer who have progressed on standards of care (enzalutamide, abiraterone) Phase 1 clinical trial initiated 1Q19 Received FDA “Fast Track” designation in May 2019 According to the American Cancer Society, prostate cancer is the second leading cause of cancer death in men in the U.S. (~174k diagnosed/yr1); 35-45k new incidences of mCRPC in the U.S. each year ARV-110: AR Degrader for Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC)1 DHEA Testosterone DHT AR AR AR AR ARE Abiraterone Enzalutamide AR PSA
ARV-110 Potently and Rapidly Degrades AR and Inhibits Proliferation Better than Enzalutamide in Preclinical Models In vitro studies ARV-110 degraded 95% to 98% of AR in multiple cell lines typically used in prostate cancer research, including VCaP cells DC50 in VCaP = 1 nM Near-maximal degradation within 4 hours of administration ARV-110 inhibits VCaP proliferation ~60x more potently than enzalutamide VCaP Cells: DMSO 3 nM 10 nM 30 nM 100 nM 300 nM 1 nM 0.3 nM 0.1 nM 0.03 nM ARV-110 AR Loading Control
ARV-110 Inhibits AR-Dependent Tumor Growth in Xenograft Models with Oral, Daily Dosing Intact (Non-castrated) VCaP: Dose po, qd Mean AUC0-24 ng*hr/ml† Mean Cmax ng/ml‡ 1 mpk 3628 224 3 mpk 8106 507 Castrated VCaP: mpk = mg/kg Enzalutamide Resistant VCaP: Values represent total drug concentrations † AUC0-24 or Area Under the Curve is a measurement of total exposure from 0-24 hours after last dose ‡ Cmax is a measurement of peak concentration
MTD, maximum tolerated dose. NOAEL, no observed adverse effect level; mpk = mg/kg ARV-110: GLP Toxicology Studies Supported Moving into Clinical Development Rat Study: Male animals, 20, 60, or 120 mpk per day; Female animals, 20, 40, or 80 mpk per day Overall, ARV-110 was well tolerated at all doses Exception: 80 mpk in females; decreased body weight and food consumption; NOAEL = 40 mpk All findings in male high-dose animals (liver hypertrophy, femur physis thickening) fully reversible; NOAEL = 120 mpk Decreased prostate weights noted in all male animals; believed attributable to ARV-110 pharmacology Design: Animals dosed daily, orally for 28 days; 14-day recovery for high-dose animals Dog Study: 3, 10, or 30 mpk; 30 mpk exceeded MTD; NOAEL = 10 mpk DLT: Gastrointestinal alteration (e.g., loose/discolored stools) at all dose levels, including with vehicle alone Dog is most sensitive species Reversible liver function enzyme elevation in some mid- and high-dose animals; considered non-adverse Decreased prostate weights in all male animals; believed attributable to ARV-110 pharmacology
ARV-110: Phase 1 Study First patient dosed March 2019 Key Objectives: Maximum Tolerated Dose/ Recommended Phase 2 Dose/ Safety Pharmacokinetics Anti-Tumor Activity (PSA, RECIST) Biomarkers Biomarkers: AR degradation in circulating tumor cells (CTCs) and pre- vs post-treatment biopsies (when available) AR (and other) gene mutations, amplifications in circulating tumor DNA (ctDNA) AR-V7 in CTCs Design: “3 + 3” dose escalation; starting dose = 35 mg, orally, once daily (po, qd) with food Dose increases dependent on toxicities: range 25% (if 1 DLT in 6 pts) to 100% (≤Grade 1 Adverse Events) Key Entry Criteria: Men with mCRPC At least two prior systemic therapies, at least one of which was abiraterone or enzalutamide Disease progression on most recent therapy Rising PSA or 2+ new lesions upon bone scan PSA, Prostate specific antigen. RECIST, Response evaluation criteria in solid tumors
ARV-110 Phase 1 Dose Escalation—Pharmacokinetics is Dose Proportional Dose po, qd Day 1 AUC0-24 (ng*h/mL) Mean Day 1 Cmax (ng/ml) Mean Day 15 AUC0-24 (ng*h/mL) Meana Day 15 Cmax (ng/ml) Mean 35 mg 160.5 11.1 1701 83 70 mg 300 19.6 2538 141 140 mg 865 54 5023 353 Phase 1 Data a Day 15 AUCs calculated using imputed 24 hour values Dose (po, qd) AUC0-24 (ng*hr/ml) Cmax (ng/ml) 1 mpk 3628 224 3 mpk 8106 507 Preclinical Efficacious Exposure Range Accumulation occurs between Day 1 and Day 15
ARV-110 Phase 1 Dose Escalation—Pharmacokinetics is Dose Proportional Dose po, qd Day 1 AUC0-24 (ng*h/mL) Mean Day 1 Cmax (ng/ml) Mean Day 15 AUC0-24 (ng*h/mL) Meana Day 15 Cmax (ng/ml) Mean 35 mg 160.5 11.1 1701 83 70 mg 300 19.6 2538 141 140 mg 865 54 5023 353 Phase 1 Data a Day 15 AUCs calculated using imputed 24 hour values Dose (po, qd) AUC0-24 (ng*hr/ml) Cmax (ng/ml) 1 mpk 3628 224 3 mpk 8106 507 Preclinical Efficacious Exposure Range Accumulation occurs between Day 1 and Day 15 Exposure at 140 mg has entered the preclinical efficacious range associated with tumor growth inhibition
ARV-110 Phase 1 Dose Escalation—Pharmacokinetics is Dose Proportional Day 15 AUC Day 15 Cmax Dose po, qd Day 15 AUC0-24 (ng*h/mL) Meana Day 15 Cmax (ng/ml) Mean 35 mg 1701 83 70 mg 2538 141 140 mg 5023 353 a Day 15 AUCs calculated using imputed 24 hour values Orange lines represent AUC and Cmax associated with tumor growth inhibition at 1 mpk and 3 mpk in preclinical models
ARV-110 Phase 1 Dose Escalation— Day 15 Pharmacokinetics Tmax† = 4 - 8 hours t1/2‡ = estimated 3 - 7 days † Time of to reach maximum concentration (Cmax) ‡ Effective half-life: rate of accumulation or elimination of a pharmacologic substance 24 hour values are imputed from time zero
ARV-110 Phase 1 Dose Escalation Safety/Tolerability: Overall Favorable Profile Observed to Date Dose Levela N Key Safety Findings 35 mg 3 No Dose Limiting Toxicities (DLTs) No Treatment Related Adverse Events (AEs) 70 mg 4 No DLTs No Grade 2/3/4 Treatment Related AEs 140 mgb 3c No DLTs No Grade 2/3/4 Treatment Related AEs 280 mg 3 TBD c Not including 1 non-evaluable patient (discontinued on day 1; patient’s condition had worsened in the interval from screening to the morning of treatment initiation consistent with rapid progression of his cancer.) b Data not yet 100% source data verified a Orally, once daily Three cohorts through 28 day dose limiting toxicity evaluation period; fourth cohort enrolling
First-in-Human Androgen Receptor PROTAC® ARV-110 Proceeding Through Dose Escalation 10 patients with mCRPC treated across three dose levels At doses thus far tested, ARV-110 demonstrating an acceptable safety profile Pharmacokinetics show dose-proportional increase in exposure Dose escalation continues into higher dose level(s) Topline data including PSA and RECIST responses from completed dose escalation –and pharmacodynamic/molecular data--planned in 1st half 2020 at major medical conference
Two Big Questions, Asked a Second Time ARV-471: Estrogen Receptor PROTAC®
All Breast Cancers1 ~80% ER+ Breast cancer is the second most common cancer in women1 ~268,000 women are expected to be diagnosed with invasive breast cancer in the US in 20191 Metastatic breast cancer accounts for ~6% of newly diagnosed cases2 80% of newly diagnosed breast cancers are estrogen receptor (ER) positive3 Fulvestrant has validated the relevance of ER degradation in breast cancer After 6 months of fulvestrant treatment, up to 50% of ER baseline levels remain4 PROTAC® Degrader ARV-471 ARV-471 is a potent degrader (DC50 = 1.8 nM) of the estrogen receptor, which is in development for the treatment of patients with ER+ locally advanced or metastatic breast cancer Phase 1 clinical trial initiated 3Q2019 After Phase 1 dose escalation, a Phase 1b trial in combination with CDK4/6 inhibitor is planned ARV-471: ER Degrader for Patients with Locally Advanced or Metastatic Breast Cancer 1 American Cancer Society; 2 Malmgren, J.A., Breast Cancer Res Treat (2018) 167:579–590; 3 National Cancer Institute, Hormone Therapy for Breast Cancer; 4 Gutteridge et. Al., Breast Cancer Res Treat 2004;88 suppl 1:S177
Orally Dosed ARV-471 Shrinks Tumors and Robustly Degrades ER in MCF7 Xenografts WESTERN BLOT PD (18 hours post last dose) % ER REDUCTION 3 mpk 95 10 mpk 97 30 mpk 94 Dose po, qd Mean AUC0-24 ng*hr/ml Mean Cmax ng/ml 3 mpk 658 84 10 mpk 2538 312 30 mpka 5717 962 TGI 85% 98% 124% mpk = mg/kg Values represent total drug concentrations a Single dose
NOAEL, no observed adverse effect level ARV-471: GLP Toxicology Studies Supported Moving into Clinical Development The studies have shown no clinical signs of toxicity following daily oral doses of ARV-471 up to 100 mg/kg/day in rats and 90 mg/kg/day in dogs, nor effects on overall animal health and well-being. Rat Study: Doses of 3, 10, 30 or 100 mpk administered to all animals; NOAEL = 100 mpk Design: Animals dosed once daily, orally, for 28 days; 28-day recovery period for high-dose animals. Dog Study: Doses of 15, 45, or 90 mpk administered to all animals; NOAEL = 90 mpk
ARV-471: Phase 1 Study First patient dosed August 2019 Biomarkers: Key Objectives: Maximum Tolerated Dose/ Recommended Phase 2 Dose/Safety Pharmacokinetics Anti-tumor activity (RECIST, CBR) Biomarkers Biomarkers: ER gene (ESR1) mutational status in ctDNA and/or tumor tissue ER, Progesterone Receptor and Ki-67 levels in pre- and post-treatment tumor biopsies in patients with accessible tumor tissue Design: “3 + 3” dose escalation; starting dose = 30 mg orally, once daily (po, qd) with food Dose increases dependent on toxicities: range 25% (if 1 DLT in 6 pts) to 100% (≤Grade 1 Adverse Events) Key Entry Criteria: ER+/HER2- advanced breast cancer At least two prior endocrine therapies in any setting, and a CDK4/6 inhibitor Up to three prior cytotoxic chemotherapy regimens CBR, clinical benefit rate
ARV-471 Phase 1 Dose Escalation— First Cohort Pharmacokinetics Dose po, qd Day 1 AUCTAU (ng*h/mL) Mean Day 1 Cmax (ng/ml) Mean Day 15 AUCTAU (ng*h/mL) Meana Day 15 Cmax (ng/ml) Mean 30 mg 1690 109 4100 224 Phase 1 Data Dose (po, qd) Mean AUC0-24 (ng*hr/ml) Mean Cmax (ng/ml) 3 mpk 658 84 10 mpk 2538 312 30 mpk 5717 962 Preclinical Efficacious Exposure Range a Day 15 AUCs calculated using imputed 24 hour values Accumulation occurs between Day 1 and Day 15 Exposure at 30 mg has entered the preclinical efficacious range associated with tumor growth inhibition
ARV-471 Phase 1 Dose Escalation— First Cohort Pharmacokinetics Tmax = 4 hours t1/2 = estimated to be ~24 hours Day 15 24 hour value is imputed from time zero
ARV-471 Phase 1 Dose Escalation—Safety/Tolerability Dose Levela N Key Safety Findings 30 mgb 3 No DLTs No Treatment Related AEs 60 mg 3 TBD b Data not yet 100% source verified Trial update planned in 2nd half 2020 a Orally, once daily First cohort through 28 day dose limiting toxicity evaluation period; second cohort enrolling
Two Big Questions of the PROTAC® Platform TWO BIG QUESTIONS
Two Big Questions of the PROTAC® Platform Today: Favorable Initial Clinical Data from PROTAC® Platform: Two Different PROTAC® Degraders Two Different Cancer Indications Two Different Patient Populations TWO BIG QUESTIONS
The Next Big Question: Will a PROTAC® Demonstrate Efficacy in the Clinic? Planned Milestone Updates 1H20: Topline Data on Completed ARV-110 Phase 1 Dose Escalation 2H20: ARV-471 Phase 1 Update
Thank You The Patients, Their Families and Caregivers Investigators and Clinical Trial Site Staff
And All Arvinas Colleagues!