Clinical PROTAC® Update: ARV-471 & ARV-110
Arvinas Releases Interim Clinical Data Further Demonstrating the Powerful Potential of PROTAC® Protein Degraders ARV-471 and ARV-110
– ARV-471 demonstrates evidence of anti-tumor activity, and potential for best-in-class safety, and estrogen receptor (ER) degradation profile and robust efficacy signals in a heavily pretreated patient population –
– Initiation of a combination trial of ARV-471 and Ibrance® (palbociclib) expected this month; three additional trials of ARV-471 in patients with breast cancer expected to begin in 2021 –
– ARV-110 continues to demonstrate a favorable safety profile, tolerability, and anti-tumor activity in a heavily pretreated patient population as Phase 1 dose escalation continues in parallel with the ARDENT Phase 2 expansion –
– The ARDENT Phase 2 expansion trial for ARV-110 is designed to evaluate the potential for accelerated approval in a molecularly defined population and broader approval in earlier mCRPC –
下载：https://ir.arvinas.com/static-files/ae52b7dd-e872-483a-bd26-070bae7d56b8
主要是ARV-471和ARV-110的更新
ARV-471和ARV-110都有机会给有着大量临床需求未被满足的患者带来获益
ARV-471是降解ER的PROTAC®，有望在耐受性、ER降解和临床获益上成为潜在的最佳的降解ER的疗法，成为在辅助及晚期治疗阶段抗内分泌治疗的选择，目前在针对高度难治患者的Ph1正在进行中，每年20万患者有着高度未被满足的临床需求
ARV-110是降解AR的PROTAC®，在后线mCRPC的治疗中观察到了AR降解和清晰的疗效信号，启动Ph2的ARDENT研究，2条潜在的注册路径：依靠特定分子分型的3L治疗加速批准+往1L/2L前线探索，每年25万患者有着高度未被满足的临床需求
ARV-471临床更新
ARV-471：
潜在的最佳ER靶向疗法，对ER的降解好于氟维司群及其他临床阶段的SERDs，在重度治疗的患者中观察到很强的疗效信号，共有1例经确认的PR和2例未经确认的PR，CBR达到42%，目前Ph1的剂量递增仍在进行中
目标是把ARV-471开发成ER+/HER2- BC的内分泌治疗的Backbone，作为可以口服的、安全且高效的ER降解剂，在此基础上联合CDK4/6i、mTORi或PI3Ki，近期目标还是晚期患者，US目标人群～5万，将来拓展到术后辅助，US目标人群大约16万
ARV-471的首次人体试验采取了传统“3+3”剂量递增，每日一次随餐口服，起始剂量30mg，主要终点是确认MTD和RP2D，关键次要终点是安全性和可耐受性、PK、PD（基线及治疗中的ER）及疗效（CBR）
入组标准：先前接受过≥2轮内分泌治疗的且不超过2轮化疗的、在CDK4/6i治疗后进展的ER+/HER2-的晚期乳腺癌，可能是唯一一个要求先前接受过CDK4/6i治疗的ER靶向疗法的临床
在CDK4/6i治疗后，66%的患者携带了非ER依赖的耐药机制，这时即便接受氟维司群治疗，疗效也很差，PFS 1.8mo，CBR 不到20%
一共入组了21例患者，中位年龄64，ECOG PS 1占52%
先前接受过的治疗线程数中位值5，先前接受过的内分泌治疗线程数中位值3，先前的治疗方案包括：100%接受过CDK4/6i、71%接受过氟维司群、24%接受过临床阶段的SERD、38%接受过化疗，可见都是重度治疗后的患者
ARV-471在所有研究的剂量水平的可耐受性都很好，任意级别的AE 52%，但都是Gr 1-2没有Gr3 AE，主要AE包括恶心24%、关节痛 19%、疲劳19%、食欲下降 14%
PK与剂量线性相关，而且第二个剂量的血药暴露就超过了临床前模型的药效阈值
定量免疫荧光显示，ARV-471 60mg QD治疗 后观察到了ER（红色）的降解
在120mg DL，ER降解62%，最高达90%，降解效果好于氟维司群的历史数据40-50%，并且不管是野生型ER还是ESR1突变，都观察到降解
1例患者之前接受过帕博西尼+6种内分泌治疗+依维莫司+2种化疗方案的，并且携带ESR1 D538G突变的患者，在接受4个疗程ARV-471治疗后确认了PR，病灶缩小了51%
另一例先前接受过包括2种CDK4/6i+3种内分泌治疗+依维莫司+4种化疗方案在内的重度治疗的、携带ESR1多个突变的患者，在接受了4个疗程的ARV-471 180mg剂量后胸壁病灶也有了明显缩小，不再出血
ARV-471在后线治疗中展现了令人鼓舞的疗效，在可评估的14例患者中共1例经确认的PR，2例未经确认的PR，8例SD，大部分患者的病灶都有缩小——而且这部分患者先前基本接受过氟维司群或临床阶段的SERD
目前爬到了180mg，CBR 42%
和其他SERDs简单比下，虽然CBR上没有绝对优势，但是患者是唯一的100%接受过CDK4/6i治疗的，而且ER的降解幅度最高。另外安全性方面，AE种类最少。
因此以ARV-471位backbone，启动了针对ER+/HER2- BC的一系列研究
20年12月启动ARV-471联合帕博西尼（为啥不选阿贝西利）一线治疗的Ph1b，而在2/3线治疗上，21H1单药会进行Ph2扩增，21H2开展ARV-471联合靶向治疗的Ph1b，同时这么对早期辅助治疗，会开展ARV-471±CDK4/6i的随机对照，直接Ph3？
一系列证据显示，针对这么一个巨大的未被满足的需求和市场，ARV-471有着成为best in class的潜质
下面是ARV-110的更新
ARV-110：可耐受性很好，目前一直递增到了700mg，在包括T878/H875突变的患者中获得40%的 PSA50缓解，同时野生型肿瘤中也看到了活性，有望成为针对前列腺癌的best in class，目前针对特定分子分型群体的Ph2 ARDENT研究正在进行中，旨在可以被加速审批，同时在探索用于前线mCRPC
在目前美国前列腺癌的治疗范式下，像Enza、Abi、Daro和Apa等2代AR已经获批了包括前线治疗在内的同时，客观上也带来了mCRPC后续各个阶段对新型治疗的未满足需求
随着治疗线程的后移，2代AR治疗的疗效变差，从CSPC阶段的PSA80高达90%，到了3L mCRPC阶段PSA50只有8-15%，再往后不足10%，目前ARV-110针对这部分后线患者的治疗正在进行中——患者有着高度的肿瘤异质性和耐药机制，近期会在mCRPC中开展评估ARV-110用于后线特定分子分型的患者并探索前线治疗，而针对更广的CSPC和NM CRPC也在积极探索ARV-100的治疗机会
而在高度难治的患者群体中，ARV-110显示了可以带来早期的临床获益，这部分患者先前治疗线程中位数高达5，75%接受过化疗，82%同时接受过恩杂鲁胺和阿比特龙，84%携带非AR突变，也就是说现有的AR疗法基本无效，另外有着高度的肿瘤异质性可能对AR的依赖性很低
在Ph1中，已经在重度治疗的缺乏治疗选择的患者中观察到了抗肿瘤疗效，PSA的降低也和血药暴露相关，后线特定分子分型的群体能从ARV-110中获得最大程度的缓解，同时在AR野生型的患者中也观察到抗肿瘤活性也支持更广的使用，另外可耐受性很好，支持递增到现有的700mg QD，同时也支持更前线的治疗，所以已经启动420mg QD剂量的Ph2 ARDENT研究
430mg剂量的血药暴露超过了恩杂鲁胺耐药模型的药效阈值，但140和280mg只是超过前列腺癌标准模型的最低药效阈值
临床结果显示，随着剂量的提高，带来更高的暴露，最终带来更高的临床活性，这种暴露量-效应关系支持了下一步Ph2的剂量选择
尽管在Ph1的递增阶段患者有着高度的肿瘤异质性，但是还是检测了突变，因为遗传背景作为决定疗效的主要因素，是Ph2阶段患者选择的依据
在后线高度异质性的患者群体中，确认了可能对ARV-110敏感的分子分型
整个人群中71%携带T878/H857突变或是AR野生型，80%(4/5)的T878/H857患者的PSA下降，40%获得PSA50，会是Ph2阶段富集的群体，有望用来支持加速审批
同样ARV-110在AR 野生型的患者中也观察到疗效，12%获得PSA50，提示可以选择更广的群体
另外安全性上也没有＞Gr2 的AE，结合疗效，支持420mg QD的Ph2扩张
ARDENT计划入组100人，注册路径上包括3L特定分子分型如T878/H857突变的群体用来加速批准，还包括前线(1/2L)的mCRPC——即只在阿比特龙 and/派人恩杂鲁胺治疗后进展、Chemo-Naive的轻度治疗患者，此外还会入组其他可能ARV-110降解及像L702H和ARv7这种ARV-110无法降解的亚组
注册路径上既考虑到后线未被满足的需求，同时也积极往前线探索
有望在前列腺癌各个阶段的治疗中解决未被满足的需求
其他
正文
NEW HAVEN, Conn., Dec. 14, 2020 (GLOBE NEWSWIRE) -- Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biopharmaceutical company creating a new class of drugs based on targeted protein degradation using its PROTAC® Discovery Engine, today announced clinical program updates for its PROTAC® protein degraders ARV-471 and ARV-110. For ARV-471, interim Phase 1 data show potential for best-in-class safety and tolerability, estrogen receptor (ER) degradation superior to that previously reported for the current standard of care agent (fulvestrant), and robust efficacy signals in heavily pretreated patients with locally advanced or metastatic ER positive / HER2 negative (ER+/HER2-) breast cancer. The efficacy signals include one Response Evaluation Criteria in Solid Tumors (RECIST) confirmed partial response (PR), two additional patients with unconfirmed PRs, and a clinical benefit rate (CBR) of 42%. For ARV-110, the ongoing dose escalation portion of the Phase 1/2 trial in men with metastatic castration-resistant prostate cancer (mCRPC) has provided additional evidence of anti-tumor activity and patient benefit, including a prostate specific antigen reduction of more than 50% (PSA50) rate of 40% in a molecularly defined patient population. Arvinas has initiated a Phase 2 dose expansion to explore a two-pronged development strategy, including the potential for accelerated approval in molecularly defined, late-line patients, and broader development in less-heavily pretreated mCRPC patients with fewer androgen receptor (AR)-independent mechanisms of tumor resistance.
Both ARV-471 and ARV-110 have been well tolerated, neither has reached a maximum tolerated dose, and the Phase 1 dose escalation trials for both programs continue. A Phase 1b combination trial of ARV-471 and Ibrance® (palbociclib) is expected to begin in December 2020, and a Phase 2 expansion cohort for ARV-471 is scheduled to begin in the first half of 2021.
“After initiating our clinical efforts just last year, we now have what we believe are clear signals of efficacy in both of our clinical-stage development programs,” said John Houston, Ph.D., Chief Executive Officer at Arvinas. “The clinical benefits we’ve seen in both patient populations, including tumor shrinkage and low incidence of adverse effects, are compelling and reinforce our belief that our PROTAC protein degraders could dramatically change the lives of patients who have few or no therapeutic options.”
“Based on data to date, we believe ARV-471 is the most promising ER-targeting therapy in the clinic, showing early signs of efficacy, a favorable tolerability profile, and better ER degradation than that previously reported for fulvestrant, the current standard of care,” said Ron Peck, Ph.D., Chief Medical Officer at Arvinas. “It is exciting to see that ARV-110 continues to be active and well tolerated in what we believe is the most heavily pretreated patient population that has ever been studied with an AR-directed therapy. Our recently initiated ARDENT Phase 2 cohort expansion is specifically designed to investigate the potential of a precision medicine approach in molecularly defined, late-line patients with few available treatment options, while also fully characterizing the safety and activity of ARV-110 in earlier line patients irrespective of molecular profile, setting ARV-110 on a potential two-pronged registrational path.”
ARV-471 Clinical Update
As of the data cut-off date of November 11, 2020, 21 adult patients with locally advanced or metastatic ER+/HER2- breast cancer completed at least one treatment cycle with ARV-471 (orally, once-daily) in the Phase 1 clinical trial. 100% of these patients were previously treated with a cyclin-dependent kinase (CDK) 4/6 inhibitor, 71% of patients received prior fulvestrant, and 23% of patients were pretreated with investigational selective estrogen receptor degraders (SERDs). Overall, patients had a median of five prior therapies.
In metastatic breast cancer, prior treatment with CDK4/6 inhibitors predicts high tumor ER-independence, rendering ER-targeting therapies ineffective. However, one patient in the ARV-471 trial had a confirmed PR with a 51% reduction in target lesion size as assessed by RECIST. Two additional patients had unconfirmed PRs and one additional patient demonstrated stable disease with >50% target lesion shrinkage. For evaluation of CBR, 12 patients had sufficient follow-up to be included. Five of 12 patients (42%) achieved CBR (CBR defined as PRs + complete responses + stable disease at 6 months). Three of these five patients had previously received fulvestrant, and another was treated with two investigational SERDs.
ARV-471 has been well tolerated at all dose levels, as of the data cut-off date. The most common treatment-related Grade 1-2 adverse events were nausea (24%), arthralgia (19%), fatigue (19%), and decreased appetite (14%). None of these led to discontinuation or dose reduction of ARV-471. No patients reported treatment-related Grade 3 of 4 adverse events, and no dose-limiting toxicities (DLTs) have been reported. A maximum tolerated dose (MTD) has not been reached and dose escalation continues.
The plasma exposures of ARV-471 have been dose proportional up to and including 360 mg orally once daily and have substantially exceeded Arvinas’ predicted thresholds of efficacy based on preclinical studies. The estimated half-life of ARV-471 is 28 hours, supporting a once-daily schedule of administration. Analysis of five paired tumor biopsies at doses up to 120 mg provide compelling proof of mechanism for ARV-471, which has demonstrated ER degradation up to 90% (average of 62%) at those doses, while dose escalation continues.
The combined profile of ARV-471, including efficacy signals in a highly refractory population, excellent tolerability profile, and high levels of ER degradation, support a potential best-in-class ER-targeting therapy.
A Phase 2 dose expansion of ARV-471 is expected to begin in the first half of 2021. Arvinas also expects to initiate a Phase 1b cohort expansion of ARV-471 in combination with Ibrance® (palbociclib) in December 2020. This trial will evaluate the safety and tolerability of ARV-471 in combination with palbociclib and seek to identify a recommended combination dose. Arvinas expects to begin two additional studies of ARV-471 in the second half of 2021: a combination trial of ARV-471 and another targeted therapy in 2L/3L metastatic breast cancer, and a window of opportunity study in adjuvant breast cancer. The combined data from these studies will inform Arvinas’ global development strategy and path forward toward the goal for ARV-471 to become the leading endocrine therapy in ER+/HER2- breast cancer.
ARV-110 Clinical Update
In the Phase 1 clinical trial in men with mCRPC, ARV-110 continues to show promising activity in a very late-line population, with PSA reductions >50% observed at doses greater than 280 mg, the last reported cohort.
In the dose escalation, ARV-110 exposures have risen dose proportionally, and at 420 mg oral daily dosing, exposures in nearly all patients have surpassed a threshold associated with tumor responses with ARV-110 in enzalutamide-resistant preclinical models of prostate cancer. Increases in exposure are associated with increased frequency of PSA reductions.
In the Phase 1 dose escalation trial, 76% of patients had been treated with prior chemotherapy, and 82% previously received both abiraterone and enzalutamide. Patients had a median of five prior lines of therapy. Multiple lines of therapy in nonmetastatic and metastatic castrate resistant prostate cancer are associated with a decreased responsiveness to AR-directed therapies and an increase in tumor heterogeneity, including in genetic mutations, which reduce the tumor’s dependence on the AR signaling axis. Genetic profiling of trial patient tumors has led to significant learnings about the ARV-110 Phase 1 patient population, especially regarding genetic variability. 84% of patients in the trial have non-AR gene mutations, and as such, they would not be expected to respond. In addition, rates of specific AR mutations have been found to be higher than reported in publications that have characterized prevalence of AR mutations in men with mCRPC.
Despite the highly heterogeneous nature of the Phase 1 patient population, Arvinas has identified a molecularly defined, late-line population with a particularly strong response to ARV-110. Two of five patients (40%) with T878 or H875 mutations in AR had PSA reductions >50%, including one patient with a confirmed PR by RECIST and tumor size reduction of 80%.
In addition, two of 15 patients (13%) with wild-type AR also had PSA reductions >50%, representing activity in a broader patient population. In the full group of patients with exposures above the minimum threshold Arvinas predicted to be efficacious by preclinical studies, four of 28 (14%) had PSA reductions >50%. These PSA50 rates are higher than would be expected from approved AR-directed therapies in such late-line patients. Specifically, PSA50 response rates from standard-of-care AR-directed therapies generally decrease to 8-15% in mCRPC patients with fewer prior therapies than the patients in the ARV-110 trial.
The dual signals of ARV-110 activity in a molecularly defined population (T878/H875) and in wild-type patients supports Arvinas’ two-pronged strategy for ARV-110 development and suggest a robust opportunity to address unmet need in patients with mCRPC.
A daily dose of 420 mg was selected as a Phase 2 expansion dose based on pharmacokinetics, safety profile, and the activity signals in both T878/H875 and wild-type patients. In the ARDENT Phase 2 expansion, T878/H875 patients will be enriched in a subgroup to ensure sufficient patient numbers to support the potential for accelerated approval in this population. A separate subgroup will enrich for less-pretreated patients (i.e., no prior chemotherapy and with only one previous second-generation AR-directed therapy, such as enzalutamide or abiraterone), to ensure sufficient numbers of patients whose tumors are expected to be more AR-dependent, less genetically complex, and more responsive to ARV-110.
The ARDENT Phase 2 expansion (N = ~100) began enrolling in October 2020, and Arvinas expects to provide interim data from the trial in the second half of 2021. In 2021, Arvinas also expects to begin at least one Phase 1b combination trial with a standard-of-care prostate cancer therapy and provide complete data from the Phase 1 dose escalation.
Anticipated 2020/2021 Milestones
ARV-471
Initiation of a Phase 1b trial in combination with Ibrance® (palbociclib) (December 2020)
Initiation of a Phase 2 dose expansion (1H21)
Completion of the Phase 1 dose escalation (1H21)
Safety data from the Phase 1b trial in combination with Ibrance® (palbociclib) (2H21)
Initiation of a window of opportunity study in adjuvant breast cancer (2H21)
Initiation of a combination trial of ARV-471 and another targeted therapy in 2L/3L metastatic breast cancer (2H21)
ARV-110
Completion of the Phase 1 dose escalation (1H21)
Interim data from the ARDENT Phase 2 dose expansion at 420 mg (2H21)
Initiation of combination trial(s) with standards-of-care (2021)
Other clinical milestones
First-in-human start for ARV-766, an AR degrader with a different profile from ARV-110 (1H21)
Arvinas Webcast Investor Meeting
Arvinas will host a conference call and webcast at 8:00 AM ET on Monday, December 14, 2020 to discuss these 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 9681734. A live webcast presentation will be available here or on the Company’s website at www.arvinas.com under Events + Presentations. A replay of the webcast will be archived on the Arvinas website following the presentation.