On October 7, 2021 Clovis Oncology, Inc. (NASDAQ: CLVS) reported that nonclinical data describing the expression of fibroblast activating protein (FAP) in a variety of solid tumor types will be presented during the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), taking place October 7-10, 2021 (Press release, Clovis Oncology, OCT 7, 2021, View Source [SID1234590920]). The analysis, conducted with its partner 3B Pharmaceuticals GmbH, measured FAP expression in multiple tumor types using immunohistochemistry (IHC) as well as the correlation between FAP expression by IHC and in vitro binding of FAP-2286, Clovis’ peptide-targeted radionuclide therapy (PTRT) clinical development candidate that targets FAP.

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"We believe these findings across multiple solid tumor types demonstrate the importance of FAP as a cancer target and underscore the potential for 177Lu-FAP-2286 to treat patients with FAP-expressing tumors," said Dr. Thomas Harding, Executive Vice President and Chief Scientific Officer of Clovis Oncology. "These provide additional validation for our ongoing Phase 1/2 LuMIERE clinical trial of FAP-2286, the first peptide-targeted radionuclide therapeutic in clinical development targeting FAP, and support investigation of FAP-2286 in a broad number of cancer indications. This is representative ofour commitment to emerge as a leader in targeted radionuclide therapy by developing innovative radiotherapies such as FAP-2286 for patients with hard-to-treat cancers."

To determine FAP protein expression in different tumor types, a pan-tumor IHC screen was performed that included 360 samples representing 16 different tumor types. For this analysis, high FAP expression was defined as an overall H-score ≥30 in more than 30% of the samples analyzed in a given tumor type. The IHC screen showed high FAP expression in nine of the 16 solid tumor types evaluated, including pancreatic ductal adenocarcinoma, cancer of unknown primary, salivary gland, mesothelioma, colon, bladder, sarcoma, squamous non–small cell lung, and squamous head and neck cancers. High FAP expression was detected in both primary and metastatic tumor samples and was independent of tumor stage or grade.

The analysis also demonstrated that in most tumor types, FAP expression was predominantly localized to the stroma surrounding the tumor cells within the tumor microenvironment. FAP expression in tumor cells was also observed: in cancers of mesenchymal origin, such as sarcoma and mesothelioma, tumor-cell expression was common, consistent, and strong; in cancers of epithelial origin, tumor-cell FAP expression was rare and, when present, appeared weaker than in the adjacent stroma.

A significant correlation was seen between FAP expression observed by IHC and in vitro FAP-2286 binding as determined by autoradiography, suggesting that FAP is an attractive target for PTRT in a wide array of tumor types.

Following are details of the Clovis-sponsored presentation:

Poster Number: LBA032 – Pan-Cancer Analysis of Fibroblast Activation Protein Alpha (FAP) Expression to Guide Tumor Selection for the Peptide-Targeted Radionuclide Therapy FAP-2286

Lead author: Tanya T. Kwan, PhD

Category: Radiotherapeutics

Date/Time: Thursday, October 7 at 9:00 am ET

The presentation and accompanying poster can also be viewed at: View Source

For more information about FAP-2286, Targeted Radionuclide Therapy (TRT), or Clovis’ TRT development program CLICK HERE.

About FAP-2286

FAP-2286 is a clinical candidate under investigation as a peptide-targeted radionuclide therapy (PTRT) and imaging agent targeting fibroblast activation protein (FAP). FAP-2286 consists of two functional elements; a targeting peptide that binds to FAP and a site that can be used to attach radioactive isotopes for imaging and therapeutic use.High FAP expression has been shown in pancreatic ductal adenocarcinoma, cancer of unknown primary, salivary gland, mesothelioma, colon, bladder, sarcoma, squamous non–small cell lung, and squamous head and neck cancers. High FAP expression was detected in both primary and metastatic tumor samples and was independent of tumor stage or grade. Clovis holds US and global rights for FAP-2286 excluding Europe, Russia, Turkey, and Israel.

FAP-2286 is an unlicensed medical product.

About Targeted Radionuclide Therapy

Targeted radionuclide therapy is an emerging class of cancer therapeutics, which seeks to deliver radiation directly to the tumor while minimizing delivery of radiation to normal tissue. Targeted radionuclides are created by linking radioactive isotopes, also known as radionuclides, to targeting molecules (e.g., peptides, antibodies, small molecules) that can bind specifically to tumor cells or other cells in the tumor environment. Based on the radioactive isotope selected, the resulting agent can be used to image and/or treat certain types of cancer. Agents that can be adapted for both therapeutic and imaging use are known as "theranostics." Clovis, together with licensing partner 3B Pharmaceuticals, is developing a pipeline of novel, targeted radiotherapies for cancer treatment and imaging, including its lead candidate, FAP-2286, an investigational peptide-targeted radionuclide therapeutic (PTRT) and imaging agent, as well as three additional discovery-stage compounds.

About the LuMIERE Clinical Study

LuMIERE is a Phase 1/2 study evaluating FAP-2286 as a peptide-targeted radionuclide therapy (PTRT) targeting fibroblast activation protein, or FAP, in patients with advanced solid tumors (NCT04939610). The Phase 1 portion of the LuMIERE study is evaluating the safety of the investigational therapeutic agent and will identify the recommended Phase 2 dose and schedule of lutetium-177 labeled FAP-2286 (177Lu-FAP-2286). FAP-2286 labeled with gallium-68 (68Ga-FAP-2286) will be utilized as an investigational imaging agent to identify patients with FAP-positive tumors appropriate for treatment with the therapeutic agent. Once the Phase 2 dose is determined, Phase 2 expansion cohorts are planned in multiple tumor types.

On October 7, 2021 Recursion (NASDAQ: RXRX), a clinical-stage biotechnology company decoding biology by integrating technological innovations across biology, chemistry, automation, machine learning and engineering, reported that the U.S. Food and Drug Administration (FDA) has granted the company Fast Track designation for the investigation of REC-2282 for treatment of patients with NF2-mutated meningiomas, including neurofibromatosis type-2 disease-related meningiomas (Press release, Recursion Pharmaceuticals, OCT 7, 2021, View Source [SID1234590918]). REC-2282 is a potentially first-in-class, orally bioavailable, CNS-penetrant small molecule HDAC inhibitor being developed for the treatment of NF2-mutated meningiomas.

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The FDA’s Fast Track designation was established to expedite the review of investigational drugs to treat serious conditions and address unmet medical needs by enabling important drugs to get to patients earlier if approved. Fast Track designation can lead to more frequent interactions with the FDA, as well as Accelerated Approval and/or Priority Review eligibility if certain criteria are met.

"The Fast Track designation for REC-2282 is an important addition to our work to develop this medicine to treat patients with neurofibromatosis type-2 and patients with sporadic meningiomas driven by mutations in the NF2 gene, for which there is a significant unmet need," said Recursion Chief Medical Officer Ramona Doyle, M.D. "I am pleased that the team continues to advance this important medicine towards a Phase 2/3, randomized, multi-center study in patients with NF2-mutated meningiomas, for which we expect to begin enrollment early next year."

Meningiomas are primary tumors of the meninges of the central nervous system. More than 34,000 patients are diagnosed with sporadic meningiomas in the US each year. In patients with progressive meningiomas, more than a third are driven by mutations in the gene NF2. NF2-mutated meningiomas are typically treated with surgery and radiotherapy or with off-label therapies of limited or unproven efficacy. The lack of approved therapies to prevent progression of NF2-mutated meningiomas, which are frequently an aggressive tumor type, represents a significant unmet medical need. In addition, the syndrome neurofibromatosis type-2, which is associated with both sporadic and autosomal dominant inherited mutations in the NF2 gene, gives rise to meningiomas in approximately half of neurofibromatosis type-2 patients. In the US and EU5, neurofibromatosis type-2 affects approximately 33,000 patients and there are no approved therapies.

On October 7, 2021 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported multiple presentations, including initial clinical data from an ongoing Phase 1b study evaluating ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide, in patients with metastatic prostate cancer progressing on enzalutamide (Press release, ORIC Pharmaceuticals, OCT 7, 2021, View Source [SID1234590917]). The abstracts and presentations are available for on-demand viewing via the online platform for AACR (Free AACR Whitepaper)-NCI-EORTC as of October 7, 2021, at 9 a.m. ET.

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Presentations:

Initial results from a Phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer
Biomarker results supporting selection of RP2D from a Phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with enzalutamide in patients with metastatic prostate cancer progressing on enzalutamide
ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetrant properties and enhanced potency in preclinical studies of HER2-positive breast cancer
"We are pleased to share initial data from our ORIC-101 clinical program in patients with metastatic prostate cancer. The combination was well tolerated without evidence of drug-drug interaction affecting enzalutamide dosing and has demonstrated preliminary evidence of antitumor activity in the relevant patient population," said Pratik S. Multani, MD, chief medical officer. "Given the tumor heterogeneity in metastatic prostate cancer, we’ve made significant progress in identifying a key patient population that may benefit from ORIC-101 and, within these patients, seen preliminary evidence of more pronounced clinical benefit in patients whose tumors express higher GR levels. Patients are continuing to enroll in the expansion cohort and we look forward to reporting an update from the Phase 1b trial in 2022."

ORIC-101: Glucocorticoid Receptor (GR) Antagonist

The Phase 1b clinical trial of ORIC-101 in combination with enzalutamide is a single arm, multicenter, open-label study conducted in two parts, intended to establish the recommended Phase 2 dose (RP2D), safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity when administered in patients with metastatic prostate cancer progressing on enzalutamide.

In the Part I dose escalation portion of the trial, three cohorts of patients were enrolled to evaluate daily dosing of ORIC-101 with doses ranging from 80 to 240 mg, in combination with 160 mg of enzalutamide once daily dosing. Following the completion of the dose escalation portion of the study, the RP2D was determined to be 240 mg of ORIC-101 and 160 mg of enzalutamide once daily.

In the Part II dose expansion portion of the trial, up to 48 patients with metastatic prostate cancer progressing on enzalutamide are expected to be enrolled and treated with the combination at the RP2D. Patients are enrolled independent of GR status, with retrospective analysis of GR expression and other potentially predictive biomarkers. Enrollment continues in the Part II dose expansion cohorts at nine clinical sites across the United States.

As of the August 20, 2021, data cut-off date:

Preliminary Safety Analyses:

25 patients were enrolled across Parts I/II of the study, which included 7 patients treated at non-RP2D doses and 18 patients treated at the RP2D of 240 mg of ORIC-101 and 160 mg of enzalutamide once daily.
RP2D was well tolerated; treatment-related adverse events were primarily Grade 1 or 2, with only four Grade 3 events, which all resolved with dose interruption.
Tolerability profile for the combination was generally consistent with that of single agent enzalutamide.
Preliminary PK Analysis:

Plasma concentrations exceeded the threshold for GR inhibition at all dose levels.
ORIC-101 exposure increased with dose.
No evidence observed of drug-drug interaction impacting enzalutamide levels.
Preliminary Biomarker Analyses:

GR pathway suppression, evaluated using GR target gene expression, was observed after one dose of ORIC-101 in peripheral blood mononuclear cells from 22 of 23 patients.
Moderate to high GR expression (IHC H-score ≥ 100) in prostate tumor cells was observed in 76% of pretreatment biopsies.
Translational efforts identified a key patient population, in line with published literature, consisting of the ~60% of patients with tumors lacking biomarkers of AR resistance (e.g., ARv7 splice variant, AR L702H point mutation) and AR independence (e.g., lineage switching).
Preliminary Antitumor Activity:

Within the key patient population (n=8), 75% (6 of 8) of patients’ tumors expressed moderate to high GR and 25% (2 of 8) of patients’ tumors expressed low GR.
The two patients with low GR came off treatment at less than two months. In contrast, the six patients with moderate to high GR demonstrated prolonged time on treatment (with two patients on treatment for over seven months, and another four patients still ongoing at varying durations at the time of the data cut).
ORIC-101 is also being evaluated in a Phase 1b trial in combination with nab-paclitaxel in up to 132 patients across four cohorts, including pancreatic ductal adenocarcinoma, ovarian cancer, triple negative breast cancer, and other advanced solid tumors. Enrollment continues in this study at 12 clinical sites across the United States and an additional update is expected in 2022.

ORIC-114: EGFR/HER2 Inhibitor

ORIC-114 is a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations. These are the first publicly disclosed preclinical data with ORIC-114 demonstrating compelling activity in HER2-positive breast cancer models.

Key Findings of the Presentation:

ORIC-114 demonstrated greater cell potency on HER2-positive breast cancer cell lines relative to non-amplified cell lines and was more potent than lapatinib and tucatinib, two approved tyrosine kinase inhibitors for the treatment of HER2-positive breast cancer.
ORIC-114 demonstrated robust tumor regressions in a HER2-positive breast cancer in vivo model without significant body weight loss.
ORIC-114 demonstrated superior brain exposure compared to other EGFR exon 20 and HER2 targeted agents.
Separately, today the company disclosed head to head in vivo preclinical data in an EGFR exon 20 NSCLC xenograft model demonstrating good tolerability and improved efficacy, including a 90% complete response rate, versus multiple clinical stage exon 20 inhibitors.

Webcast and Conference Call

ORIC will host a conference call and webcast today at 9:00 a.m. ET. To participate in the conference call, please dial (833) 651-0991 (domestic) or (918) 922-6080 (international) and refer to conference ID 3575856. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation.

About ORIC-101

ORIC-101 is a potent and selective small molecule antagonist of the glucocorticoid receptor, which has been linked to resistance to multiple classes of cancer therapeutics across a variety of solid tumors. Preclinical in vitro and in vivo data suggest ORIC-101 is able to address key resistance mechanisms of multiple classes of cancer treatments, including taxanes and androgen receptor modulators. Based on preclinical and clinical studies, ORIC-101 is expected to have reduced drug-drug interaction liabilities than other glucocorticoid receptor antagonists. Currently, there are no glucocorticoid receptor antagonists approved by the FDA for the treatment of cancer. Following the successful completion of two Phase 1a trials in over 50 healthy volunteers, ORIC initiated two separate Phase 1b trials of ORIC-101 in combination with (1) Abraxane (nab-paclitaxel) in advanced or metastatic solid tumors and (2) Xtandi (enzalutamide) in metastatic prostate cancer.

On October 7, 2021 AffyImmune Therapeutics, Inc., a clinical stage biotechnology company developing and deploying its Tune & Track platform for the use of CAR T cells to treat solid tumors, reported the close of a $30 million Series A+ funding by ORI Capital (ORI) (Press release, AffyImmune Therapeutics, OCT 7, 2021, View Source [SID1234590916]). The Company’s "Tune & Track" platform finely tunes the affinity of CAR T cells to reduce toxicity and increase CAR T cell longevity while allowing in vivo monitoring through a proprietary tracking system.

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The funding will be used to advance the Phase 1 study of AffyImmune’s lead asset, AIC1000, for the treatment of anaplastic thyroid cancer and refractory poorly differentiated thyroid cancer. In addition, AffyImmune will be able to conduct IND-enabling efforts for two additional pipeline candidates, and fund select drug discovery activities. AffyImmune also plans to double its headcount in the next nine months, with a focus on expanding its in-house discovery and leadership teams.

"We are delighted to strengthen AffyImmune’s relationship with ORI with this additional financing," said AffyImmune President & COO Eric von Hofe, Ph.D. "ORI’s dedication to transformative science and deep industry knowledge have been invaluable to our company strategy and growth, and their latest investment highlights the potential of our cutting-edge Tune & Track platform to revolutionize the treatment of solid tumors across a variety of cancers."

"We’re excited to further our investment in AffyImmune, as existing CAR T therapies have not been able to treat solid tumors or have only been effective in a small number of solid cancer patients," said Simone Song, Founder and Senior Partner at ORI Capital and Chairperson of AffyImmune’s Board of Directors. "AffyImmune’s pioneering Tune & Track technology platform will address the critical challenges in CAR T drug development for solid tumors including toxicity, antigen loss, T cell exhaustion, tumor microenvironment, and T cell trafficking. The Tune & Track platform will be life-changing for cancer patients faced with a diagnosis of advanced solid tumors."

As part of the financing, Elaine Yang, Director at ORI Capital, will join the Board of Directors of AffyImmune. "I am excited for this new role and the opportunity to provide counsel and support during AffyImmune’s next phase of growth," said Ms. Yang. "AffyImmune is advancing a leading pipeline of affinity-tuned CAR T therapies to treat solid tumors based on its Tune and Track technology platform, and I look forward to working with their management team and Board," said Ms. Yang.

On October 7, 2021 Loxo Oncology at Lilly, a research and development group of Eli Lilly and Company (NYSE: LLY), reported that preclinical characterization data for two new agents, LOXO-783 and LOXO-435, will be presented at the 2021 AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), held October 7-10, 2021 (Press release, Eli Lilly, OCT 7, 2021, View Source [SID1234590915]). The data will be presented as part of the plenary session titled "New Drugs on the Horizon II" as well as in individual poster presentations.

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LOXO-783 is a potent, highly mutant-selective and brain-penetrant allosteric PI3Kα H1047R inhibitor that is designed to spare wild-type PI3Kα, other PI3K isoforms, and other kinases. LOXO-435 is a potent and highly isoform-selective FGFR3 inhibitor with preserved activity against FGFR3 gatekeeper resistance mutations. Investigational new drug applications (INDs) are planned for both programs in 2022.

"LOXO-783 and LOXO-435 each represent years of diligent work by our discovery teams to build molecules that meet exacting target product profiles. In the case of both PI3Kα H1047R-mutated cancers and FGFR3-mutated cancers, patients deserve medicines purpose-built to their disease biology and we believe that these molecules have the potential to markedly improve on the efficacy and tolerability of existing agents," said Jacob Van Naarden, chief executive officer of Loxo Oncology at Lilly and President of Lilly Oncology. "We look forward to filing INDs for both programs in 2022 and subsequently moving into the clinic."

Details on oral and poster presentations are below:

Presentation Title: Discovery of mutant-selective PI3Kα and isoform-selective FGFR3 inhibitors: Insights from the Loxo Oncology at Lilly Discovery Model
Presentation Date & Time: Saturday, October 9, 4:00 p.m. ET
Session: Plenary Session 6: New Drugs on the Horizon II
Presenter: David Hyman, M.D.

Poster Title: Preclinical characterization of LOXO-435 (LOX-24350), a potent and highly isoform-selective FGFR3 inhibitor
Abstract Number: 141
Available: Thursday, October 7, 9 a.m. ET
Presenter: Joshua Ballard

Poster Title: Preclinical characterization of LOXO-783 (LOX-22783), a highly potent, mutant-selective and brain-penetrant allosteric PI3Kα H1047R inhibitor
Abstract Number: 142
Available: Thursday, October 7, 9 a.m. ET
Presenter: Anke Klippel, Ph.D.

About Loxo Oncology at Lilly
Loxo Oncology at Lilly was created in December 2019, combining the Lilly Research Laboratories oncology organization and Loxo Oncology, which was acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus and spirit of a biotech with the scale and resources of large pharma, with the goal of rapidly delivering impactful new medicines for people with cancer. Our approach centers on creating new oncology medicines that unequivocally work early in clinical development and will matter to patients.