On June 14, 2022 Clovis Oncology, Inc. (NASDAQ: CLVS) reported an oral presentation detailing initial Phase 1 data from the Clovis Oncology-sponsored Phase 1/2 LuMIERE clinical study (NCT04939610) investigating the safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of its targeted radiotherapy candidate, FAP-2286 labelled with lutetium-177 (177Lu-FAP-2286) (Press release, Clovis Oncology, JUN 14, 2022, View Source [SID1234615965]). Overall, in nine patients treated in the first two dose cohorts,177Lu-FAP-2286 demonstrated a manageable safety profile and encouraging evidence of activity, including a confirmed RECIST partial response in one patient. In addition, updated data from an investigator-initiated Phase 1 study of FAP-2286 labelled with gallium-68 (68Ga-FAP-2286) as a novel imaging agent to identify metastatic cancer in patients with solid tumors are also being presented today (NCT04621435). These datasets will be presented in oral presentations by Jonathan McConathy, M.D., Ph.D., Associate Professor and Director of the Division of Molecular Imaging and Therapeutics in the University of Alabama at Birmingham Department of Radiology in the Marnix E. Heersink School of Medicine, and Brad Kline, Clinical Research Coordinator at the University of California, San Francisco (UCSF), respectively, at the Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting 2022 in Vancouver, British Columbia.

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FAP-2286 targets fibroblast activation protein (FAP), a promising theranostic target with expression across many tumor types. FAP-2286 is the first peptide-targeted radionuclide therapy (PTRT) and imaging agent targeting FAP to enter clinical development and is the lead candidate in Clovis Oncology’s targeted radionuclide therapy (TRT) development program. The Phase 1 portion of the LuMIERE study is evaluating the safety of the investigational therapeutic agent 177Lu-FAP-2286 to identify the recommended Phase 2 dose and schedule. The safety and tumor uptake of the imaging agent 68Ga-FAP-2286 is also being evaluated, with plans for Phase 2 expansion cohorts in multiple tumor types to initiate in Q4 2022.

"These initial results demonstrate that FAP is a promising theranostic target with expression across many types of solid tumors," said Jonathan McConathy, M.D., Ph.D., Associate Professor and Director of the Division of Molecular Imaging and Therapeutics in the University of Alabama at Birmingham Department of Radiology in the Marnix E. Heersink School of Medicine. "These LuMIERE data from the first two dose cohorts demonstrated a manageable safety profile, with some preliminary evidence of activity, both of which are encouraging as we seek to better understand the potential of FAP-2286 as a treatment and imaging agent across a wide range of malignancies."

Initial results from the Phase 1 portion of the ongoing Phase 1/2 LuMIERE study found treatment-emergent adverse events (TEAEs) to be generally mild to moderate among the nine patients in the safety population receiving 3.7 or 5.55 GBq/dose of the investigational therapeutic agent 177Lu-FAP-2286. Three patients (33.3%) had a Grade ≥3 TEAE of back pain (11.1%), abdominal distension (11.1%), increased bilirubin (11.1%) and hyponatremia (11.1%); none were judged as related to 177Lu-FAP-2286. There was one serious adverse event (SAE) of back pain not related to 177Lu-FAP-2286. No dose-limiting toxicities were observed in the 3.7 or 5.55 GBq cohorts (n=3 evaluable in each cohort).

At the two dose levels evaluated to date, organ dosimetry revealed target organ exposure within the expected range to support administration of multiple doses. There was tumor uptake across a range of tumor types with prolonged tumor retention of 177Lu-FAP-2286 after dosing.

A confirmed RECIST partial response was reported in one heavily pre-treated patient in the 3.7 GBq dose cohort with pseudomyxoma peritonei of appendiceal origin who completed six administrations of 177Lu-FAP-2286. A decrease in the level of the serum tumor marker carcinoembryonic antigen (CEA) was also observed in the patient over the course of 177Lu-FAP-2286 administration.

Recruitment for the third dose cohort (7.4 GBq) is ongoing.

"This first presentation of data from the Phase 1/2 LuMIERE study supports the hypothesis that FAP-2286 gets to the tumor, stays in the tumor, and avoids off-target tissue, and these initial Phase 1 data further support the potential clinical utility of FAP-2286 as a targeted radionuclide therapy to treat a variety of advanced solid tumors," said Patrick J. Mahaffy, President and CEO of Clovis Oncology. "We look forward to presenting additional clinical data from the LuMIERE study at another nuclear medical meeting and initiating Phase 2 expansion cohorts in multiple tumor types later in 2022."

Presentation of the initial LuMIERE Phase 1 data, titled "177Lu-FAP-2286 in Patients With Advanced or Metastatic Solid Tumors: Initial Data From a Phase 1/2 Study Investigating Safety, Pharmacokinetics, Dosimetry, and Preliminary Antitumor Activity (LuMIERE)" (Abstract #2271), is scheduled for Tuesday, June 14 at 11:00 am PT, as part of the Basic Oncology: Early Phase Human Studies I session from 10:00 – 11:30 am PT.

Presentation of the investigator-initiated imaging study, titled "First-in-human evaluation of 68Ga-FAP-2286, a fibroblast activation protein targeted radioligand" (Abstract #2279), evaluating the ability of imaging agent 68Ga-FAP-2286 to detect metastatic cancer in patients with solid tumors, is scheduled for Tuesday, June 14 at 1:50 pm PT, as part of the Basic Oncology: Early Phase Human Studies II session from 1:00 – 2:30 pm PT.

These presentations can also be viewed at View Source following their presentations on June 14.

For more information about FAP-2286, targeted radionuclide therapy (TRT), or Clovis’ TRT development program, please visit targetedradiotherapy.com.

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. 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.

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.

On June 14, 2022 Alphamab Oncology (stock code: 9966.HK) reported that the first patient was dosed in a Phase I clinical study (KN052-CHN-001) of KN052, its proprietary PD-L1/OX40 bispecific antibody, in patients with advanced solid tumors in China (Press release, Alphamab, JUN 14, 2022, View Source [SID1234615964]).

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With the development of immunotherapy and further understanding of tumor pathogenesis, cancer therapy has entered a new era, among which PD-(L)1 inhibitors have become a star product. However, PD-1/PD-L1 inhibitors did not bring satisfied response rate when used as monotherapy, and innovative treatment regimens are expected. KN052 is the world’s first PD-L1/OX40 bispecific antibody entering first-in-human clinical study. It can effectively reverse tumor induced immune inhibition by blocking the PD-L1/PD-1 pathway and promote the immune response by activating OX40. In preclinical studies, KN052 showed significantly stronger activity than either single antibody or in combination.

KN052-CHN-001 is a Phase I clinical study in Chinese patients with advanced solid tumors to evaluate the safety, tolerability, pharmacokinetics and anti-tumor activity of KN052, and to determine the recommended dose for further development.

Professor Zhengbo Song from Zhejiang Cancer Hospital, the principal investigator, commented, "OX40 is a member of the TNF receptor superfamily. The mechanism of action of OX40 agonism can result in conditions favorable to immune responses, where activated T cells increase in number, while the induction of Tregs is suppressed in the periphery. The combination of OX40 and an immune checkpoint inhibitor is expected to enhance the efficacy. We look forward to exploring the safety and preliminary efficacy of KN052 in this clinical study."

About KN052

KN052 is a PD-L1/OX40 bispecific antibody developed in house by Alphamab Oncology. It can simultaneously bind PD-L1 and OX40, effectively blocking the PD-L1/PD-1 pathway and activating OX40. In February 2022, the IND for KN052 was approved by the National Medical Products Administration (NMPA) to initiate Phase I clinical trials in China.

On June 14, 2022 Case Western Reserve University reported that A drug used to target IDH1 mutations in select cancers also appears to inhibit the wild-type form of the enzyme, under certain conditions (Press release, Case Western Reserve University, JUN 14, 2022, View Source [SID1234615963]). This feature explains why a large group of different cancers are vulnerable to the drug.

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This discovery opens up the possibility that the drug, Ivosidenib or AG-120, could become more broadly applicable against a variety of cancers, given that mutant IDH1 is present in just 1% of cancers. The findings were recently published in Nature Cancer.

Jordan Winter
"Historically, only a few groups have cared about wild-type IDH1," said Jordan Winter, Division Chief of Surgical Oncology at University Hospitals (UH) Seidman Cancer Center and senior author on the study. Winter, also a professor in the Department of Surgery at the Case Western Reserve University School of Medicine and Member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center, is the John and Peggy Garson Family Endowed Chair in Pancreatic Cancer Research and Jerome A. and Joy Weinberger Family Master Clinician in Surgical Oncology.

"IDH1 therapeutic investigations have principally focused on the development of mutant IDH1 inhibitors," he said. "Less than a handful of reports have focused on wild-type IDH1 inhibition. We showed, along with a few others, that wild-type IDH1 is an important target. We think that Ivosidenib, previously called AG-120, may be applicable to the large majority of cancers—the one percent with mutant IDH1 and the remaining 99% with wild-type IDH1."

Ali Vaziri-Gohar
Fundamental to this discovery is the observation that cancer cells rely on IDH1 metabolism to thrive in a harsh and nutrient-deprived tumor microenvironment. Nutrient limitation universally present in pancreatic tumors could open a new therapeutic window, explains the study’s first author Ali Vaziri-Gohar, postdoctoral fellow in the Department of Surgery at the Case Western Reserve School of Medicine.

"Wild-type IDH1 activity is a metabolic requirement for cancer cells living in a harsh metabolic milieu," he said. "We found that IDH1 is very important for cancer cells’ survival in a stressful microenvironment. When the cancer cells have less oxygen and less glucose or glutamine, anything that hurts them, they need a defense mechanism to protect them, which is this important molecule IDH1."

In laboratory experiments, Winter, Vaziri-Gohar and colleagues demonstrated that genetically suppressing IDH1 reduced growth of pancreatic cancer cells in cell culture under low nutrient conditions and in mouse models of pancreatic cancer. They found, too, that the FDA-approved inhibitor of mutant IDH1, Ivosidenib, was surprisingly potent against the wild-type form of the protein–especially when paired with the important condition of low magnesium. This latter point had been overlooked in prior studies.

Vaziri-Gohar said this finding was a bit of scientific serendipity.

"Initially, we were using this drug as a negative control," he said. "Then we found we can use this drug against cancers that have wild-type isoforms if we reduced levels of magnesium. We tested this hypothesis in cell culture and saw that when the magnesium levels reduced in the tissue culture, they responded to the inhibitor with and lowered activity of the enzyme. This in turn decreased cancer cell survival. However, under the normal cell culture conditions with standard magnesium levels found in the blood or culture media, they didn’t respond to this drug. We then realized that magnesium levels were much lower in tumors than in standard culture conditions, so that the drug was actually effective against pancreatic and other cancers when given to animals harboring these tumors."

Reduced tumor sizes by FDG-PET imaging reflected in the red signal next to yellow arrows, in six mouse models receiving ivosidenib (AG-120) compared to control models without drug.
The presence of low magnesium enhanced allosteric inhibition by the drug, and ambient low glucose levels enhanced cancer cells’ dependence on wild-type IDH1. Thus, two conditions present in tumors rendered them sensitive to the drug: low magnesium and low nutrients.

Winter and Vaziri-Gohar have now tested Ivosidenib in mouse models of pancreatic, colorectal, ovarian and lung cancer, as well as melanoma. In each of these instances, the anti-tumor effect of Ivosdenib was comparable or superior to a previous study of anti-IDH1-mutant tumor therapy.

Other drugs developed as mutant-IDH1 inhibitors similarly were effective against tumors without the mutation. In the immunocompetent mouse pancreatic cancer model, Ivosidenib improved median survival by more than two fold.

It was also important to the study that these findings were replicated in a completely separated lab, in an experiment performed on the other side of the Atlantic Ocean. A respected mouse model researcher, Jennifer Morton of the Beatson Institute in Scotland, performed this experiment in a genetically engineered mouse that develops pancreatic cancer.

The next step in the team’s research is a clinical trial, made possible by funding from the Gateway for Cancer Research and the John and Peggy Garson Family. Along with his colleague David Bajor, Winter plans to enroll 15 patients with resectable pancreatic cancer in a Phase I trial of Ivosidenib in combination with standard of care, FOLFIRINOX. Patients will receive three months of treatment before surgery, gauging their response to therapy via imaging, biochemical blood markers and, ultimately, through pathology once surgery is complete.

"The primary endpoint is just to determine safety of the drug with the existing chemotherapy regimen, because it’s never been given together," Winter said. "We’re going to compare it to patients who get chemotherapy prior to surgery without the Ivosidenib. However, one of the great things about this trial is that because all of the patients are going to be undergoing surgery, we are going to have all the tumors to analyze and we will be able to assess the tumors for the same metabolic changes previously observed in the lab. We’re going to be looking at those same data points, those same markers of response in the patients’ tumors to try to demonstrate the biologic activity inside pancreatic cancer in the patients."

Vaziri-Gohar said he’s thankful for the spirit of collaboration across institutions that has allowed the project to progress to this point.

"Beyond the science, it was so gratifying to work with so many people towards a common goal," he said. "That’s the most important thing to me. That we worked as a team and hopefully our discovery will help patients. We are so lucky that we have all of these researchers and institutions involved."

Winter is optimistic about what might be achieved.

"In our hands and in pre-clinical models, wild-type IDH1 represents a true metabolic vulnerability in cancer cells and is a bona fide therapeutic target across a wide range of wild-type IDH1 cancers," he said. "Mutant-IDH1 inhibitors, including FDA-approved Ivosidenib, are potent wild-type IDH1 inhibitors under conditions present in tumors. Since pancreatic and other tumors share this feature, these drugs are compelling investigational agents for these expanded indications."

On June 14, 2022 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision oncology biopharmaceutical company, reported that it has filed a Certificate of Amendment to its Amended and Restated Certificate of Incorporation to effect a 1-for-20 reverse stock split, effective as of 5:00 p.m. Eastern Time today (Press release, Calithera Biosciences, JUN 14, 2022, View Source [SID1234615962]). The reverse stock split was effected by Calithera in accordance with the authorization, and within the split ratio range, adopted by Calithera stockholders at the 2022 Annual Meeting of Stockholders held on June 1, 2022.

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The reverse stock split is intended to enable Calithera to regain compliance with the $1.00 minimum bid price required for continued listing on the Nasdaq Global Select Market. The new CUSIP number for Calithera’s common stock following the reverse stock split is 13089P 507.

At the effective time of the reverse stock split, every issued and outstanding twenty shares of Calithera’s pre-split common stock, par value $0.0001 per share, including shares subject to outstanding stock options and warrants and shares available for grant under Calithera’s equity benefit plans, will automatically be combined into one share of Calithera’s post-split common stock. The reverse stock split will affect all stockholders uniformly and will not affect any stockholder’s ownership percentage of Calithera’s shares (except to the extent that the reverse stock split would result in some of the stockholders receiving cash in lieu of fractional shares). Stockholders will receive cash in lieu of fractional shares based on today’s closing sales price of Calithera’s common stock as quoted on the Nasdaq Global Select Market. American Stock Transfer and Trust Company, Calithera’s transfer agent, will provide instructions to stockholders regarding the process for exchanging their shares and stock certificates. Upon completion of the reverse stock split, there will be approximately 4,865,000 shares of Calithera’s common stock outstanding, excluding outstanding and unexercised stock options and warrants, subject to adjustment for fractional shares. In addition, Calithera has Series A convertible preferred shares outstanding which are initially convertible into approximately 857,843 post-split shares of common stock (subject to certain anti-dilution protections which if triggered will result in the issuance of additional shares of common stock).

Additional information regarding the reverse stock split approved by stockholders can be found in Calithera’s definitive proxy statement filed with the Securities and Exchange Commission on April 20, 2022.

On June 14, 2022 Dren Bio, Inc. ("Dren Bio" or the "Company") reported the completion of their $65 million Series B financing, pushing the Company’s total capital received to date over $156 million (Press release, Dren Bio, JUN 14, 2022, View Source [SID1234615961]). Following the financing, Dren Bio is well-capitalized to reach multiple key inflection points across both its drug discovery programs over the coming years.

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"We are truly grateful for all the support we continue to receive from such an outstanding syndicate of investors," said Nenad Tomasevic, Ph.D., Chief Executive Officer of Dren Bio. "This financing comes at the perfect time as we prepare to initiate the first clinical trial evaluating DR-01, our lead asset, in patients with Large Granular Lymphocytic leukemia or cytotoxic lymphomas in mid-2022. In addition to advancing DR-01, the proceeds from this latest round will also enable us to further expand the development of our internal pipeline using our proprietary Targeted Myeloid Engager and Phagocytosis Platform."

The Series B financing was co-led by Aisling Capital and HBM Healthcare Investments, with participation by new marquee investors Pfizer, ArrowMark Partners and Revelation Partners. There was also significant participation in the round by Dren Bio’s existing insiders SR One, 8VC, Taiho Ventures, BVF Partners, Mission BioCapital and Alexandria Venture Investments, amongst others. In connection with the closing of the financing, the Company announced that Andrew Schiff, M.D., of Aisling Capital, and Chandra P. Leo, M.D., of HBM Partners, will join its Board of Directors.

"We were thoroughly impressed by Dren Bio’s diversified R&D portfolio that encompasses two distinct therapeutic antibody programs including their attractive proprietary platform," said Dr. Schiff, Managing Partner at Aisling Capital. "We are excited by the opportunity to support Dren Bio in progressing on their mission to deliver revolutionary therapies to patients with severe unmet needs, starting with difficult-to-treat cancers."

Dr. Leo, of HBM Partners, added, "Over the last 18 months, Dren Bio has delivered robust preclinical data for their lead asset DR-01 and for their unique technology to induce myeloid cell engagement and phagocytosis. With this new financing, the Company is well positioned to rapidly advance DR-01 towards clinical proof-of-concept and to demonstrate the broad potential of their highly differentiated platform."

Proceeds from the financing will enable Dren Bio to continue advancement of its broad internal pipeline comprised of multiple development candidates approaching the clinic. The Company’s lead asset, DR-01, is designed to precisely eliminate a subset of immune cells which are the underlying cause of certain hematologic malignancies and well-defined autoimmune disorders, both of which will be evaluated using its current funding. Dren Bio’s position as an emerging leader in the antibody therapeutics space is further strengthened by the exceptional prospects of its Targeted Myeloid Engager and Phagocytosis Platform. Bispecific antibodies generated using the proprietary platform have been shown to produce effects that are well-differentiated from other competing technologies including T cell engagers, antibody-dependent cellular cytotoxicity ("ADCC") antibodies and antibody-drug conjugates. In addition to their profound and multi-pronged mechanism of action, initial development candidates have been very well tolerated in non-human primates, which should enable their utilization in both oncology and non-oncology indications. With its current funding, Dren Bio now has the opportunity to demonstrate the vast potential of its platform to produce therapies for a wide array of patients.