On June 23, 2022 Targovax ASA (OSE: TRVX), a clinical-stage immuno-oncology company developing immune activators to target hard-to-treat solid tumors, reported that the US FDA has approved an IND application for TG01 combined with QS-21 STIMULON, which allows the preparations to initiate clinical trials in the USA to proceed (Press release, Targovax, JUN 23, 2022, View Source [SID1234616200]).

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In May, an IND application for the enhanced TG01 mutant RAS cancer vaccine, with QS-21 STIMULON as adjuvant, was filed with the US FDA. The FDA has now approved this IND application, which means that the new and improved TG01 version has been authorized to proceed with clinical studies in the USA.

Targovax has previously demonstrated promising clinical data for an earlier version of TG01 in KRAS mutant pancreatic cancer. For technical and commercial reasons, Targovax has made significant improvements in TG01 to strengthen immune activation and simplify handling at the hospital and improve patient convenience.

In this new format, TG01 will be co-administered with the FDA approved adjuvant QS-21 STIMULON, provided by collaboration partner Agenus. QS-21 STIMULON is expected to enhance TG01 efficacy by driving stronger and broader mutant RAS immune responses. TG01 and QS-21 STIMULON will be mixed and dosed as a single injection, rather than two separate injections as in prior trials. Moreover, the injection will be given sub-cutaneously instead of intra-dermally. These modifications will make the administration of TG01 more patient friendly and simpler to manage for healthcare personnel.

Dr. Erik Digman Wiklund, Chief Executive Officer of Targovax ASA, said: "This IND is a major milestone for our KRAS program, and it is the first time a TG vaccine receives approval to initiate clinical studies in the USA. We are confident that the significant upgrades we have made to TG01 will strengthen the clinical benefit for patients, simplify administration, and make TG01 a more attractive product overall. We are now working actively with academic centers to start collaborative clinical studies with the new and improved TG01 vaccine in mutant RAS cancer patients in 2022."

About QS-21 STIMULON

In March 2022, Targovax announced a collaboration with Agenus to utilize the proprietary adjuvant QS-21 STIMULON as an immune-stimulatory component of the TG vaccines for future development and commercialization. QS-21 STIMULON has consistently demonstrated powerful antibody and cell-mediated immune responses both in cancer trials and commercially as a component of the Shingrix and Mosquirix vaccines. QS-21 STIMULON is expected to further potentiate TG by driving stronger anti-RAS T-cell responses and is routinely co-administered with vaccines sub-cutaneously.

On June 23, 2022 Paige, a global leader in clinical AI applications in pathology, reported it received CE-IVD and UKCA marks for HER2Complete, an artificial intelligence (AI) software designed to identify patients with breast cancer whose tumors have expressions of human epidermal growth factor receptor 2 (HER2) protein (Press release, Paige AI, JUN 23, 2022, View Source [SID1234616216]).* This is the first CE-IVD and UKCA designated tool to explore the novel space of HER2-low. In a recent study, HER2Complete was able to detect levels of HER2 expression in HER2-negative (IHC-0) and HER2-low (IHC1+/2+) hematoxylin and eosin (H&E)-stained tissue samples, the first and only AI biomarker assay capable of doing so.

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HER2 is a protein that promotes breast cancer cell growth, and breast cancer cells with excess levels of HER2 are called HER2-positive.1 Targeted therapies for HER2-positive tumors have been a mainstay of cancer treatment over the past two decades. Recent evidence suggests there may be a subgroup of patients who are considered HER2-negative through standard immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) testing but may actually have low or ultra-low levels of HER2, and therefore may be responsive to particular investigative therapies.2,3 It has been challenging to identify these patients reliably and reproducibly using conventional methods, calling for the development of novel ways to assess a patient’s HER2 status that are more accurate and sensitive than traditional assays, which were designed and optimized to detect high levels of HER2 expression.

In contrast to traditional IHC tests for HER2, Paige deploys HER2Complete to detect HER2 expression based on protein and mRNA levels on digital images of H&E-stained tissue samples, with results generated rapidly at the click of a button. Recent work has shown that HER2Complete can also identify HER2 expression in patients currently classified as IHC negative (or IHC-0), in addition to expression in HER2-low (IHC1+ and 2+/FISH negative) patients. This approach complements existing IHC testing to potentially identify true HER2-expressing breast cancers without the need for special staining approaches and with a very rapid turnaround using only the diagnostic biopsy or resection slides. Further, this tool has been used to detect true HER2-negative disease, whose definitive identification based on a lack of IHC and mRNA HER2 expression may accelerate efforts for developing new therapies for this important group of patients who may not benefit from HER2 targeted therapies. This approach doesn’t require any special labelling of the tissue sample and can be done rapidly and easily on standard tissue preparations using methods that already exist in labs across the globe.

"AI brings a transformational approach to diagnostics and allows us to identify low levels of HER2 in tissue that we would not be able to detect using current assays," said David Klimstra, M.D., Founder and Chief Medical Officer at Paige. "We are working to enable the next generation of HER2 testing to provide the information physicians need to guide the use of next generation HER2 therapy. We believe that this assay will allow us to reliably identify increased likelihood of HER2 expression, even on samples where HER2 expression was misclassified by legacy diagnostics as low or null."

"Our product is potentially a very targeted and cost-effective solution to identify a subset of patients who have previously been unidentified," said Jill Stefanelli, Ph.D., President and Chief Business Officer at Paige. "Paige is developing an end-to-end solution to detect and further characterize breast cancer so that pathologists and oncologists get comprehensive insights into an individual’s cancer. We look forward to assessing the clinical utility with multiple potential partners in order to link this test to treatment outcomes."

*In the United States, the software is available for Research Use Only and not for use in diagnostic procedures.

On June 22, 2022 Aura Biosciences Inc. (NASDAQ: AURA), a clinical-stage biotechnology company developing a novel class of virus-like drug conjugate (VDC) therapies for multiple oncology indications, reported results from a retrospective, matched case control study (Press release, Aura Biosciences, JUN 22, 2022, View Source [SID1234616167]). This retrospective analysis assessed the visual acuity of patients following treatment with plaque radiotherapy compared with prospective data on visual acuity in subjects with early-stage choroidal melanoma treated with belzupacap sarotalocan by intravitreal administration in the Phase 1b/2 trial (NCT03052127).

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"These results point to the high unmet medical need for a first line vision preserving therapy for the treatment of early-stage choroidal melanoma given the high levels of irreversible visual acuity loss with the current standard of care with radiotherapy," said Carol Shields, MD, Chief of the Ocular Oncology Service at Wills Eye Hospital and Professor of Ophthalmology at Thomas Jefferson University. "Being able to treat the disease early, avoid radiotherapy and spare long-term vision loss in many patients, as well as potentially reducing the risk of metastatic disease, could represent a paradigm shift in our approach to the treatment of choroidal melanoma. This would be a significant improvement in the quality of life for patients with this life-threatening rare disease."

Results from the Retrospective Study

Study Design

This retrospective, matched case control study compared visual acuity outcomes for 43 patients from Aura’s Phase 1b/2 trial evaluating intravitreal administration of belzupacap sarotalocan in patients with early-stage choroidal melanoma (AU-011-101, NCT03052127) to 150 patients from the subject database of a previously completed and published study where patients with small choroidal melanoma had been treated with plaque radiotherapy (Shields, et al. "Visual Outcome and Millimeter Incremental Risk of Metastasis in 1780 Patients With Small Choroidal Melanoma Managed by Plaque Radiotherapy." JAMA Ophthalmology. September 27, 2018). Both cohorts of patients were at high risk for vision loss due to having the tumor edge within 3.0 mm of the fovea. The patients were matched for tumor height, tumor diameter, distance from the fovea and baseline visual acuity, which are among the core factors that impact visual acuity after treatment.

Key Findings:

The vision results of patients with early-stage choroidal melanoma treated with radiotherapy showed the long term, progressive and irreversible loss of visual acuity in patients where tumors were close to the fovea.

The loss of vision in radiotherapy patients was ≥3 lines in a majority of patients as early as 2 years and ≥6 lines as early as 3 years.

We believe the comparison of the belzupacap sarotalocan and radiotherapy results supports the potential benefit of a targeted treatment achieving a statistically significant difference in visual acuity preservation as soon as two years including for both logMAR (Logarithm of the Minimum Angle of Resolution) vision (p = 0.0094) and change in logMAR vision (p = 0.0323).

We believe the progressive loss of visual acuity with radiotherapy observed in this retrospective study underscores the urgent need for a vision preserving targeted therapy.

The findings of this retrospective study were consistent with published clinical data supporting the irreversible loss of visual acuity after treatment with radiotherapy.

"We are committed to developing the first potential targeted therapy for patients with early-stage choroidal melanoma. We believe the visual acuity results of the retrospective matched case control study are exciting because they support the high unmet medical need for a long-term vision preserving therapy," said Dr. Cadmus Rich, Chief Medical Officer and Head of R&D of Aura Biosciences. "Belzupacap sarotalocan is currently being evaluated in a Phase 2 dose escalation clinical trial (AU-011-202, NCT04417530) using suprachoroidal administration in patients with early-stage choroidal melanoma. We remain on track to initiate our pivotal trial by the end of 2022."

Study Limitations include the retrospective nature and utilizing a matched case control design. The mean follow-up for patients treated with belzupacap sarotalocan in this initial analysis was 15.6 months. Due to the retrospective nature of this analysis, it is hypothesis-generating; no formal conclusions can be drawn. Aura has also initiated a prospective matched case control study to further evaluate the long-term visual acuity results of belzupacap sarotalocan from the Phase 2 trial AU-011-202 using suprachoroidal administration versus radiotherapy.

On June 22, 2022 Mustang Bio, Inc. ("Mustang") (NASDAQ: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases, reported that the U.S. Food and Drug Administration ("FDA") has granted Orphan Drug Designation to MB-106, Mustang’s CD20-targeted, autologous CAR T cell therapy for the treatment of Waldenstrom macroglobulinemia ("WM" or "Waldenstrom"), a rare type of B-cell non-Hodgkin lymphoma ("B-NHL") (Press release, Mustang Bio, JUN 22, 2022, View Source [SID1234616183]). MB-106 is being developed in a collaboration between Mustang and Fred Hutchinson Cancer Center ("Fred Hutch") to treat patients with relapsed or refractory B-NHLs and chronic lymphocytic leukemia ("CLL").

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The FDA grants Orphan Drug Designation to drugs and biologics that are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the U.S. Orphan Drug Designation provides certain incentives, such as tax credits toward the cost of clinical trials upon approval and prescription drug user fee waivers. If a product receives Orphan Drug Status from the FDA, that product is entitled to seven years of market exclusivity for the disease in which it has Orphan Drug designation, which is independent from intellectual property protection.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "We are very pleased to receive Orphan Drug Designation from the FDA, as it is an important regulatory milestone for Mustang’s MB-106 program for the treatment of Waldenstrom macroglobulinemia, a rare B-NHL with a significant unmet medical need. We look forward to dosing the first patient in our multicenter Phase 1/2 clinical trial evaluating the safety and efficacy of MB-106 for relapsed or refractory B-NHL and CLL under Mustang’s IND shortly. In the Phase 1 portion of this trial, MB-106 dose escalation will proceed in three separate arms, and Waldenstrom patients will be included in the indolent lymphoma arm in parallel with accrual of patients to the aggressive lymphoma and CLL arms."

MB-106 data presented earlier this month at the European Hematology Association (EHA) (Free EHA Whitepaper) 2022 Hybrid Congress continue to demonstrate high efficacy and a very favorable safety profile across all five dose levels. The overall response ("ORR") was 96% across all dose levels and all indications (n=26). In particular, the 100% complete response rates by PET scan of patients with WM (n=2) as well as of patients with B-NHL previously treated with CD19-directed CAR T cell therapy (n=2) underscore the potential for MB-106 to treat these patient populations with high unmet needs. Durable responses were observed in a wide range of hematologic malignancies including follicular lymphoma, CLL, diffuse large B-cell lymphoma and WM. The possible outpatient administration of this therapy makes it potentially even more compelling. Currently no CAR T therapy is specifically approved for WM.

Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.

About Waldenstrom Macroglobulinemia
Waldenstrom macroglobulinemia ("WM"), also known as lymphoplasmacytic lymphoma, is a rare type of non-Hodgkin lymphoma ("NHL"), a malignant disorder of the bone marrow and lymphatic tissues. The proliferation of cancer cells can crowd out normal cells in these tissues, leading to low levels of red blood cells, white blood cells, and platelets which, in turn, causes fatigue, shortness of breath, infections, bruising, and bleeding. In addition, the cancer cells make large amounts of the large antibody protein immunoglobulin M, or IgM, which cause the blood to become thick. This hyperviscosity of the blood affects its flow through the smaller blood vessels, leading to some of the other manifestations of the disease, such as visual and neurological symptoms. WM is a rare disorder with an incidence of approximately 3 per million people per year, and 1,400 new cases are diagnosed in the U.S. each year. The median age at diagnosis is 70 years.

About MB-106 (CD20-targeted autologous CAR T Cell Therapy)
CD20 is a membrane-embedded surface molecule which plays a role in the differentiation of B-cells into plasma cells. The CAR T was developed by Mustang’s research collaborator, Fred Hutch, in the laboratories of the late Oliver Press, M.D., Ph.D., and Brian Till, M.D., Associate Professor in the Clinical Research Division at Fred Hutch, and was exclusively licensed to Mustang in 2017. The lentiviral vector drug substance used to transduce patients’ cells to create the MB-106 drug product produced at Fred Hutch has been optimized as a third-generation CAR derived from a fully human antibody. MB-106 is currently in a Phase 1/2 open-label, dose-escalation trial at Fred Hutch in patients with B-NHLs and CLL. The same lentiviral vector drug substance produced at Fred Hutch will be used to transduce patients’ cells to create the MB-106 drug product produced at Mustang Bio’s Worcester, MA, cell processing facility for administration in the multicenter Phase 1/2 clinical trial that is now open to enrollment under Mustang Bio’s IND. It should be noted that Mustang Bio has introduced minor improvements to its cell processing to facilitate eventual commercial launch of the product. In addition, prior to commercial launch, Mustang Bio will replace the Fred Hutch lentiviral vector drug substance with vector produced at a commercial manufacturer. Additional information on these trials can be found at View Source using the identifier NCT05360238 for the Mustang multicenter trial and NCT03277729 for the ongoing trial at Fred Hutch.

On June 22, 2022 AVEO Oncology (Nasdaq: AVEO), a commercial stage, oncology-focused biopharmaceutical company, reported that it has entered into a clinical trial collaboration and supply agreement in North America with Eli Lilly and Company (Lilly) to evaluate ficlatuzumab in combination with ERBITUX (cetuximab), an anti-EGFR antibody, in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) (Press release, AVEO, JUN 22, 2022, View Source [SID1234616168]). Ficlatuzumab is AVEO’s investigational potent humanized immunoglobulin G1 monoclonal antibody that targets hepatocyte growth factor.

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"This clinical trial collaboration and supply agreement with Lilly follows a similar engagement we entered into with Merck KGaA, Darmstadt, Germany earlier this year, both of which we believe serve as validation for our ficlatuzumab clinical development plan. We expect these collaborations will play an important role in the advancement of the combination of ficlatuzumab and cetuximab," said Michael Bailey, president and chief executive officer of AVEO. "We reported positive Phase 2 clinical data last year that show ficlatuzumab in combination with cetuximab has the potential to play a meaningful role in the treatment of patients with human papillomavirus (HPV) negative R/M HNSCC, which is associated with particularly poor outcomes. We continue to be in discussions with regulators on the final design of a potential pivotal study for this combination therapy, which we expect to commence in the first half of 2023."

Under the terms of the agreement, Lilly will provide cetuximab clinical drug supply in the U.S. and Canada for AVEO’s potential registrational study, which will assess ficlatuzumab with cetuximab in HPV negative R/M HNSCC. AVEO will serve as the study sponsor and will be responsible for trial execution.

In June 2021, AVEO announced positive results from a randomized Phase 2 study of ficlatuzumab alone or in combination with cetuximab in patients with pan-refractory metastatic HNSCC. Of note, patients with HPV negative disease, a subgroup normally associated with poorer outcomes, who received the ficlatuzumab and cetuximab combination demonstrated both a superior overall response rate, including two patients with complete responses, and median progression free survival superior to historical data for current standards of care. In September 2021, the FDA awarded Fast Track designation for the combination of ficlatuzumab and cetuximab in HPV negative relapsed/recurrent HNSCC. A copy of the presentation is available at www.aveooncology.com.

AVEO recently commenced manufacturing of ficlatuzumab clinical supply in the second quarter of 2022, with the potential registrational study expected to be initiated in the first half of 2023. AVEO expects to continue to discuss potential ficlatuzumab pivotal study designs with the FDA and to continue ongoing partnership dialogues.

About Ficlatuzumab

Ficlatuzumab (formerly known as AV-299) is a potent hepatocyte growth factor (HGF) immunoglobulin G1 (IgG1) inhibitory antibody that binds to the HGF ligand with high affinity and specificity. HGF is the natural ligand of c-Met and blocking HGF inhibits signaling through the HGF/c-Met signaling pathway. Ficlatuzumab is currently being evaluated in squamous cell carcinoma of the head and neck (HNSCC) and pancreatic cancer. The U.S. Food and Drug Administration designated as a Fast Track development program the investigation of ficlatuzumab and ERBITUX (cetuximab) for relapsed/recurrent HNSCC in September 2021.