On July 6, 2021 APEIRON Biologics AG reported the start of a Phase Ib clinical trial with its product candidate APN401 for the treatment of solid tumors (Press release, Apeiron Biologics, JUL 6, 2021, View Source [SID1234584602]). The principle of cell therapy with APN401 by inhibiting the immune checkpoint Cbl-b aims at the patient’s own immune cells. These are modified to recognize and destroy cancer cells without being permanently genetically altered.

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The open-label, multi-center Phase Ib clinical trial is expected to enroll approximately 60 patients at multiple sites in Austria. The study objective is to evaluate the safety, tolerability and immunological effects of the treatment on patients with various solid tumors. This will build on the experience of the two previous Phase I clinical studies, which already successfully demonstrated good tolerability and the first signs of clinical efficacy by activating the immune cells that are crucial to tumor defense.

The clinical study is divided into two parts. Part A of the study aims to determine the optimal dosing, i.e. the quantity of treated cells reinfused back to the patient. Patients will receive APN401 treatment every three weeks. In part B of the study, patients with specific tumor indications (three groups of 15 patients each) will be treated to generate further efficacy signals, which will be used to determine the tumor indication for a subsequent Phase II clinical study. The Phase I clinical study will start at the Medical University of Vienna (MUW) where the GMP-certified production of the cell therapy and treatment of the patients will take place.

For the treatment, the patient’s own peripheral blood mononuclear cells (PBMCs) are collected, specifically modified outside the body using RNAi technology and then reinfused into the patient. APEIRON uses a specially developed system for this purpose, which enables an automated process from cell processing to reinfusion within just one day. This GMP-certified system increases patient safety and the reproducibility of the manufacturing process. APEIRON’s technology thus enables personalized cell therapy in solid tumors.

Peter Llewellyn-Davies, CEO of APEIRON Biologics AG, says: "We are thrilled to be contributing a groundbreaking cancer treatment with this truly pioneering step in development of our APN401 cell therapy. The short outpatient administration process, which can also be used for solid tumors, plays a key advantage compared to other autologous cell therapies. APN401 could offer critically ill patients, with previously difficult-to-treat cancers, new individualized treatment options and thus new hope. The APEIRON team is highly motivated to develop much needed new treatment options with this major next step."

Dr. Romana Gugenberger, Chief Medical & Scientific Officer (CMSO) of APEIRON Biologics AG, explains: "The immune system is the most effective weapon against tumor disease and offers many advantages over conventional therapies such as chemotherapy. Cbl-b is a master checkpoint in the immune system that controls important processes of the immune response, especially in cancer. APN401, by blocking Cbl-b using RNA interference (RNAi), is designed to reactivate the patient’s immune system, allowing it to fight solid tumors. The flexibility of RNAi technology could expand the applicability of cell therapy to additional immune checkpoints and holds enormous potential for new therapeutic approaches."

Prof. Dr. Nina Worel, Head of Cell Therapy at the Department of Transfusion Medicine at AKH / Medical University of Vienna and lead investigator of the study, adds: "Patients with advanced solid tumors urgently need new, safe and effective therapeutic options. Using cell therapy to enable the patient’s immune system to directly attack the tumor is a very promising approach. APEIRON’s APN401 could become superior in safety and efficacy to standard oncology therapies as well as to currently available cell therapies, due to its rapid applicability and central immune activation. We are excited to initiate this study here in Vienna and other sites and gain new insights."

About APN401
Immune checkpoints are receptors with immunoregulatory activity. Tumor cells can make use of these immune checkpoints to escape recognition by the immune system. Cbl-b represents a new class of intra-cellular immune checkpoints in contrast to the immune checkpoint molecules PD-1/PD-L1 and CTLA-4, which are localized at cell surfaces.

APN401, an autologous cell therapy, was designed to transiently, i.e. temporarily, inactivate Cbl-b ex-vivo in autologous PBMCs. These altered autologous PBMCs are then returned to the patient, with the entire procedure performed on an outpatient basis over one day. APN401 is well tolerated, has a good safety profile, and has shown early evidence of clinical activity in patients with advanced solid tumors in two Phase I studies

On July 5, 2021 BioMed X, a leading independent research institute, reported the start of its eighth joint research program with Merck KGaA, Darmstadt, Germany (Press release, Biomed x, JUL 5, 2021, View Source [SID1234584774]). The new program will explore the role of extrachromosomal DNA in cancer and it will complement the research of two ongoing oncology programs at BioMed X in the fields of DNA damage response and RNA splicing.

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Extrachromosomal circular DNA (ecDNA) was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different cancer types. Elevated levels of ecDNA have been considered to be correlated with poor clinical outcome in human cancers.

"We are pleased to extend our collaboration even further in the field of cancer research," Christian Tidona, Founder and Managing Director of the BioMed X Institute said. "This new program will strengthen our expertise at the forefront of deep cancer biology which can potentially lead to better treatment options for patients."

The key aim of the new project will be to generate a comprehensive atlas of extrachromosomal DNA in human cancer tissues, to investigate how (onco)genes in ecDNA could contribute to tumorigenesis, disease progression, tumor heterogeneity, metastasis, and treatment resistance and to develop novel therapeutic strategies based on oncogenic alterations in ecDNA.

Further details about this call for application can be found on the website of the BioMed X Institute at www.bio.mx. Interested candidates are invited to apply via the BioMed X crowdsourcing platform at www.bio.mx/apply before August 29, 2021.

On July 5, 2021 Jazz Pharmaceuticals reported that it is flying high after hitting two back-to-back regulatory milestones late last month (Press release, Jazz Pharmaceuticals, JUL 5, 2021, View Source [SID1234584747]). The first was obtaining a seven-year Orphan Drug Exclusivity for Xywav, the latest contender from its array of treatments for daytime sleepiness. Then, days later, the Dublin-based biopharma announced notching a speedy FDA approval for its blood cancer drug.

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On June 30th, Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) was greenlighted as a component of a chemotherapy regimen designed for treating acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) in both children and adults. The drug received accelerated approval from the agency under the Real-Time Oncology Review (RTOR) program.

"We are excited to bring this important new treatment to patients who are in critical need, and we are grateful to FDA for the approval of Rylaze based on its established safety and efficacy profile. We are pleased Rylaze was approved before the trial is complete and are diligently working to advance additional clinical trial data," said Bruce Cozadd, Chairman, and CEO of Jazz Pharmaceuticals, in a statement.

"We are committed to quickly engaging with FDA to evolve the Rylaze product profile with additional dosing options and an IV route of administration."

L-Asparignase as an ALL Treatment

ALL is a rare type of blood cancer but still accounts for 30% of all cancers in children. In 1953, a discovery by Dr. John Graydon Kidd led to the widespread use of L-asparaginase as a treatment for ALL. It was found that the deprivation of the amino acid, L-asparagine, sends the leukemic cells into starvation mode, eventually killing them owing to the blockage in DNA, RNA, and protein synthesis.

Over the years, asparaginase derived from Escherichia coli was typically used as first-line therapy, but around two-thirds of patients were found to develop an allergic reaction. Such patients continued treatment with Erwinia chrysanthemi asparaginase.

Encouraging Trial Data

Rylaze is a recombinant erwinia asparaginase produced from a novel Pseudomonas fluorescens expression platform. The FDA approval was based on encouraging data from an ongoing Phase 2/3 trial that assessed the drug’s safety, tolerability, and efficacy. The study evaluated Rylaze in pediatric and adult patients with ALL or LBL who have had an allergic reaction to E. coli-derived asparaginases and have not previously received asparaginase from erwinia chrysanthemi.

Results from the first of three cohorts showed that patients who received 25 mg/m2 of Rylaze through intramuscular injection achieved intended levels of serum asparaginase activity, and nearly 94% of them maintained ≥ 0.1 U/mL of enzyme levels at 48 hours after administration.

"The accelerated development and approval of Rylaze marks an important step in bringing a meaningful new treatment option for many ALL patients – most of whom are children – who cannot tolerate E. coli-derived asparaginase medicine," said Dr. Luke Maese, Assistant Professor at the University of Utah, Primary Children’s Hospital and Huntsman Cancer Institute.

"Before the approval of Rylaze, there was a significant need for an effective asparaginase medicine that would allow patients to start and complete their prescribed treatment program with confidence in supply," he added.

Jazz reported total revenue of $2.36 Billion in 2020, of which $1,757.0 million was brought in by its combined oxybate business. Meanwhile, its total oncology net product sales accounted for $554.5 million. With the approval of some new oncology drugs, the company would be expected to exceed that number this year.

On July 5, 2021 Imugene Limited (ASX:IMU), a clinical stage immuno-oncology company, reported the company presented on the HER-Vaxx cancer immunotherapy program at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer 2021 Annual Meeting (Press release, Imugene, JUL 5, 2021, View Source [SID1234584745]).

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The abstract presentation was entitled ‘HERIZON: A PHASE 1B/2 OPEN-LABEL STUDY OF IMU-131 HER2/NEU PEPTIDE VACCINE PLUS STANDARD OF CARE CHEMOTHERAPY WITH RANDOMIZATION IN PHASE 2 IN PATIENTS WITH HER2/NEU OVEREXPRESSING METASTATIC OR ADVANCED ADENOCARCINOMA OF THE STOMACH OR GASTROESOPHAGEAL JUNCTION’ Updated Interim Analysis Results.

The presentation expanded on previously presented interim analysis data presented at AACR (Free AACR Whitepaper)2021.

To recap previously released results:
• Interim analysis in the randomized Phase 2 study showed statistically significant overall survival Hazard Ratio (HR) of 0.418 (80% 2-sided CI: 0.186, 0.942); HER-Vaxx showed a reduced risk of death of 58.2% in the HER-Vaxx plus chemotherapy group as compared to chemotherapy alone.
• The median overall survival (OS) for patients receiving HER-Vaxx plus chemotherapy was 14.2 months, compared to 8.8 months in patients treated with chemotherapy alone.
• The Phase 2 data represent a clinical proof-of-concept signal for HER-Vaxx when added to chemotherapy and indicate that B-cell activating immunotherapy vaccines can induce clinically active antibody responses.
• Recruitment of the Phase 2 trial was completed in January 2021.

The ESMO (Free ESMO Whitepaper) presentation highlights and presents the following new data:
• HER-Vaxx treatment resulted in a 50% Overall Response Rate (ORR) compared to 29% in patients treated with chemotherapy alone. The ORR measures the percentage of patients who responded to treatment with a partial response (PR) or better. 2 IMUGENE LIMITED ACN 009 179 551
• Treatment with HER-Vaxx clearly demonstrates patients develop high levels of HER2-specific antibodies early in the treatment protocol and are maintained during treatment and maintenance phase with only a few booster injections.
• Tumour response is correlated with the amount of antibody levels. Patients with antibody levels higher than 1050ng/ml received greater than 50% tumour reduction and may serve as a potential biomarker.
• In contrast to patients on chemotherapy alone, the reduction of tumour size is substantially higher in patients that received HER-Vaxx + chemotherapy.

Overall, this data demonstrates HER-Vaxx may provide treatment benefits consistent with traditional monoclonal antibodies with a corresponding adaptive immune response without added toxicity.

Imugene’s HER-Vaxx is a B-cell activating cancer immunotherapy designed to treat tumours that overexpress the HER-2/neu receptor, such as gastric, breast, ovarian, lung and pancreatic cancers. The immunotherapy is constructed from several B cell epitopes derived from the extracellular domain of HER2/neu. It has been shown in pre-clinical studies and in Phase 1 and 2 studies to stimulate a potent polyclonal antibody response to HER-2/neu, a well-known and validated cancer target.

On July 5, 2021 Prescient Therapeutics Limited (ASX:PTX) reported that outstanding findings from in silico immunogenicity testing of OmniCAR’s key binding components – SpyTag and SpyCatcher (Press release, Prescient Therapeutics, JUL 5, 2021, View Source;utm_medium=rss&utm_campaign=positive-results-from-immunogenicity-testing-send-prescients-shares-higher [SID1234584687]).

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SpyTag/SpyCatcher system is a technology used to combine proteins; SpyTag is a 13-amino acid peptide which reacts with SpyCatcher to form a bond.

Following the significant update, shares of the ASX-listed clinical-stage oncology firm jumped 14.130% and were trading at AU$0.260 (at 02:48 PM AEST).

PTX highlighted that the in silico tests confirm the non-immunogenic profile of SpyTag and SpyCatcher. These findings substantially de-risk the OmniCAR platform and are crucial for progressing Prescient’s OmniCAR in-house programs and external partnership/collaborations.

Immunogenicity testing assesses the immune response against a new treatment, which can negatively affect efficacy and safety. In CAR-T cell therapies, elevated levels of immunogenicity can negatively impact the expansion and persistence of CAR-T cells, affecting the treatment’s overall safety and clinical response.

WATCH NOW: Expert Talks With Mr Steven Yatomi Clarke, CEO and Managing Director of Prescient Therapeutics

In silico test demonstrates low immunogenicity of SpyTag and SpyCatcher
Prescient highlighted that the immunogenicity of OmniCAR’s binding system components – SpyTag and SpyCatcher – were analysed in silico by an independent US research provider. The study was performed to determine if these components could generate unfavourable immune responses which could have a negative impact on the therapy.

Source: PTX Update, 5 July 2021

The findings revealed that both SpyTag and SpyCatcher had extremely low immunogenicity. Notably, their immunogenicity was found to be lower than a panel of humanised therapeutic antibodies already approved for human use.

ALSO READ: Prescient Therapeutics’ major strides in anti-cancer programs set the stage for a sturdy 2021

It is interesting to note that in silico immunogenicity testing is widely considered to be over-predictive as contemporary algorithms cannot account for cellular antigen processing.

Steven Yatomi-Clarke, the CEO and Managing Director of Prescient, commented-

The crucial development follows the completion of the manufacturing and delivery of the OmniCAR platform’s critical components, including cell binders for numerous cancer targets and lentiviral vectors utilised to manufacture CAR-T cells.

READ MORE: Prescient Therapeutics reaches a major CAR-T manufacturing milestone

Prescient’s OmniCAR programs are being developed for:

Acute myeloid leukemia (AML).
Her2+ solid tumours (breast, gastric and ovarian cancers).
Glioblastoma multiforme or GBM (the most common form of brain cancer).
PTX has developed OmniCAR as a platform, allowing collaborations and partnerships under licence with third parties wanting to integrate OmniCAR for enhancing their respective cell therapies.

The platform is based on technologies developed at the University of Pennsylvania and the University of Oxford. Interestingly, Prescient owns a global licence for the commercialisation of the technologies.

DO READ: Prescient Therapeutics inks new deal with Peter Mac to rev up its OmniCAR programs

Prescient highlights that the positive findings from the in silico immunogenicity test show that if these therapies are given to patients, their immune systems will not impair the therapy itself. Furthermore, the Company is thrilled to progress its in-house next-generation cell therapies for cancer treatments.