IL-13Rα2

iStock/ wildpixel Emboldened by technological advances and a deeper knowledge of glioblastoma, Merck, Kazia Therapeutics, CorriXR Therapeutics and others are targeting the often-fatal brain tumor. The tide could be turning for a rare but devastating brain tumor called glioblastoma. While the past two decades have been a wasteland of clinical failures, new therapeutic forays from Merck, Kazia Therapeutics and other companies are sparking hope for patients. While considered a rare cancer, glioblastoma multiforme (GBM) is also the most common and aggressive primary brain tumor in adults. The five-year survival rate is less than 5% and, despite continued efforts, the wait has been long for new successful therapies. “Glioblastoma has been a very, very challenging target to hit,” John Friend, CEO of Kazia Therapeutics, told BioSpace , adding that there have been no truly successful new therapeutics for the indication since Merck’s temozolomide was approved in 1999. “We’ve seen really no benefits whatsoever of any assets in over 20 years.” In 2017, Bristol Myers Squibb’s Opdivo failed to improve overall survival in a Phase III trial over Genentech’s Avastin. Two years later, in 2019, a Phase III failure of its experimental gene therapy for GBM sent Tocagen’s stock tumbling, ultimately ending in a reverse merger with Forte Biosciences. Also in 2019, an independent data monitoring committee recommended AbbVie stop a Phase III study of its antibody-drug conjugate Depatux-M in GBM after an interim analysis revealed a lack of survival benefit. These failures and others have led a lot of pharma and biotech companies to shy away from glioblastoma, Friend said. However, there has been a recent uptick in investor and drugmaker interest in neuro-oncology. Biopharma pipelines are progressing with investigational small molecules, immunotherapies and oncolytic viruses that could change the course of this killer disease. Among the furthest along is Kazia with its brain penetrant P13K small molecule, while many earlier-stage programs, including those owned by Merck and Black Diamond Therapeutics, continue to make their way to and through the clinic. What’s exciting today, said Vanessa Almendro, co-founder of the Brain Tumor Investment Fund, is that there “is starting to be an understanding of the risks and the opportunities in the space.” She compared it to where melanoma was 20 years ago when subtypes came on the scene to guide therapeutic decisions. “Today we can subtype these indications,” Almendro told BioSpace . “We are starting to understand how to better match therapy modalities to the right patient in clinical trials.” Small Molecules at the Forefront As therapeutic technologies advance, Almendro predicted that small molecules will still be at the forefront for glioblastoma. “That’s the modality we understand best,” she said. This hypothesis gained traction in October when Merck entered the GBM ring, scooping up Modifi Biosciences for $30 million upfront with milestone payments potentially equaling $1.3 billion. Modifi is developing a new class of orally delivered small molecules aimed at killing cancer cells via DNA modification, with potential in glioblastoma. DNA repair defects are a hallmark of tumor cells and a major driver of therapeutic resistance. Modifi’s temozolomide-based drug MOD-246 aims to eradicate cancer via DNA repair pathways—in glioblastoma’s case, by targeting cells that lack the MGMT protein. Investigational New Drug–enabling studies are underway with clinical trials expected to begin in 2025. Further along in development is Kazia’s paxalisib, an oral, small molecule inhibitor originally developed by Genentech. Currently in Phase II/III trials, paxalisib inhibits the action of PI3K, a key controller of cell growth and division active in many forms of cancer. While PI3K has been an established therapeutic target for years in breast cancer and lymphomas, Friend said the challenge with glioblastoma has always been bypassing the blood brain barrier (BBB). Paxalisib is designed to cross the BBB. Data from a Phase II/III study in July helped identify the specific subset of patients for which the drug is most effective. Friend explained that a high level of methylation on the promoter region of the MGMT protein signifies a better response to temozolomide and improved survival rates. The median survival rate for unmethylated patients is less than half that of methylated patients—12 months versus 26 to 28 months—meaning paxalisib is showing most benefit in the patients with the worst prognoses. Early treatment is also important. While patients with recurrent disease showed no benefit in the trial, newly diagnosed unmethylated patients showed a 33% improvement in overall survival. Kazia will meet with the FDA in December to discuss potential pathways to approval for paxalisib in newly diagnosed patients with GBM. Meanwhile, Black Diamond Therapeutics is developing an epidermal growth factor receptor (EGFR) inhibitor, BDTX-1535 , for glioblastoma. Over 50% of GBM patients express one or more oncogenic epidermal growth factor receptor alterations, according to the company, making it a potential target for EGFR inhibitors. Following a completed Phase I trial , Black Diamond is recruiting a Phase 0/I study for patients with recurrent GBM prior to a planned resection. Cell and Gene Therapies: The Next Frontier Carl June, the father of CAR T cell therapy, predicted earlier this year that CAR Ts will be a breakthrough therapy for brain cancer. “I think about five years down the line, we’re going to have FDA-approved CARs for glioblastoma,” he said in a statement from his institution, UPenn’s Perelman School of Medicine. And indeed, progress is being made toward that end. Backed by Gilead subsidiary Kite, researchers at Penn Medicine shared results in March from an ongoing Phase I trial of six patients with recurrent glioblastoma treated with a “dual target” CAR T aimed at EGFR and interleukin-13 receptor alpha 2. It was the first time a CAR T cell therapy with two targets was administered to patients with GBM. MRI scans 24 to 48 hours after intrathecal administration showed reduced tumor sizes in all six patients. The reductions have been sustained out to several months later in a “subset of patients,” Penn reported. A concern with CAR T therapy, particularly when delivered to the brain, is neurotoxicity. In the Penn trial, researchers reported neurotoxicity in all six patients that was substantial but manageable. “Cell therapies are likely to be the next frontier,” Almendro said. Despite the challenges and complicated manufacturing, “this is where we think the field is going,” she said. Meanwhile, CorriXR Therapeutics is tackling drug resistance by targeting the tumors’ NRF2 pathway through gene therapy. A genetic knockout to NRF2 can alleviate the issues that cause resistance to the standard of care, CorriXR CEO Deborah Moorad explained. “We’re not just adding more drug on top of something,” she told BioSpace . “We’re truly looking at how we can take that DNA of the tumor apart and effectively treat the patient.” The company is taking its asset into IND-enabling studies for cancer of the oral cavity first, with glioblastoma planned as its second target. Targeting Immune Response Though located in the brain, glioblastoma causes widespread immunosuppression. Some researchers and companies are turning to therapeutic vaccines in an attempt to achieve an immune response to the tumors. Researchers at Roswell Park Comprehensive Cancer Center are developing a vaccine called SurVaxM that stimulates CD4 and CD8 T cells to home in on the survivin protein on tumor cells. SurVaxM also helps produce antibodies to attack tumor cells. In a Phase II study, patients treated with the vaccine achieved a median of over 12 months of progression-free survival versus four months for those on standard of care. Overall survival increased from 15 months with standard of care to over 30 months for those treated with SurVaxM. A Phase IIb study is underway at the cancer center. Separately, at the NCI Center’s Neuro-Oncology Branch, a team of researchers is developing a vaccine from tumor cells collected from the patient during surgery. The cells are treated with radiation in the lab until they can no longer grow but are not dead, and mixed with a second component that boosts immune response. The vaccine could potentially be used after chemotherapy to remove residual tumor cells or to convert “cold” tumor cells into “hot” ones to make them susceptible to checkpoint inhibitors, according to the scientists. The GBM market is currently valued at just under $3 billion and is expected to reach $5.7 billion by 2033, according to Precedence Research. The report revealed that revenue over the last four years has dropped for surgical treatment as targeted therapy and immunotherapies have grown. Moorad said she believes the interest has been there all along for glioblastoma. “The technology is just kind of catching up. We’re going to see more [investment] moving forward,” she said. “People are being bold.”

MDNA113 is a novel IL-13Rα2 tumor-targeted and “masked” BiSKIT (Bifunctional SuperKine for ImmunoTherapy), engineered to deliver an anti-PD1-IL-2 Superkine (anti-PD1-IL-2SK) to the tumor microenvironment (TME), where it is conditionally activated by tumor-associated proteases MDNA113 treatment achieved complete tumor regression of IL-13Rα2 expressing tumors, highlighting its potential to treat a vast range of malignancies, including immunologically “cold tumors” that annually affect over two million cancer patients worldwide Internationally recognized academic teams in the UK showed promising pre-clinical results with a long-acting IL-2SK (MDNA11) and anti-PD1-IL-2SK BiSKIT, in mouse models of glioblastoma (GBM) and patient-derived GBM explants Updated MDNA11 clinical results from the ABILITY-1 study will be presented tomorrow at SITC TORONTO and HOUSTON, Nov. 08, 2024 (GLOBE NEWSWIRE) -- Medicenna Therapeutics Corp. (“Medicenna” or the “Company”) (TSX: MDNA, OTCQX: MDNAF), a clinical-stage immunotherapy company focused on the development of Superkines, announced that new preclinical data from its BiSKIT (MDNA113) and IL-2 super agonist (MDNA11) programs will be presented today at the 39th Annual Meeting of SITC being held in Houston, Texas. In addition, as announced previously, updated clinical results from the MDNA11 Phase 1/2 ABILITY-1 study will be presented tomorrow, Saturday November 9, 2024 at SITC. “We are excited to demonstrate our ability to generate novel therapeutics such as MDNA113, to address unmet needs in oncology, by smartly leveraging both our IL-2 and IL-13 Superkine platforms in one molecule,” said Fahar Merchant, Ph.D., President and CEO of Medicenna. “Today’s data demonstrates the effectiveness of MDNA113 to inhibit tumor growth, particularly in IL-13Rα2 positive tumors, and showcase its potential to completely protect and prevent metastasis in an aggressive breast cancer model when administered just once prior to surgery. In a separate presentation, independent work from our academic collaborator in the UK demonstrated the capacity of MDNA11 and anti-PD1-IL-2SK BiSKIT to significantly extend overall survival in an aggressive GBM mouse model and stimulate activity of resident effector immune cells in fresh human GBM explants.” MDNA113 is based on the Company’s IL-2 and IL-13 Superkine Platforms, the former being used to develop MDNA11, a long-acting IL-2 super agonist, currently being evaluated in the Phase 1/2 ABILITY-1 study for the treatment of advanced and/or metastatic solid tumors. Key highlights from the presentations are: MDNA113 is a conditionally activatable anti-PD1-IL-2SK with a cleavable IL-13SK dual masking/tumor-targeting domain to limit systemic immune stimulation while maximizing anti-tumor response Mice treated with MDNA113 showed reduced peripheral lymphocyte expansion without impacting anti-PD1/PDL1 blockade, and better tolerability when compared to unmasked anti-PD1-IL-2SK.Cleavage by tumor-specific proteases removes the IL-13SK targeting and masking domain of MDNA113, restoring the synergy between IL-2R agonism and anti-PD1 blockadeEfficacy of MDNA113 is substantially enhanced in mice harboring MC38 tumors that have been engineered to overexpress IL-13Rα2, resulting in complete tumor regression in a vast majority of animalsSingle neoadjuvant treatment (pre-surgery) with MDNA113 in a highly invasive orthotopic 4T1.2 model of triple negative breast cancer resulted in 100% survival by preventing metastasis and enrichment of cytotoxic GrzB-positive CD8+T cells within the tumor microenvironment. Stimulation of IL-2 signaling with highly selective IL-2R super-agonists enhances immune effector cell response in mouse and patient-derived glioblastomas Long-acting IL-2SK (i.e., MDNA11) and anti-PD1-IL-2SK (i.e., therapeutic core of MDNA113) significantly extended the survival of mice bearing aggressive orthotopic GBMs when compared to control mice or mice treated with native IL-2 or anti-PD1.GBMs from anti-PD1-IL-2SK treated mice showed higher frequency of infiltrating CD8+T and NK cells with no change in immune suppressive Tregs.Ex-vivo primary patient-derived fresh GBM explants treated with IL-2SK or anti-PD1-IL-2SK showed increased CD8+ T and NK cell populations concomitant with reduced tumor cell burden. Copies of the two presentations will be available on the “Scientific Presentations” page of Medicenna’s website after the conference. About MDNA113 MDNA113 is a novel, first-in-class tumor-targeted and tumor-activated bi-functional anti-PD1-IL2 Superkine with exceptionally high affinity for IL-13Rα2 without binding to the functional IL-13R⍺1. IL-13Rα2 is overexpressed in a wide range of solid tumors, including cold tumors with minimal to no expression in normal tissues. IL-13Rα2 expressing tumors also have abundant matrix metalloprotease in the tumor microenvironment that may efficiently activate MDNA113. IL-13Rα2 expression is associated with poor clinical outcome in multiple tumor types including prostate cancer, pancreatic cancer, ovarian cancer, liver cancer, breast cancer and brain cancer, with an annual world-wide incidence of over 2 million. About MDNA11 MDNA11 is an intravenously administered, long-acting ‘beta-enhanced not-alpha’ IL-2 Superkine specifically engineered to overcome the shortcomings of aldesleukin and other next generation IL-2 variants by preferentially activating immune effector cells (CD8+ T and NK cells) responsible for killing cancer cells, with minimal or no stimulation of immunosuppressive Tregs. These unique proprietary features of the IL-2 Superkine have been achieved by incorporating seven specific mutations and genetically fusing it to a recombinant human albumin scaffold to improve the pharmacokinetic (PK) profile and pharmacological activity of MDNA11 due to albumin’s natural propensity to accumulate in highly vascularized sites, in particular tumor and tumor draining lymph nodes. MDNA11 is currently being evaluated in the Phase 1/2 ABILITY-1 study (NCT05086692) as both monotherapy and in combination with pembrolizumab. About Medicenna Therapeutics Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 Superkines and first-in-class Empowered Superkines. Medicenna’s long-acting IL-2 Superkine, MDNA11, is a next-generation IL-2 with superior affinity toward CD122 (IL-2 receptor beta) and no CD25 (IL-2 receptor alpha) binding, thereby preferentially stimulating cancer-killing effector T cells and NK cells. Medicenna’s IL-4 Empowered Superkine, bizaxofusp (formerly MDNA55), has been studied in 5 clinical trials enrolling over 130 patients, including a Phase 2b trial for recurrent GBM, the most common and uniformly fatal form of brain cancer. Bizaxofusp has obtained FastTrack and Orphan Drug status from the FDA and FDA/EMA, respectively. Medicenna’s early-stage high-affinity IL-2β biased IL-2/IL-15 Super-antagonists, from its MDNA209 platform, are being evaluated as potential therapies for autoimmune and graft-versus host diseases. Medicenna’s early-stage BiSKITs™ (Bifunctional SuperKine ImmunoTherapies) and the T-MASK™ (Targeted Metalloprotease Activated SuperKine) programs are designed to enhance the ability of Superkines to treat immunologically “cold” tumors. For more information, please visit www.medicenna.com, and follow us on Twitter and LinkedIn. Forward-Looking Statements This news release contains forward-looking statements within the meaning of applicable securities laws. Forward-looking statements include, but are not limited to, express or implied statements regarding the future operations of the Company, estimates, plans, strategic ambitions, partnership activities and opportunities, objectives, expectations, opinions, forecasts, projections, guidance, outlook or other statements that are not historical facts, such as statements on the therapeutic potential and safety profile of MDNA11 and MDNA113. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. Results in early-stage pre-clinical or clinical studies may not be indicative of full results or results from later stage or larger scale clinical studies and do not ensure regulatory approval. You should not place undue reliance on these statements, or the scientific data presented. Forward-looking statements are often identified by terms such as “will”, “may”, “should”, “anticipate”, “expect”, “believe”, “seek”, “potentially” and similar expressions. and are subject to risks and uncertainties. There can be no assurance that such statements will prove to be accurate and actual results and future events could differ materially from those anticipated in such statements. Important factors that could cause actual results to differ materially from the Company’s expectations include the risks detailed in the latest annual information form of the Company and in other filings made by the Company with the applicable securities regulators from time to time in Canada. The reader is cautioned that assumptions used in the preparation of any forward-looking information may prove to be incorrect. Events or circumstances may cause actual results to differ materially from those predicted, as a result of numerous known and unknown risks, uncertainties, and other factors, many of which are beyond the control of the Company. The reader is cautioned not to place undue reliance on any forward-looking information. Such information, although considered reasonable by management, may prove to be incorrect and actual results may differ materially from those anticipated. Forward-looking statements contained in this news release are expressly qualified by this cautionary statement. The forward-looking statements contained in this news release are made as of the date hereof and except as required by law, we do not intend and do not assume any obligation to update or revise publicly any of the included forward-looking statements. This news release contains hyperlinks to information that is not deemed to be incorporated by reference in this new release. Investor/Media Contact: Christina CameronInvestor Relations, Medicenna Therapeutics(647) 953-0673ir@medicenna.com

MB-108 is an oncolytic virus designed to treat malignant glioma. Credit: meeboonstudio via Shutterstock. Mustang Bio has received orphan drug designation from the US Food and Drug Administration (FDA) for MB-108, a herpes simplex virus type 1 oncolytic virus and a component of MB-109, designed to treat malignant glioma. MB-109 is Mustang’s regimen that combines MB-101, a chimeric antigen receptor (CAR)-T-cell therapy targeting interleukin 13 receptor alpha 2, with MB-108, which is licenced from Nationwide Children’s Hospital. Preclinical data has suggested that the combination therapy could potentially optimise outcomes for patients with recurrent glioblastoma multiforme (GBM). By converting immunologically ‘cold’ tumours into ‘hot’ ones, MB-108 may enhance the efficacy of the MB-101 CAR-T cell therapy. Separately, data on MB-101 and MB-108 indicated that both therapies were well-tolerated in patients with recurrent GBM. Notably, two patients treated with MB-101 alone, who had ‘hot’ tumours with high levels of cluster of differentiation 3+ T cells, achieved complete responses lasting over seven and 31+ months. These remarkable outcomes were observed in the two patients with the most immunologically active tumours among the 53 participants in the City of Hope Phase I trial. The ongoing Phase I clinical trials for MB-101 at City of Hope and MB-108 at the University of Alabama at Birmingham, US, are continuing to enrol patients. The future development of the MB-109 programme for recurrent GBM and high-grade astrocytomas is dependent on securing additional funding or forming strategic partnerships. Additionally, the company is planning to request MB-101’s ODD from the FDA for treating malignant gliomas. Mustang Bio president and CEO Manuel Litchman said: “The orphan drug designation for MB-108 is significant for Mustang, as it could provide additional market exclusivity and we hope to advance MB-108, in combination with MB-101, as a potential treatment option for patients living with malignant glioma, including patients with recurrent glioblastoma and high-grade astrocytomas, where there is historically a median overall survival of six months. “Our novel therapeutic strategy, combining our MB-108 oncolytic virus with MB-101 CAR-T-cell therapy, could be the first-ever industry-sponsored trial of its kind for the treatment of malignant glioma.” Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy