On September 27, 2022 AstraZeneca reported Koselugo (selumetinib) has been approved in Japan for the treatment of paediatric patients three years of age and older with plexiform neurofibromas (PNs) in neurofibromatosis type 1 (NF1) with clinical symptoms, such as pain and disfigurement, and PNs which cannot be completely removed by surgery without risk of substantial morbidity (Press release, AstraZeneca, SEP 27, 2022, View Source [SID1234621470]).1

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The approval by the Japanese Ministry of Health, Labour and Welfare (MHLW) is based on positive results from the SPRINT Stratum 1 Phase II trial sponsored by the National Institutes of Health’s National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP). The trial showed Koselugo, an oral treatment option, reduced the size of inoperable tumours in children.1,2 Additionally, a Phase I trial in Japanese paediatric NF1 patients with symptomatic and inoperable PNs was also evaluated as a basis for the approval, with the trial showing tumour reduction.

NF1 is a debilitating genetic condition affecting one in 3,000 individuals worldwide, most commonly diagnosed in children under 10.3,4 In 30-50% of patients, tumours develop on the nerve sheaths (plexiform neurofibromas) and can cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder or bowel dysfunction.2,5-8

Professor Yoshihiro Nishida, MD, PhD, Department of Rehabilitation Medicine at Nagoya University, Nagoya, Japan, and Japan Phase I trial investigator said: "People living with plexiform neurofibromas caused by neurofibromatosis type 1 often face painful physical, emotional and social burdens. This approval marks a major step forward in addressing the debilitating impact these plexiform neurofibromas have on paediatric patients living with neurofibromatosis type 1 in Japan. Koselugo provides a suitable intervention to treat symptomatic plexiform neurofibromas, which may improve long-term patient activities of daily living and quality of life."

Marc Dunoyer, Chief Executive Officer, Alexion, said: "As the first medicine approved in Japan for paediatric patients with symptomatic, inoperable plexiform neurofibromas in neurofibromatosis type 1, Koselugo offers new hope for patients and families affected by this incurable genetic disease, whose only previous treatment option was repeated surgery. This approval is a testament to our longstanding commitment to rare disease research and we are energised by the opportunity to further accelerate innovation and care for the neurofibromatosis type 1 community."

The SPRINT Stratum 1 Phase II trial showed Koselugo demonstrated an objective response rate (ORR) of 66% (33 of 50 patients, confirmed partial responses) in paediatric patients with PNs in NF1 when treated with Koselugo as twice-daily oral monotherapy.1 ORR is defined as the percentage of patients with confirmed complete (disappearance of PNs) or partial response (at least 20% reduction in tumour volume).1 The most common adverse reactions in the SPRINT trial were vomiting, blood creatine phosphokinase increase, diarrhoea and nausea.1

Results from the SPRINT Stratum 1 Phase II trial were published online in The New England Journal of Medicine.2

In addition to Japan, Koselugo is also approved in the US and EU for the treatment of paediatric patients with NF1 and symptomatic, inoperable PNs. Further regulatory submissions are underway.

Notes

NF1
NF1 is a debilitating genetic condition that is caused by a spontaneous or inherited mutation in the NF1 gene.9 NF1 is associated with a variety of symptoms, including soft lumps on and under the skin (cutaneous neurofibromas) and skin pigmentation (so-called ‘café au lait’ spots) and, in 30-50% of patients, tumours develop on the nerve sheaths (plexiform neurofibromas).5,9 These plexiform neurofibromas (PNs) can cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder or bowel dysfunction.2,5-8 PNs begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.5,8-10

SPRINT
The SPRINT Stratum 1 Phase II trial was designed to evaluate the objective response rate and impact on patient-reported and functional outcomes in paediatric patients with NF1-related inoperable PNs treated with Koselugo (selumetinib) monotherapy.2 This trial sponsored by NCI CTEP was conducted under a Cooperative Research and Development Agreement between NCI and AstraZeneca with additional support from Neurofibromatosis Therapeutic Acceleration Program (NTAP).

Koselugo
Koselugo (selumetinib) is the first and only approved therapy by the Japanese MHLW for the treatment of paediatric patients three years of age and older with plexiform neurofibromas (PNs) in neurofibromatosis type 1 (NF1) with clinical symptoms, such as pain and disfigurement, and PNs which cannot be completely removed by surgery without risk of substantial morbidity.1 Koselugo blocks specific enzymes (MEK1 and MEK2), which are involved in stimulating cells to grow.1 In NF1, these enzymes are overactive, causing tumour cells to grow in an unregulated way. By blocking these enzymes, Koselugo slows down the growth of tumour cells.1

Koselugo is approved for use in the US, EU and Japan and has received Orphan Drug Designation in Russia, Switzerland, South Korea, Taiwan and Australia, and health authorities worldwide are reviewing regulatory submissions.

AstraZeneca and MSD Strategic Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Rahway, NJ, US, known as MSD outside the US and Canada, announced a global strategic collaboration to co-develop and co-commercialise Lynparza and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

Alexion
Alexion, AstraZeneca Rare Disease, is the group within AstraZeneca focused on rare diseases, created following the 2021 acquisition of Alexion Pharmaceuticals, Inc. As a leader in rare diseases for 30 years, Alexion is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialisation of life-changing medicines. Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on haematology, nephrology, neurology, metabolic disorders, cardiology and ophthalmology. Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in more than 50 countries.

On September 27, 2022 Transgene (Euronext Paris: TNG) (Paris:TNG), a biotech company that designs and develops virus-based immunotherapeutics against cancer, reported it will host today an R&D event for investors and research analysts in Paris (Press release, Transgene, SEP 27, 2022, View Source [SID1234621469]).

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Hedi Ben Brahim, CEO of Transgene, commenting on the Company’s R&D Day said: "Today’s event will highlight our world leading scientific and translational expertise which has allowed us to design the next generation of virus-based immunotherapies against cancer. We will provide updated data on the previous Phase Ib/II trial of TG4001 and avelumab in HPV16-positive cancer patients and the updated clinical follow up of patients enrolled in the two Phase I trials with TG4050, which are all positive and consistent with previous findings. In addition, we will outline the progress we have made with our exciting Invir.IO platform, which via intravenous administration could significantly broaden the potential of oncolytic viral therapies. I would like to thank our expert speakers for participating in our R&D event which I am confident will demonstrate that Transgene remains on track to deliver a number of important value adding clinical milestones over the next 18 months."

The event, which features presentations by leading clinicians and scientists from around the world, as well as key members of the Transgene management team, provides insights on:

– TG4001, with updated data from the previous trial (Phase Ib/II) evaluating the combination of TG4001 and avelumab in HPV16-positive cancers;
– TG4050, with updated follow up data from the two Phase I trials in ovarian cancer and head and neck cancer;
– The progress of the Invir.IO platform, with a focus on a novel oncolytic virus vectorizing human IL-12 that has been designed to be administered intravenously.

The R&D Day’s key speakers, which also includes key members of Transgene’s management team, are:

Jean-Pierre Delord, MD, PhD, General Manager of IUCT Oncopole of Toulouse, will present: "TG4001 – a HPV16 Therapeutic vaccine in Phase II".
Christian Ottensmeier, MD, PhD, FRCP, Professor of Immuno-oncology at the University of Liverpool, The Clatterbridge Cancer Center NHS Foundation Trust, will present: "From the design of the myvac platform to first immunological and clinical readouts, Update on the head and neck trial of TG4050".
Matthew Block, MD, PhD, Medical oncologist at the Mayo Clinic, will present: "TG4050, a personalized therapeutic vaccine in the treatment of ovarian cancer".
Adel Samson, MD, PhD, Clinical Associate Professor, CRUK Clinician Scientist and Honorary Medical Oncologist from the University of Leeds, will present: "Assessing novel routes of administration (IV or locoregional route) with TG6002".
Pedro Romero, MD, Chief Editor of the JITC and Deputy scientific managing director of the Lausanne Branch of the Ludwig Institute for Cancer Research, will present: "Opportunities in the immuno-oncology field".
The full agenda of the Transgene R&D Day can be accessed on Transgene’s website, www.transgene.fr, in the Investor Events and presentation section.

The live webcast will also be accessible via the following link: R&D Day live presentation.

On September 27, 2022 Targovax ASA (OSE: TRVX), a clinical-stage immuno-oncology company developing immune activators to target solid tumors, reported that the FDA has accepted the protocol and given the formal go-ahead to proceed with the planned ONCOS-102 phase 2 trial in melanoma. Study initiation activities are proceeding according to the communicated timeline, with the aim to start enrolling patients in late 2022 or early 2023 (Press release, Targovax, SEP 27, 2022, View Source [SID1234621468]).

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PD-1 CPI refractory advanced melanoma is a major unmet medical need affecting up to 25,000 patients per year globally in the major markets. The diagnosis has poor prognosis and there are currently no approved treatment options available. In a recently reported phase 1 trial, ONCOS-102 demonstrated a highly competitive response rate (ORR) of 35% in this patient population in combination with a PD-1 CPI. Importantly, the strong ORR outcome was corroborated by biomarker data showing significant increase in T-cell infiltration and broad and persistent activation of immune-related gene signatures in responding patients.

Based on these promising early clinical results, Targovax is planning to conduct a larger, phase 2 multi-cohort study to further explore and validate the benefit of ONCOS-102 in PD-1 CPI refractory melanoma. This phase 2 study will be run in collaboration with Targovax’s partner Agenus, who will provide their Fc-enhanced CTLA-4 (botensilimab) and PD-1 (balstilimab) CPIs for combination with ONCOS-102.

In the first part of the study, two groups will evaluate the safety and efficacy of (1) a higher dose of ONCOS-102 to be tested as a monotherapy and (2) the low and new higher dose of ONCOS-102 in combination with the PD-1 CPI balstilimab. Following confirmation of the safety of the increased ONCOS-102 dose, the study will proceed into its second part adding two more groups. In group (3) ONCOS-102 will for the first time be combined with a CTLA-4 CPI (botensilimab) and, ultimately, in (4) the triple combination of ONCOS-102, balstilimab and botensilimab will be tested.

Dr. Lone Ottesen, Chief Medical Officer of Targovax ASA, said: "We are very pleased to get the formal go-ahead from the FDA for our phase 2 melanoma study. With the proposed design, we will answer important clinical questions relating to safety, dosing and contribution of components that are critical to enable subsequent registrational trials. I am particularly excited about the combination with the next generation Fc-enhanced CTLA-4 CPI botensilimab, which is expected to enhance systemic activity and deepen tumor responses. We anticipate that the triple combination of ONCOS-102 with PD-1 and CTLA-4 blockade will boost response rates above the already strong 35% ORR, and firmly establish ONCOS-102 as class-leading candidate in PD-1 CPI refractory melanoma".

On September 27, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported the initiation of its Phase 3 global registrational study of zilovertamab, ZILO-301 (NCT05431179), for the treatment of patients with relapsed/refractory mantle cell lymphoma (MCL) (Press release, Oncternal Therapeutics, SEP 27, 2022, View Source [SID1234621466]). The Company obtained its first Institutional Review Board (IRB) approval for the study and expects to promptly begin patient screening and enrollment.

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"The initiation of the first Phase 3 study of zilovertamab, ZILO-301, represents a key milestone for Oncternal, our partners, investors and patients with R/R MCL," said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. "We are looking forward to opening between 50-100 sites across the globe to support what we expect to be the first BLA approval of zilovertamab. ZILO-301 also represents the first registrational study for a therapeutic targeting the novel ROR1 pathway, which we believe can help address significant unmet needs in multiple hematological malignancies and other solid tumors."

About ZILO-301
The Phase 3 clinical trial entitled "A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Zilovertamab (A ROR1 Antibody) Plus Ibrutinib Versus Ibrutinib Plus Placebo in Subjects with Relapsed or Refractory Mantle Cell Lymphoma" (NCT05431179) will evaluate the potential benefit of zilovertamab for patients who have only experienced stable disease (SD) or a partial response (PR) after having received four months of oral ibrutinib therapy (560 mg daily) during the open-label lead-in phase of the study. Patients with such an inadequate response (PR or SD) will be randomized (1:1) to receive zilovertamab (600mg administered by IV every 2 weeks for 3 administrations and then every 4 weeks thereafter) or placebo, while continuing to receive oral ibrutinib. Across 50-100 international sites, the study aims to enroll 365 patients and to randomize approximately 250 patients after the 4-month lead-in phase.

An interim analysis, designed to support submission of a BLA seeking accelerated FDA approval, will be conducted based on an endpoint of Objective Response Rate (ORR) plus Duration of Response (DOR). The final analysis, intended to support regular FDA approval, will be based on a primary endpoint of progression-free survival (PFS). Secondary efficacy endpoints include ORR, DOR, Complete Response (CR) Rate, Overall Survival (OS), and the proportion of subjects experiencing grade 3 or 4 neutrophil count decrease.

On September 27, 2022 Nanoligent SL, a Spanish biotech company specialized in the development of cancer treatments based on unique protein conjugates, reported the completion of a Seed financing round of total € 2.8 M (Press release, Nanoligent, SEP 27, 2022, https://www.nanoligent.com/index.php/2022/09/27/nanoligent-raised-2-8-m/ [SID1234621464]). The final closing of the Seed round consists of € 1 M investment by i&i Biotech Fund I (i&i Bio), an early-stage Life Science fund with teams in Luxemburg and Prague which is backed by the European Investment Fund. i&i Bio joined previous Nanoligent investors, Italian Angels for Growth, the largest network of business angels in Italy, and AVANTECA Partners, a Swiss privately held asset management firm.

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Jaromir Zahrádka, managing partner of i&i Bio, said: "Nanoligent is the fifth investment of our fund and it belongs to a group of targeted oncology therapies in our portfolio. We are excited by deep scientific background and uniqueness of the technology. The platform is developed by highly motivated, experienced, and fully engaged team of scientists and managers. Based on obtained scientific data, the project has a great potential to become an effective treatment for multiple metastatic-cancer types."

Nanoligent is focused on the development of new drugs for the treatment of more than 20 different metastatic cancer types. The lead molecule is based on the targeted elimination of cancer cells overexpressing the CXCR4 receptor, a recognized biomarker for poor prognosis and therapy resistance. Nanoligent is developing a new proprietary nano-technological platform, with the potential to overcome current limitations of Antibody-Drug-Conjugates.

"Less than a third of newly diagnosed metastatic patients respond to current therapies, making metastasis one of the most pressing unsolved challenges in cancer. With the support of i&i Bio together with our existing investors, we secure our current milestone to provide the first drug candidate of our portfolio of metastasis-targeted therapies" said Montserrat Cano, CEO of Nanoligent.

The seed round financing will allow Nanoligent to foster the development of multiple drug candidates and advance the pre-clinical development of its lead candidate in a variety of tumor types.

"We are happy to welcome the i&i Biotech Fund I in Nanoligent. As in previous cases, we have been impressed by the depth of their scientific due diligence and the professionality of their management. They are going to be an important partner for Nanoligent and we are delighted to continue to co-invest with i&i Bio," said Michele Marzola who, together with Alessandro Toniolo, are co-champions from IAG in this investment.

Two of the investors already joined the Nanoligent’s Board which includes: Michele Marzola (IAG), Michael Milos (Avanteca Partners), Manuel Rodríguez (Chairman) and Montserrat Cano (CEO).

"The i&i Biotech Fund I is the right partner for the further development of Nanoligent. They have shown in depth scientific knowledge as well as being well connected within the pharmaceutical network. We all together are looking forward to bringing Nanoligent’s development plan effectively to the next stages," said Michael Milos from AVANTECA Partners.