On July 6, 2022 Mnemo Therapeutics, a biotechnology company developing transformational immunotherapies, reported a publication in Nature Communications demonstrating that the histone lysine methyltransferase enzyme Suv39h1 plays not only a key role in T cell persistence, but also in T cell activation and exhaustion (Press release, Mnemo Therapeutics, JUL 6, 2022, View Source [SID1234616521]). This research was conducted at Institut Curie between the lab of Sebastian Amigorena, Ph.D., CNRS research director, head of the Immune Responses and Cancer Team (Immunity and Cancer Unit – Institut Curie/Inserm) and scientific co-founder of Mnemo, and the lab of Eliane Piaggio, Ph.D., Inserm research director and head of the Translational Immunotherapy Team (Immunity and Cancer Unit, Institut Curie/Inserm).

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"T cell exhaustion and lack of persistence are two key challenges that hinder effective and durable immunotherapy treatments for tumors," said Mnemo Chief Executive Officer, Robert LaCaze. "Through Suv39h1 inactivation, Mnemo aims to create therapies with increased durability and activity."

Previous research, exclusively licensed to Mnemo from the lab of Dr. Amigorena, demonstrated that Suv39h1 is a key enzyme involved in the epigenetic regulation of immune cell memory, and that deletion of Suv39h1 results in increased immune cell memory and more durable therapeutic responses. The research demonstrated in the Nature publication goes on to show that this enzyme is a key factor in regulating T cell exhaustion.

"As is known, the potency of current treatments such as immune checkpoint inhibitors (i.e. anti-PD-1) is limited by repeated stimulation of T cells in a tumor rich environment, resulting in T cell exhaustion," said Dr. Amigorena. "The current study showcases that Suv39h1 acts as an epigenetic checkpoint inhibitor that, when coupled with anti-PD-1 treatment, results in increased T cell activity and decreased T cell exhaustion."

Key takeaways from the study include:

Suv39h1 KO CD8+ T cells are more responsive to T-cell receptor (TCR) activation and become highly cytolytic following PD-1 blockade, resulting in increased tumor killing potency.
Deletion of Suv39h1 resulted in higher CD8+ T cell tumor infiltration when coupled with anti-PD-1 treatment.
CD8+ T cells in Suv39h1 KO mice treated with anti-PD-1 displayed the highest level of a protease (GZMb) responsible for T cell induced apoptosis of tumor cells, despite displaying elevated levels of biomarkers associated with exhaustion.
Suv39h1 deletion resulted in increased chromatin accessibility in regions responsible for immune cell signaling and cytotoxicity during anti-PD-1 treatment, compared to WT with anti-PD-1 treatment.
Inhibition of Suv39h1 via small molecules mimicked Suv39h1 deletion in mouse models, reinforcing that this enzyme is playing a direct role in T cell activity.
"Limited potency, durability, and cancer-specific targets impede the efficacy of current immunotherapies, leading to off-target side effects and patient relapse," said Mnemo Co-Founder and Chief Operating Officer, Alain Maiore. "Alongside our EnfiniT Discovery Engine that identifies novel cancer targets, this research demonstrates Mnemo’s commitment to addressing multiple bottlenecks in the efficacy of immunotherapy, as well as bringing solutions to patients."

References: CD8+T cell responsiveness to anti-PD-1 is epigenetically regulated by Suv39h1 in melanomas. Leticia Laura Niborski, Paul Gueguen, Mengliang Ye, Allan Thiolat, Rodrigo Nalio Ramos, Pamela Caudana, Jordan Denizeau, Ludovic Colombeau, Raphaël Rodriguez, Christel Goudot, Jean-Michel Luccarini, Anne Soudé, Bruno Bournique, Pierre Broqua, Luigia Pace, Sylvain Baulande, Christine Sedlik, Jean-Pierre Quivy, Geneviève Almouzni, José L. Cohen, Elina Zueva, Joshua J. Waterfall, Sebastian Amigorena & Eliane Piaggio.

On July 5, 2022 Ayala Pharmaceuticals, Inc. (Nasdaq: AYLA), a clinical-stage oncology company focused on developing and commercializing small molecule therapeutics for patients suffering from rare tumors and aggressive cancers reported positive interim results from Part A of the ongoing RINGSIDE Pivotal Phase 2/3 clinical trial evaluating AL102 in desmoid tumors. AL102 is a potent, selective, oral gamma-secretase inhibitor (GSI) (Press release, Ayala Pharmaceuticals, JUL 5, 2022, View Source [SID1234616469]).

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"We are very excited with the interim data from Part A of the RINGSIDE study, although early, demonstrating initial substantial anti-tumor activity for AL102 as a single agent as measured by MRI scans," said Roni Mamluk, Ph.D., Chief Executive Officer of Ayala. "We are also encouraged with the safety data showing that AL102 appears to be well tolerated. We look forward to presenting a more advanced and comprehensive data set at a medical meeting later in the year. The results from Part A will be used to determine the dose of AL102 to be evaluated in Part B of RINGSIDE, the randomized portion of the study, which Ayala is on track to initiate in the third quarter of 2022."

Interim Results as of the Cut-Off Date of May 1, 2022

Patient enrollment in Part A of RINGSIDE was completed in February 2022. Patients were dosed in AL102 monotherapy cohorts of 1.2 mg (daily), 2mg (2 days on, 5 days off), or 4mg (2 days on, 5 days off).
The activity of AL102 is being evaluated by change in tumor volume (central MRI readings) and response (per RECIST 1.1) determined by the investigator.
MRI scans showed decreases in tumor size in most of the 13 patients who had reached the 16-week time point.
One patient has reached a unconfirmed partial response at week 16 per RECIST.
AL102 was well tolerated at all dose levels with no dose-limiting toxicities and no Grade 4/5 adverse events were observed.
The most common treatment-related adverse events were Grade 1-2, including diarrhea, fatigue, skin rash, and nausea.
Gary Gordon, M.D., Ph.D., Chief Medical Officer of Ayala commented: "RINGSIDE is the first study to investigate AL102 exclusively in desmoid tumor patients and it has been designed to evaluate a range of different doses and dose schedules. Successful management of this disease will likely require chronic treatment and one of the key goals of our development program is to understand the optimal balance between efficacy, safety, and patient acceptability. We are encouraged by the early but very promising efficacy data and emerging favorable side effect profile for AL102 reported in these interim results."

About the RINGSIDE study
The RINGSIDE pivotal Phase 2/3 study is a randomized multi-center trial. Part A of the study is evaluating the efficacy, safety, tolerability, and tumor volume by MRI after 16 weeks of AL102 in adult and adolescent patients with desmoid tumors. It enrolled 42 patients and is evaluating 3 doses of AL102. Patients who participated in Part A will be eligible to enroll into an open-label extension study at the selected dose, and long-term efficacy and safety will be monitored. Part B of the study will be double-blind, placebo-controlled, and will start immediately after dose selection from part A, enrolling up to 156 patients with progressive disease, randomized between AL102 or placebo. The study’s primary endpoint will be progression-free survival (PFS) with secondary endpoints including objective response rate (ORR), duration of response (DOR) and patient-reported Quality of Life (QOL) measures.
For more information on the RINGSIDE Phase 2/3 study with AL102 for the treatment of desmoid tumors, please visit ClinicalTrials.gov and reference Identifier NCT04871282 (RINGSIDE).

About Desmoid Tumors
Desmoid tumors, also called aggressive fibromatosis or desmoid-type fibromatosis, are rare connective tissue tumors that typically arise in the upper and lower extremities, abdominal wall, head and neck area, mesenteric root and chest wall with the potential to arise in additional parts of the body. Desmoid tumors do not metastasize, but often aggressively infiltrate neurovascular structures and vital organs. People living with desmoid tumors are often limited in their daily life due to chronic pain, functional deficits, general decrease in their quality of life and organ dysfunction. Desmoid tumors have an annual incidence of approximately 1,700 patients in the United States and typically occur in patients between the ages of 15 and 60 years. They are most commonly diagnosed in young adults between 30-40 years of age and are more prevalent in females. Today, surgery is no longer regarded as the cornerstone treatment of desmoid tumors due to high rate of recurrence post-surgery and there are currently no FDA-approved systemic therapies for the treatment of unresectable, recurrent or progressive desmoid tumors.

On July 5, 2022 Skyhawk Therapeutics, Inc. reported the signing of an exclusive worldwide collaboration agreement with Sanofi to discover and develop novel small molecules that modulate RNA splicing for challenging oncology and immunology targets (Press release, Skyhawk Therapeutics, JUL 5, 2022, View Source [SID1234616486]).

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Frank Nestle
Global Head of Research and Chief Scientific Officer, Sanofi
"We look forward to this collaboration with Skyhawk, a pioneer in developing novel small molecules that modulate critical RNA splice sites. Skyhawk’s SkySTAR platform integrating proprietary computational biology tools, kinetic models, and conformational structural models of RNA, offers an exciting opportunity to build drugs that treat disease targets which today have limited or no therapeutic options."

Bill Haney
Chief Executive Officer, Skyhawk Therapeutics
"Sanofi is a global leader in the development and commercialization of innovative therapies, and we look forward to working with their talented team to build novel small molecule therapeutics that modify RNA splicing for the treatment of critical diseases of high unmet need. We are excited to develop drugs for challenging targets with Sanofi and look forward to working together on these potentially first- and best-in-class programs."

Terms of the Agreement
Under the collaboration agreement, Sanofi will pay Skyhawk $54 million upfront. Skyhawk will grant Sanofi exclusive licenses to worldwide intellectual property rights to candidates discovered and developed under the collaboration that are directed to program targets. Following DC status, Sanofi will assume responsibility for further development and commercialization. Skyhawk is also eligible to receive over $2 billion in potential milestone payments, as well as potential royalties on future sales.

On July 5, 2022 Nordic Nanovector ASA (OSE: NANOV) reported an update on PARADIGME, its Phase 2b trial of Betalutin (177Lu lilotomab satetraxetan) in 3rd-line relapsed and anti-CD20 refractory follicular lymphoma (3L R and R FL) (Press release, Nordic Nanovector, JUL 5, 2022, View Source [SID1234616506]). Following a comprehensive review and independent data evaluation of PARADIGME and a subsequent request for regulatory agency interaction, the Board of Directors (Board) has taken the difficult decision to discontinue the study. No further patients will be enrolled into PARADIGME.

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The PARADIGME trial enrolled a total of 109 patients. The Company will now ensure a wind-down of PARADIGME in a structured manner ensuring patients receive the best possible care during this period.

While Betalutin, at the selected dose of 15 MBq/kg after a pre-dose of 40 mg lilotomab (40/15), has continued to display an attractive safety profile and positive signs of efficacy in some patients, the Board considers that the observed profile does not fully meet the objectives set out for the PARADIGME study. Only one out of three patients responded to the treatment with the average duration of the response of approximately six months. As a result, the Board is of the opinion that the demonstrated profile is no longer sufficiently competitive to bring Betalutin to the market in the third line relapsed and refractory FL indication, within a timeframe that makes financial and commercial sense for the Company.

The Company still believes there could be a market for Betalutin in light of its safety profile, promising efficacy in earlier lines of therapy and unique feature of being delivered as a one-time dose. However, a potential new development programme would need to be conducted in a different patient population and line of treatment. The Company will therefore explore potential partnerships and will also seek advice from the US Food and Drug Administration (FDA) to discuss if there could be a possible way forward for Betalutin in an alternative setting.

The Company will now focus its efforts and resources on developing its pipeline of proprietary CD37-targeting products from which Nordic Nanovector believes it can create value for shareholders over the longer term. These pipeline opportunities include:

Humalutin, a radioimmunotherapy candidate based on a chimeric anti-CD37 antibody and the beta-emitting radionuclide lutetium-177 for non-Hodgkin lymphoma (NHL).
Alpha37, an alpha-emitting radioimmunotherapy candidate based on a chimeric anti-CD37 antibody conjugated to lead-212, currently being explored with partner OranoMed for relapsed/refractory chronic lymphocytic leukaemia.
A portfolio of fully humanized anti-CD37 antibodies with potential in haematological cancers and autoimmune diseases.
A CD37 DOTA CAR-T cell opportunity in haematological cancers, which is the subject of a research collaboration with the University of Pennsylvania.
Following the decision to discontinue PARADIGME, the Board has also decided to implement a restructuring of the Company with immediate effect with the purpose of reducing costs where necessary to enable support of essential activities associated with development of the pipeline.

The Company’s cash position at the end of Q2 2022 was approximately NOK 280m (end of Q1 NOK 356.3m). Full Q2 results will now be reported on 31 August.

Chairman, Jan H. Egberts commented: "The decision to discontinue PARADIGME is extremely disappointing not only for the Nordic Nanovector team, but also for patients, healthcare providers and our shareholders as there continues to be an unmet medical need in frail and elderly patients with Follicular Lymphoma. The new independently reviewed data from PARADIGME, in an increasingly competitive market and with the slow speed of recruitment makes progressing PARADIGME further very difficult. Consequently, the Board no longer sees a viable path to commercialisation in the current indication that would make sense for the Company and its shareholders. We are extremely grateful to all the clinical investigators and patients who have participated in PARADIGME.

CEO, Erik Skullerud commented: Our focus will now shift to our pipeline of other CD37-targeting assets, which give us multiple shots on goal, including Humalutin, Alpha37, a portfolio of fully humanized anti-CD37 antibodies and the CD37 CAR-T. We look forward to communicating our development plans for these assets in more detail in the coming months."

Nordic Nanovector will host a webcast at 08.30 CEST on Wednesday 6 July, elaborating on the strategic decision to stop PARADIGME and including a Q&A session. To join the webcast please sign up via our website www.nordicnanovector.com.

On July 5, 2022 Bio-Techne Corporation (NASDAQ:TECH), reported it has completed the acquisition of Namocell, Inc (Press release, Bio-Techne, JUL 5, 2022, View Source [SID1234616470]). The Namocell acquisition adds easy-to-use single cell sorting and dispensing platforms that are gentle to cells and preserve cell viability and integrity. Namocell’s instruments and consumables are critical technologies in various workflows in both biotherapeutics and diagnostics, including cell and gene therapy development and commercialization, cell engineering, cell line development, single cell genomics, antibody discovery, synthetic biology, and rare cell isolation.

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