On June 20, 2024 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported the presentation of preclinical data from the Company’s highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program at the 4th American Association for Cancer Research (AACR) (Free AACR Whitepaper) International Meeting: Advances in Malignant Lymphoma (Press release, HotSpot Therapeutics, JUN 20, 2024, View Source [SID1234644465]).

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MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin’s lymphoma, as well as other lymphomas and selected solid tumors. Leveraging the Company’s proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1’s protease function.

"Given the NF-kB pathway’s role as an oncogenic driver in a range of hematological and solid tumors, the scaffolding function of MALT1, a key activator of the pathway, represents an attractive therapeutic target," said Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot. "At HotSpot, we’ve utilized our Smart AllosteryTM platform to develop HST-1021, a potentially first-in-class MALT1 scaffolding inhibitor. These preclinical data support the highly differentiated profile of HST-1021, demonstrating its broad and potent inhibitory activity with no observed adverse effects on T cells."

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 scaffolding inhibitor development candidate:

HST-1021 demonstrated potent inhibition of NF-kB and AP1 activity in vitro, two key markers of MALT1 scaffolding activity.
In contrast to MALT1 protease inhibitors, HST-1021 had no observed effect on MALT1 protease activity or T-cell function, and HST-1021 did not deplete Treg cells in vivo. HotSpot believes this supports the potential for mitigation of the risk of autoimmune disease resulting from chronic MALT1 protease function inhibition and could allow for broad combination use.
HST-1021 demonstrated more significant and broader anti-tumor activity as compared to a MALT1 protease inhibitor.

On June 20, 2024 ImmunityBio, Inc. (NASDAQ: IBRX) reported the initial treatment of multiple patients in the United States to receive therapy with ANKTIVA (nogapendekin alfa inbakicept-pmln), ImmunityBio’s recently approved immunotherapy for Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (Press release, ImmunityBio, JUN 20, 2024, https://immunitybio.com/immunitybio-announces-insurance-coverage-of-anktiva-across-multiple-states-with-first-commercial-doses-administered-just-weeks-after-fda-approval-opening-new-era-for-immunotherapy-beyond/ [SID1234644450]). ANKTIVA was approved by the U.S. Food and Drug Administration (FDA) on April 22, 2024 for the treatment of patients with BCG-unresponsive NMIBC CIS with or without papillary tumors.

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The intravesical therapy employs a combination of ANKTIVA, an IL-15 agonist in combination with BCG. The combination is the first FDA-approved immunotherapy in NMIBC that functions by activating the body’s NK and killer T-cell immune system to attack tumor cells, while simultaneously activating memory T cells, leading to a prolonged duration of complete response exceeding 47 months for some patients.

"We are grateful to be able to offer this first-in-class immunotherapy to qualified bladder cancer patients less than two months after the therapeutic was approved by the FDA," said Patrick Soon-Shiong, M.D., Executive Chairman and Global Chief Scientific and Medical Officer at ImmunityBio. "The interest in this next era of immunotherapy beyond checkpoint inhibitors—the era of cytokines—from urologists treating NMIBC patients has been strong and we look forward to offering more patients an alternative to bladder removal."

The first patients to receive commercial doses are located throughout the U.S. and several are being treated by community urologists, as the therapy does not require any special handling or equipment that would limit its use to specialty medical centers.

"In addition to its unique mechanism of action, ANKTIVA can be readily administered by urologists in their own offices and clinics enabling more patients to receive it in familiar settings from their own providers," said Richard Adcock, President and CEO of ImmunityBio. "We look forward to ANKTIVA reaching more and more eligible NMIBC patients and for our science to deliver even more therapies from our pipeline."

ANKTIVA received Breakthrough Therapy Designation and approval from the FDA based on the safety and efficacy outcome of complete responses (CR) and duration of complete response (DOR) in BCG-unresponsive NMIBC CIS. The 77 evaluable patients in this single-arm, multicenter trial received ANKTIVA with BCG maintenance therapy for up to 37 months. The tumor status was assessed with cystoscopy and urine cytology and will continue for up to five years after each patient began their participation in the trial.

The CR rate for the 77 evaluable patients was 62% with the upper end of the confidence interval being 73%. The duration of complete response as of the November 2023 cut-off was more than 47 months and is ongoing to date. These prolonged duration of complete response results beyond 24 months with ANKTIVA and BCG exceed the benchmark for the magnitude of meaningful clinical results suggested by a panel of experts at the International Bladder Cancer Group.

In May, ImmunityBio announced it had drug substance sufficient for 170,000 doses of ANKTIVA for commercial and clinical trial use.

ImmunityBio CARE

The ImmunityBio CARE program is designed to help patients access ImmunityBio’s innovative treatment for NMIBC CIS. The program offers services and resources for benefits investigation, prior authorization support and tracking, coding and billing assistance, claim denial guidance and payer specific appeal assistance. More information for patients and healthcare professionals is available on Anktiva.com.

How ANKTIVA Works
The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of key immune cells—NK and CD8+ killer T cells—that are involved in killing cancer cells. By activating NK cells, ANKTIVA overcomes the tumor escape phase of clones resistant to T cells and restores memory T cell activity with resultant prolonged duration of complete response.

ANKTIVA is a first-in-class IL-15 agonist IgG1 fusion complex, consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15 receptor alpha, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. This fusion complex of ANKTIVA mimics the natural biological properties of the membrane-bound IL-15 receptor alpha, delivering IL-15 by dendritic cells and drives the activation and proliferation of NK cells with the generation of memory killer T cells that have retained immune memory against these tumor clones. The proliferation of the trifecta of these immune killing cells and the activation of trained immune memory results in immunogenic cell death, inducing a state of equilibrium with durable complete responses. ANKTIVA has improved pharmacokinetic properties, longer persistence in lymphoid tissues, and enhanced anti-tumor activity compared to native, non-complexed IL-15 in-vivo.

Selected Safety Information for ANKTIVA

The most common (≥15%) adverse reactions, including laboratory test abnormalities, are increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills, and pyrexia.

On June 20, 2024 InnoCare Pharma (HKEX: 09969; SSE: 688428), a leading biopharmaceutical company focusing on the treatment of cancer and autoimmune diseases, reported that China National Medical Products Administration (NMPA) has accepted and granted priority review to a biologics license application (BLA) for tafasitamab in combination with lenalidomide for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT) (Press release, InnoCare Pharma, JUN 20, 2024, View Source [SID1234644466]).

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Dr. Jasmine Cui, Co-founder, Chairwoman and CEO of InnoCare, said, "Today’s BLA acceptance marks an important milestone for InnoCare. DLBCL is the most common type of non-Hodgkin lymphoma globally, and there is a significant unmet need for DLBCL patients in China. We believe that tafasitamab regimen will bring a novel treatment therapy to DLBCL patients in China."

Tafasitamab, a humanized Fc-modified cytolytic CD19-targeting immunotherapy, in combination with lenalidomide has already been approved for the treatment of eligible DLBCL patients in Hong Kong. Furthermore, under the early access program in the Bo’ao Lecheng International Medical Tourism Pilot Zone and the Guangdong-Hong Kong-Macao Greater Bay Area, prescriptions of tafasitamab in combination with lenalidomide were issued at the Ruijin Hainan Hospital and Guangdong Clifford Hospital for eligible DLBCL patients.

Tafasitamab is approved under accelerated approval by the U.S. Food and Drug Administration (FDA), and conditional approved by the European Medicines Agency (EMA), in combination with lenalidomide for the treatment of relapsed or refractory DLBCL adult patients who are not eligible for ASCT.

DLBCL is the most common type of non-Hodgkin lymphoma (NHL), and its incidence accounts for 31% to 34% of NHL globally. In China, DLBCL accounts for 45.8% of all NHLs1.

About Tafasitamab

Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In 2010, MorphoSys licensed exclusive worldwide rights to develop and commercialize tafasitamab from Xencor, Inc. Tafasitamab incorporates an XmAb engineered Fc domain, which mediates B-cell lysis through apoptosis and immune effector mechanism including Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP).

MorphoSys and Incyte entered into: (a) in January 2020, a collaboration and licensing agreement to develop and commercialize tafasitamab globally; and (b) in February 2024, an agreement whereby Incyte obtained exclusive rights to develop and commercialize tafasitamab globally.

In August 2021, Incyte entered into a collaboration and license agreement with InnoCare for the development and exclusive commercialization of tafasitamab in hematology and oncology in Greater China.

In the United States, Monjuvi (tafasitamab-cxix) received accelerated approval by the U.S. Food and Drug Administration in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT). In Europe, Minjuvi (tafasitamab) received conditional Marketing Authorization from the European Medicines Agency in combination with lenalidomide, followed by Minjuvi monotherapy, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplant (ASCT).

XmAb is a registered trademark of Xencor, Inc.

Monjuvi, Minjuvi, the Minjuvi and Monjuvi logos and the "triangle" design are registered trademarks of Incyte.

On June 20, 2024 Mendus AB ("Mendus" publ; IMMU.ST), a biopharmaceutical company focused on immunotherapies targeting tumor recurrence, reported that updated clinical data from the ALISON clinical trial with its lead product vididencel in ovarian cancer will be presented at the ESMO (Free ESMO Whitepaper) Gynaecological Cancers Annual Congress, being held from June 20-22, 2024 in Florence, Italy (Press release, mendus, JUN 20, 2024, View Source [SID1234644451]). The trial reached its primary objective of inducing tumor-directed immune responses in at least 10 patients treated with vididencel.

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Ovarian cancer is the deadliest gynaecological cancer, mainly due to its high recurrence rate. Improving disease free and overall survival in advanced high grade serous ovarian carcinoma (HGSC) after primary treatment remains challenging. The Phase 1 ALISON trial explores the potential of vididencel to induce clinically relevant immune responses in ovarian cancer. The trial is fully enrolled (17 participants) and all participants have completed the vididencel treatment phase per April 2024. Vididencel-induced immune responses against tumor antigens that are regularly upregulated in HGSC were observed in 10 out of 15 patients evaluated so far, with 3 patients not reaching a vaccine induced response (VIR) due to high baseline responses. Vididencel treatment only gave mild adverse reactions, predominantly at the site of injection. The observed immune responses following vididencel treatment may provide the basis for an effective anti-tumor response. At week 22, 10 patients had stable disease and 7 patients had imaging-confirmed recurrence. To further evaluate clinical benefit, long-term follow-up of patients is ongoing.

Mendus anticipates to report the primary read-out of the ALISON trial based on immune response evaluation of all treated patients in 2024Q4.

Please see below for abstract details:

Abstract Number: 50P (poster presentation)

Abstract Title: Vididencel, a cell-based cancer vaccine, induces tumor-directed immune responses in high-grade serous ovarian carcinoma patients

Authors: A. Vledder, H. van Zeeburg, K. Brummel, A.L. Eerkens, N. van Rooij, A. Plat, J. Rovers, M. de Bruyn, H. Nijman

Session Date & Time: Thursday, 20 June 2024 between 12:30 – 13:30 CEST

After presentation, the poster will be made available on the Mendus website.

On June 20, 2024 Tubulis reported that the first patient has been treated in its first Phase I/IIa trial (NAPISTAR 1-01, NCT06303505) (Press release, Tubulis, JUN 20, 2024, View Source [SID1234644467]). The study is evaluating Tubulis’ next-generation antibody-drug conjugate (ADC) TUB-040 in patients with platinum-resistant high-grade ovarian cancer (PROC) or relapsed/refractory adenocarcinoma non-small cell lung cancer (NSCLC), who have exhausted other available treatment options. TUB-040 targets NaPi2b, a highly overexpressed antigen in ovarian cancer and lung adenocarcinoma. The candidate is the first to enter the clinic from the company’s growing pipeline and represents one of Tubulis’ two lead candidates developed using its proprietary suite of platform technologies, which enable the creation of uniquely matched ADCs with superior biophysical properties.

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The multicenter, first-in-human, dose escalation and optimization Phase I/IIa study aims to investigate the safety, tolerability, pharmacokinetics, and efficacy of TUB-040 as a monotherapy. The trial will be conducted in the US as well as the UK, Spain, Belgium, and Germany. Phase Ia comprises the dose escalation and will determine safety and the maximum tolerated dose or the identified dose for optimization, whereas Phase IIa will focus on dose optimization, safety, and preliminary efficacy of TUB-040. The first patient has been dosed in the US following IND approval by the FDA.

"ADCs are beginning to show their potential as a core treatment modality replacing conventional chemotherapy for several solid tumor indications. Based on our preclinical data we are convinced that TUB-040 can represent a new option for the effective treatment of NSCLC and ovarian cancer patients," said Günter Fingerle-Rowson, MD, PhD, Chief Medical Officer at Tubulis. "The novel P5 technology we use in TUB-040 improves upon current limitations due to off-target toxicity and restricted durability, the main challenges of current ADC treatments. By achieving reduced non-target toxicity together with a more specific, more powerful, and continued on-tumor delivery of the payload, we aim to improve long-term anti-tumor responses and, ultimately, clinical outcomes for patients."

"Initiating our first clinical trial represents an important milestone for the entire Tubulis team and underscores our vision to innovate on all fronts of the ADC design for patient benefit," said Dominik Schumacher, PhD, Chief Executive Officer and Co-founder of Tubulis. "Our objective is to achieve clinical proof-of-concept for our lead candidate, TUB-040, and validate our differentiated platform approach to ADC development."

TUB-040 consists of a humanized, target-specific, Fc-silenced IgG1 antibody equipped with Tubulis’ proprietary Tubutecan linker-payload technology, which is based on P5 conjugation chemistry and the topoisomerase-1 inhibitor Exatecan. Tubulis recently presented a comprehensive preclinical data set at AACR (Free AACR Whitepaper), demonstrating the superior stability and minimal loss of linker-payload conjugation for their lead candidate. In a range of preclinical models, Tubulis was also able to show high and long-lasting anti-tumor responses, even at lower expression levels of NaPi2b, with an excellent safety and tolerability profile.

About TUB-040 and the P5 Technology

Tubulis’ lead antibody-drug conjugate (ADC) TUB-040 is directed against Napi2b, an antigen highly overexpressed in ovarian cancer and lung adenocarcinoma. It consists of an IgG1 antibody targeting Napi2b connected to the Topoisomerase I inhibitor Exatecan through a cleavable linker system based on the company’s proprietary P5 conjugation technology with a homogeneous DAR of 8. P5 conjugation is a novel chemistry for cysteine-selective conjugation that enables ADC generation with unprecedented linker stability and biophysical properties. It originated from the fundamental work of Prof. Christian Hackenberger at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), which unlocked the use of phosphorus chemistry for superior bioconjugation. Preclinical pharmacokinetic analysis also demonstrated that TUB-040 efficiently delivers its payload to the tumor while reducing off-site toxicities. The candidate is currently being investigated in a multicenter Phase I/IIa study (NAPISTAR 1-01, NCT06303505) that aims to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TUB-040 as a monotherapy.