On January 4, 2024 JW Therapeutics (HKEx: 2126), an independent and innovative biotechnology company focusing on developing, manufacturing and commercializing cell immunotherapy products, reported that the National Medical Products Administration (NMPA) of China accepted the supplemental Biological License Application (sBLA) for its anti-CD19 autologous chimeric antigen receptor T (CAR-T) cell immunotherapy product Carteyva (relmacabtagene autoleucel injection) for the treatment of adult patients with relapsed or refractory Mantle Cell Lymphoma (r/r MCL) (Press release, JW Therapeutics, JAN 4, 2024, View Source [SID1234638989]). This is the third marketing application on Carteyva submitted by JW Therapeutics, and is expected to be the first cell therapy product approved in China for the treatment of patients r/r MCL. Carteyva was granted, by NMPA, Breakthrough Therapy Designation in Mar 2022, as well as Priority Review in Dec. 2023.

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MCL is a rare and heterogeneous B cell non-Hodgkin lymphoma which is currently incurable with existing therapies[1]. MCL, associated with a poor prognosis, mainly occurs in elderly men who were not diagnosed until advanced stage[2]. Significant progress has been made in the last decade as the treatment paradigm has shifted from traditional chemoimmunotherapy toward targeted therapies such as bruton tyrosine kinase inhibitors (BTKi). Despite the use of BTKi in r/r MCL has improved their survival outcomes, many patients will ultimately relapse with shortened remission durations (6~10 months) [3]. Notwithstanding the above, there are still unmet medical needs for a safe, effective novel approach to overcome the limitations of current treatments of r/r MCL.

The sBLA was supported by the clinical results from a single-arm, multi-center, pivotal study on Carteyva in adult participants with r/r MCL in China. In the study, participants with r/r MCL who had been treated with a CD20-targeting antibody, anthracycline or bendamustine, or BTKis were included. After being treated with lymphodepleting chemotherapy, participants received relma-cel (100×106 CAR+ T cells). As of Oct 25, 2023, a total of 59 participants received relma-cel infusion. Of 56 efficacy evaluable participants, relma-cel demonstrated remarkable clinical responses achieving high rates of objective response rate (ORR) and complete response rate (CRR) (3 months best ORR 81.36%, 3 months best CRR 66.10%) and the incidence of severe (grade ≥ 3) cytokine release syndrome (CRS) was 6.8%, the incidence of severe (grade ≥ 3) neurotoxicity (NT) was 6.8%.

Mark J. Gilbert, MD, Chief Medical Officer of JW Therapeutics, noted: "We are delighted to have a product that can deliver meaningful efficacy in this disease, nearly 70% of participants with r/r MCL have achieved complete remission after treatment with relma-cel, and the overall safety data demonstrated that the treatment was generally well tolerate. Carteyva is expected to become the first commercial CAR-T cell product for the treatment of r/r MCL in China."

On January 4, 2024 AbbVie (NYSE: ABBV), and Umoja Biopharma (Umoja), an early clinical-stage biotechnology company, reported two exclusive option and license agreements to develop multiple in-situ generated CAR-T cell therapy candidates in oncology using Umoja’s proprietary VivoVecTM platform (Press release, AbbVie, JAN 4, 2024, View Source [SID1234638988]). The first agreement provides AbbVie an exclusive option to license Umoja’s CD19 directed in-situ generated CAR-T cell therapy candidates. This includes UB-VV111, Umoja’s lead clinical program for hematologic malignancies currently at the IND-enabling phase. Under the terms of the second agreement, AbbVie and Umoja will develop up to four additional in-situ generated CAR-T cell therapy candidates for discovery targets selected by AbbVie.

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"As we continue to strengthen our oncology portfolio, we believe that in-situ CAR-T cell therapy represents a paradigm shift utilizing genetic medicine concepts," said Jonathon Sedgwick, Ph.D., vice president and global head of discovery research at AbbVie. "We look forward to working with Umoja’s team to advance next-generation in-situ CAR-T therapies, and potentially expand the patient populations and indications benefitting from conventional CAR-T approaches."

Umoja’s VivoVecTM gene delivery platform combines third generation lentiviral vector gene delivery with a novel T-cell targeting and activation surface complex. This enables T cells in the body to manufacture their own cancer-fighting CAR-T cells in vivo. This has the potential to eliminate a number of challenges associated with traditional CAR-T approaches including reliance on gathering a patient’s own or donor cells which are modified externally before being delivered back to the patient, the associated time lag and manufacturing challenges of ex vivo cell modification, and the need for patient’s lymphodepletion.

"AbbVie is an ideal partner for Umoja given their broad expertise in development and commercialization of novel therapeutics in hematology, oncology, and beyond," said David Fontana, Ph.D., chief operating and business officer at Umoja.

"By bringing together AbbVie’s like-minded pursuit of addressing patient unmet needs with our investments in vector biology and fully-owned commercial-scale manufacturing, we look forward to progressing multiple VivoVec drug candidates into the clinic in the coming years," added Andrew Scharenberg, M.D., co-founder and chief executive officer at Umoja.

Under the terms of the two agreements, Umoja received upfront payments and an equity investment from AbbVie. Additionally, for the two agreements combined, Umoja may be eligible to receive up to $1.44B in aggregate for option exercise fees, development and regulatory milestones, with the potential for Umoja to earn additional sales-based milestones and tiered royalties on worldwide net sales.

On January 4, 2024 The Menarini Group ("Menarini"), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. ("Stemline"), a wholly-owned subsidiary of the Menarini Group focused on bringing transformational oncology treatments to cancer patients, along with clinical stage generative artificial intelligence (AI)-driven biotechnology company Insilico Medicine ("Insilico"), reported that they have entered into an exclusive licensing agreement granting Stemline the global rights to develop and commercialize a novel, small molecule KAT6A inhibitor designed using Insilico’s AI platform, as a potential treatment for hormone sensitive cancers and other oncology indications (Press release, Menarini, JAN 4, 2024, View Source [SID1234638987]).

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Breast cancer is the most commonly diagnosed tumor type and the leading cause of cancer death among women, globally.[1] Approximately 70% of breast cancers are estrogen receptor positive (ER+), and endocrine therapy remains the backbone of therapy for patients with ER+ breast cancer. However, tumors can develop a resistance to endocrine therapy, which in turn can lead to disease progression. This is a significant clinical challenge and highlights the urgent need for novel therapies to help overcome treatment resistance.

KAT6A is known to play an important role in several cancers. Overexpression of KAT6A correlates with poor clinical outcomes in patients with ER+/HER2- breast cancer, the most common subtype of breast cancer. In preclinical studies, the molecule has demonstrated potent inhibition against KAT6A in multiple CDX and PDX models with good efficacy and safety. Insilico presented data on the molecule at the San Antonio Breast Cancer Symposium in early December.

"We are delighted to enter a collaboration with Insilico that harnesses the power of generative AI as a leader in the field, to explore a promising new treatment approach and potentially unlock transformative new cancer therapies," said Elcin Barker Ergun, CEO of the Menarini Group. "Having brought the first innovation in endocrine therapy after almost 20 years to the U.S. and Europe with elacestrant for ER+, HER2- breast cancer patients, our aim is to further augment patient outcomes, and targeting KAT6A can potentially serve that in breast cancer and beyond."

The novel molecule was designed by Insilico’s R&D team with the help of its end-to-end Pharma Generative AI platform to inhibit KAT6A and block endocrine receptor (ER) at the transcriptional level, giving it the potential to overcome resistance to endocrine therapies due to mutation or ligand-independent constitutive activation of ER. Currently, endocrine therapy in combination with CDK4/6 inhibitors is the standard treatment for ER+/HER2- breast cancer patients with advanced or metastatic disease. Novel combinations with CDK4/6 inhibitors and/or new oral SERDs are needed to further extend outcomes.

"We are excited by the promise of our latest generative AI-designed therapy to provide a new potential treatment option for breast cancer patients," says Alex Zhavoronkov, PhD, founder and co-CEO of Insilico Medicine. "With their innovative vision and deep focus in bringing transformational therapeutics in oncology, Stemline is the ideal partner to lead this molecule into development and through clinical trials."

Under the terms of the agreement, Stemline will provide a $12 million upfront payment to Insilico. The combined value of the deal, including all development, regulatory, and commercial milestones, is over $500 million, followed by royalties up to double digits.

On January 4, 2024 Viracta Therapeutics, Inc. (Nasdaq: VIRX), a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide, reported a clinical update, including its roadmap for advancing Nana-val’s clinical development in 2024 (Press release, Viracta Therapeutics, JAN 4, 2024, View Source [SID1234638985]). Nana-val (nanatinostat in combination with valganciclovir), is the company’s all-oral investigational therapy targeting Epstein-Barr virus-associated cancers.

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Anticipated Key 2024 Milestones
Pivotal NAVAL-1 study of Nana-val in patients with relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphomas

Complete enrollment of Stage 2 in the R/R EBV+ peripheral T-cell lymphoma (PTCL) cohort of patients treated with Nana-val (n=11) in the first quarter of 2024.
Report Stage 1 data from both arms of the R/R EBV+ PTCL cohort (in patients treated with nanatinostat, with [n=10] or without [n=10] valganciclovir) in the first half of 2024.
Meet with the U.S. Food and Drug Administration (FDA) to discuss additional requirements for accelerated approval by mid-2024.
Enroll patients with R/R EBV+ PTCL into the post-Phase 2 expansion cohort to support potential accelerated approval.
Present Stage 2 data from patients with R/R EBV+ PTCL in the second half of 2024.
Report Stage 1 data from patients with R/R EBV+ diffuse large B-cell lymphoma (DLBCL) and R/R EBV+ post-transplant lymphoproliferative disorder (PTLD) by year-end 2024.
Phase 1b/2 study of Nana-val in patients with advanced EBV+ solid tumors (Study 301)

Determine the recommended Phase 2 dose (RP2D) by investigating the novel split daily dosing (SDD) regimen at higher dose levels of Nana-val in the second half of 2024.
Initiate a dose-optimization cohort to confirm the RP2D as part of the study’s Phase 2 expansion by year-end 2024.
"Our primary focus in 2024 is the speed to market strategy for Nana-val in patients with relapsed or refractory EBV-positive PTCL, supported by its accelerating pace of enrollment into Stage 2 and plans to engage with the FDA to discuss Nana-val’s potential accelerated approval pathway in mid-2024," said Mark Rothera, President and Chief Executive Officer of Viracta. "Additionally, we are encouraged by the progress of the Phase 1b/2 trial of Nana-val in patients with advanced EBV-positive solid tumors, which is now enrolling and treating patients with the novel split daily dosing regimen, and we remain on track to expand the study into Phase 2 in 2024. The growing clinical data together with the recent orphan drug designation granted by FDA for the treatment of nasopharyngeal carcinoma further positions Nana-val as a tumor-agnostic approach to address the high unmet medical need for patients with EBV-associated cancers, including both lymphomas and solid tumors. With an anticipated cash runway into 2025, we are well-positioned for a successful 2024."

Recent Clinical Trial Updates
Pivotal NAVAL-1 study of Nana-val in patients with R/R EBV+ lymphomas

Completed enrollment of Stage 1 in the R/R EBV+ PTCL cohort of patients, and enrollment into Stage 2 continues to accelerate, as nearly half of the Stage 2 patients have been enrolled.
The protocol was amended to additionally enable enrollment of second-line R/R EBV+ DLBCL patients and R/R EBV+ PTLD patients, including pediatric EBV+ PTLD patients ≥ 12 years of age.
Phase 1b/2 study of Nana-val in patients with advanced EBV+ solid tumors (Study 301)

Initiated enrollment of the sixth dose cohort of patients with recurrent or metastatic (R/M) EBV+ nasopharyngeal carcinoma (NPC) evaluating the new SDD regimen.
In December 2023, the FDA granted an orphan drug designation (ODD) to Nana-val for the treatment of NPC, the fifth ODD granted to Nana-val by the FDA and the seventh ODD for Nana-val globally.
Confirmed partial responses without dose-limiting toxicities through the initial five dose cohorts. Further, new preclinical data presented at ESMO (Free ESMO Whitepaper) Asia Congress 2023 support continued dose-escalation to enhance Nana-val’s antitumor activity.
Best responses through the fifth dose cohort included two confirmed partial responses and five stable diseases out of 17 patients.
About NAVAL-1
NAVAL-1 (NCT05011058) is a global, multicenter, clinical trial of Nana-val in patients with relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphoma. This trial employs a Simon two-stage design where, in Stage 1, participants are enrolled into one of three indication cohorts based on EBV+ lymphoma subtype. If two objective responses are achieved within a lymphoma subtype in Stage 1 (n=10), then additional patients will be enrolled in Stage 2 for a total of 21 patients. EBV+ lymphoma subtypes demonstrating promising antitumor activity in Stage 2 may be further expanded following discussion with regulators to potentially support registration.

About the Phase 1b/2 Study of Nana-val in Patients with Advanced EBV+ Solid Tumors (Study 301)
This Phase 1b/2 trial (NCT05166577) is an open-label, multinational clinical trial evaluating Nana-val alone and in combination with pembrolizumab. The Phase 1b dose escalation part is designed to evaluate safety and to select the recommended Phase 2 dose (RP2D) of Nana-val in patients with recurrent or metastatic (R/M) Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinoma (NPC). Along with the U.S. Food and Drug Administration’s Project Optimus initiative, at the start of Phase 2, up to 40 patients with R/M EBV+ NPC will be randomized to receive either the RP2D or a dose level below the RP2D in a dose-optimization cohort. Once the RP2D has been confirmed, up to 60 patients with R/M EBV+ NPC will be randomized to receive Nana-val at the RP2D with or without pembrolizumab to further evaluate antitumor activity, safety and tolerability, pharmacokinetics, and potential pharmacodynamic biomarkers. Additionally, patients with other advanced EBV+ solid tumors will be enrolled to receive Nana-val at the RP2D in a Phase 1b dose expansion cohort.

About Nana-val (Nanatinostat and Valganciclovir)
Nanatinostat is an orally available histone deacetylase (HDAC) inhibitor being developed by Viracta. Nanatinostat is selective for specific isoforms of Class I HDACs, which are key to inducing viral genes that are epigenetically silenced in Epstein-Barr virus (EBV)-associated malignancies. Nanatinostat is currently being investigated in combination with the antiviral agent valganciclovir as an all-oral combination therapy, Nana-val, in various subtypes of EBV-associated malignancies. Ongoing trials include a pivotal, global, multicenter, open-label Phase 2 basket trial in multiple subtypes of relapsed or refractory (R/R) EBV+ lymphoma (NAVAL-1) as well as a multinational Phase 1b/2 clinical trial in patients with recurrent or metastatic (R/M) EBV+ NPC and other advanced EBV+ solid tumors.

About EBV-Associated Cancers
Approximately 90% of the world’s adult population is infected with EBV. Infections are commonly asymptomatic or associated with mononucleosis. Following infection, the virus remains latent in a small subset of cells for the duration of the patient’s life. Cells containing latent virus are increasingly susceptible to malignant transformation. Patients who are immunocompromised are at an increased risk of developing EBV-positive (EBV+) lymphomas. EBV is estimated to be associated with approximately 2% of the global cancer burden including lymphoma, nasopharyngeal carcinoma (NPC), and gastric cancer.

On January 4, 2024 Sensei Biotherapeutics, Inc. (Nasdaq: SNSE), a clinical stage immuno-oncology company focused on the discovery and development of next-generation therapeutics for cancer patients, reported corporate updates on its research and development programs and upcoming milestones (Press release, Sensei Biotherapeutics, JAN 4, 2024, View Source [SID1234638984]).

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"In 2023, we significantly advanced our lead clinical asset while prudently maintaining our strong balance sheet," said John Celebi, President and Chief Executive Officer. "We believe SNS-101, which has demonstrated potentially best-in-class pharmacokinetics and tolerability at clinical doses far beyond other VISTA-targeted immunotherapies, has strong potential as a transformative option in multiple cancer indications. Given the favorable data thus far, we are expanding the SNS-101 Phase 1/2 clinical trial to include additional patients in a more focused set of indications as an intermediate stage to further optimize the Phase 2 study design with additional patient data while we prepare for an anticipated end of Phase 1 meeting with FDA by Q4 2024. As a result, we are dedicating additional resources to support this expanded clinical program while pausing the IND-enabling studies originally planned for our next TMAb product candidate. We expect these adjustments to extend our cash runway into the fourth quarter of 2025."

Highlights and Milestones

SNS-101

SNS-101 is a conditionally active antibody harnessing the acidic tumor microenvironment to target the immune checkpoint VISTA (V-domain Ig suppressor of T cell activation). VISTA is implicated in numerous cancer indications and its expression correlates with low survival rates. Sensei is conducting a multi-center Phase 1/2 clinical trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of SNS-101 as both a monotherapy and in combination with Regeneron’s PD-1 inhibitor Libtayo (cemiplimab) in patients with advanced solid tumors. Recent updates include:

As of January 2, 2024:
A total of 25 patients have been treated with SNS-101 across various dose levels, with 16 patients in the monotherapy arm and nine patients in the combination arm. There have been no dose limiting toxicities (DLT) observed across both the monotherapy arm and the combination arm.
In the monotherapy dose escalation arm, patients have cleared all planned dosing cohorts of 0.3, 1, 3, 10 and 15 mg/kg.
In the combination dose escalation arm, six patients have been enrolled in the first cohort and have cleared the DLT period at a dose level of 3.0 mg/kg SNS-101 + Libtayo. The second cohort at a dose level of 10.0 mg/kg SNS-101 + Libtayo has been enrolled and is pending clearance of the DLT period as determined by the study safety monitoring committee.
Following completion of dose escalation and prior to initiating the Phase 2 portion, the Company plans to enroll up to 40 additional patients in both monotherapy and in combination with Libtayo in specific tumor types to further optimize the design of the Phase 2 trial.
In the monotherapy dose expansion arm, Sensei plans to enroll up to 10 patients with microsatellite stable (MSS) colorectal cancer (CRC) at a dose level of 15 mg/kg.
In the combination dose expansion arm, Sensei plans to enroll up to 30 patients with MSS CRC, head and neck cancer (H&N), non-small cell lung cancer (NSCLC), and melanoma. The dose level will be determined following completion of the combination dose escalation phase of the study.
The solid tumor types were selected to focus the cancer indications on a basket of more commonly occurring histologies, including both "hot" (NSCLC, H&N, Melanoma) and "cold" (CRC) tumors where we believe SNS-101 has potential to provide clinical benefit based on VISTA biology and supporting preclinical data. All patients with "hot" tumors enrolling into the expansion arm are expected to have been previously treated with a PD1/L1 checkpoint inhibitor. Additional tumor types and doses may be considered for both the monotherapy and combination expansion arms.
Sensei expects to open enrollment in the monotherapy expansion arm later this month. The combination expansion arm will begin following completion of the combination dose escalation phase of this study.
Anticipated milestones for the SNS-101 Phase 1/2 clinical trial include:

Initial safety and pharmacokinetic data for the combination dose escalation arm of SNS-101 and Libtayo in Q1 2024
Topline data for the SNS-101 monotherapy dose escalation arm in Q2 2024
Topline data for the combination dose escalation arm of SNS-101 and Libtayo in Q3 2024
Initial data for the SNS-101 dose expansion cohorts by the end of 2024
Additional Corporate Updates

Sensei announces that Ron Weitzman, M.D., F.A.C.P., has joined Sensei as part-time Chief Medical Officer. Dr. Weitzman joined Sensei as a consultant in August 2022 and has been instrumental in the design and implementation of the ongoing Phase 1/2 clinical trial. Dr. Weitzman brings over 25 years experience leading oncology clinical studies ranging from early to late-stage clinical development, including a pivotal study for cabozantanib that led to its FDA approval. Dr. Weitzman has held leadership roles at various global biopharmaceutical companies, including Exelixis, Genentech and Novartis, and has served as a consulting CMO to various biotechnology companies for nearly a decade. Dr Weitzman is board-certified by the American Board of Internal Medicine in Medical Oncology and is an active member of the American College of Physicians.
Sensei has decided to realign its resources to fully support the Phase 1/2 clinical trial of SNS-101. As a result, Sensei will pause IND-enabling work on its preclinical-stage TMAb programs, including SNS-102 (VSIG4), SNS-103 (CD39) and SNS-201 (VISTAxCD28). During this time, preclinical work to characterize selected lead antibodies, including their mechanisms of action, and target biology is expected continue.
In 2023, Sensei selected lead candidates for both SNS-102 and SNS-201. SNS-102 is a conditionally active antibody targeting VSIG4 that is 585-fold more selective for VSIG4 at low pH conditions. SNS-201 is a bispecific antibody incorporating a CD28 agonist arm and a pH-sensitive anti-VISTA arm designed to conditionally activate CD28 under low pH conditions, such as those found in the tumor microenvironment, leading to T cell activation in the tumor while minimizing off-tumor toxicity.
This realignment of resources is expected to extend cash runway into the fourth quarter of 2025.