On January 4, 2024 Adaptimmune Therapeutics plc (Nasdaq: ADAP), a leader in cell therapy to treat cancer, reported the Company’s plans for its emerging sarcoma franchise including projections for peak US sales of up to $400 million (Press release, Adaptimmune, JAN 4, 2024, View Source [SID1234638960]).

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The Company will present plans for the franchise at the JP Morgan Healthcare Conference on January 11th from 8:15 to 8:55 a.m. PST at the Westin, San Francisco. The presentation will be webcast and a replay will be available at the same link.

Adrian Rawcliffe, Adaptimmune’s Chief Executive Officer: "2024 is the year Adaptimmune transforms into a commercial cell therapy company with the anticipated approval and launch of afami-cel, the first asset in our sarcoma franchise. By 2026, we plan to have two marketed cell therapies for sarcoma. These therapies will redefine the treatment paradigm for people with sarcoma and are projected to deliver US peak sales of up to $400m. Our sarcoma franchise has tremendous upside with potential for expansion and is only the beginning of our solid tumor cell therapy aspirations."

On January 4, 2024 Integral Molecular, a leading biotech company specializing in antibody discovery against undruggable protein targets, reported that it has entered into an antibody license agreement with Seismic Therapeutic (Press release, Integral Molecular, JAN 4, 2024, View Source [SID1234638976]). Under the terms of the agreement, Integral Molecular will provide an exclusive license to Seismic Therapeutic for a collection of fully humanized, highly specific, preclinical antibodies to add to their platform, library, and pipeline of molecules in the immunology space. Seismic Therapeutic will assume full responsibility for all research, development, and commercialization activities related to these antibodies.

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The antibodies licensed by Seismic Therapeutic were identified using Integral Molecular’s MPS Antibody Discovery platform. This platform is built upon the company’s 20+ years of experience in working with the most challenging protein targets and ability to deliver preclinical lead candidate molecules. Unique aspects of this platform include the use of advanced immunization strategies including combinations of RNA, DNA and protein boosting via Lipoparticles, and evolutionarily divergent host animals (chickens) capable of generating diverse panels of antibodies against highly conserved targets.

"We are thrilled that Seismic chose Integral Molecular as a partner for their antibody discovery efforts," said Ross Chambers, PhD, VP of Antibody Discovery at Integral Molecular. "Using chickens as immunization hosts was important for Seismic’s project, as conventional approaches like mouse immunization would not have produced the diverse antibodies needed for their program. We wish Seismic Therapeutic much success as they continue to develop these antibodies."

On January 4, 2024 Medivir AB (Nasdaq Stockholm: MVIR), a pharmaceutical company focused on developing innovative treatments for cancer in areas of high unmet medical need, reported that Medivir’s licensee, Tango Therapeutics (NASDAQ: TNGX; Tango), has dosed the first patient with TNG348, a novel USP1 inhibitor (Press release, Tango Therapeutics, JAN 4, 2024, View Source [SID1234638993]). Tango received U.S. Food and Drug Administration clearance on its Investigational New Drug application for TNG348 in September 2023.

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TNG348 is a novel USP1 (ubiquitin-specific protease 1) inhibitor for the treatment of BRCA1/2-mutant and other homologous recombination deficiency (HRD)+ cancers. HRD+ cancers, including BRCA1/2 mutations, represent up to 50% of ovarian cancers, 25% of breast cancers, 10% of prostate cancers and 5% of pancreatic cancers. Tango is developing TNG348 from the preclinical USP1 program licensed from Medivir in 2020.

In the study, TNG348 will be evaluated both as single agent and in combination with olaparib (PARP-inhibitor) in patients with BRCA1/2-mutant and other HRD+ cancers. Preclinical data has shown synergistic effect with PARP inhibitors in PARP naïve models, including models with resistance to PARP inhibitors.

– "The preclinical data generated by Tango for TNG348 is promising and dosing the first patient in a clinical study is encouraging for patients with HRD+ cancers. The efforts undertaken by Tango to develop TNG348 into a clinical-staged drug are impressive and we will continue to follow the clinical development of TNG348 with great anticipation," says Jens Lindberg, CEO of Medivir.

Under the licensing agreement, Medivir is entitled to multiple development and commercial milestone payments as well as royalties on future sales. Dosing the first patient in a clinical trial triggers a milestone payment.

On January 4, 2024 ADC Therapeutics reported business updates (Press release, ADC Therapeutics, JAN 4, 2024, View Source [SID1234642026]).

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"During 2023, we took a number of decisive actions to help position the Company for success in 2024 and beyond. We prioritized our pipeline, strengthened our organization and implemented a disciplined capital allocation model to generate cost efficiencies," said Ameet Mallik, Chief Executive Officer of ADC Therapeutics. "We believe we are starting to see signs of the commercial turnaround. We are also encouraged to see positive initial signals in the LOTIS-7 trial of ZYNLONTA in combination with bispecifics as well as early signs of antitumor activity in the Phase 1b trial of ADCT-601. We now expect our cash runway to extend into the fourth quarter of 2025 and believe we are on a path to unlock the substantial value in the Company."

Recent Highlights and Developments

ZYNLONTA (loncastuximab tesirine-lpyl)

ZYNLONTA net sales for the fourth quarter of 2023 are expected to be approximately $16.5 million.
The Phase 1 LOTIS-7 trial of ZYNLONTA in combination with bispecifics glofitamab or mosunetuzumab for the treatment of patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL) is actively enrolling patients. The dose-limiting toxicity (DLT) period has been cleared for the first dosing level of ZYNLONTA 90 µg/kg in both arms, and there have been no discontinuations due to adverse events (AEs). To date, each of the first five patients eligible for assessment in this dosing level has shown a response (partial response or complete response) at first scan.​
An oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2023 Annual Meeting from the University of Miami investigator-initiated trial exploring ZYNLONTA in combination with rituximab in high-risk relapsed or refractory FL indicated a best overall response rate of 96.3% and a complete response rate of 85.2%​. After a median follow-up of 9.7 months, the median progression-free survival (PFS) was not reached, and the 12-month PFS was 92.3%​. The majority of AEs were grade 1. Grade 3 AEs included neutropenia (n=2; 6.2%), and one case each (3.1%) of hyperglycemia, increased ALT, fatigue, dyspnea and skin infection. Neutropenia was the only grade 4 AE (n=1; 3.1%).
Pipeline

ADCT-601 (targeting AXL): In the Phase 1b trial, the maximum-tolerated dose has been reached, and the study is currently in dose optimization. There have been early signs of antitumor activity in both monotherapy and in combination. The dose-optimization/ expansion phase is comprised of a monotherapy arm including patients with sarcoma, pancreatic cancer and AXL-expressing non-small cell lung cancer (NSCLC) and a combination arm with gemcitabine in patients with sarcoma and pancreatic cancer.
ADCT-901 (targeting KAAG1): The Company has decided to discontinue this program due to limited signs of efficacy in the dose escalation phase and to reallocate capital to prioritized programs.
ADCT-602 (targeting CD22): Dose escalation and expansion in the Phase 1 trial in collaboration with MD Anderson Cancer Center for patients with relapsed or refractory acute lymphoblastic leukemia is progressing, and additional clinical trial sites are being added to accelerate enrollment.
Early-stage pipeline: The Company is advancing a portfolio of investigational ADCs including those targeting Claudin-6, NaPi2b and PSMA. These candidates utilize exatecan with a novel hydrophilic linker as a highly potent and differentiated payload.
Balance Sheet
The Company ended the fourth quarter of 2023 with cash and cash equivalents of ~$278.5 million.

Guidance
The Company expects the following based on its current business plan:

Decrease in total operating expenses expected in full year 2023 and 2024 as compared to 2022
Cash runway expected into 4Q 20252 (previously: mid-2025)
Expected Milestones in 2024

ZYNLONTA

Achieve commercial brand profitability in 2024
LOTIS-5: Complete enrollment in 2024
LOTIS-7: Additional safety and efficacy data from the dose-escalation and dose-expansion portions of the Phase 1 study in 2024
Pipeline

ADCT-601 (targeting AXL)

Additional data updates from the Phase 1 study in patients with sarcoma, pancreatic cancer and NSCLC in 2024
ADCT-602 (targeting CD22)

Additional data from Phase 1 study in 2024
Please refer to the Company’s Form 8-K and accompanying presentation filed with the Securities and Exchange Commission today for additional information.

About ZYNLONTA (loncastuximab tesirine-lpyl)

ZYNLONTA is a CD19-directed antibody drug conjugate (ADC). Once bound to a CD19-expressing cell, ZYNLONTA is internalized by the cell, where enzymes release a pyrrolobenzodiazepine (PBD) payload. The potent payload binds to DNA minor groove with little distortion, remaining less visible to DNA repair mechanisms. This ultimately results in cell cycle arrest and tumor cell death.

The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved ZYNLONTA (loncastuximab tesirine-lpyl) for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), DLBCL arising from low-grade lymphoma and also high-grade B-cell lymphoma. The trial included a broad spectrum of heavily pre-treated patients (median three prior lines of therapy) with difficult-to-treat disease, including patients who did not respond to first-line therapy, patients refractory to all prior lines of therapy, patients with double/triple hit genetics and patients who had stem cell transplant and CAR-T therapy prior to their treatment with ZYNLONTA. This indication is approved by the FDA under accelerated approval and in the European Union under conditional approval based on overall response rate and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Please see full prescribing information including important safety information about ZYNLONTA at www.ZYNLONTA.com.

ZYNLONTA is also being evaluated as a therapeutic option in combination studies in other B-cell malignancies and earlier lines of therapy.

On January 4, 2024 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer and autoimmune disease, reported its 2024 Platform Vision that redefines the future of CAR T by leveraging the unique attributes of allogeneic CAR T products (Press release, Allogene, JAN 4, 2024, View Source [SID1234638961]).

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"Until now, CAR T development has been defined by how autologous CAR Ts are made and used. As a management team with extensive experience in both autologous and allogeneic CAR Ts, and the only Company with the breadth of data to demonstrate comparability between the two, we are uniquely positioned to potentially redefine development and trial design of allogeneic CAR T products that allows us to do what no autologous CAR T has done before," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "We believe this entirely new approach to development creates an advantage for our investigational AlloCAR T products now and in the future while providing a clinical framework to generate far more competitive CAR T products and dramatically expand market opportunity."

The Foundation: Pivotal ALPHA3 1L Consolidation Trial in Large B Cell Lymphoma (LBCL)
In a commanding pivot for the CD19 program, the Company will focus development of its investigational product cemacabtagene ansegedleucel, or cema-cel (previously known as ALLO-501A) as part of the first line (1L) treatment plan for newly diagnosed and treated LBCL patients who are likely to relapse and need further therapy. The groundbreaking design of the ALPHA3 1L consolidation trial builds upon the results demonstrated in the Phase 1 ALPHA2 trial and leverages an investigational cutting-edge diagnostic test developed by Foresight Diagnostics to identify patients who have minimal residual disease (MRD) at the completion of 1L chemoimmunotherapy for treatment with cema-cel.

Although 1L R-CHOP is curative for many with LBCL, approximately 30% of patients who initially respond will relapsei. The standard of care after 1L treatment has been simply to "watch and wait" for the disease to relapse. ALPHA3 takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD following six cycles of R-CHOP, positioning it to become the standard "7th cycle" of frontline treatment available to all eligible patients with MRD. ALPHA3 builds on the growing understanding that administration of CAR T therapies to patients with low disease burden improves both safety and efficacy outcomes. Cema-cel’s Phase 1 safety profile, with low rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), already permits its use in the outpatient setting in relapsed/refractory (r/r) patients and may further improve in patients with no radiological evidence of disease.

Start-up activities for the ALPHA3 trial have been initiated. The study will randomize approximately 230 patients who are MRD positive at the end of 1L therapy to either consolidation with cema-cel or the current standard of care (observation). The design, with a primary endpoint of event free survival (EFS), will initially include two lymphodepletion arms (one with standard fludarabine and cyclophosphamide plus ALLO-647 and one without ALLO-647).

The outcome of this pivotal trial could allow cema-cel to be embedded in the 1L setting to boost cure rates, potentially rendering later-line treatment obsolete, and making cema-cel available in community cancer centers where most earlier line patients seek care. As a result of this differentiated vision for cema-cel which competitively places its use ahead of other CAR T therapies, the Company will focus on quickly advancing this market-defining ALPHA3 trial and deprioritize the currently enrolling third line (3L) ALPHA2 and EXPAND trials.

The Higher Bar: ALPHA2 Cema-Cel Trial in Chronic Lymphocytic Leukemia (CLL)
There is a growing need for effective treatment in CLL post-Bruton tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitor (BCL2i) therapies. While recent autologous CD19 CAR T data has been a positive step for patients with r/r CLL, these therapies are still not meeting the efficacy bar or expectations set in r/r LBCL. This is likely due in part to T cell dysfunction and high circulating tumor burden in CLL, making the isolation of functional T cells for autologous CAR T manufacturing difficult.

There is strong scientific rationale to believe that an AlloCAR T product derived from healthy donor cells could raise the bar and potentially create a clinically meaningful advance for these late-stage patients, with a one-time dose and simpler administration and logistics.

The new Phase 1 ALPHA2 cohort of 12 patients treated with the investigational product cema-cel provides the opportunity to set a higher bar where patients with CLL are not reliant on their own T cells’ fitness to benefit from the curative potential of CAR T. This study, driven by investigator enthusiasm, will leverage currently active ALPHA2 trial sites in the U.S. which should allow it to advance quickly. It is expected to begin enrolling in Q1 2024 with initial data projected by YE 2024.

The Disruptor: ALLO-329 CD19 Dagger in Autoimmune Disease (AID)
The Company is applying its deep understanding of CAR Ts to design a next-generation allogeneic CAR T with reduced or chemotherapy-free conditioning that the Company believes can sustain the scale of the AID market while meeting the unique requirements for these patients where they seek care.

The risk tolerance of these patients is very different than those with cancer, in large part because of patient demographics, wide availability of effective therapies, and rheumatologists’ general lack of experience with chemotherapy, leukapheresis procedures and cell therapies.

Incorporation of the Dagger technology into an off-the-shelf CD19 product for use in AID is designed to reduce or eliminate the need for standard chemotherapy while targeting CD19+ B-cells and CD70+ activated T-cells, both of which play a role in AID. Initiation of this Phase 1 trial with ALLO-329 is expected in early 2025.

The Key: TRAVERSE ALLO-316 in Renal Cell Carcinoma (RCC)
A fundamental discovery in early CAR T trials was the use of tocilizumab and steroids, the "safety key" needed to mitigate treatment-associated CRS without compromising CAR T function or efficacy. The Company believes it may have made the same cornerstone discovery in the TRAVERSE trial in renal cell carcinoma.

During the careful advancement of the TRAVERSE trial with ALLO-316, the Company has observed remarkable allogeneic CAR T cell expansion and persistence driven by its unique CD70 CAR that allows elimination of alloreactive host lymphocytes. This biology has brought the potential for clinical efficacy not often seen in patients with r/r RCC but has also resulted in a hyperinflammatory response in some patients as CD70 CAR T cells expand and persist.

Leveraging recent advances in the management of hyperinflammation following autologous CAR T administration, the Company has developed a diagnostic and treatment algorithm similar to what the management team previously helped develop for CRS and ICANS. Like tocilizumab and steroids, this algorithm may mitigate the treatment-associated hyperinflammatory response without compromising the CAR T function needed to eradicate solid tumors. The Company has recently implemented a protocol amendment to further maximize the benefit-risk of ALLO-316 in patients with CD70+ RCC.

The next update from this trial is planned for a medical forum in Q2 2024 and will discuss the algorithm that is believed to be a critical advance for both the TRAVERSE trial as well as the industry at large. A more robust data update from the ongoing trial with the updated protocol is planned for later in 2024.

The Source: Proprietary Cell Forge 1 Allogeneic CAR T Manufacturing Facility
Cell Forge 1 (CF1), the Company’s wholly owned and fully integrated manufacturing facility, serves as a crucial strategic asset given the potential outlook for allogeneic CAR T product demand. We believe the ability to scale and control manufacturing will allow the Company to deliver a consistently high-quality allogeneic CAR T product.

Financial Runway Extended into 2026
The refined approach of the 2024 Platform Vision results in a streamlined trial footprint as well as a focused pipeline prioritization, allowing the Company to implement a planned restructuring of resources in Q1 2024. The result will reduce cash burn and is expected to extend the Company’s financial runway into 2026. Full 2024 guidance will be provided in the Company’s Q4/YE 2023 quarterly call.

JP Morgan Preview Conference Call
The 2024 Platform Vision Conference Call will be hosted on Thursday, January 4, 2024, at 2:00 p.m. PT/5:00 p.m. ET and include presentations and/or commentary by:

David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder
Zachary Roberts, M.D., Ph.D., Executive Vice President, Research & Development and Chief Medical Officer
Alex Herrera. M.D., Chief, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation at The City of Hope
Dr. Chang will also present the 2024 Platform Vision at the 42nd Annual J.P. Morgan Healthcare Conference on Wednesday, January 10, 2024, at 8:15 a.m. Pacific Time. This event will be held in San Francisco at the Westin St. Francis.

Conference Call Details
Allogene will host a live conference call today at 2:00 p.m. Pacific Time / 5:00 p.m. Eastern Time to discuss the 2024 Vision for Allogene. If you would like the option to ask a question on the conference call, please use this link to register. Upon registering for the conference call, you will receive a personal PIN to access the call, which will identify you as the participant and allow you the option to ask a question.

JP Morgan Conference
A live audio webcast of the presentation will be made available on the Company’s website at www.allogene.com under the Investors tab in the News and Events section.

Following these live audio webcasts, replays will be available on the Company’s website for approximately 30 days. The materials presented will be available on the Allogene website.

About Cemacabtagene Ansegedleucel (Previously Known as ALLO-501A)
Cemacabtagene ansegedleucel, or cema-cel is a next generation anti-CD19 AlloCAR T investigational product for the treatment of large B cell lymphoma (LBCL). This product candidate is currently being studied in an ongoing potentially pivotal Phase 2 trial in relapsed/refractory (r/r) LBCL. The ALPHA3 pivotal Phase 2 trial in first line (1L) consolidation for the treatment of LBCL is expected to begin mid-2024. In June 2022, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation to cema-cel in third line (3L) r/r LBCL.