On January 4, 2024 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with genetically defined cancers, reported a corporate update outlining clinical development plans and anticipated corporate milestones for 2024 (Press release, Black Diamond Therapeutics, JAN 4, 2024, View Source [SID1234638964]).

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"We made significant progress in 2023 and sharpened our focus on our clinical programs: BDTX-1535 in both EGFR mutant NSCLC and GBM, and BDTX-4933 in KRAS mutant NSCLC," said Mark Velleca, M.D., Ph.D., Chief Executive Officer of Black Diamond Therapeutics. "In 2024, we anticipate key readouts from each of these programs, including Phase 2 data from BDTX-1535 in NSCLC. Moreover, recent FDA feedback enables the enrollment of first-line NSCLC patients into the Phase 2 trial, reflecting the potential of BDTX-1535 to benefit patients in earlier lines of therapy. Due to disciplined spend, we expect our cash to be sufficient for this year’s milestones and to extend into the second quarter of 2025."

Clinical Program Updates/Anticipated 2024 Milestones

BDTX-1535 in patients with Epidermal Growth Factor Receptor (EGFR) mutant Non-Small Cell Lung Cancer (NSCLC)

Dose escalation results were presented at the AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) in October 2023. Phase 2 data in second/third-line patients with EGFR mutant NSCLC are expected in the third quarter of 2024. The Company intends to discuss Phase 2 results with the U.S. Food and Drug Administration (FDA) to finalize a pivotal clinical trial design.
BDTX-1535 received Fast Track Designation for the treatment of patients with EGFR mutant C797S-positive NSCLC whose disease has progressed on/after a third-generation EGFR tyrosine kinase inhibitor (TKI).
Following End of Phase 1 feedback received from the FDA in the fourth quarter of 2023, a Phase 2 cohort in first-line patients with non-classical EGFR mutant NSCLC is being initiated.
The Company is also exploring the potential development of BDTX-1535 in first-line patients who are post-osimertinib adjuvant treatment.
BDTX-1535 in patients with EGFR mutant Glioblastoma (GBM)

Following release of top-line Phase 1 data in December 2023, presentation of Phase 1 trial results is anticipated at a medical meeting in the second quarter of 2024.
Enrollment is ongoing in a "window of opportunity" trial sponsored by the Ivy Brain Tumor Center in patients with recurrent glioma who are undergoing a planned resection. Results from this trial are expected to be presented at a medical meeting in the second quarter of 2024.
The Company expects that results from the dose escalation and "window of opportunity" trials will inform the next steps in the GBM development program, including a potential randomized trial in the first-line setting.
BDTX-4933 in patients with KRAS mutant NSCLC

BDTX-4933 was designed as a "RAF/RAS clamp" to target the activated RAF conformation in the context of either RAF or RAS mutations, a mechanism distinct from earlier generation RAF inhibitors.
Enrollment in a Phase 1 trial began in September 2023 in patients with KRAS mutant NSCLC. Results from this trial are anticipated in the fourth quarter of 2024.
About BDTX-1535
BDTX-1535 is an oral, brain-penetrant MasterKey inhibitor of oncogenic epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC), including classical driver mutations, families of non-classical driver mutations (e.g., L747P, L718Q), acquired resistance C797S mutation, and complex mutations. BDTX-1535 is a fourth-generation tyrosine kinase inhibitor (TKI) that potently inhibits, based on preclinical data, more than 50 oncogenic EGFR mutations expressed across a diverse group of patients with NSCLC in multiple lines of therapy. Based on preclinical data, BDTX-1535 also inhibits EGFR extracellular domain mutations and alterations commonly expressed in glioblastoma (GBM) and avoids paradoxical activation observed with earlier generation reversible TKIs. A "window of opportunity" trial of BDTX-1535 in patients with GBM is ongoing (NCT06072586) and a Phase 2 trial is currently ongoing in patients with NSCLC (NCT05256290).

About BDTX-4933
BDTX-4933 is an oral, brain-penetrant RAF MasterKey inhibitor designed to target oncogenic alterations in KRAS, NRAS and BRAF, while also avoiding paradoxical activation. In preclinical studies, BDTX-4933 has demonstrated a potential best-in-class profile, showing potent target engagement, inhibition of MAPK signaling and strong anti-tumor activity/tumor regression across tumor models driven by either KRAS, NRAS or BRAF mutations. BDTX-4933 also exhibits high central nervous system (CNS) exposure leading to dose-dependent tumor growth inhibition and a survival benefit in an intracranial tumor model harboring oncogenic BRAF mutation. The ongoing BDTX-4933 Phase 1 clinical trial is currently in dose escalation with emphasis on KRAS mutant NSCLC patients (NCT05786924).

On January 4, 2024 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leader in T-cell immunotherapy, leveraging its novel allogeneic Epstein-Barr virus (EBV) T-cell platform to develop transformative therapies for patients with cancer and autoimmune diseases, reported that Pascal Touchon, President and Chief Executive Officer, will present at the 42nd Annual J.P. Morgan Healthcare Conference on Thursday, January 11, at 9:45 a.m. PST / 12:45 p.m. EST in San Francisco, California (Press release, Atara Biotherapeutics, JAN 4, 2024, View Source [SID1234638963]).

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A live webcast of the presentation will be available by visiting the Investors and Media section of atarabio.com. An archived replay of the webcast will be available on the Company’s website for 30 days following the live presentation.

On January 4, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage biopharmaceutical company focused on precision oncology through synthetic lethality, reported a corporate update highlighting recent developments and plans for advancement of its pipeline of DNA Damage Response (DDR) anti-cancer agents in 2024 (Press release, Aprea, JAN 4, 2024, View Source [SID1234638962]).

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"Having made substantial progress over the past twelve months, we are well positioned for ongoing success in 2024 as we execute on our mission to be a global leader in synthetic lethality," said Dr. Oren Gilad, President and CEO of Aprea. "We continue to advance towards achieving our milestones in the ongoing dose-escalation Phase 1 study of our novel macrocyclic ATR inhibitor, ATRN-119, and are finalizing submission of the IND for our next-generation, best-in-class WEE1 inhibitor, APR-1051. This IND is supported by a compelling pre-clinical package showing highly potent and selective anti-tumor activity, limited off-target effects, and favorable pharmacokinetics."

Update on Phase 1/2a Ongoing Trial of ATR Program, ATRN-119

Enrollment of patients continues in the dose escalation portion of the Phase 1/2a clinical trial (study AR-276-01) evaluating ATRN-119 in patients with advanced solid tumors having mutations in defined DDR-related genes. The primary objective of the Phase 1 part of this trial is evaluating the tolerability and pharmacokinetics of ATRN-119 when administered orally on a continuous, once-daily schedule. The daily dosing of ATRN-119 provides continuous ATR inhibition that may be preferable to intermittent dosing for both efficacy and safety, potentially supporting an important competitive advantage over the current class of ATR inhibitors. The secondary objective is the evaluation of antitumor efficacy.

The most recent analysis of the data cut (January 2, 2024) shows that two patients have achieved stable disease – one each in the 50 mg and 200 mg cohorts. Importantly, both these patients’ tumors have mutations that have been predicted to confer sensitivity to ATR inhibition. The dose-limiting toxicity period for cohort 4 (350 mg) has been completed. The most recent patient with stable disease from cohort 3 (200mg), with a history of five prior lines of therapy is at approximately four months of treatment duration with ATRN-119, and, following clearance of the 350 mg cohort, is expected to be increased from 200 mg to 350 mg daily, as per the dose escalation trial protocol.

ATRN-119 is being developed as the first and only macrocyclic ATR inhibitor. Macrocycles restrict the number of conformations that a molecule can form, potentially resulting in increased potency and increased selectivity. These properties are expected to permit higher dosing that is potentially more effective with increased tolerability and decreased off-target activity. The company plans to amend the design of the ongoing study beyond the current 800 mg high-dose cohort to incorporate additional higher dose groups.

Upon the addition of the higher dose cohorts, Aprea expects to determine the recommended Phase 2 dose (RP2D) in the second half of 2024. Following dose escalation, the Phase 2a dose expansion part of the study may include patients with NSCLC, breast, colorectal, prostate, and ovarian cancers with selected genetic mutations.

Importantly, the potential for reduced hematologic toxicity from ATRN-119 suggests it may be an ideal DDR inhibitor for novel combination therapies. These potential combinations include ATRN-119 with PARP inhibitors, WEE1 inhibitors, and Antibody-Drug Conjugates (ADCs). The latter of these possibilities could provide a significant breakthrough for the use of ADCs linked to standard chemotherapies, as these promising biopharmaceuticals are often constrained by aberrant drug release and dose-limiting toxicities. Combination with ATRN-119 would potentially amplify the DNA-damaging effects of these ADCs in the targeted tumor cells, thus affording greater efficacy at lower ADC doses.

A more comprehensive dataset from the Phase 1 part of AR-276-01 will be submitted for presentation at a medical meeting in the first half of 2024. For more information, please refer to clinicaltrials.gov NCT04905914.

Investigational New Drug (IND) for WEE1 Program, APR-1051

Aprea completed IND-enabling studies and is finalizing the submission of the IND application with the FDA to begin clinical trials of APR-1051 in the first half of the year. APR-1051 is being developed as a next-generation, potential best-in-class inhibitor of WEE1 kinase with the following properties:

APR-1051 has a different molecular structure from all other WEE1 inhibitors currently in development with improved selectivity for the target. The improved properties of APR-1051 relative to the other WEE1 inhibitors include its limited effects on red blood cell counts, hERG inhibition, and body weight loss in pre-clinical studies.
The selectivity of APR-1051 may solve a long-standing problem with WEE1 inhibitors. Preclinical studies have shown that APR-1051 is site-specific to WEE1 and does not significantly inhibit the PLK1, PLK2, and PLK3 family of kinases, potentially increasing the cancer-killing effects of WEE1i inhibition and reducing hematological toxicity caused by PLK off-targeting. PLK off-target activity has been a challenge for other WEE1 inhibitors. Recent studies indicate that PLK1 off-targeting partially counters the intracellular effects of WEE1 inhibition and could potentially contribute to the myelosuppression observed with other WEE1 inhibitors.
Specific genetic mutations driving patient selection have been identified.
The company expects to receive FDA clearance on the IND during Q1 2024. Clinical development is in line with FDA requirements for a dose escalation trial to evaluate safety and pharmacokinetics. Leading institutions and a Principal Investigator have been identified for the trial.

Company to Participate in 2024 Corporate Access Event

Aprea will be hosting institutional investor and business development meetings at the Annual Corporate Access Event in San Francisco, hosted by our investor relations firm LifeSci Partners. Management will be available for meetings on Wednesday, January 10, 2024. To schedule a meeting, interested parties can register here or send an email to [email protected].

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.

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."