On November 7, 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 corporate updates and announced financial results for the quarter ended September 30, 2024 (Press release, Allogene, NOV 7, 2024, View Source [SID1234647917]).

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"We are proud of the progress made in the third quarter of 2024 to advance our investigational allogeneic cell products in key "firsts" – our first-line consolidation trial in large B-cell lymphoma with cema-cel, ALLO-316 as the first allogeneic CAR T product candidate to demonstrate positive results in solid tumors, and the first CD19/CD70 dual CAR T candidate specifically designed for autoimmune disease," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "We believe these efforts have the potential to redefine treatment paradigms, tailoring therapies to meet the unique needs of large patient populations, and enabling broader real-world adoption. Allogene remains dedicated to driving innovation that improves outcomes for patients with both cancer and autoimmune diseases."

Program Updates

Cema-Cel: Pivotal ALPHA3 1L Consolidation Trial in Large B Cell Lymphoma (LBCL)
The pivotal Phase 2 ALPHA3 trial is the main focus for the Company. The trial was initiated in June 2024 and now has almost 30 sites activated and screening for patients with minimal residual disease (MRD).

This groundbreaking study is evaluating the use of cemacabtagene ansegedleucel (cema-cel) as part of the first line (1L) treatment regimen for patients with LBCL who are likely to relapse after standard 1L treatment. ALPHA3 is the first pivotal trial to offer CAR T as part of 1L treatment consolidation.

This innovative ALPHA3 trial will identify patients at high risk for relapse after 1L treatment by utilizing Foresight CLARITY powered by PhasED-Seq, a novel and highly accurate Investigational Use Only (IUO) test for MRD. This randomized trial will enroll approximately 240 patients and is designed to demonstrate a meaningful improvement in event free survival (EFS) in patients treated with cema-cel relative to patients who receive the current standard of care (observation). ALPHA3 is expected to complete enrollment in 1H 2026. Efficacy analyses are expected to occur in 2026 and will include an interim EFS analysis monitored by the independent Data Safety Monitoring Board (DSMB) in 1H 2026 and the data readout of the primary EFS analysis by YE 2026. A potential biologics license application (BLA) submission is targeted for 2027.

ALLO-329: CD19/CD70 Dual CAR with Dagger Technology in Autoimmune Disease (AID)
The Company will present pre-clinical data for its next-generation investigational AlloCAR T candidate for autoimmune indications, ALLO-329, at the American College of Rheumatology’s annual meeting, ACR Convergence 2024, November 18, 2024, in Washington, D.C.

ALLO-329 offers a novel approach to treating autoimmune diseases as the first allogeneic CD19/CD70 dual CAR T product specifically designed to target CD19+ B-cells and CD70+ activated T-cells, both of which are key players in autoimmune diseases. The investigational product utilizes CRISPR-based site-specific integration and incorporates the Company’s clinically validated Dagger technology, which aims to reduce or eliminate the need for lymphodepletion, believed to be a potentially significant obstacle to the wider adoption of CAR T therapies in autoimmune applications.

The Company plans to file an investigational new drug (IND) application in Q1 2025 and expects to have proof-of-concept by YE 2025.

ALLO-316: TRAVERSE Trial in Renal Cell Carcinoma (RCC)
The Company will present an update to the ongoing Phase 1 TRAVERSE trial in an oral presentation at the 2024 International Kidney Cancer Symposium (IKCS, November 8, 2024) and at a poster session at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) Annual Meeting (November 9, 2024). The trial evaluates ALLO-316, the Company’s first AlloCAR T product candidate for the treatment of solid tumors. The Phase 1 TRAVERSE trial is enrolling patients with advanced or metastatic renal cell carcinoma (RCC) who have progressed following treatment with an immune checkpoint inhibitor and VEGF-targeting therapy. These presentations highlight strong evidence of anti-tumor activity of ALLO-316 following standard FC (fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2)) lymphodepletion in patients with CD70 positive RCC tumors.

As of the October 14, 2024 data cutoff, 39 patients had been enrolled in the ongoing Phase 1 trial, of which 26 were confirmed to have CD70 positive RCC and were evaluable for efficacy outcomes. The median time from enrollment to the start of therapy was five days. Data from dose escalation cohorts as well as a newly opened Phase 1b expansion cohort are included in the presentations. The Phase 1b expansion cohort is evaluating safety and efficacy of ALLO-316 at DL2 (80M CAR T cells) following a standard FC lymphodepletion.

Following a single infusion of ALLO-316 in heavily pretreated patients, the trial demonstrated best Overall Response Rate (ORR) of 50% and Confirmed Response Rate of 33% in those patients with CD70 Tumor Proportion Score (TPS) of ≥50% who received the Phase 1b expansion regimen. Patients with a TPS of ≥50% comprise the majority of patients with advanced or metastatic RCC. Of those with a TPS ≥50, 76% (16/21) experienced a reduction in tumor burden. Two of six (33%) patients with high TPS who received the Phase 1b expansion regimen showed durable responses ongoing at ≥4 months.

The most common all-grade adverse events were cytokine release syndrome (CRS) (with only one grade ≥3), fatigue (59%), neutropenia (56%), decreased white blood cell count (54%), anemia (51%), and nausea (51%). Immune effector cell-associated neurotoxicity syndrome (ICANS) was minimal at 8% and no graft-versus-host disease (GvHD) occurred.

Two dose limiting toxicity (DLT) events of autoimmune hepatitis and cardiogenic shock were reported. Each event occurred in two separate participants who received FCA (FC plus ALLO-647) lymphodepletion and DL2 of ALLO-316. Three Grade 5 treatment-related adverse events were reported: 1) cardiogenic shock, which was one of the two DLT events; 2) sepsis from multi-drug resistant Klebsiella pneumoniae in a participant who received DL4 of ALLO-316 – this participant had a prior episode of muscle abscess and bacteremia from the same multi-drug resistant Klebsiella and was receiving anakinra and dexamethasone for hyperinflammation; and 3) failure to thrive in a participant 16 months after treatment with ALLO-316 – this subject had tumor response of stable disease (SD) at month 12 and no interval scans to evaluate disease status prior to death.

On October 29, 2024, the Company announced that it had received Regenerative Medicine Advanced Therapy (RMAT) designation for ALLO-316 for adult patients with advanced or metastatic RCC. The RMAT designation was based on Phase 1 clinical data from the TRAVERSE trial indicating the potential of ALLO-316 to address the unmet need for patients with difficult-to-treat RCC who have failed multiple standard RCC therapies, including an immune checkpoint inhibitor and a VEGF-targeting therapy.

2024 Third Quarter Financial Results

Research and development expenses were $44.7 million for the third quarter of 2024, which includes $5.6 million of non-cash stock-based compensation expense.
General and administrative expenses were $16.3 million for the third quarter of 2024, which includes $7.8 million of non-cash stock-based compensation expense.
Net loss for the third quarter of 2024 was $66.3 million, or $0.32 per share, including non-cash stock-based compensation expense of $13.4 million and $10.7 million in non-cash impairment of long-lived asset expense.
The Company had $403.4 million in cash, cash equivalents, and investments as of September 30, 2024.
Based on its cash, cash equivalents and investments as of September 30, 2024, the Company continues to expect its cash runway to fund operations into the second half of 2026. Guidance remains unchanged from the most recent update with an expectation of a decrease in cash, cash equivalents, and investments of approximately $200 million in 2024. GAAP Operating Expenses are expected to be approximately $300 million, including estimated non-cash stock-based compensation expense of approximately $60 million. These estimates exclude any impact from potential business development activities.

Conference Call and Webcast Details
Allogene will host a live conference call and webcast today at 2:00 p.m. Pacific Time / 5:00 p.m. Eastern Time to discuss financial results and provide a business update. 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. The listen-only webcast will be made available on the Company’s website at www.allogene.com under the Investors tab in the News and Events section. Following the live audio webcast, a replay will be available on the Company’s website for approximately 30 days.

On November 7, 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 that it will concurrently present new data from the Phase 1 TRAVERSE trial in an oral presentation at the 2024 International Kidney Cancer Symposium (IKCS) and a poster session at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) Annual Meeting (Press release, Allogene, NOV 7, 2024, View Source [SID1234647916]). The trial evaluates ALLO-316, the Company’s first AlloCAR T product candidate for the potential treatment of solid tumors. The ongoing Phase 1 TRAVERSE trial is enrolling patients with advanced or metastatic renal cell carcinoma (RCC) who have progressed following treatment with an immune checkpoint inhibitor and VEGF-targeting therapy. These presentations highlight compelling evidence of CAR T activity and anti-tumor efficacy in 26 patients with RCC tumors known to be CD70 positive who were evaluable for efficacy outcomes.

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"ALLO-316, the leading "off-the-shelf" CAR T product candidate currently in development for solid tumors, continues to show remarkable potency in the TRAVERSE trial. Data from the Phase 1 study demonstrating significant anti-tumor activity in patients with metastatic disease resistant to multiple therapeutic classes, even with standard lymphodepletion, potentially marks a major advancement in the field," said Zachary Roberts, M.D., Ph.D., EVP, Research and Development and Chief Medical Officer of Allogene. "The unprecedented cell expansion and persistence driven by CD70 CAR-intrinsic Dagger technology, along with strong evidence of tumor infiltration by CAR T cells, highlights the distinctive features of ALLO-316. We believe these findings from our Phase 1 trial lay the groundwork for a new generation of allogeneic cell therapies."

As of the October 14, 2024 data cutoff, 39 patients had been enrolled in the ongoing Phase 1 trial, of which 26 were confirmed to have CD70 positive RCC and were evaluable for efficacy outcomes. The median time from enrollment to the start of therapy was five days. Data from dose escalation cohorts and ongoing Phase 1b expansion cohort are included in the presentations. The Phase 1b expansion cohort is evaluating safety and efficacy of ALLO-316 at DL2 (80M CAR T cells) following a standard FC500 (fludarabine (30 mg/m2/day) and cyclophosphamide (500 mg/m2/d) for 3 days) lymphodepletion regimen. The Phase 1b expansion cohort is expected to ultimately include approximately 20 patients. Additional data from the Phase 1b expansion cohort is expected to be announced in mid-2025.

Following a single infusion of ALLO-316 in heavily pretreated patients, the trial demonstrated best Overall Response Rate (ORR) of 50% and Confirmed Response Rate of 33% in those patients with CD70 Tumor Proportion Score (TPS) of ≥50% who received DL2. Patients with a TPS of ≥50% comprise the majority of patients with advanced or metastatic RCC. Of those with a TPS ≥50, 76% (16/21) experienced a reduction in tumor burden. Two of six (33%) patients with high TPS who received the Phase 1b expansion regimen showed durable responses ongoing at ≥4 months.

Response Rates by CD70 Status and Dose

Patients Evaluable for Disease Outcomesa (N=34)
CD70 Positive (N=26)

CD70 Negative
or Unknown
(N=8)
All
(N=26) FCAb
(N=8) FCc
(N=18) DL2 FC500
(Phase 1b)
(N=8)
Best overall response,d n/N (%)
High TPS (≥50)
Low TPS (<50) 7/26 (27)
7/21 (33)
0/5 (0) 1/8 (13)
1/6 (17)
0/2 (0) 6/18 (33)
6/15 (40)
0/3 (0) 3/8 (38)
3/6 (50)
0/2 (0) 0/8 (0)
NA
NA
Confirmed ORR,e n/N (%)
High TPS (≥50)
Low TPS (<50) 5/26 (19)
5/21 (24)
0/5 (0) 1/8 (13)
1/6 (17)
0/2 (0) 4/18 (22)
4/15 (27)
0/3 (0) 2/8 (25)
2/6 (33)
0/2 (0) 0/8 (0)
NA
NA
aPatients evaluable for disease outcome includes those who received ALLO-316 and had at least one tumor assessment.
bStandard fludarabine and cyclophosphamide plus ALLO-647
cIncludes FC300 and FC500
dBest overall response across visits did not require confirmation for CR/PR.
eConfirmed overall response of CR/PR required confirmation at the subsequent visit.

The most common all-grade adverse events were cytokine release syndrome (CRS) (with only one grade ≥3), fatigue (59%), neutropenia (56%), decreased white blood cell count (54%), anemia (51%) and nausea (51%). Immune effector cell-associated neurotoxicity syndrome (ICANS) was minimal at 8% and no graft-versus-host disease (GvHD) occurred.

Safety: Most Prevalent TEAEs (>40% Any Grade Incidence) and AESI

Adverse Event, n (%) All Patients (N=39) DL2 FC500 (N=11)
All Grades Grade ≥3 All Grades Grade ≥3
Any TEAE 39 (100) 29 (81) 11 (100) 8 (73)
CRS 24 (62) 1 (3) 8 (73) 0
Fatigue 23 (59) 1 (3) 2 (18) 0
Neutropenia 22 (56) 20 (51) 7 (64) 7 (64)
White blood cell count decreased 21/(54) 19 (49) 8 (73) 8 (73)
Anemia 20 (51) 13 (33) 7 (64) 5 (46)
Nausea 20 (51) 0 3 (27) 0
Thrombocytopenia 18 (46) 10 (26) 7 (64) 3 (27)
Pyrexia 16 (41) 2 (5) 4 (36) 0
AEs of Special Interest Any Grade Grade ≥3 Any Grade Grade ≥3
Infectiona
Viral infections 24 (62)
13 (33) 12 (31)
2 (5) 5 (46)
2 (18) 2 (18)
0
Neurotoxicityb
Headache 17 (44)
8 (21) 12 (31)
2 (5) 5 (46)
2 (18) 2 (18)
0
IEC-HS 5 (13) 1 (3) 2 (18) 0
ICANS 3 (8) 0 3 (27) 0
Graft-versus-host disease 0 0 0 0
TEAE included all AEs that started from the first dose date of study drug in each treatment period up to start of another treatment period, death, or the date prior to initiation of another anti-cancer agent, whichever occurred first. IEC-HS includes the preferred terms IEC-HS, HLH, Hemophagocytic lymphohistiocytosis, and atypical HLH. Two patients developed an inflammatory syndrome prior to the existence of IEC-HS as a term in MedDRA, which has been updated as of September 2023.
aInfection events (62%) were primarily low grade; the most common was viral infections (33%) with cytomegalovirus infection and COVID-19 (any grade, 18% and 15%; Grade ≥3, 0% and 5%, respectively).
bNeurotoxicity includes system organ class of nerve system disorders and psychiatric disorders with onset date up to Study Day 30 post ALLO-316 infusion.

Two DLT events of autoimmune hepatitis and cardiogenic shock were reported. Each event occurred in 2 separate participants who received FCA (FC300 plus ALLO-647) lymphodepletion and DL2 of ALLO-316. Three Grade 5 treatment-related adverse events were reported: 1) cardiogenic shock, which was one of the 2 DLT events; 2) sepsis from multi-drug resistant Klebsiella pneumoniae in a participant who received DL4 of ALLO-316. This participant had a prior episode of muscle abscess and bacteremia from the same multi-drug resistant Klebsiella and was receiving anakinra and dexamethasone for hyperinflammation; 3) failure to thrive in a participant 16 months after treatment with ALLO-316. This subject had tumor response of stable disease (SD) at month 12 and no interval scans to evaluate disease status prior to death.

About ALLO-316 (TRAVERSE)
ALLO-316 is an AlloCAR T investigational product targeting CD70, which is highly expressed in renal cell carcinoma (RCC). CD70 is also selectively expressed in several cancers, creating the potential for ALLO-316 to be developed across a variety of both hematologic malignancies and solid tumors. The ongoing Phase 1 TRAVERSE trial is designed to evaluate the safety, tolerability, and activity of ALLO-316 in patients with advanced or metastatic clear cell RCC. In October 2024 the U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy (RMAT) designation based on the potential of ALLO-316 to address the unmet need for patients with advanced or metastatic RCC. The FDA previously granted Fast Track Designation (FTD) to ALLO-316 in March 2023. In April 2024, the Company announced a $15 million award from the California Institute for Regenerative Medicine (CIRM) to support the ongoing TRAVERSE trial with ALLO-316 in RCC.

On November 7, 2024 ADC Therapeutics SA (NYSE: ADCT), a commercial-stage global leader and pioneer in the field of antibody drug conjugates (ADCs), reported financial results for the third quarter ended September 30, 2024, and provided recent operational updates (Press release, ADC Therapeutics, NOV 7, 2024, View Source [SID1234647915]).

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"We are excited about the advancements in our ZYNLONTA trials in earlier lines of diffuse large B-cell lymphoma therapy and look forward to reporting more on the combination with glofitamab in our LOTIS-7 trial, as well as reaching the expected full enrollment in LOTIS-5 before year-end," said Ameet Mallik, Chief Executive Officer of ADC Therapeutics. "We are discontinuing ADCT-601 targeting AXL and will prioritize our exatecan-based platform for solid tumors moving forward. With our expected cash runway into mid-2026, we believe we are well positioned to execute our strategy and advance multiple value-generating catalysts going forward."

Third Quarter 2024 Operational Updates & Recent Highlights

•Full enrollment expected by year-end in LOTIS-5.Enrollment for the Phase 3 confirmatory trial evaluating ZYNLONTA in combination with rituximab in patients with 2L+ diffuse large B-cell lymphoma (DLBCL) is expected to be completed by year-end 2024 with a data update expected in late 2025 once the pre-specified number of events is reached.

•LOTIS-7 enrollment continues with expected interim data update in December 2024.Enrollment continued in the Part 2 dose expansion of LOTIS-7, a Phase 1b open-label clinical trial evaluating ZYNLONTA in combination with the bispecific antibody glofitamab in patients with relapsed or refractory DLBCL. An interim update on safety and efficacy in a subset of patients is expected in December with additional data anticipated in the first half of 2025.

•Abstracts accepted for presentation at the 66th annual American Society of Hematology (ASH) (Free ASH Whitepaper) 2024 Annual Meeting. Updated data from the investigator-initiated Phase 2 clinical trial, conducted at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, evaluating ZYNLONTA in combination with rituximab in patients with relapsed or refractory follicular lymphoma will be shared during an oral presentation titled, "Loncastuximab tesirine with rituximab induces robust and durable complete metabolic responses in high-risk relapsed/refractory follicular lymphoma" (Abstract #337) on December 7, 2024 at 4 p.m. PT.

Updated data from the investigator-initiated Phase 2 clinical trial, conducted at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, evaluating ZYNLONTA for the treatment of relapsed or refractory marginal zone lymphoma (MZL) will be presented during a poster presentation titled, "Limited duration loncastuximab tesirine induces a high rate of complete responses in patients in relapsed/refractory marginal zone lymphoma – report of first planned interim futility analysis of a multicenter Phase II study" (Abstract #3032) on December 8, 2024 from 6 – 8 p.m. PT.

•Discontinuation of ADCT-601 program targeting AXL. Based on the available clinical data and capital requirements for continued development, the Company will discontinue the Phase 1b ADCT-601 program targeting AXL as a single agent and/or in combination for patients with sarcoma, pancreatic cancer and non-small cell lung cancer. Although early signs of antitumor activity were observed during the dose escalation phase, we were unable to demonstrate a favorable benefit-risk profile during the dose optimization/expansion phase.

•ADCT-602 targeting CD22 dose escalation progressing. The Phase 1/2 clinical trial, sponsored by The University of Texas MD Anderson Cancer Center, evaluating ADCT-602 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia continues to progress and dose escalation continues at 60 µg/kg dose.

•IND-enabling studies ongoing in early-stage pipeline. Progress continues in the Investigational New Drug (IND) enabling studies for the Company’s exatecan-based programs for ADCs targeting Claudin-6, PSMA and NaPi2b, while our ASCT2 targeting ADC is in the drug candidate selection stage. The Company has selected one target to move toward IND which is expected to be disclosed in 2025.

Third Quarter and Year-to-Date 2024 Financial Results

•Product Revenues: ZYNLONTA generated net product revenues of $18.0 million for the third quarter ended September 30, 2024 and $52.9 million for the first nine months of 2024 as compared to $14.3 million and $52.4 million for the same periods in 2023. The quarter-over-quarter increase is driven by higher sales volume, a higher selling price and lower gross-to-net deductions. The year-to-date increase is primarily attributable to a higher price, partially offset by lower sales volume.

•Research and Development (R&D) Expense: R&D expense was $32.5 million and $82.5 million for the three and nine months ended September 30, 2024, respectively. This compares to R&D expense of $27.1 million and $96.8 million for the same periods in 2023. The increase during the three months ended September 30, 2024 is due primarily to focused investment in prioritized development programs, including ADCT-601 and ZYNLONTA. The decrease during the nine months ended September 30, 2024 is due primarily to the implementation of productivity initiatives and focused investment in prioritized development programs.

•Selling and Marketing (S&M) Expense: S&M expense was $10.7 million and $32.8 million for the three and nine months ended September 30, 2024, respectively. This compares to S&M expense of $13.7 million and $43.5 million for the same periods in 2023. The decreases in S&M expense were primarily due to lower marketing and advertising costs and personnel related expenses.

•General & Administrative (G&A) Expense: G&A expense was $10.0 million and $32.3 million for the three and nine months ended September 30, 2024, respectively. This compares to G&A expense of $9.6 million and $37.1 million for the same periods in 2023. The quarter-over-quarter increase in G&A expense was primarily related to higher personnel related expenses, partially offset by lower insurance costs while the year-to-date decrease was primarily related to lower personnel related expenses as well as lower insurance and IT expenses.

•Net Loss: Net loss for the quarter ended September 30, 2024 was $44.0 million, or a net loss of $0.42 per basic and diluted share, as compared to net loss of $46.7 million, or a net loss of $0.57 per basic and diluted share for the same period in 2023. Net loss for the nine months ended September 30, 2024 was $127.1 million, or a net loss of $1.35 per basic and diluted share, as compared to net loss of $155.0 million, or a net loss of $1.90 per basic and diluted share for the nine months ended September 30, 2023. The decrease for the three months ended September 30, 2024 is primarily related to higher revenues and a lower equity in net loss of our joint venture partially offset by higher operating expenses. The decrease for the nine months ended September 30, 2024 is primarily due to lower operating expenses.

•Adjusted Net Loss: Adjusted net loss, which is a non-GAAP financial measure, was $29.4 million, or an adjusted net loss of $0.28 per basic and diluted share for the quarter ended September 30, 2024 as compared to adjusted net loss of $32.4 million, or $0.39 per basic and diluted share, for the same period in 2023. Adjusted net loss for the nine months ended September 30, 2024 was $84.9 million, or an adjusted net loss of $0.90 per basic and diluted share, as compared to net loss of $106.3 million, or an adjusted net loss of $1.30 per basic and diluted share for the nine months ended September 30, 2023. The decrease in adjusted net loss for the three months ended September 30, 2024 is primarily related to higher revenues and a lower equity in net loss of our joint venture partially offset by higher operating expenses. The decrease in adjusted net loss for the nine months ended September 30, 2024 is primarily attributable to lower operating expenses.

•Cash and cash equivalents: As of September 30, 2024, cash and cash equivalents were $274.3 million, compared to $278.6 million as of December 31, 2023. In May 2024 the Company completed an underwritten offering resulting in net proceeds of approximately $97.4 million, extending the expected cash runway into mid-2026.

Conference Call Details

ADC Therapeutics management will host a conference call and live audio webcast to discuss third quarter 2024 financial results and provide a company update today at 8:30 a.m. Eastern Time. To access the conference call, please register here. The participant toll-free dial-in number is 1-800-836-8184 for North America and Canada. A live webcast of the call will be available under "Events & Presentations" in the Investors section of the ADC Therapeutics website at ir.adctherapeutics.com. The archived webcast will be available for 30 days following the call.

About ZYNLONTA

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 November 7, 2024 Adagene Inc. ("Adagene") (Nasdaq: ADAG), a company transforming the discovery and development of novel antibody-based therapies, reported data at the SITC (Free SITC Whitepaper) 39th Annual Meeting, taking place in Houston, Nov. 6 – 10, 2024 (Press release, Adagene, NOV 7, 2024, View Source [SID1234647914]). The two poster presentations provide new insights on the increased therapeutic index (TI) for ADG126 and reinforce its clinical safety and efficacy profiles in combination with pembrolizumab* including in advanced Metastatic Microsatellite-stable (MSS) Colorectal Cancer (CRC).

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"CTLA-4 has an essential role in harnessing the immune system to improve outcomes for patients with cold and PD-L1 low or negative tumors, and CTLA-4 inhibition has been shown to prime T cells contributing to enhanced combination therapy activity," said Daneng Li, MD, Associate Professor in the Department of Medical Oncology & Therapeutics Research at the City of Hope Comprehensive Cancer Center, and a study investigator. "With its increased therapeutic index (TI), ADG126 has demonstrated in clinic that a unique epitope and masking technology can be deployed to deplete CTLA-4 mediated intratumoral T regulatory cells (Tregs), as anti-PD-1 alone has a minimum effect."

In the first poster, Deciphering Improved Clinical Therapeutic Index (TI) of Muzastotug (ADG126), a Masked Anti-CTLA-4 SAFEbody over its Unmasked Form (ADG116) as Monotherapy or in Combination with anti-PD-1 Therapy (toripalimab), data demonstrate how the improved TI of ADG126 allows for higher and repeat dosing to unleash its efficacy to the maximum potential, while maintaining an improved safety profile. Analyses of the masked ADG126 SAFEbody and its unmasked version, ADG116, show the improved TI relative to commercially available anti-CTLA-4 therapies (e.g., ipilimumab) via enhanced epitope-dependent ADCC and T cell priming. By targeting the constitutively over-expressed CTLA-4 on T regulatory cells (Tregs) in the tumor microenvironment (TME) for potent CTLA-4 mediated intratumoral Treg depletion, ADG126 achieves tumor-specific targeting with minimal on-target off-tumor toxicities.

Key highlights include:

· The unique epitope of ADG126 and its activated form (ADG116) drives species cross-reactivity enabling the same antibody to be used across mice, monkey and human studies, with a unified set of physiologically relevant parameters for population pharmacokinetic (PK) modeling. Analyses show a significantly higher and sustained steady state tumor-specific engagement of CTLA-4 with the masked ADG126, suggesting increased exposure in the TME and a stronger ADCC effect.

· New analyses show the seamless translation of preclinical PK analyses to clinical PK data, including:

o head-to-head comparison of ADG126 to ipilimumab in MC38 mice (colon cancer model), a single dose of ADG126 showed a three-fold increased active (e.g., cleaved) drug exposure in homogenized tumor tissue samples at 10 mg/kg versus a single dose of ipilimumab at 1 mg/kg while maintaining similar plasma active drug exposures.

o A second analysis in the MC38 mice model showed two consecutive doses of ADG126 at 20 mg/kg increased the tumor cleaved and total PK versus a single dose, demonstrating continuous intratumoral cleavage of intact ADG126 and accumulation within the TME. This reflects the effectiveness of ADG126 repeat dosing to increase drug exposure within the TME, supporting its mechanism with CTLA-4 mediated intratumoral Treg depletion.

The second poster, Phase 1b/2, Multicenter Dose Escalation and Expansion Study of Muzastotug (ADG126, a Masked Anti-CTLA-4 SAFEbody) in Combination with Pembrolizumab in Advanced/Metastatic MSS CRCs, presents additional follow up data from an ongoing trial showing the best-in-class therapeutic potential of ADG126 in combination with anti-PD-1 therapy in patients with the most common form of colorectal cancer, MSS CRC.

The trial, conducted in patients with advanced MSS CRC without liver metastases, showed that ADG126 administered at 10 mg/kg Q6W or Q3W in combination with pembrolizumab (200 mg/Q3W) demonstrated an encouraging efficacy signal, durable disease control and an early survival benefit in MSS CRC patients, with dose-dependent efficacy and objective responses per RECIST criteria observed for the Q3W schedule.

New findings in the poster at SITC (Free SITC Whitepaper) 2024 include:

· In MSS CRC patients, a lower rate of key TRAEs (i.e., diarrhea, colitis, etc.) with ADG126 at the 10 mg/kg dosing level in combination with pembrolizumab relative to lower doses of 1-2 mg/kg of an Fc engineered anti-CTLA-4 antibody in clinical development when used in combination with anti-PD-1. Clinical PK, particularly the monitoring of active species of ADG126 in peripheral blood, supports long-term safety of the combination therapy.

· The rate of Grade 3 and higher TRAEs for ADG126 in combination with pembrolizumab was also shown to be much lower than historically reported with currently approved standard of care combinations. In the combination cohort, there was no Grade 3 or higher colitis, which is common with other anti-CTLA-4 therapies.

· A case study of one responder who received two prior lines of therapy before receiving ADG126 in combination with pembrolizumab showed an 80% decrease in target lesions (50 mm at baseline). This confirmed partial response (PR) correlated with a 100% decrease in carcinoembryonic antigen (CEA) levels versus baseline. Individualized PK data also demonstrated the correlation of tumor shrinkage and plasma exposure. After five cycles, the patient experienced TRAEs, after which dosing was modified and treatment resumed, showing durable clinical benefit for over 12 months. This response is one of four PRs reported from the ongoing 10 mg/kg Q3W combination cohort of MSS CRC patients without liver metastases (n=24).

· Repeat doses of ADG126 10 mg/kg in combination with pembrolizumab shows encouraging dose-dependent clinical efficacy and well-tolerated safety in accordance with plasma cleaved ADG126 concentrations. These data support that ADG126 may be a potential best-in-class anti-CTLA-4 and may be considered as a backbone therapy.

Follow up continues for MSS CRC patients treated with ADG126 10 mg/kg doses in combination with pembrolizumab. In addition, Adagene is evaluating a single dose of ADG126 at 20 mg/kg followed by a 10 mg/kg Q3W maintenance dose in combination with pembrolizumab in a cohort of 12 enrolled patients with data expected in 2025.

Poster Presentation Details

Both posters can be viewed during SITC (Free SITC Whitepaper) on Saturday, November 9 at the George R. Brown Convention Center (Level 1, Exhibit Halls AB). They will also be available on the Publications page of the company’s website here.

On November 7, 2024 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating cancer and neurodegenerative disease through the inhibition of SEMA4D, reported the signing of several proprietary project agreements with Amgen, Merck, Chugai, Absci, Gigagen (Grifols), Merus, Soleil, ThirdArc and Incyte, employing Vaccinex’s ActivMAb technology to generate antibodies to complex antigen targets (Press release, Vaccinex, NOV 7, 2024, View Source [SID1234647901]). In addition, Vaccinex has signed agreements to provide Charles River Labs, OmniAb, Adimab and other undisclosed strategic partners with materials to facilitate their antibody discovery programs using transgenic animal species for immunization or very large synthetic antibody libraries. The financial terms of the agreements are undisclosed.

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Vaccinex’s proprietary ActivMAb Technology enables expression of functional, properly folded complex proteins such as GPCRs and Ion Channels on the relatively simple membrane of poxvirus providing a source of antigen for various antibody discovery strategies. These strategies may involve development of antibody and antibody-based immunotherapies including bi-specifics, antibody drug conjugates (ADC), CAR-T cells, T cell engagers, etc. "Our technology is a powerful component of antibody discovery strategies targeting complex membrane proteins and enables both our own R&D efforts and those of our partners," said Ernest Smith, Chief Scientific Officer of Vaccinex. "These agreements and partnerships with established companies underscore ActivMAb’s unique ability to address previously hard to drug targets in a format ideally suited for antibody discovery."

Vaccinex will present data and examples of successful antibody discovery campaigns against potential oncology targets using the ActivMab Technology at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 29th Annual Meeting held November 8-10, 2024, in Houston, TX.

Meeting SITC 39th Annual Meeting
Date:
Saturday, Nov. 9, 2024
Location: Exhibit Halls A B George R. Brown Convention Center
Poster Title: Discovery of high affinity functional antibodies specific for CXCR5, P2X7 and other multi-pass membrane receptors
Poster Number 1100
Presenter Elizabeth Evans, PhD, Chief Operating Officer, Vaccinex, Inc.

About ActivMAb
ActivMAb is a proprietary antibody discovery platform developed by Vaccinex with unique capabilities for important multi-pass membrane targets such as G-protein-coupled receptors (GPCRs) and ion channels. The ActivMAb technology has multiple applications including discovery of antibodies specific for complex membrane antigens, discovery of antibodies with optimized developability, and protein optimization for expression and activity. Its novel capabilities enable selection of unique antibody drugs against difficult high-value targets, including multi-pass membrane proteins against which small molecule drugs have demonstrated low efficacy or high toxicity. The first clinical candidate selected through use of this technology (CHS-114, a fully human monoclonal antibody targeting CCR8), is in clinical development for cancer immunotherapy by Coherus Biosciences, Inc.