On December 17, 2024 Affimed N.V. (Nasdaq: AFMD) ("Affimed", or the "Company"), a clinical-stage immuno-oncology company committed to giving patients back their innate ability to fight cancer, reported updated clinical data from the ongoing AFM24-102 trial of AFM24/atezolizumab combination therapy in heavily pretreated NSCLC patients (Press release, Affimed, DEC 17, 2024, View Source [SID1234649156]). Results continue to demonstrate meaningful clinical activity in both NSCLC EGFRwt and EGFRmut patients with good tolerability. In addition, the Company reported findings from a post-hoc exposure-response analysis in patients treated with 480 mg AFM24 showing higher AFM24 exposure is associated with significantly better response rates, improved PFS and overall survival (OS). Based on these data, the future development program for AFM24 will use a dose of 720 mg weekly, a dose that has already been successfully tested in the phase 1 study of AFM24 showing a manageable safety profile.

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"With the compelling data from both EGFR wild-type and mutant cohorts, along with the exposure-response analysis we are unlocking the possibilities for the AFM24/atezolizumab combination in treating heavily pretreated NSCLC patients," said Dr. Shawn Leland, PharmD, RPh, Chief Executive Officer of Affimed. "These findings highlight our opportunity to further refine and advance this treatment with a clear focus on patients who stand to benefit the most. We are excited about the path ahead and are committed to exploring innovative strategies to bring this promising therapy to those in need."

NSCLC EGFR Wild-type Cohort Update

Patient population: As of the November 14, 2024 data cut, there were 43 patients in the full analysis set (FAS) and 33 patients in the per protocol set (PPS), defined as having one post baseline scan according to RECIST. Reasons for non-evaluability were early symptomatic deterioration (6), non-related AEs (2), too early (2). Patients had a median of 2 prior lines of therapy (range: 1–7). All patients had received platinum-based combinations and PD(L) 1 targeting checkpoint inhibitors (CPIs), and two-thirds had received taxanes. Importantly, all but one patient discontinued their previous CPI because of progression.

Safety: The AFM24 and atezolizumab combination therapy was well tolerated with no unexpected safety findings. Infusion related reactions (IRRs) were the most common adverse event (AE) reported, in 54% of patients; IRRs were manageable, mostly present during the first infusion, and fully resolved. Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), a known side effect of atezolizumab, were reported in 21% and 16% of patients respectively.

Anti-tumor activity and durability (N=33, PPS): The combination demonstrated an ORR of 21% (7 responses: 1 complete response (CR), 5 partial responses (PR) and 1 additional not yet confirmed PR), tumor shrinkage in 48% of patients (16/33 patients) and a DCR of 76%. In the 7 responders, 5 had never achieved an objective response on prior CPIs and only 2 patients had a PR on previous CPI containing treatment (both to a triplet of platinum, pemetrexed and CPI). The preliminary median PFS is 5.6 months, and 36% of patients are currently on treatment.

NSCLC EGFR Mutant Cohort Update

Patient population: As of the November 14, 2024 data cut, 28 patients were in the FAS (reasons for non-evaluability at the cut-off were: ongoing with no scan yet 5, early deterioration 4, non-related AEs 2), with updated results presented for the first 17 patients in the PPS. All patients had received prior EGFR specific TKI therapy, and 77% had received platinum-based chemotherapy.

Anti-tumor activity and durability (N=17, PPS): AFM24 combined with atezolizumab showed promising activity in refractory NSCLC EGFRmut patients achieving an ORR of 24% (4 confirmed responses: 1 CR, 3 PRs), a DCR of 71% and tumor shrinkage in 41% of patients. With a median follow-up of 9 months, the median PFS was 5.6 months. Five (29%) patients are on treatment for over 10 months, demonstrating long term tumor control.

Post-Hoc Exposure-Response Analysis

Analysis process: A post-hoc exposure-response analysis was conducted including NSCLC EGFRwt and EGFRmut subjects (n= 44) treated with 480 mg AFM24 in both the AFM24-101 monotherapy study or the AFM24-102 AFM24 combination with atezolizumab study. Low and high exposure groups were calculated using a median cut-point of patient`s mean trough values.

Safety, anti-tumor activity and durability: Baseline characteristics were balanced between the high and low exposure groups and there were no differences in body mass index or percentage of administered dose that would explain differences in exposure. The high exposure group showed an ORR of 46% and a PFS of 7.4. A sensitivity analysis using quartiles of exposure supported a clear relationship between exposure and outcome indicating that higher doses of AFM24 will likely result in improved efficacy. The PK profile of 720 mg AFM24 weekly, as tested successfully in the phase 1 trial and further pharmacokinetic modelling indicate that 720 mg will achieve exposure levels that are equal or above the plasma concentrations observed for the high exposure group.

"Advanced-stage NSCLC remains one of the most challenging cancers to treat, and our findings bring new hope," said Dr. Andreas Harstrick, MD, Chief Medical Officer of Affimed. "We see compelling efficacy results with the AFM24/atezolizumab combination in heavily pretreated NSCLC patients, independent from the mutational status. The results are remarkable as we achieve this with a purely immunotherapy-based approach in patients that are often not able or not willing to take additional toxic therapies. The insights in the relation of exposure and efficacy will allow us to further improve on the efficacy and provide a clear path forward as we strive to unlock new possibilities for EGFR NSCLC patients."

About AFM24

AFM24 is a tetravalent, bispecific ICE that activates the innate immune system by binding to CD16A on innate immune cells and epidermal growth factor receptors (EGFR), a protein widely expressed on solid tumors, to kill cancer cells. Generated by Affimed’s fit-for-purpose ROCK platform, AFM24 represents a distinctive mechanism of action that uses EGFR as a docking site to engage innate immune cells for tumor cell killing through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

On December 17, 2024 Actuate Therapeutics, Inc. (NASDAQ: ACTU) ("Actuate" or the "Company"), a clinical-stage biopharmaceutical company focused on developing therapies for the treatment of high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β), reported new positive data from its ongoing and fully enrolled randomized Phase 2 trial of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) in first line treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) (Actuate-1801 Part 3B) (Press release, Actuate Therapeutics, DEC 17, 2024, View Source [SID1234649155]).

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A pre-specified analysis was triggered by reaching >70% death events in the GnP control arm (data cut off November 15, 2024). The analysis of interim data demonstrated treatment with elraglusib in combination with GnP resulted in statistically significant increases in 1-year survival rate (p value of 0.002) and median overall survival (p value of 0.016, hazard ratio of 0.63) versus treatment with GnP alone. The combination treatment also resulted in increased Objective Response Rates (ORR) and Disease Control Rates (DCR) in the elraglusib/GnP combination arm versus the GnP control arm.

"These interim results are highly encouraging and underscore the transformative potential of elraglusib in the treatment of metastatic pancreatic cancer," said Daniel Schmitt, President & Chief Executive Officer of Actuate. "The improvement in median and overall long-term survival, disease control rate and overall response rate compared to GnP alone, combined with elraglusib’s favorable risk-benefit profile, offers the possibility of improved outcomes for patients with limited treatment alternatives. We are excited to continue evaluating the potential of elraglusib, a novel immune-oncology GSK-3 targeted approach for mPDAC, and look forward to engaging with the FDA in 1H 2025 to share topline data and discuss next steps, including a proposed phase 3 registration trial.

Inhibition of GSK-3β may inhibit tumor growth and improve survival through several complimentary mechanisms that include enhancement of chemotherapy activity, activation of innate anti-tumor immunity and regulation of gene expression, leading to alterations in tumor metabolism and Epithelial-to-Mesenchymal Transition (EMT).

Study highlights include:

· The interim data met the trial primary endpoint with a 1-year survival rate of 43.6% in the elraglusib-GnP combination arm versus 22.5% in the GnP control arm (p=0.002);
o Eighteen and twenty-four month survival rates also demonstrated benefit of 20.9% vs 0% and 16.7% vs 0% in the elraglusib-GnP combination vs GnP arms, respectively.
· As of the November 15, 2024 cutoff, 38% of subjects were still alive in the elraglusib-GnP combination arm vs 19% in the GnP control arm.
· A statistically significant 37% reduction in risk of death and increased median overall survival were observed in the elraglusib-GnP combination arm (mOS 9.3 months) vs the GnP control arm (mOS 7.2 months), (HR=0.63 p=0.016).
· The trial also met its primary safety endpoint. Treatment-emergent adverse events (TEAEs) and Serious Adverse Events (SAEs) in the elraglusib-GnP combination arm were similar to those observed in the GnP arm, indicating a favorable risk-benefit profile for the elraglusib-GnP combination.
· At the interim cutoff of November 15, 2024, the ORR was 27.7%, DCR was 42.6 %, and PFS was 5.6 months in the elraglusib-GnP combination arm versus 20.5%, 33.3% and 4.9 months in the GnP arm, respectively.
· To date, there have been 2 patients in the elraglusib/GnP combination arm with previously inoperable metastatic lesions with noted reductions in target lesions and referred for successful resection, 1 of which resulted in 100% reduction in total tumor burden after surgery. In addition, there have been 1 Complete Response and 1 Partial Response with 100% reduction in target lesions in the elraglusib GnP combination arm versus 0 in the control arm to date.

"Pancreatic cancer is one of the most aggressive and lethal cancers with less than 5% survival rate in the US at 5 years. We are encouraged by consistent evidence of significant clinical benefit and anti-tumor activity in the elraglusib combination arm across multiple endpoints in this study," said Dr. Andrew Mazar, Actuate’s Scientific Co-Founder and Chief Operating Officer. "Further, the favorable risk-benefit profile observed to date may provide a treatment option for many patients with metastatic pancreatic cancer that may not tolerate more aggressive and less tolerable chemotherapy approaches."

The ongoing Actuate-1801 Part 3B study (NCT03678883) is a randomized, controlled Phase 2 trial of elraglusib with GnP versus GnP alone in first line mPDAC. The trial enrolled 286 mPDAC patients with no prior systemic treatment for metastatic disease, who were randomized 2:1 to the elraglusib treatment arm (elraglusib + GnP) or the control arm (GnP alone). Elraglusib is administered at a dose of 9.3 mg/kg by IV infusion on Day 1 of each week of a 28-day cycle. The primary endpoint is 1-year survival rate, with mOS the primary parameter for summarization of survival data at the end of the study. Secondary endpoints are DCR, ORR, PFS and AE.

On December 17, 2024 Sairopa B.V., reported it has achieved a milestone event in its exclusive clinical development and option agreement with Exelixis, Inc. (Nasdaq: EXEL) involving ADU-1805, an innovative anti-SIRPα antibody with the potential to enhance the immune system’s ability to combat cancer (Press release, Sairopa, DEC 17, 2024, View Source [SID1234649153]).

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Under the terms of the agreement, Exelixis has an exclusive option to license worldwide development and commercialization rights for ADU-1805 and other anti-SIRPα antibodies following the review of data from Sairopa’s phase 1 clinical studies. As part of its collaboration with Exelixis, Sairopa has previously received from Exelixis an upfront payment of $40 million, a $35 million milestone payment upon Investigational New Drug (IND) clearance of ADU-1805 with the U.S. Food and Drug Administration, and $35 million in milestone payments linked to advances within the clinical development of ADU-1805, in monotherapy as well as in combination with a PD-1 inhibitor.

"Today’s operational update signifies a step forward in the partnered effort to develop next-generation therapies for cancer patients worldwide," said Gurvinder S. Chahal, Chief Business Officer of Sairopa. "The advances seen within our clinical program are a testament to the diligent work and innovative science behind our partnership with Exelixis, bringing us closer to realizing our mission of modulating the immune system to improve outcomes for cancer patients."

The safety and pharmacokinetics of ADU-1805 are currently being evaluated in a first-in-human, open-label, multicenter, multi-arm phase 1 study. To date, patients have been enrolled across the U.S. and several European countries, with assessments ongoing in both the ADU-1805 monotherapy and the ADU-1805 plus pembrolizumab dose escalation arms.

This collaboration combines Exelixis’ proven track record in oncology drug development and commercialization with Sairopa’s expertise in generating innovative cancer immunotherapies, setting the stage for potentially transformative treatments in oncology.

On December 17, 2024 AB Science SA (Euronext – FR0010557264 – AB) reported an update on its AB8939 program in acute myeloid leukemia (AML) (Press release, AB Science, DEC 17, 2024, View Source [SID1234649151]).

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AB8939 target product profile

AB8939 is a next generation synthetic microtubule destabilizer and stem cell targeted ALDH1/2 inhibitor with key differentiating factors for treatment of refractory/relapsing acute myeloid leukemia (AML).

▪AB8939 blocks proliferating leukemia cells through microtubules AB8939 destabilizes microtubule, is not subjected to multidrug resistance as it does not bind to PgP, responsible of efflux outside the cells and AB8939 is not degraded by the enzyme myeloperoxidase.

▪AB8939 targets leukemia cancer stem cells though inhibition of ALDH AB8939 inhibits ALDH1/2 and favors the bone marrow repopulation of normal progenitors. ▪AB8939 is well suited for the treatment of relapsed or refractory AML AB8939 has activity seen across refractory AML cell lines, has an additive effect with referenced first line treatment for AML, namely cytarabine, azacitidine and venetoclax.

▪AB8939 has a potential use in AML with MECOM AB8939 has shown a signal of efficacy in AML with MECOM gene rearrangement, a subset of patients that show extreme resistance to chemotherapies and exhibit the worst survival prognosis

▪AB8939 shows absence of hematological toxicity based on clinical data

Addressable market with AB8939 in relapsed/refractory AML

Treatments in relapsed or refractory AML represent an estimated market size potential above EUR 2 billion per annum.

Non clinical pharmacology

Animal experiments have shown the following properties for AB8939 relevant for the treatment of AML: ▪AB8939 is active against chemotherapy naive or chemotherapy refractory/relapsing patient’s AML cancers cells ex vivo ▪AB8939 eradicates blasts in Blood and Bone Marrow in 5-AraC-resistant (Cytarabine) PDX

▪AB8939 increases survival and has an additive effect in combination with reference treatment Azacitidine and Venetoclax

▪ALDHs expression is a hallmark of cancer stem cells (CSCs) and AB8939 is an inhibitor of ALDH1/2. Therefore, AB8939 is a targeted therapy for leukemia cancer stem cells

▪AB8939 eradicates Leukemia Cancer Stem Cells in a human PDX AML model

Phase 1 preliminary safety

The objective of the phase 1 is to determine the maximum tolerated dose (MTD) for three different cycles of AB8939. The first step of the phase 1 has been completed with 28 patients enrolled, evaluating the maximum tolerated dose after 3 consecutive days of AB8939 treatment. The second step of the phase 1 is close to completion and enrolled 10 patients, evaluating the maximum tolerated dose after 10 consecutive days of AB8939 treatment. The next step is to evaluate the maximum tolerated dose after 14 consecutive days of AB8939 treatment in combination with venetoclax or azacitidine and in combination with venetoclax plus azacitidine, both drugs being widely used on AML and for which AB8939 has shown an additive effect.

Preliminary activity in MECOM

MECOM is associated with a dismal outcome, with almost all patients dying within 12 months after relapse. AB8939 is a stem cell ALDH targeted therapy with potential use in AML with MECOM.

▪ALDH gene expression is a marker of survival prognosis in AML. The higher the expression, the worse the prognosis

▪MECOM is associated with the worst prognosis in AML

▪MECOM is a rearrangement or a mutation of the chromosome 3 locus Q26 that codes for the transcription factor gene EVI1 (Ecotropic virus integration site-1)

▪The expression of ALDH1A1 is regulated by EVI1 and has an outstanding role in the formation and transformation of hematopoietic cells and in particular leukemia stem cells

▪The hypothesis is that in MECOM, the rearrangement of chromosome 3 Q26 leads to EVI1 over-expressing ALDH1A and induces high resistance of leukemia stem cells, and AB8939 should have an impact on leukaemia stem cells by inhibiting ALDH1 AB8939 has shown activity on MECOM rearrangement, based on non-clinical data and early clinical data in relapsing/refractory line of treatment, with 50% response rate observed. Planned phases 2 The next steps in the clinical development will be discussed with FDA and EMA. The first intended step is to develop AB8939 in patients with MECOM AML, through a single arm study with less than 60 patients supporting an accelerated approval based on response rate.

The second objective is to position AB8939 in broader forms of AML and position AB8939 in relapsed or refractory AML. The third objective is to capture the full market potential of AB8939 and position AB8939 in first line in combination with standard of care.

Intellectual property

AB8939 intellectual property rights in AML are secured until 2036 through a ‘composition of matter’ patent and potentially until 2044 in AML with chromosome abnormality, including MECOM, through a ‘second medical use’ patent. AB Science is the sole proprietary holder of AB8939 and its family of compounds.

On December 17, 2024 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a clinical-stage biotechnology company developing novel LAG-3 immunotherapies for cancer and autoimmune disease, reported favourable initial safety data from the placebo-controlled, double-blind first-in-human Phase I study evaluating IMP761 (Press release, Immutep, DEC 17, 2024, View Source [SID1234649141]). Through the first three of five single ascending dose cohorts in healthy participants, there have been no treatment related adverse events.

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Dr. Frédéric Triebel, CSO of Immutep, said: "We are very encouraged by the safety data generated to date for IMP761, the world’s first LAG-3 agonist antibody, in this Phase I setting. Derisking this promising asset in this proof-of-concept study in healthy subjects assessing its safety and immunosuppressive efficacy on an antigenspecific T-cell mediated intra-dermal reaction is an important step for this exciting program in autoimmune diseases. Given that IMP761 is potentially addressing the root cause of many different autoimmune diseases, we are eager to see this study generating more data."

The trial in up to 49 participants is being conducted by the Centre for Human Drug Research (CHDR) in Leiden, the Netherlands. In addition to the safety analysis, CHDR is implementing its keyhole limpet haemocyanin (KLH) challenge model to evaluate IMP761’s pharmacological activity. Additional safety data and assessment of pharmacokinetic/pharmacodynamic (PK/PD) relationships to follow in the first half of CY2025.

The LAG-3 (lymphocyte-activation gene-3) immune checkpoint has been identified as a promising target for an agonist antibody to treat rheumatoid arthritis, Type 1 diabetes, and multiple sclerosis, among potentially many other autoimmune diseases.1,2,3 This first-in-class agonist LAG-3 antibody is designed to restore balance to the immune system by enhancing the "brake" function of LAG-3 to silence dysregulated self-antigenspecific memory T cells that cause many autoimmune diseases. In preclinical studies, IMP761 has led to a large decrease in inflammatory cytokines and demonstrated its effectiveness in suppressing antigen-specific T cell–mediated immune responses.4