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

On December 16, 2024 Candid Therapeutics, Inc. ("Candid"), a clinical-stage biotechnology company focused on becoming the leader in advancing T-cell engagers for autoimmune diseases, and EpimAb Biotherapeutics, Inc. ("EpimAb" or "EpimAb Biotherapeutics") a clinical-stage biopharmaceutical company specializing in the discovery and development of multi-specific antibodies for diseases with high unmet need, reported that the companies have entered a strategic research collaboration to discover and develop novel T-cell Engager program candidates for various autoimmune indications (Press release, Candid Therapeutics, DEC 16, 2024, View Source [SID1234649149]).

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"EpimAb team has impressed us with their scientific expertise and antibody design capabilities. We are excited to partner with EpimAb as we broaden our pipeline of novel TCEs for autoimmune indications," said Dr. Ken Song, Chairman, President and CEO of Candid.

"We are excited to enter this partnership with Candid, a company with the leadership and resources to realize full potential of TCEs in autoimmune indications," said Dr. Chengbin Wu, CEO and founder of EpimAb. "We are proud of the versatility of our proprietary bispecific and TCE platforms and the partnership with Candid provides further validation of our approach."

Under the terms of the agreement, EpimAb is entitled to obtain an upfront payment, and development and sales milestones totaling over $1 billion, assuming multiple drug candidates are advanced through commercialization, as well as royalties on net sales. Candid has exclusive worldwide rights to develop and commercialize programs discovered under the collaboration.

On December 16, 2024 Personalis, Inc. (Nasdaq: PSNL) and Tempus AI, Inc. (Nasdaq: TEM) reported that the companies have expanded their commercial relationship (Press release, Personalis, DEC 16, 2024, View Source [SID1234649148]). The companies agreed in November 2023 to collaborate and bring ultra-sensitive MRD testing to market and launched their efforts at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. Tempus is serving as the exclusive commercial diagnostic partner for Personalis’ ultra-sensitive tumor-informed MRD product, NeXT Personal Dx, for broad patient adoption in breast and lung cancers, and for immunotherapy monitoring across all solid tumors.

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Following a positive reaction from the diagnostic market, the companies have agreed to expand their relationship to the biopharma industry. Under this expanded relationship, Tempus will be enabled to offer Personalis’ NeXT Personal MRD product to pharmaceutical and biotech customers who wish to bundle MRD testing with other Tempus offerings in a given study.

"While we already offer NeXT Personal through our own biopharma channel, we are pleased to leverage Tempus’ integrated platform as well for these biopharma customers who desire to combine NeXT Personal with other Tempus products," said Chris Hall, CEO of Personalis. "We believe the expansion of the relationship with Tempus will accelerate market penetration of our leading ultra-sensitive MRD platform and allow us to better capitalize on the opportunity."

On December 16, 2024 MAIA Biotechnology, Inc., (NYSE American: MAIA) ("MAIA", the "Company"), a clinical-stage biopharmaceutical company developing targeted immunotherapies for cancer, reported that the FDA has designated THIO for the treatment of pediatric-type diffuse high-grade gliomas (PDHGG) as a drug for a "rare pediatric disease (Press release, MAIA Biotechnology, DEC 16, 2024, View Source [SID1234649147])."

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"THIO is a versatile anti-cancer agent that has demonstrated positive results in multiple difficult to treat cancer types, including pediatric high-grade glioma, which is among the most treatment-resistant cancers in children. THIO is shown to activate the immune system while evading tumor immunosuppression, a novel therapeutic approach for this devastating childhood disease," said MAIA Chairman and Chief Executive Officer Vlad Vitoc, M.D. "We are proud to receive the FDA’s Rare Pediatric Disease designation for THIO, which significantly bolsters our plans for continuing research in the PDHGG indication."

MAIA’s Vice President and Head of Regulatory and Quality K. Robinson Lewis added, "Rare pediatric disease designation also offers a highly valuable incentive for MAIA. Upon FDA approval of a future new drug application in PDHGG, MAIA would be eligible to receive a priority review voucher that can be redeemed or sold as an asset at a very high valuation."

Rare pediatric disease priority review vouchers (PRVs) can be redeemed by drug developers for FDA priority review of a different product or transferred or sold to another sponsor. Since 2015, FDA priority review vouchers have sold as assets at an average amount of $100 million.1

Previous research showcased THIO’s potency as a treatment for a PDHGG subtype known as diffuse intrinsic pontine glioma (DIPG). A research collaboration between MAIA and Nationwide Children’s Hospital found that THIO combined with ionizing radiation (IR) resulted in significantly decreased cell proliferation and produced potent anticancer effects in highly aggressive DIPG. The data was presented in April 2024 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting.

MAIA collaborated with Only Orphans Cote for THIO’s designation request. Only Orphans Cote is a foremost provider of regulatory services and strategies for FDA orphan drug designations and marketing authorization.

In addition to its rare pediatric disease designation in PDHGG, THIO holds orphan drug designations (ODD) in three cancer types: hepatocellular carcinoma (HCC), small cell lung cancer (SCLC) and glioblastoma. MAIA believes that THIO is the only direct telomere-targeting agent currently in clinical development.

About THIO

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a first-in-class investigational telomere-targeting agent currently in clinical development to evaluate its activity in Non-Small Cell Lung Cancer (NSCLC). Telomeres, along with the enzyme telomerase, play a fundamental role in the survival of cancer cells and their resistance to current therapies. The modified nucleotide 6-thio-2’-deoxyguanosine (THIO) induces telomerase-dependent telomeric DNA modification, DNA damage responses, and selective cancer cell death. THIO-damaged telomeric fragments accumulate in cytosolic micronuclei and activates both innate (cGAS/STING) and adaptive (T-cell) immune responses. The sequential treatment with THIO followed by PD-(L)1 inhibitors resulted in profound and persistent tumor regression in advanced, in vivo cancer models by induction of cancer type–specific immune memory. THIO is presently developed as a second or later line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.