On April 8, 2022 Scorpion Therapeutics, Inc. ("Scorpion Therapeutics" or the "Company"), a pioneering oncology company redefining the frontier of precision medicine through its Precision Oncology 2.0 strategy, reported preclinical proof-of-concept data for STX-478, the Company’s first development candidate from its STX-H1047-PI3Kα program (Press release, Scorpion Therapeutics, APR 8, 2022, View Source [SID1234611753]). STX-478, formerly ST-814, is a highly differentiated, allosteric and central nervous system ("CNS")-penetrant small molecule specifically designed to inhibit the H1047X-mutant form of phosphoinositide 3-kinase alpha ("PI3Kα"), one of the most frequent variations in PI3Kα and a validated oncogenic disease driver across a variety of solid tumors. The data will be presented on Wednesday, April 13 in a late-breaking poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2022 in New Orleans, Louisiana.

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"We are pleased to announce preclinical proof-of-concept data for STX-478, a potential best-in-class mutant-selective PI3Kα inhibitor and our first development candidate," said Axel Hoos, M.D., Ph.D., chief executive officer of Scorpion Therapeutics. "These data are a perfect exemplar of our approach to deliver potential best-in-class molecules against validated targets through our Precision Oncology 2.0 strategy, which aims to optimize drug design to achieve target product profiles that directly address unmet patient needs. In only 18 months since program initiation, we believe we have developed a highly differentiated inhibitor of PI3Kα that overcomes the two major limitations of currently available agents – lack of selectivity for mutant PI3Kα and limited CNS penetrance – to potentially deliver superior efficacy across an array of tumor types. We are now focused on progressing STX-478 through IND-enabling studies and look forward to submitting our first IND application in the first half of 2023."

PI3Kα is one of the most highly mutated targets in cancer and mutations at the H1047X residue represent the highest frequency variants in PI3Kα. More than 55,000 people in the United States annually are diagnosed with cancers driven by mutations at this residue.1 The frequency of PI3Kα mutations in driving tumor progression has made the target a high priority for drug discovery. However, currently available treatments are limited by their inhibition of the normal, or wild-type, version of PI3Kα in healthy tissues, which can lead to significant metabolic side effects, including hyperglycemia, that hinder the ability of patients to tolerate these therapies. In addition, despite the fact that up to 50% of all solid tumor patients will develop significant morbidity and mortality from brain metastases, existing options have little to no CNS penetrance, and are therefore unable to treat tumors that have progressed into the brain.

In the preclinical data presented at AACR (Free AACR Whitepaper), STX-478 demonstrated exceptional selectivity for PI3Kα against the kinome, with activity against PI3Kα kinase domain mutants, including the most commonly occurring variant, H1047R. Additionally, STX-478 demonstrated activity across a spectrum of PI3KαH1047X cell line-derived xenograft models and tumor types, while avoiding the metabolic dysfunction induced by currently marketed therapies and achieving superior tumor growth inhibition. Pharmacokinetic analyses suggest that STX-478 benefits from outstanding drug-like properties, with adequate CNS exposure to treat brain tumors or metastases. The predicted long half-life and minimum peak-to-trough plasma concentrations support once-daily dosing and a favorable therapeutic index in patients.

"Through our proprietary drug-hunting platform, we have developed an atomic-level understanding of the activating mutations in PI3Kα and successfully designed STX-478 to selectively target mutant PI3Kα, while avoiding the normal, or wild-type, form in healthy tissues," said Darrin Stuart, Ph.D., chief scientific officer of Scorpion Therapeutics. "Despite widespread recognition of PI3Kα as a clinically validated oncogene, currently marketed agents are not wild-type sparing and therefore can be associated with significant dose-limiting toxicities. The new data to be presented at AACR (Free AACR Whitepaper) demonstrate the potential of STX-478 to deliver superior safety, tolerability and efficacy, and we look forward to advancing our small molecule to deliver better solutions to patients with cancer."

Based on these data, Scorpion Therapeutics named STX-478 as the lead development candidate from its STX-H1047-PI3Kα program in March 2022. STX-478 is currently advancing through preclinical development with an investigational new drug application submission expected in the first half of 2023.

On April 8, 2022 OncoOne, a biotechnology company focused on discovering precision medicines for cancer and autoimmune diseases, reported the presentation of preclinical proof-of-concept data on its lead candidate ON203, a therapeutic monoclonal antibody targeting oxMIF, and the radiodiagnostic 89Zr-ON102, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022, held from April 8-13, in New Orleans, Louisiana (Press release, OncoOne, APR 8, 2022, View Source [SID1234611752]). ON203 demonstrated tumor growth suppression in two cancer mouse models and superior tumor cell killing effects in vitro as compared to a first generation anti-oxMIF antibody which had reached clinical evaluation. Conference participants can access the data in both a poster format and an online oral presentation via the conference website. The poster #313 will be presented on Sunday, April 10 in the poster session "Antibodies and Immune Therapies", from 1:30 – 5:00 pm CDT.

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"OncoOne has applied its drug discovery and development expertise combined with a unique depth of knowledge on the potential of oxMIF, the disease-related isoform of the highly prevalent cytokine, MIF, to develop ON203 as a valuable potential treatment for solid tumors," said Randolf Kerschbaumer, PhD., CEO of OncoOne. "The preclinical data presented at AACR (Free AACR Whitepaper) further validates our approach as we prepare to initiate the evaluation of ON203 in a Phase I clinical trial in patients with solid tumors."

Alexander Schinagl, PhD., CTO of OncoOne added: "The concept of targeting oxMIF is gaining attention, as demonstrated by this week’s publication of the redox dependent oxMIF structure by Erin Skeens and coworkers in the Cell Press journal, Structure".1

The poster entitled "Novel bioengineered monoclonal antibodies targeting oxidized macrophage migration inhibitory factor as anti-cancer therapeutics and diagnostics" highlights the improved properties of OncoOne’s next-generation anti-oxMIF antibodies, as compared to the first generation anti-oxMIF antibody that was well tolerated in Phase I and II clinical trials. Bioengineering significantly reduced hydrophobicity of ON203 and ON102, leading to improved stability and strongly reduced aggregation but retaining specificity and the low nM affinity for oxMIF. This resulted in an improved biodistribution and tumor retention in mice harboring solid tumors of the colon. In vivo studies of ON203 in mouse models of prostate cancer further demonstrated significantly improved efficacy, showing that ON203 effectively suppressed tumor growth without acute signs of toxicity. OncoOne will advance ON203 toward the clinic as a highly optimized oxMIF targeting treatment option for patients with solid tumors as a monotherapy and in combinatory approaches with other immunotherapies or checkpoint inhibitors.

The poster will be available on OncoOne’s website upon conclusion of the AACR (Free AACR Whitepaper) 2022 Annual Meeting.

On April 8, 2022 Immune-Onc Therapeutics, Inc. ("Immune-Onc"), a private, clinical-stage cancer immunotherapy company developing novel biotherapeutics targeting myeloid checkpoints, reported two poster presentations on its clinical stage program IO-108, a novel myeloid checkpoint inhibitor targeting Leukocyte Immunoglobulin-Like Receptor B2 (LILRB2, also known as ILT4), at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Immune-Onc Therapeutics, APR 8, 2022, View Source [SID1234611751]).

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Tumor-associated myeloid cells are immunosuppressive cells that contribute to impaired anti-tumor responses, and limit the efficacy of currently approved cancer immunotherapies, such as T cell checkpoint inhibitors. LILRB2 is a receptor expressed primarily by myeloid cells that has several ligands known to contribute to immune suppression in the tumor microenvironment (TME).

"The pioneering work of our scientific team shows that IO-108 binds to LILRB2 with high affinity and specificity and blocks the interaction of LILRB2 with multiple immunosuppressive ligands. As a result, IO-108 activates and enhances anti-tumor immune responses ex vivo and inhibits the growth of solid tumors in preclinical models," said Charlene Liao, Ph.D., chief executive officer of Immune-Onc. "Collectively, these studies have enabled a comprehensive clinical biomarker plan and further support the ongoing Phase 1 clinical study of IO-108 as a novel immunotherapy for multiple solid tumor types, including those that are resistant to or relapsed after T cell checkpoint inhibitor treatments."

Ex vivo studies show that treatment with IO-108 produces pro-inflammatory activity and an enhanced antigen-presenting cell (APC) phenotype to multiple stimuli, including T cell activators, and STING and TLR agonists. As a single agent, IO-108 reverts the anti-inflammatory myeloid cell phenotype caused by "tumor conditioning" to pro-inflammatory phenotype and promotes the differentiation of monocytes and immature dendritic cells into pro-inflammatory dendritic cells, which are critical in generating productive anti-tumor immune responses.

IO-108 enhances the effect of PD-1 blocking antibodies in CD4+ T cell activation by allogeneic macrophages. Moreover, IO-108 monotherapy inhibits the growth of solid tumors in a preclinical model, which is associated with immune cell activation. Importantly, IO-108 presents a favorable pharmacokinetic and safety profile in preclinical models.

In the ongoing Phase 1 study of IO-108 in adult patients with advanced or refractory solid tumors (NCT05054348), IO-108 is studied at 60, 180, 600 and 1800 mg in monotherapy and at 180, 600 and 1800 mg in combination with 200 mg of pembrolizumab, administered intravenously every three weeks. IO-108 has been well-tolerated to date, both as a monotherapy and in combination with pembrolizumab, and dose-limiting toxicity has not been observed so far, at up to 600 mg in monotherapy and 180 mg in combination with pembrolizumab. Enrollment is ongoing with the last patient in expected in the second quarter of 2022.

Details of Immune-Onc’s AACR (Free AACR Whitepaper) 2022 presentations are as follows:

Abstract Number: 601
Title: IO-108, A fully human therapeutic antibody blocking the myeloid checkpoint LILRB2/ILT4, promotes innate and adaptive anti-cancer immunity in preclinical studies
Presentation Time: April 10, 2022, 1:30 PM – 5:00 PM ET
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 38

Abstract Number: CT209
Title: A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors (NCT05054348)
Presentation Time: April 12, 2022, 9:00 AM – 12:30 PM ET
Location: New Orleans Convention Center, Exhibit Halls D-H, Poster Section 34

ABOUT LILRB2 (ILT4)

LILRB2, also known as ILT4, is expressed mostly by myeloid cells, including monocytes, macrophages, dendritic cells, and neutrophils. In solid tumors, activation of LILRB2 by its ligands, including HLA-G, ANGPTLs, SEMA4A, and CD1d, induces a tolerogenic phenotype in myeloid cells, thereby promoting poor T cell activation and consequent tumor immune evasion.

On April 8, 2022 Orum Therapeutics, a private biotechnology company pioneering the development of tumor-directed targeted protein degraders (TPDs), reported that preclinical data for ORM-5029, a potential first-in-class TPD therapy for HER2-positive cancers, at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2022 (Press release, Orum Therapeutics, APR 8, 2022, View Source [SID1234611750]). ORM-5029 is one of two lead programs from the company’s Antibody neoDegrader Conjugate (AnDC) platform based on its Dual-Precision Targeted Protein Degradation (TPD²) approach.

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ORM-5029 is designed to selectively deliver catalytic GSPT1 protein degraders to HER2-expressing tumor cells via antibody targeting. Orum developed a proprietary class of GSPT1 degrader molecules, paired them with a HER2-targeting antibody, pertuzumab, and screened numerous candidate conjugates to identify a molecule with the desired therapeutic profile. The data presented at AACR (Free AACR Whitepaper) 2022 describes initial preclinical evaluation of potency, efficacy, and pharmacodynamic (PD) response of ORM-5029.

"Targeted protein degradation holds much therapeutic promise, but classic TPD approaches face clinical development hurdles, including optimizing potency, exposure, and tolerability," said Peter U. Park, Ph.D., Chief Scientific Officer of Orum Therapeutics. "We believe that we can fulfill the promise of TPD by developing novel small molecule degraders combined with the precise cellular delivery mechanism of antibodies. Compared to either small molecule GSPT1 degraders or standard-of-care antibody drug conjugates, ORM-5029 exhibited superior in vitro and in vivo potency, robust efficacy in low-HER2 settings, and dose-dependent efficacy. These data provide compelling evidence to support our unique approach to targeted protein degradation and continue development of ORM-5029."

Key data takeaways:

ORM-5029 displays robust efficacy both in vitro and in vivo compared to other small molecule GSPT1 degraders and approved antibody drug conjugates (ADCs)
ORM-5029 exhibits potent activity in HER2-low models both in vitro and in vivo
Dose-dependent efficacy of ORM-5029 correlates with robust and rapid PD modulation of tumor GSPT1 protein levels
Orum’s proprietary payload, SMol006, is a potent degrader with high selectivity for GSPT1 and is compatible with any ADC linker and conjugation technologies.
AACR 2022 is taking place both virtually and in-person at the Ernest N. Morial Convention Center in New Orleans from April 8-13. The poster presentation titled, "ORM-5029: A first-in-class targeted protein degradation therapy using antibody neodegrader conjugate (AnDC) for HER2-expressing breast cancer," will be available for viewing to registered attendees from Friday, April 8, through Wednesday, July 13, on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website. The poster (abstract # 3933) will be presented in person on April 13 from 9:00 am to 12:30 pm in Session PO.ET06.06 – Emerging New Anticancer Agents in Exhibit Halls D-H, Poster Section 22, Poster Number 7.

The poster is available on request; please email us at [email protected].

About Orum’s AnDC Platform

Orum’s Antibody neoDegrader Conjugate (AnDC) platform uses the Company’s unique Dual-Precision Targeted Protein Degradation (TPD²) approach to build novel targeted protein degraders (TPD) combined with the precise tumor cell delivery mechanisms of antibodies to generate innovative, first-in-class cell-specific TPD for the treatment of cancer. The company has developed new molecular glue degrader payloads to specifically degrade an intracellular target protein within cancer cells via the E3 ubiquitin ligase pathway. Conjugated to antibodies, neoDegraders are designed to be delivered specifically to cancer cells and degrade the intracellular target protein and cause tumor cell death.

On April 8, 2022 Orphagen Pharmaceuticals Inc., a biotech company pioneering the screening, discovery, and development of small molecule ligands that modulate orphan or unexplored members of the nuclear receptor family, reported a late-breaking presentation of new preclinical data for OR-449 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 being held April 8-13 both virtually and in-person in New Orleans (Press release, Orphagen, APR 8, 2022, View Source [SID1234611749]). The data presented demonstrate efficacy in a preclinical model of a Leydig cell tumor (LCT) of OR-449, the company’s first-in-class small molecule antagonist to the nuclear receptor steroidogenic factor-1 (SF-1 or NR5A1) and support the continued development of OR-449 as a novel targeted therapy for the treatment of LCTs as well as adrenocortical cancer (ACC), the primary indication for which it is being developed.

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"OR-449 was strategically designed at Orphagen and is the first antagonist to SF-1 to be taken into development – potent and orally bioavailable small molecules of this class have not previously been identified," said Scott Thacher, Ph.D., CEO and Founder of Orphagen. "The data presented at AACR (Free AACR Whitepaper) 2022 demonstrate that OR-449, a potent SF-1 antagonist, has clear potential for clinical efficacy in malignant LCTs as well as ACC. There is an urgent need for new therapies for LCT and ACC, and we are focused on completing IND-enabling studies of OR-449 with the goal of filing an investigational new drug application by the end of the year."

The incidence of ACC in the U.S. is 300 patients per year, and existing therapies are very limited. LCTs represent about 3% of all testicular cancers. Testicular cancer is in turn one of the most frequently diagnosed cancers in American males between the ages of 15 and 35. Malignant LCTs, though rare, are an estimated 10% of all LCTs. They are resistant to chemotherapy and radiation, responding primarily to surgery. Median survival from diagnosis is two years for these patients.

Summary of Results

OR-449 exhibits striking anti-proliferative activity in the rat Leydig tumor cell (LCT) line R2C, inhibiting DNA synthesis by >90% at 1 mM with an estimated IC50 of 68 nM.
In cell lines lacking SF-1 expression, such as HEK293, OR-449 has no anti-proliferative activity up to 20 mM, indicating that the anti-proliferative effect on R2C is SF-1-mediated and is not due to cytotoxicity.
OR-449 inhibits R2C xenograft tumor growth in immunocompromised mice at oral doses of 3, 10, and 30 mg/kg/day, with complete inhibition at a daily dose of 30 mg/kg.
Based on an mRNA response signature first identified in R2C culture, OR-449 appears to directly engage with SF-1 in the R2C tumors.
The in vivo potency and efficacy of OR-449 in the R2C model corresponds to what we previously reported for SJ-ACC3 (Crowe et al, ENDO 2021), a pediatric ACC patient-derived tumor xenograft (PDX) model.
These results highlight that OR-449 antagonism of SF-1 is a novel targeted therapeutic approach with potential utility in the treatment of ACC and malignant LCTs. Orphagen has initiated IND-enabling studies of OR-449 with an anticipated IND-filing date at the end of 2022.

The poster (abstract #LB144) titled, "Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors," will be available on the AACR (Free AACR Whitepaper) Annual Meeting 2022 website for registered attendees to view from Friday, April 8 through Wednesday, July 13. The poster will also be available via the company on request. The poster will be presented in person on Tuesday, April 12 from 9 am to 12:30 pm CT at the New Orleans Convention Center, Exhibit Halls D-H, Poster Section 27, Poster Board Number 17.

The authors acknowledge the support of the following NIH grants: R43 DK 102221, R43 CA 150540, R43 HD 068078, R43 CA 099875, R44 CA 265639.

Reference: Crowe, et al. A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010

About OR-449

OR-449 is the lead candidate identified from Orphagen’s proprietary screening technology, which has led to successful discovery of the first drug-like small molecules to several orphan nuclear receptors. OR-449 is a first-in-class, orally bioavailable small molecule antagonist to SF-1, an orphan nuclear receptor that is essential for the embryonic growth and development of adrenal and gonadal tissues. Clinical targets for SF-1 antagonism by OR-449, such as ACC and malignant LCT, are derived from these tissues and express very high levels of this novel drug target.