On March 15, 2023 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-class1 therapeutics that combine both targeted and immune-mediated mechanisms, reported that Nathan Standifer Ph.D., Executive Director of Translational Science at Tempest, will present a poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2023 Spring Scientific Meeting taking place March 15-17, 2023 in Denver, CO and virtually (Press release, Tempest Therapeutics, MAR 15, 2023, View Source [SID1234628828]). The poster highlights biomarker data from the Phase 1 trial of TPST-1120, an oral selective PPAR⍺ antagonist, showing an association between observed clinical benefit and fatty acid oxidation perturbations and gene expression.

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Poster presentation details:

Title: TPST-1120, a first-in-human peroxisome-proliferator activated receptor-alpha (PPAR-α) antagonist: scientific rationale, clinical activity and biomarker assessments
Date: Thursday, March 16, 2023
Time: 6:00 – 7:30 p.m. MT
Abstract Number: 78

On March 15, 2023 Syndax Pharmaceuticals, Inc. (Nasdaq: SNDX) reported that data from the Phase 1 portion of the ongoing Phase 1/2 AUGMENT-101 trial of revumenib in patients with nucleophosmin mutant (mNPM1) and KMT2A-rearranged (KMT2Ar) relapsed/refractory (R/R) acute leukemia and an analysis describing MEN1 mutations observed in the study have been published in the journal Nature (Press release, Syndax, MAR 15, 2023, View Source [SID1234628827]). Revumenib is the Company’s highly selective, oral menin inhibitor.

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The Phase 1 publication entitled "The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia" includes positive data from 68 patients with R/R acute leukemia evaluable for safety, 60 patients of whom had mNPM1 or KMT2Ar acute leukemia and were evaluable for efficacy. In these heavily pretreated patients with a median of four prior therapies, 30% (18/60) experienced a CR/CRh with a median duration of CR/CRh response of 9.1 months. Revumenib was well-tolerated, and there were no discontinuations due to treatment-related adverse events. The Phase 1 data were recently featured in two oral presentations at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"We are excited to have our Phase 1 AUGMENT-101 data published in such a prominent peer-reviewed journal. As we continue to deepen our understanding of the tumor biology driven by the menin-KMT2A interaction, we gain more evidence to support the potential of revumenib as a best-in-class treatment for both mNPM1 and KMT2Ar acute leukemias," said Michael A. Metzger, Chief Executive Officer. "With the expectation of topline data from the pivotal AUGMENT-101 trial beginning in the third quarter of 2023, followed by a potential New Drug Application filing by the end of 2023, revumenib could become the first menin inhibitor approved for patient use."

A separate companion article published in Nature entitled "MEN1 mutations mediate clinical resistance to menin inhibition" describes somatic mutations in MEN1 that confer resistance to menin inhibitor treatment and further confirm the dependency of mNPM1 and KMT2Ar acute leukemias on the menin-KMT2A interaction. This represents the first report that menin inhibitors exert sufficient selective pressure to drive evolution of escape mutants that confer resistance to all first generation menin inhibitors and impact both mNPM1 and KMT2Ar acute leukemia. These data were highlighted in an oral presentation at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"The robust clinical dataset from a heavily pretreated relapsed/refractory patient population demonstrates that revumenib monotherapy was associated with encouraging clinical benefit, including deep molecular remissions and durable responses, with minimal toxicities," said Ghayas C. Issa, M.D., Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and a corresponding author of the Phase 1 publication. "The identified resistance, a class effect among first-generation menin inhibitors, further validates the menin-KMT2A interaction as the key driver for both mNPM1 and KMT2Ar leukemias. Future and ongoing trials may indicate whether treating patients in earlier settings and in combination would provide higher response rates in mNPM1 or KMT2Ar acute leukemia patients who are less likely to have developed functional mutations."

Overview of Phase 1 Data
The Phase 1 publication in Nature includes data from 68 patients evaluable for safety, 60 patients of whom were evaluable for efficacy, as of a March 2022 data cutoff. Patients were heavily pretreated with a median of four prior therapies, and 46% (31/68) of the patients had at least one prior stem cell transplant. Within the efficacy evaluable population, the overall response rate was 53% (32/60) with a CR/CRh rate of 30% (18/60), and 78% (14/18) of patients with CR/CRh attaining measurable residual disease (MRD) negativity. The median time to CR/CRh response in the trial was 1.9 months, and the median duration of CR/CRh response was 9.1 months in the efficacy evaluable population as of data cutoff. A total of 38% (12/32) of responders proceeded to transplant, with nine in remission at the time of the data cutoff, seven of whom have been in remission for greater than six months and four who have been in remission for greater than a year. Eleven (92%) patients who underwent a transplant were MRD negative prior to transplant.

Revumenib was well-tolerated, and no new safety signals were identified in the trial, including in patients who proceeded to stem cell transplant. There were no discontinuations due to treatment-related adverse events. The only dose limiting toxicity was asymptomatic Grade 3 QT prolongation, observed in 10% of patients treated at or below the RP2D and 13% of patients treated at all doses tested. No ventricular arrythmias or other clinical sequelae related to QTc prolongation were reported. Differentiation syndrome occurred in 16% of patients, all which were Grade 2, and patients responded to standard management of steroids with or without hydroxyurea.

About Revumenib
Revumenib is a potent, selective, small molecule inhibitor of the menin-KMT2A binding interaction that is being developed for the treatment of KMT2A-rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1-mutant AML. Revumenib is currently being evaluated in several clinical trials, including the Company’s pivotal AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Robust clinical activity with durable responses have been reported in the Phase 1 portion of AUGMENT-101. Revumenib was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was also granted Breakthrough Therapy Designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

About AUGMENT-101
AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of orally administered revumenib. The Phase 1 dose escalation portion of AUGMENT-101 included two cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. Arm A enrolled patients not receiving a strong CYP3A4 inhibitor, while Arm B enrolled patients receiving a strong CYP3A4 inhibitor. The Phase 2 pivotal portion of AUGMENT-101 is currently underway. Patients will be enrolled across the following trial populations: patients with NPM1-mutant AML, patients with KMT2Ar AML, and patients with KMT2Ar ALL, each of which may serve as the basis for regulatory filings. Following the receipt of Breakthrough Therapy designation from the FDA for revumenib for the treatment of R/R acute leukemia harboring a KMT2A rearrangement, regardless of age or tumor type, and based on discussions with the FDA, the Company will pool data from the AUGMENT-101 cohorts enrolling R/R KMT2Ar AML and R/R KMT2Ar ALL to file a single NDA for the treatment of adult and pediatric KMT2Ar acute leukemia. The primary endpoint for each of the trials is efficacy as measured by complete remission rate (CR + CRh), with key secondary endpoints including duration of response (DOR) and overall survival (OS).

About KMT2A (MLL) Rearranged Acute Leukemia
Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia known to have a poor prognosis, with less than 25% of adult patients surviving past five years. KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.

KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques. The median overall survival (OS) after standard of care first-line treatment, including intensive chemotherapy and transplant, is less than one year and the majority of patients suffer relapse within five years. Most R/R patients treated with second-line therapy relapse within the first year. With third line treatment or beyond, only a small percentage of patients achieve complete remission (CR), and the median OS is less than three months. There are currently no approved therapies indicated for KMT2A- rearranged acute leukemia.

About NPM1-Mutant Acute Myeloid Leukemia
NPM1-mutant acute myeloid leukemia (AML), which is distinguished by mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%. Similar to KMT2A- rearranged acute leukemia, NPM1-mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-KMT2A interaction. NPM1-mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1-mutant AML.

On March 15, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast and gynecological cancers harboring ESR1 mutations, reported an e-poster at the St. Gallen International Breast Cancer Conference detailing its Phase 2 clinical trial evaluating neoadjuvant lasofoxifene in molecularly selected HR+/HER2-, locally advanced breast cancer (Press release, Sermonix Pharmaceuticals, MAR 15, 2023, View Source [SID1234628826]).

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The 18th St. Gallen conference, titled Primary Therapy of Early Breast Cancer. Evidence, Controversies, Consensus, is being held March 15-18 in Vienna.

The open-label, randomized, multicenter trial is a new arm of the Endocrine Optimization Pilot Protocol (EOP), a sub-study of the ongoing I-SPY 2 TRIAL (Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular analysis 2). The I-SPY family of trials are sponsored and managed by Quantum Leap Healthcare Collaborative (QLHC), which partners with a consortium that includes the U.S. Food and Drug Administration (FDA), industry, patient advocates, philanthropic sponsors, and clinicians from 41 major U.S. cancer research centers.

"Sermonix is pleased to present the I-SPY 2 EOP study protocol during this year’s St. Gallen conference, which is among the most influential and widely attended annual medical congresses solely focused on breast cancer," said Dr. David Portman, founder and chief executive officer of Sermonix. "The EOP arm of the I-SPY 2 trial is an important and valuable addition to our own ongoing clinical development activities, and we look forward to this incremental data as we execute our own registrational ELAINE-3 Phase 3 combination study of lasofoxifene with abemaciclib in the metastatic setting."

"The data generated on lasofoxifene to date is very compelling, particularly as it relates to vaginal and sexual health, areas where the current standard-of-care endocrine therapy, aromatase inhibitors, are known to cause serious side effects," said Dr. Laura Esserman of the University of California San Francisco, founder and leader of the I-SPY Program. "We are pleased to include lasofoxifene in the I-SPY 2 EOP and eager to assess its efficacy in light of its more favorable tolerability profile."

e-Poster Details:

Title: (Trial in Progress) A Phase 2, Open-Label, Randomized Multicenter Trial to Evaluate Neoadjuvant Lasofoxifene in Molecularly Selected HR+/HER2- Clinical Stage 2/3 Breast Cancer
Poster #: P132
Summary: Chemotherapy offers limited benefit for early-stage breast cancer patients with molecular low risk, clinical high risk, hormone receptor positive (HR+)/HER2-negative tumors. Studies have shown neoadjuvant endocrine therapy (NET) can downstage breast tumors and facilitate breast conservation compared to neoadjuvant chemotherapy in women with locally advanced HR+/HER2- breast cancer. Aromatase inhibition (AI) (+/- ovarian function suppression (OFS)) is the standard NET for locally advanced, HR+/HER2- breast cancer. However, the toxicity profile of AI/OFS causes poor tolerance, thus more tolerable and effective treatments are needed.

This Endocrine Optimization Protocol (EOP) is a Phase 2, open-label, randomized multicenter platform sub-study within the ongoing I-SPY 2 clinical trial. Patients will be randomized to receive: 1) lasofoxifene 5 mg daily, 2) AI, or 3) other concurrent experimental arms (if applicable), for six consecutive 28-day periods. The primary endpoint is feasibility (≥80% of enrolled patients completing protocol-defined study therapy). Secondary endpoints include safety and efficacy, as measured by pathological and clinical response and patient reported outcomes, and the identification of potential biomarkers of response for subsequent validation.

Sermonix is supplying lasofoxifene and providing financial support to QLHC for this study. The I-SPY program includes 41 sites, and all I-SPY cancer center sites have the EOP program open.

For more information about the trial: NCT01042379.

All e-posters will be accessible on terminals in the E-Poster Area on Level 1 for the duration of the conference.

About Lasofoxifene

Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with abemaciclib in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

On March 15, 2023 Inhibikase Therapeutics, Inc. (Nasdaq: IKT) ("Inhibikase" or "Company"), a clinical-stage pharmaceutical company developing protein kinase inhibitor therapeutics to modify the course of Parkinson’s disease, Parkinson’s-related disorders and other diseases of the Abelson Tyrosine Kinases, reported an interim update from the dose escalation portion of its ‘501’ bioequivalence study of IkT-001Pro, the Company’s prodrug formulation of imatinib mesylate designed to enhance the safety and efficacy of imatinib (marketed as Gleevec) in patients with Chronic Myelogenous Leukemia (CML) (Press release, Inhibikase Therapeutics, MAR 15, 2023, View Source [SID1234628825]).

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The 501 trial is evaluating IkT-001Pro at four single ascending doses in the dose escalation portion of the study to select the bioequivalent dose, followed by a dose confirmation portion to confirm the bioequivalent dose. The study will enroll a total of 59 male and female healthy volunteers, aged 25 to 55. The study is designed to evaluate the safety profile of IkT-001Pro as well as compare the pharmacokinetic exposure of IkT-001Pro to the standard of care dose of 400 mg imatinib mesylate in order to identify a bioequivalent dose.

As of March 15, 2023, the Company has enrolled 19 of 27 healthy volunteers in the dose calibration portion of the study, completing 3 of 4 planned escalating doses at 300, 400 and 500 mg IkT-001Pro. To date, IkT-001Pro has shown a favorable safety profile, with only 4 mild adverse events observed, none of clinical significance. IkT-001Pro has high oral bioavailability and a pharmacokinetic profile of delivered imatinib that closely matches the exposure of imatinib delivered as 400 mg imatinib mesylate. Upon completion of the dose escalation phase, the Company will conduct a confirmatory analysis of the bioequivalent dose of IkT-001Pro in 32 additional healthy volunteers using a two-period crossover design. The Company remains on track to complete the 501 trial in the second quarter of 2023.

"We have made great progress in our 501 trial, since dosing the first patients in December," stated Dr. Milton Werner, President and Chief Executive Officer. "To date, our observations in the trial have followed expectations and are in line with our previously reported preclinical data, where we demonstrated that delivery of imatinib as IkT-001Pro was well tolerated. With the rapid completion of the first three dose cohorts, we are on track to complete the 501 trial in the second quarter of 2023."

Following the completion of the 501 trial, Inhibikase plans to initiate a discussion with the FDA on the parameters for approval of IkT-001pro under the 505(b)(2) statute.

About IkT-001Pro
IkT-001Pro is a prodrug formulation of imatinib mesylate and has been developed to improve the safety of the first FDA-approved Abelson (Abl) kinase inhibitor, imatinib (marketed as Gleevec). Imatinib is commonly taken for hematological and gastrointestinal cancers that arise from Abl kinase mutations found in the bone marrow or for gastrointestinal cancers that arise from c-Kit and/or PDGFRa/b mutations in the stomach; c-Kit, PDGFRa/b and Abl are all members of the Abelson Tyrosine Kinase protein family. IkT-001Pro has the potential to be a safer alternative for patients and may improve the number of patients that reach and sustain major and/or complete cytogenetic responses in stable-phase CML and/or reduce the relapse rate for these patients. In preclinical studies, IkT-001Pro was shown to be as much as 3.4 times safer than imatinib in non-human primates, reducing burdensome gastrointestinal side effects that occur following oral administration. Imatinib delivered as IkT-001Pro was granted Orphan Drug Designation for stable-phase CML in September 2018.

About Chronic Myelogenous Leukemia
Chronic myeloid leukemia1 is a slowly progressing cancer that affects the blood and bone marrow. In CML, a genetic change takes place in immature myeloid cells — the cells that make most types of white blood cells. This change creates an abnormal gene product called BCR-ABL which transforms the cell into a CML cell. Leukemia cells increasingly grow and divide in an unregulated manner, eventually spilling out of the bone marrow and circulating in the body via the bloodstream. Because they proliferate in an uncontrolled manner, the excessive production of myeloid cells acts like a liquid tumor. In time, the cells can also settle in other parts of the body, including the spleen. CML is a form of slow-growing leukemia that can change into a fast-growing form of acute leukemia that is difficult to treat.

On March 15, 2023 Immunoprecise Antibodies Ltd. (NASDAQ: IPA) ("Immunoprecise" or "IPA" or the "Company"), an AI-driven biotherapeutic research and technology company, reported that Talem Therapeutics LLC, an independently operating subsidiary of IPA, and Libera Bio S.L., have signed a collaboration agreement to jointly address intracellular targets (Press release, ImmunoPrecise Antibodies, MAR 15, 2023, View Source [SID1234628824]). It is estimated that 75% of disease-causing targets are located inside cells1. Some of the most elusive cancer targets are expressed inside tumor cells. Because they are so difficult to address, they have sometimes been deemed "undruggable" and thus represent high unmet medical needs.

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Numerous pathways intersect inside tumor cells, such as the MAPK pathway or the "Hedgehog Pathway", and may generate conditions for tumors to develop, grow and evade the immune system. Disrupting signals at one or more points within these pathways may slow down the growth of the tumors and inhibit their proliferation. Small molecules have been successfully developed to this end, but they often present a significant lack of specificity resulting in toxicity, leading to undesirable side effects for patients. Engineering antibodies to force them inside tumor cells has also been attempted, but it is a complex process, often wrought with failure. The collaboration between Talem and Libera Bio will leverage a nanotechnology that has been proven in vivo to deliver antibodies inside tumor cells and provides a potential solution to this medical challenge.

Libera Bio’s Multifunctional Polymeric Nanocapsules (MPN Technology) offer an elegant way to deliver antibodies inside tumor cells. The relevant antibodies are encapsulated in multi-layer nanocapsules of approximately 1/10,000th of a millimeter in diameter. The nanocapsules are specifically designed around the physicochemical properties of antibodies, to protect them from degradation in the blood stream. Libera Bio believes that this might be the only nanotechnology with in vivo proof of concept of delivering whole antibodies intracellularly. In addition, MPNs can deliver other biologic modalities or combinations of a biologic and a small molecule in the same nanocapsule. Passively or actively targeted, the MPNs deliver these compounds through a cell membrane and to intracellular targets.

Whole antibodies, close to their natural form, can be delivered in this manner. Talem will leverage its antibody discovery and development expertise and access, including without limitation, the LENSai Technology from BioStrand B.V., an independently operating subsidiary of IPA. BioStrand has developed a proprietary, AI-driven platform to optimize the design of such antibodies. BioStrand computationally generates and rapidly screens a large set of diverse antibody candidates against a prioritized list of targets, including intracellular targets.

Talem and Libera Bio will jointly develop novel antibodies for use with MPN delivery, with the goal of offering them to larger pharma companies to conduct late-stage development and commercialization. The work launches with the investigation of two intracellular targets with very high unmet patient needs to offer options to the oncologists treating them. "As we continue to push the boundaries of cancer therapy, the ability to target intracellular proteins has been the ‘Holy Grail’ in oncology. Libera Bio’s ground-breaking approach of enabling biologics to penetrate the cell membrane and reach previously ‘undruggable’ targets is an exciting development that has the potential to transform the way we treat cancer," said Dr. Jennifer Bath, CEO and President of Immunoprecise Antibodies Ltd.

"The Libera Bio team has been very impressed with the combination of modern in silico tools and wet lab capabilities at the IPA Family of companies. We are looking forward to this alliance that just may yield dozens of new options for cancer treatment," added Olivier Jarry, Co-Founder and CEO of Libera Bio.

Verdine GL, Walensky LD. The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. 2007;13(24):7264-70. doi:10.1158/1078-0432.CCR-07-2184.