On July 17, 2024 Anagenex, a pioneering drug discovery company pairing large-scale data generation with proprietary artificial intelligence (AI) to discover the next generation of small molecule medicines, reported the company has nominated PRMT5 and MAT2A as its first two preclinical programs (Press release, Anagenex, JUL 17, 2024, View Source [SID1234644943]). PRMT5 is an essential gene required for cell survival. Inhibition of the metabolic protein MAT2A leads to PRMT5 inhibition. Both of these proteins are viewed as potential cancer therapeutic targets.

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Anagenex has built a platform that pairs large-scale data generation enabled by artificial intelligence (AI) to find and develop hits to multiple targets simultaneously, exploring entire pathways to identify the most promising compounds to modify disease biology.

Anagenex prioritizes targets with clear human validation. Targets with a human biomarker are four times more likely to be approved, however hundreds remain un-drugged because these often belong to novel target classes or challenging mechanisms. Synthetic lethal oncology, a situation in which loss of function of two genes together result in cell death, while loss of either gene alone does not, is a particularly fruitful area for targets because they often come with an associated human biomarker and massive unmet medical need persists.

Anagenex’s first programs addressing PRMT5 and MAT2A fit this validated human target hypothesis. PRMT5 is a pan-essential gene and MAT2A inhibition leads to inhibition of PRMT5. Both leverage MTAP deletion, a gene that is lost in 15% of all solid tumors, providing a unique mechanism to target therapies exclusively to tumors. While competitive programs are showing value in the clinic, Anagenex’s unique platform has been able to identify highly novel compounds for these targets which it believes will help patients by increasing selectivity and brain penetrance.

"Today none of the programs in the clinic have been able to unlock the majority of patients who might be eligible for PRMT5 and MAT2A inhibitors," said Ryan Kruger, Chief Scientific Officer of Anagenex. "PRMT5 needs to be hit extremely effectively but hitting PRMT5 in normal tissue creates dose-limiting side-effects. MTAP loss provides us with a magic bullet to inhibit PRMT5 only in tumor cells either through the inhibition of MAT2A or through inhibition of PRMT5 directly."

The most effective PRMT5 compounds in the clinic are 74-fold selective for tumors over regular cells, but preclinical and clinical data suggests that at least 250-fold selectivity is needed to provide treatment benefit to most patients. Brain penetrance is also important because 40% of patients in the primary indication, Non-Small Cell Lung Carcinoma (NSCLC), experience progression to brain metastases that are often fatal.

Anagenex has developed a series of scaffolds with extreme selectivity, and preliminary work is demonstrating that some of those are brain penetrant. Anagenex is targeting to nominate one of these programs as a development candidate in 2H 2025.

"Essentially all of the competitive compounds targeting PRMT5 and MAT2A are exploring the same scaffolds," stated Kruger. "Simply rehashing chemistry others have explored won’t generate the breakthroughs patients need. Fortunately, our platform has discovered several scaffolds that are completely unrelated to those currently being clinically evaluated, giving us a fresh endeavor to help patients in a whole range of cancers."

In parallel to the announcement of the targets within Anagenex’s synthetic lethal oncology portfolio, the Company is planning to expand into immunology in 2024, leveraging its unique discovery platform to solve the most challenging immune disorders. This follows Anagenex’s initiation of a partnership with Nimbus Therapeutics across a variety of targets, which was previously announced in late-2023.

"Our platform is uniquely suited to finding chemical matter for any target, fulfilling our mission to find a molecule for every malady," said Nicolas Tilmans, Anagenex CEO. "The true power of our platform is in the scalability, and its capability to screen many targets in parallel, then investigate them with up to 100 million target-focused compounds. This scale of early-stage compound investigation ensures that we will generate multiple compounds that will make it to the clinic."

On July 17, 2024 Egle Therapeutics, a biotechnology company focused on advancing the next generation of regulatory T cell-focused therapies for oncology and auto-immunity, reported that it will deliver an oral presentation at The Promise of Interleukin-2 Therapy meeting taking place in Paris from September 4th to 7th, 2024 (Press release, Egle Therapeutics, JUL 17, 2024, View Source [SID1234644942]).

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The presentation, entitled "EGL-003, a novel IL-2 mutein to selectively expand and activate regulatory T cells and improve therapeutic efficacy in autoimmune disease", will show evidence that EGL-003, a non-targeted Fc-fused IL-2 agonist mutein, selectively binds to regulatory T cells (Treg) and induces Treg IL-2 signaling.

The resulting increase of Treg frequencies was observed in vitro and in different mouse models. Accordingly, EGL-003 significantly improved clinical, macroscopic, and histological parameters in a DSS-induced colitis mouse model with expansion of tissue-resident Tregs.

EGL-003 is the first drug candidate being developed for treatment of autoimmune diseases in Egle’s pipeline and has advanced into IND-enabling studies.

Session Title: IL-2 and Treg cell therapies; Session Date and Time: Friday September 6th, 2024 2:00 PM – 3:30 PM; Location: Poster Section 4; Poster Board Number: 23 Published Abstract Number: 4079

On July 17, 2024 Biotheryx, Inc., a biopharmaceutical company discovering and developing a portfolio of first-in-class protein degraders with a focus on validated targets in cancer and inflammatory diseases, reported that the first patient has been dosed in its Phase 1 clinical trial evaluating BTX-9341, an investigational oral and bifunctional degrader of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), as a monotherapy and in combination with fulvestrant for patients with advanced and/or metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer who have previously received CDK4/6 inhibitor therapy either in the adjuvant or metastatic setting (Press release, BioTheryX, JUL 17, 2024, View Source;breast-cancer-302198738.html [SID1234644940]).

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"BTX-9341 is a potent and selective CDK4/6 degrader that has shown significant anti-tumor activity in both CDK4/6 inhibitor naïve and resistant preclinical models. We are optimistic that it will meet a critical unmet medical need for patients with HR+/HER2- breast cancer who have received prior CDK4/6 inhibitor therapy," said Leah Fung, Ph.D., CEO of Biotheryx. "Dosing the first patient in this trial represents a significant milestone for Biotheryx, the patients we aim to serve and the scientists who have made this possible."

The Phase 1 clinical trial will begin with dose escalation of BTX-9341 as a monotherapy, followed by a combination with fulvestrant and will conclude with dose expansion of BTX-9341 in combination with fulvestrant. The trial will assess safety, tolerability, pharmacokinetic and pharmacodynamic activity of BTX-9341 as a monotherapy and in combination with fulvestrant. Once the recommended Phase 2 dose of the combination has been determined, there will be a formal evaluation of efficacy in an expansion cohort.

"We are thrilled to have dosed the first patient with BTX-9341 at The START Center for Cancer Research," stated START Co-Founder and Co-Director of Clinical Research, Dr. Amita Patnaik, MD, FRCPC. "BTX-9341 is a highly novel, first-in-class, potent and selective degrader of CDK4/6, representing an innovative therapeutic approach. It has the potential to transform the care of patients with advanced and/or metastatic HR+/HER2- breast cancer, particularly those who have received prior CDK4/6 inhibitor therapies. This milestone is perfectly aligned with START’s mission to accelerate drug development and provide early access to cutting-edge anticancer therapies, bringing hope to patients and their families."

In preclinical studies, orally administered BTX-9341 demonstrated in vivo CDK4/6 degradation and improved anti-tumor activity as a monotherapy compared to current standard of care treatment regimens. BTX-9341 also demonstrated synergies with selective estrogen receptor degraders including fulvestrant, elacestrant and camizestrant in CDK4/6 naïve and resistant models.

About BTX-9341

BTX-9341 is a first-in-class, oral degrader of CDK4/6, important targets for a range of cancers and clinically validated in HR+/HER2- breast cancer. In preclinical breast cancer models, BTX-9341 demonstrated superiority to CDK4/6 inhibitors through potent and highly selective catalytic degradation of CDK4 and CDK6, robust inhibition of Cyclin E and CDK2 transcription, cell cycle arrest and ultimately superior in vivo efficacy in breast cancer xenografts. Beyond this increased efficacy potential, BTX-9341 is differentiated from CDK4/6 inhibitor approaches through the ability to overcome key resistance mechanisms that limit the impact of inhibitors in second line HR+/HER2- breast cancer.

On July 17, 2024 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported it will present initial clinical data, with a focus on safety, exposure, and pharmacodynamic measures, from the monotherapy dose-escalation portion of the Phase 1 study of HST-1011, an oral, selective inhibitor of Casitas B-lineage lymphoma proto-oncogene (CBL-B), in a Proffered Paper oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024, taking place September 13-17, 2024, in Barcelona, Spain (Press release, HotSpot Therapeutics, JUL 17, 2024, View Source [SID1234644939]).

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Presentation details are as follows:

Title: First-in-Human (FIH) Phase 1 Data of HST-1011, an Oral CBL-B Inhibitor, in Patients with Advanced Solid Tumors
Session Name: Proffered Paper session: Investigational immunotherapy
Session Date and Time: Fri., Sep. 13, 2024, 16:00-17:30 CEST
Presentation Time: 16:50-17:00 CEST
Location: Burgos Auditorium – Hall 5, Fira Barcelona Gran Via
Presentation Number: 991O

On July 17, 2024 Propanc Biopharma, Inc. (OTC Pink: PPCB) ("Propanc" or the "Company"), a biopharmaceutical company developing novel cancer treatments for patients suffering from recurring and metastatic cancer, reported that the Company’s lead asset, PRP, could solve the problem that impacts the response rate of immune checkpoint inhibitors treating PD-L1-High (Programmed Death-Ligand 1) solid tumors, such as lung cancer (Press release, Propanc, JUL 17, 2024, View Source [SID1234644937]). Propanc’s Chief Scientific Officer and Co-Founder Dr Julian Kenyon, MD, MB, ChB, predicts that pretreatment of PD-L1-high solid tumors with PRP as a combinatorial approach could reverse the promotion of epithelial to mesenchymal transition (EMT) pathways induced by PD-L1, a fundamental process by which malignant cells promote tumor growth and metastasis. Tumor cells that undergo the EMT are motile and invasive, spreading and seeding new tumors, as well as become immortal, no longer dying off naturally. They are also non-dividing, which means they are resistant to standard treatment approaches.

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Use of immune therapy, such as checkpoint inhibitors, have become increasingly widespread for treating solid tumors as an effective method to stop the immune system from turning off before cancer is eliminated completely. The immune system relies on T cells to fight cancer. These specialized cells are extremely powerful and have the potential to damage healthy cells. The Immune Checkpoint Inhibitors Market is US$47.22 Billion in 2023, and expected to reach US$158.26 Billion by 2031 according to FutureWise Research. Despite growing popularity, response rates range between 15 to 30% in most solid tumors. As a result, scientific research is being conducted to consider how to improve response rates.

A recent study published in the British Journal of Cancer (May, 2024), highlights that EMT induced by tumor cell-intrinsic (i.e., belonging naturally) PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-High lung cancer. PD-L1 is a protein that acts as a kind of "brake" to keep the body’s immune system under control. PD-L1 may be found on some normal cells and in higher-than-normal amounts on some types of cancer cells. When PD-L1 binds to another protein called PD-1 (Programmed Death protein, found on T cells), it keeps T cells from killing the PD-L1-containing cells, including cancer cells. Anticancer drugs called immune checkpoint inhibitors bind to PD-L1 and block its binding to PD-1. This releases the ‘brakes’ on the immune system and leaves T cells free to kill cancer cells. "The implication is that PRP will enable PD-L1 non responders to become responders," according to Dr Kenyon.

Dr Kenyon explained further, "Cancer immunotherapy is being increasingly used in cancers. For immunotherapy, normal PD-1 receptors are needed. Many tumors do not have this and these are mostly (PD-L1-High) tumors expressing EMT pathways. PRP induces cell differentiation in cancer cells, which reverses EMT pathways and reduces metastatic potential (ability to spread). This means that PRP could correct this overexpression and so be an ideal combinatorial treatment with cancer immunotherapy."

"Dr Kenyon and the Propanc R&D team continue to explore ways that PRP can be developed to improve and extend the lives of cancer sufferers worldwide. We are committed to advancing PRP into the clinic and as we progress, understanding better how PRP can be used both as a stand-alone therapy and an addition to the treatment process so that cancer sufferers, who may not respond to certain treatment modalities, can be given renewed hope where the standard of care has failed, or encountered resistance," said Mr. James Nathanielsz, Propanc’s Chief Executive Officer. "We continue to work tirelessly on these important objectives, and reassure shareholders that we are currently executing plans to achieve our vision to develop a long-term therapy for the treatment and prevention of metastatic cancer from solid tumors, which remains the main cause of patient death for sufferers. We look forward to providing updates when material events occur."

About PRP:

PRP is a mixture of two proenzymes, trypsinogen and chymotrypsinogen from bovine pancreas, administered by intravenous injection. A synergistic ratio of 1:6 inhibits growth of most tumor cells. Examples include pancreatic, ovarian, kidney, breast, brain, prostate, colorectal, lung, liver, uterine, and skin cancers. Orphan Drug Designation status of PRP has been granted from the US Food and Drug Administration (FDA) for treatment of pancreatic cancer.

To view the Company’s "Mechanism of Action" video on the Company’s lead asset, PRP, please click on the following link: View Source