On December 16, 2021 A-Alpha Bio, a biotechnology company that works with pharmaceutical industry partners to enable and accelerate drug discovery with massively multiplexed measurements of protein-protein interactions, and Kymera Therapeutics, Inc., a clinical-stage biopharmaceutical company developing targeted protein degraders, reported a partnership to discover and characterize novel pairs of E3 ubiquitin ligases and high-value therapeutic targets for the rational and prospective design and development of molecular glues (Press release, A-Alpha Bio, DEC 16, 2021, View Source [SID1234636942]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The partnership is the first announced by A-Alpha Bio in the cutting-edge and rapidly growing area of targeted protein degradation and leverages the AlphaSeq platform to quantitatively measure protein-protein binding in a high-throughput manner along with a proprietary library of approximately 40 E3 ubiquitin ligases. Under the terms of the agreement, A-Alpha Bio will discover and characterize druggable interactions between a curated list of high-value targets and its library of E3 ligases that Kymera can use as an input to its Pegasus platform for the rational discovery and development of molecular glues. Kymera will have the option to take a license for up to two targets for further development. A-Alpha Bio will receive upfront and research payments and be eligible for downstream milestones.

Molecular glues, a new class of small-molecule drugs, are exciting for their potential to degrade previously undruggable protein targets, providing a valuable new tool to address areas of critical, unmet need. With over 600 human E3 ubiquitin ligases and numerous targets of interest, a major challenge for molecular glue discovery is prospectively identifying a ligase-target pair that has the potential for targeted degradation. The AlphaSeq platform can efficiently analyze up to millions of protein-protein interactions and measure each interaction strength, including very weak interactions that can be stabilized by a molecular glue. Once promising ligase-target pairs are discovered, AlphaSeq can again be used with mutagenic libraries of the ligase and target to further interrogate druggability and provide structural insights to aid in the subsequent rational discovery of a therapeutic glue.

"Use of rational approaches for the discovery of molecular glues have been limited to empirical exploration of Cereblon and IMiD glues with a small set of oncology targets mostly due to lack of broad understanding of how to enable novel interactions. A-Alpha Bio’s novel approach to identify weak protein-protein interactions at scale and ability to deeply characterize the molecular basis for new interactions is truly a game-changing innovation," said Nello Mainolfi, PhD, Co-Founder, President and CEO, Kymera Therapeutics. "This collaboration presents a unique opportunity to discover those interactions and then use Kymera’s deep know-how in hit finding and degradation discovery to develop a new generation of molecular glues against new undrugged and un-ligandable targets as well as to expand the repertoire of E3 ligases that can be used for targeted protein degradation."

A-Alpha Bio’s proprietary platform, AlphaSeq, represents the first high-throughput and quantitative approach for measuring protein-protein binding. To date, A-Alpha Bio’s partners have leveraged AlphaSeq to enable and accelerate antibody discovery by simultaneously measuring millions of interactions between antibodies and antigens or antigen mutants for high-throughput determination of properties like affinity, specificity, cross-reactivity, and epitope. The discovery of molecular glue targets for targeted protein degradation represents an exciting new application for AlphaSeq that expands its scope to address previously undruggable intracellular targets.

"We are thrilled to collaborate with the incredible Kymera team to discover and validate molecular glue targets. Kymera is a leader in the targeted protein degradation space and their pioneering work makes them an ideal partner for A-Alpha Bio," said David Younger, PhD, Co-Founder and CEO of A-Alpha Bio. "Kymera and A-Alpha share a commitment to innovation and to expanding the potential of targeted protein degradation by unlocking new ligases and new previously undruggable targets. By combining Kymera’s deep domain expertise in targeted protein degradation and the multiplexing power and sensitivity of our AlphaSeq assay, we are confident that together we can unlock novel therapeutics against previously undruggable targets."

To learn more, please visit: View Source

On December 16, 2021 Cothera Bioscience, the parent company of Percans Oncology, reported that it had successfully completed the first administration for the first patient in the Phase 1/2 clinical trial of CTB-02 for the treatment of pan-KRAS/BRAF mutant colorectal cancer in Australia (Press release, Cothera Bioscience, DEC 16, 2021, View Source [SID1234618850]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

CTB-02 is a first-in-class targeted combination therapy discovered by the i-CR technology platform that has been independently developed by Cothera Bioscience and clinically verified for the treatment of KRAS/BRAF mutant colorectal cancer. CTB-02 has demonstrated strong inhibitory activity against KRAS/BRAF mutant colorectal cancer in multiple animal models, especially those based on patient transplanted tumor PDX. Colorectal cancer (CRC) is a common malignant tumor disease. According to the statistics, there were nearly two million new cases and one million deaths from this disease worldwide in 2020, among which there were about 560,000 new cases and 290,000 deaths in China. The incidence of colorectal cancer has been significantly increasing in China. KRAS mutation is the most important genetic variation in colorectal cancer, and has been detected in 40% of patients with metastatic colorectal cancer (mCRC). KRAS mutations may lead to sustained activation of the RAS-RAF-MEK pathway, resulting in tumor resistance to EGFR monoclonal antibodies. In CRC, KRAS mutations are significantly associated with resistance to EGFR-targeted drugs such as cetuximab. BRAF is a component of the RAS-RAF-MEK signaling pathway. About 10% of mCRC patients have BRAF activation mutations that are mutually exclusive with KRAS mutations. BRAF mutations, mostly the V600E subtype, have been demonstrated to be associated with a poor overall prognosis in studies.

"This is the first clinical trial of CTB-02," said Dr. Chun Jiang, cofounder of Cothera Bioscience and the executive vice president leading product development. "KRAS mutant colorectal cancer currently has no approved targeted therapies and there is a huge unmet clinical need. CTB-02 has presented an effect not only on KRAS G12C mutant colorectal cancer, but also on other KRAS mutations in cells as well as CDX and PDX animal experiments. We are fully committed to advancing this clinical trial and expect CTB-02 to lead to a breakthrough in the treatment of patients with KRAS/BRAF mutant colorectal cancer."

On December 16, 2021 Lyell Immunopharma, Inc. (Lyell), (Nasdaq: LYEL), a T-cell reprogramming company dedicated to the mastery of T cells to cure patients with solid tumors, reported that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application to initiate a Phase 1 clinical trial for LYL797, Lyell’s first therapeutic candidate incorporating T-cell reprogramming technologies for the treatment of solid tumors. LYL797 is an investigational chimeric antigen receptor (CAR) T-cell therapy for patients with receptor tyrosine kinase-like orphan receptor 1-positive (ROR1+) solid tumors (Press release, Lyell Immunopharma, DEC 16, 2021, View Source [SID1234609996]). LYL797 incorporates two Lyell technologies designed to address major barriers to successful Adoptive Cell Therapy (ACT): Gen-R, a genetic reprogramming technology that endows T cells with the ability to resist exhaustion, and Epi-R, an epigenetic reprogramming technology that creates populations of T cells with the properties of durable stemness. Durable stemness is the quality that enables T cells to self-renew, proliferate and persist, and create daughter cells with anti-tumor functionality. Lyell expects to begin screening patients with relapsed/refractory triple-negative breast cancer (TNBC) who have failed at least two lines of therapy by the end of the first quarter for the Phase 1 dose escalation phase of the trial and plans to expand the trial to include patients with non-small cell lung cancer (NSCLC) when a recommended dose is determined.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Lyell is applying our understanding of T-cell biology to address what we believe are the primary barriers to consistently effective cell therapies for difficult to treat solid tumors," said Liz Homans, Chief Executive Officer of Lyell. "Submission and clearance of our first IND is an important milestone for Lyell, and we remain on track to generate data for LYL797 in 2022 and plan to share initial data when we have a meaningful number of patients and an indication of clinical effect, which we expect to occur in 2023. We also remain on track to submit three additional INDs for our TIL and partnered TCR programs by the end of 2022."

"This is the first time the FDA has cleared an IND that includes a specific genetic modification to address T-cell exhaustion, a phenomenon that is recognized as being a major barrier to the eradication of tumors by T cells," stated Rick Klausner, MD, Chair of Lyell’s Board of Directors. "We look forward to testing this first-generation technology platform in the clinic, thus specifically addressing the question of exhaustion as a barrier to successful cell therapy in solid tumors."

"While CAR T-cell therapies have proven effective in hematologic malignancies, patients with solid tumors have seen limited benefit from these approaches due to a tumor microenvironment that leads to T-cell exhaustion and a loss of durable stemness," said Tina Albertson, MD, PhD, Chief Medical Officer and Head of Development of Lyell. "LYL797 is the first program to clinically evaluate our two T cell reprogramming technologies which are designed to overcome these barriers, with the goal of developing more effective therapies for patients with solid tumor cancers."

Phase 1 Trial Design

The Phase 1 clinical trial is designed to evaluate the safety and anti-tumor activity of LYL797 in patients with ROR1+ TNBC or NSCLC.

The trial is an open label, dose escalation and expansion trial in patients with relapsed/refractory TNBC or NSCLC who have failed at least two lines of therapy. Once a dose is identified during dose escalation in TNBC, up to 15 patients with TNBC and 15 patients with NSCLC are expected to be enrolled at the recommended dose. The primary endpoint of this Phase 1 trial is safety and tolerability of LYL797. Secondary endpoints include clinical activity based on the evaluation of antitumor activity as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and characterization of the pharmacokinetic profile of LYL797. Exploratory biomarkers of T-cell function – exhaustion and stemness – will also be assessed.

About TNBC and NSCLC

Breast cancer is the second most common cancer in American women. Approximately 10-15% of patients with breast cancer have TNBC and triple negative status tends to be more common in women who are younger than age 40, who are African American, or who have a BRCA1 mutation. In the United States, approximately 135,000 women suffered from TNBC in 2017. TNBCs present a high tendency to metastasize, and patients are at a higher risk to relapse compared to other types of breast cancers. TNBCs differ from other types of invasive breast cancer in that they grow and spread faster, have limited treatment options, and a worse prognosis. Once TNBC has spread to other parts of the body, the 5-year survival rate is only 11.5%. ROR1 is overexpressed in approximately 60% of patients with TNBC and ROR1 expression is correlated with poorer outcomes.

Lung cancer is the second most common cancer and is the leading cause of cancer mortality worldwide. NSCLC accounts for 84% of all lung cancers. ROR1 is overexpressed in approximately 40% of the patients with NSCLC. For people with localized NSCLC, the overall 5-year survival rate is ~60%. For regional NSCLC, the 5-year survival rate is ~35%. Based on current data, when NSCLC metastasizes, the 5-year survival rate is 6%.

About LYL797

LYL797 is a novel, ROR1-targeted CAR T-cell product that incorporates genetic and epigenetic reprogramming technologies, Gen-R and Epi-R, to overcome barriers of CAR T-cell therapies in solid tumors. Gen-R is an ex vivo genetic reprogramming technology that engineers CAR T cells to overexpress c-Jun. Dysregulation of activator protein 1 (AP-1) has been implicated in CAR T-cell exhaustion, and studies have demonstrated that overexpression of c-Jun renders CAR T cells less susceptible to exhaustion through the AP-1 pathway, enhancing both anti-tumor efficacy and persistence in preclinical models of hematologic and solid tumors. Epi-R is a proprietary technology that is designed to produce populations of T cells which have the properties of durable stemness – the quality that enables T cells to self-renew, proliferate and persist, and create daughter cells with anti-tumor functionality.

Preclinical in vitro and in vivo experiments of LYL797 against ROR1+ solid tumors have demonstrated that LYL797 maintains stem-like phenotypes and can resist exhaustion while inhibiting tumor growth in models of tumor cells expressing ROR1.

On December 16, 2021 Alpine Immune Sciences and Ireland’s Horizon Therapeutics reported a licensing and collaborative research and development agreement valued at up to $1.5 billion to generate up to four preclinical candidates for autoimmune and inflammatory diseases (Press release, Biosortia Pharmaceuticals, DEC 16, 2021, View Source [SID1234607737]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Horizon will have exclusive rights to develop and commercialize the candidates from Seattle-based Alpine’s unique discovery platform. Overall, the collaboration and licensing agreement between the two cross-Atlantic companies includes a lead, potential first-in-class preclinical candidate, as well as a research collaboration to jointly develop the additional novel candidates.

On December 16, 2021 Novadiscovery (NOVA), a leading health tech company using in silico clinical trials to predict drug efficacy and optimize clinical trial development, reported that it has expanded its collaboration with Janssen, initially entered in 2020 (Press release, Debiopharm, DEC 16, 2021, View Source [SID1234598568]). NOVA is now applying its collaborative clinical trial simulation platform, JINKO, to expand the existing lung cancer model to support Janssen market access and global medical affairs strategies.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This agreement follows an agreement which saw NOVA use publicly-available knowledge and data to create a bedrock predictive disease model for lung adenocarcinoma which was then validated using an independent database from Paz-Ares1 study (Lux-Lung7 cohort) and benchmarked using the Bayesian model developed by Nagase et al. in 20202.

The companies will now work together to use the JINKO platform to add layers of biological complexity to the initial disease model and then run in silico trial simulations.

"The initial proof-of-concept success means Janssen’s leap-of-faith into in silico has been justified, which makes us very proud," said François-Henri Boissel, CEO. "We are looking forward to deploying JINKO and developing disease models that will provide real insight for drugmakers, streamlining clinical development and getting life-saving treatments to patients faster."

"Janssen is dedicated to employing the most advanced and innovative technologies to ensure new treatments progress through clinical development as efficiently as possible so patients benefit from approved medicines without unnecessary delay. NOVA’s generated proof-of-concept of its predictive disease models through our preliminary work over the past year and we look forward to continuing our ground-breaking work." said Véronique Schmitt, Director of Market Access, Governmental Affairs & Early Products Development – Janssen France.