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Boundless Bio Presents Data on Extrachromosomal DNA (ecDNA) Driven Resistance to KRASG12C Inhibitors at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics 2021

On October 7, 2021 Boundless Bio, a next-generation precision oncology company developing innovative therapeutics directed against extrachromosomal DNA in aggressive cancers, reported that it will present a poster at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) (Press release, Boundless Bio, OCT 7, 2021, View Source [SID1234590946]). The poster, LBA005: Detection of KRAS amplification on extrachromosomal DNA (ecDNA) upon acquired resistance to KRASG12C inhibitors, is available to registered attendees starting at 9AM EST today.

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"Over the past decade, targeted therapies have delivered significant health improvement to patients with oncogene-driven cancers, with KRASG12C inhibitors being the most recent example," said Zachary Hornby, President and Chief Executive Officer of Boundless Bio. "Despite the use of potent inhibitors against oncodrivers like KRAS, resistance inevitably emerges. ecDNA driven oncogene copy number amplifications, a mechanism that is distinct from second site mutations, is a frequent cause of resistance in cancer cells. Boundless Bio, in collaboration with the Dana-Farber Cancer Institute and Mirati Therapeutics, has shown that, in colorectal patients treated with KRASG12C inhibitors, ecDNA based amplification played an important role in resistance to KRASG12C inhibitor therapy. These results further substantiate our mission to develop novel therapeutic strategies that can address ecDNA-enabled cancers."

"We are pleased to collaborate with Boundless Bio on this important work to identify mechanisms of acquired resistance to KRASG12C inhibitors," said Dr. Mark Awad, M.D., Ph.D., Assistant Professor of Medicine at Harvard Medical School and Clinical Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute. "There is mounting evidence that cancers rely on oncogene amplification to drive tumor growth and resistance, and some of this copy number amplification may be occurring on extrachromosomal DNA. The development of innovative therapies for ecDNA-driven cancers will hopefully provide new treatment options for our patients in the future."

Study Summary

We first confirmed the presence of ecDNA in tumor biopsy samples collected by the Dana-Farber Cancer Institute from clinical trial patients treated with the KRASG12C inhibitor, adagrasib. Analysis of next-generation sequencing (NGS) data using proprietary Boundless Bio software enabled detection of circular DNA structures encompassing the KRAS locus. Consistent with this finding, fluorescence in situ hybridization (FISH) analysis by Boundless Bio scientists confirmed the presence of KRAS amplifications on ecDNA.

Next, an in vivo study was performed to investigate whether resistance to KRASG12C inhibitor monotherapy is mediated through an ecDNA mechanism. We used a genetically modified CT26 murine colorectal cancer model expressing KRASG12C alleles. In line with recent clinical data, both adagrasib and sotorasib induced transient tumor regressions in the CT26 model that subsequently resumed tumor growth following several weeks of continuous therapy. Strikingly, in both adagrasib and sotorasib resistant tumors, bioinformatic analysis of whole-genome sequencing data and FISH analysis from isolated recurrent tumors identified high levels of ecDNA mediated amplification of KRASG12C compared to vehicle-treated samples. The kinetics of KRAS amplification on ecDNA was also determined, showing increased KRAS copy number within two weeks after initiation of KRASG12C inhibitor treatment. Such rapid onset of resistance after tumor regression is consistent with previous in vivo studies with other ecDNA enabled tumor models. Cultures from ex vivo experiments also maintain resistance due to KRAS amplified ecDNA. Collectively, these observations implicate ecDNA as an important mediator of resistance to KRASG12C inhibitor monotherapy.

This study, along with previously published studies, confirm the evasive dynamics of ecDNA-driven oncogene copy number amplification upon therapeutic pressure on oncodrivers such as EGFR, FGFR, and now mutant KRAS. Because ecDNA can be distributed heterogeneously throughout tumors, resistance to targeted therapies can be rapid, aggressive, and difficult to treat. Here we confirm the critical need for novel therapeutic strategies directed to the function of ecDNA within cancer cells and the urgency to bring these therapies to patients with oncogene amplified cancers.

About ecDNA

Extrachromosomal DNA ("ecDNA") are circular units of nuclear DNA found within cancer cells, and which contain highly transcriptionally active genes, including oncogenes, but are physically distinct from chromosomes and lack centromeres. ecDNA replicate within cancer cells and, due to their lack of centromeres, can be asymmetrically passed to daughter cells during cell division, leading to focal gene amplification and copy number heterogeneity in cancer. By leveraging the plasticity afforded by ecDNA, cancer cells have the ability to increase or decrease copy number of select oncogenes located on ecDNA to enable survival under selective pressures, including targeted therapy, immunotherapy, chemotherapy, or radiation, thereby making ecDNA one of cancer cells’ primary mechanisms of growth, recurrence, and treatment resistance. ecDNA are not found in healthy cells but are present in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.

Forma Therapeutics’ FT-7051 is Well-tolerated and Demonstrates Evidence of Activity in Initial Results from Ongoing Phase 1 Courage Study in Men with Metastatic Castration-resistant Prostate Cancer

On October 7, 2021 -Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease, prostate cancer and other rare hematologic diseases and cancers, reported positive initial results from a Phase 1 trial of its novel CBP/p300 inhibitor, the oral small molecule FT-7051, in men with metastatic castration-resistant prostate cancer (mCRPC) (Press release, Forma Therapeutics, OCT 7, 2021, View Source [SID1234590945]). Initial clinical data from the Courage Study, an ongoing first-in-human Phase 1 trial presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper), showed an encouraging safety profile of FT-7051, as well as high specificity to the CBP/p300 pathway.

"Preliminary data from the Courage Study are promising," said Andrew J. Armstrong, M.D., principal investigator of the Courage Study, and Professor of Medicine, Pharmacology and Cancer Biology, and Director of Research at the Duke Cancer Institute Center for Prostate and Urologic Cancers. "Managing the balance between safety, tolerability and efficacy is a key element of targeting this pathway, and thus far the doses studied are achieving pharmacodynamic target engagement with acceptable tolerability."

Preliminary results reported today include data as of Sept. 1, 2021, from eight men enrolled in the trial. FT-7051 was administered in 28-day cycles, with 21 days of dosing followed by seven days of no dosing. Three patients remain on study; five patients left the study (four due to disease progression and one withdrawal of consent). The adaptive trial design is intended to efficiently explore safe and efficacious doses of FT-7051. Prior to enrollment, all of the men had received diagnoses of mCRPC, castration-levels of serum testosterone and rising levels of the biomarker prostate specific antigen (PSA) after the failure of at least two lines of therapy with an approved androgen-receptor pathway inhibitor.

The initial pharmacokinetic (PK) analysis of FT-7051 documented rapid absorption, which produced maximum blood concentrations within two hours. The 150 mg dose achieved drug concentrations that approached the predicted efficacious dose based on modeling with preclinical results. Skin biopsies of the men participating in the study demonstrated a reduction in H3K27AC, a marker of activity in the CBP/p300 pathway, the target of FT-7051.

The majority of the treatment-emergent adverse events (TEAEs) were mild or moderate, at Grade 2 or lower, with no events leading to treatment discontinuation. One patient experienced Grade 3 hyperglycemia, which was medically managed. Following a dose reduction, this patient remained on treatment and experienced an ongoing PSA decline of greater than 50% at 12 weeks and greater than 80% at 16 weeks. Based upon these safety results, dose escalation is ongoing. The trial is continuing according to its adaptive design to further understand the safety and tolerability of FT-7051, gather data on clinical response including PSA and radiographic tumor response, as well as the assessment of secondary endpoints of clinical response.

"There is substantial need for new therapies to treat those with mCRPC as they progress while on existing lines of anti-androgen or chemotherapy," said David N. Cook, Ph.D., senior vice president, Forma Therapeutics’ chief scientific officer. "Thanks to the eight patients who participated in the Courage Study to date, we have made progress in understanding the potential of CBP/p300 inhibition in prostate cancer and look forward to continuing our dose escalation study."

Presentation Details

Abstract P202: Initial Findings from an Ongoing First-in-human Phase 1 Study of the CBP/p300 Inhibitor FT-7051 in Men with Metastatic Castration-Resistant Prostate Cancer (Link)
Abstract P204: Targeting the p300/CBP Epigenetic Pathway to Overcome Hormone Therapy Resistance in Advanced Prostate Cancer
Forma continues to enroll men into the Courage Study. For more information, please visit View Source or View Source

About CBP/p300

Tumor resistance to anti-androgen therapies can arise due to mutations and other changes within the androgen receptor (AR). Androgen binds to two paired proteins in ARs, CBP and p300, in a location that is highly resistant to mutations known as the bromodomain. FT-7051 is designed to attach to the CBP/p300 bromodomain potently and selectively, which then blocks androgen binding and reduces AR activation. In preclinical studies, FT-7501 demonstrated activity in both prostate cancer models that were sensitive or resistant to the approved androgen-inhibitor medicine enzalutamide.

About Prostate Cancer

Prostate cancer is the second most frequent cancer in men globally, accounting for more than 1.4 million new diagnoses and 6.8 percent of all male cancer deaths in 2020.1 In the United States, more than 248,000 men will be diagnosed with prostate cancer in 2021, and the disease will account for more than 34,000 deaths.2 When cancer has spread beyond the prostate and surgery or radiation are not an option, first-line treatment suppresses the male hormone androgen because it can stimulate prostate cancer cell growth.3,4 This treatment, called medical castration, slows progression for about two years, but most men will develop resistance and their cancer will progress.5,6 The five-year survival rate of men with metastatic prostate cancer is 30 percent.7

Rocket Pharmaceuticals to Present at the 2021 Cell & Gene Meeting on the Mesa

On October 7, 2021 Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT), a clinical-stage company advancing an integrated and sustainable pipeline of genetic therapies for rare childhood disorders, reported that Gaurav Shah, M.D., chief executive officer, will deliver an in-person company presentation at the 2021 Cell & Gene Meeting on the Mesa, being held as a hybrid conference virtually and in Carlsbad, CA (Press release, Rocket Pharmaceuticals, OCT 7, 2021, View Source [SID1234590944]). The Rocket Pharmaceuticals presentation will take place on Tuesday, October 12 at 2:15 p.m. PST.

A live audio webcast of the presentation will be available to registered attendees within the virtual platform and within 24 hours of the Rocket presentation the video will be available for on-demand viewing.

Sapreme Boosts Development of its Endosomal Escape Technology Platform and Proprietary Pipeline with EUR 15M Series A

On October 7, 2021 Sapreme, a biotechnology company focused on improving the delivery and efficacy of macromolecule therapeutics, reported that it has closed a EUR 15 million Series A financing round to accelerate the buildout of its endosomal escape technology platform and support the further progress of its proprietary pipeline and corporate development activities (Press release, Sapreme Technologies, OCT 7, 2021, View Source [SID1234590943]). Led by founding investor Aglaia Oncology Funds, together with Aglaia-associated partners, the round follows promising 2020 and 2021 preclinical data demonstrating the effectiveness of Sapreme’s endosomal escape compound, SPT001.

Sapreme was founded in 2016 to develop improved macromolecular therapeutics such as antibody targeted antisense oligonucleotides (ASOs) for the treatment of cancer and other indications. Sapreme’s innovative endosomal escape platform is designed to allow therapeutics to reach their target without becoming entrapped by the endosome. Endosomal entrapment poses a significant hurdle for the drug discovery and development industry, currently limiting the development of a broad range of potential macromolecular therapeutics to ‘undruggable’ intracellular targets. An effective solution to endosomal entrapment could be of immense value to the therapeutic landscape, as it enables the development of truly differentiated therapeutics to such novel targets.

"The continued support of Aglaia and its backers is invaluable to us as we continue to showcase the potential of our platform and establish our proprietary therapeutics pipeline," stated Guy Hermans, Ph.D., Chief Executive Officer of Sapreme. "These proceeds will allow us to mature our platform and to generate preclinical data needed to showcase the full scope of our technology."

In addition to earlier data supporting the use of its platform in oncology and in combination with various drug modalities, the company recently unveiled new in vivo data demonstrating its ability to significantly enhance delivery of oligonucleotides to the liver using GalNAc targeting – currently a mainstay in the therapeutic oligo development field. The data revealed consistent high levels of gene expression knockdown in the liver at reduced oligonucleotide doses.

"Having engaged in multiple studies with industry players throughout the past year, we see the opportunity to expand these collaborations to a range of new indications and drug modalities in the months ahead. Our current collaborators apply Sapreme’s endosomal escape technology to their proprietary drug candidates to improve intracellular target engagement manyfold, such as we have reported on earlier. We now look forward to further scale the platform and advancing our internal drug development pipeline, which following the Series A, we are well-positioned to do," commented Henrik Luessen, Chief Business Officer of Sapreme. (Press release, Sapreme Technologies, OCT 7, 2021, View Source [SID1234590943])

Jounce Therapeutics Progresses INNATE Study of JTX-8064 (LILRB2/ILT4 Inhibitor) Monotherapy and Pimivalimab (PD-1 Inhibitor) Combination Therapy in Patients with Advanced Solid Tumors

On October 7, 2021 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported the initiation of patient enrollment in INNATE tumor-specific expansion cohorts for both JTX-8064 monotherapy and combination therapy of JTX-8064 with its internal PD-1 inhibitor, pimivalimab (Press release, Jounce Therapeutics, OCT 7, 2021, View Source [SID1234590942]). JTX-8064, the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform, is a humanized IgG4 monoclonal antibody designed to specifically bind to the macrophage receptor Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4). By inhibiting LILRB2 binding with its ligands, JTX-8064 reprograms immune-suppressive macrophages to an immune-active state in preclinical studies, potentially enhancing the T cell response and anti-tumor immunity.

"We are very pleased to announce that we have started dosing patients in the tumor-specific JTX-8064 monotherapy and pimivalimab combination expansion cohorts of our INNATE study," said Beth Trehu, M.D., chief medical officer at Jounce Therapeutics. "We have made enormous progress in INNATE, having advanced the study from initiation of monotherapy dose escalation to the opening of tumor-specific, proof-of-concept, combination expansion cohorts in just nine months. This progress has been driven by the continued dedication of our employees, enthusiasm from investigators and, based on the science, our belief that the mechanism of action of JTX-8064 has the potential to address the major emerging unmet need in immuno-oncology, overcoming PD-(L)1 inhibitor resistance. We look forward to sharing updates on our continued execution of the INNATE study."

Proof-of-concept (POC) expansion cohorts in INNATE will address three different segments of IO patient populations; first, patients whose tumors progressed on or after a prior PD-1 or PD-L1 inhibitor (PD-(L)1i) and whose tumors exhibited primary or acquired resistance; second, IO naïve patients with tumors where no PD-(L)1i treatment is approved; and third, IO naïve patients with tumors that have a PD-(L)1i approval. POC expansion cohorts in INNATE follow a Simon’s two-stage design with the potential to enroll up to 29 patients per combination cohort and 47 patients in the monotherapy cohort if pre-specified criteria are met. If POC is established after evaluation of 29 or 47 patients, respectively, Jounce intends to move JTX-8064 rapidly into registrational trials on a cohort by cohort basis. INNATE will also assess pharmacodynamic and potential predictive biomarkers to guide future development, aligning with Jounce’s philosophy of developing the right immunotherapies for the right patients.

The INNATE trial (NCT04669899) is divided into 4 parts:

Part 1: JTX-8064 monotherapy dose escalation in solid tumors (completed July 2021)
Part 2: JTX-8064 + pimivalimab dose escalation in solid tumors (enrollment completed)
Part 3: JTX-8064 monotherapy expansion cohort in 2nd- to 4th-line PD-(L)1i naïve, platinum-resistant ovarian cancer (initiated August 2021)
Part 4: JTX-8064 + pimivalimab in indication-specific expansion cohorts (initiated October 2021)
Combination expansion cohorts include:
2nd- to 3rd-line non-small cell lung cancer that has progressed on or after a PD-(L)1i
2nd-line+ clear cell renal cell carcinoma that has progressed on or after a PD-(L)1i
2nd- to 4th-line triple-negative breast cancer that has progressed on or after a PD-(L)1i
2nd- to 3rd-line cutaneous squamous cell carcinoma that has progressed on or after a PD-(L)1i
1st-line PD-(L)1i naïve, PD-L1+ head and neck squamous cell carcinoma
2nd- to 4th-line PD-(L)1i naïve, platinum-resistant, ovarian cancer
2nd- to 4th-line PD-(L)1i naïve, undifferentiated pleomorphic sarcoma and liposarcoma
About JTX-8064
JTX-8064 is a humanized IgG4 monoclonal antibody designed to specifically bind to Leukocyte Immunoglobulin Like Receptor B2 (LILRB2/ILT4) and block interactions with its ligands. JTX-8064 is the first tumor-associated macrophage candidate developed from Jounce’s Translational Science Platform. Preclinical data presented at the 2020 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting and the 2019 and 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meetings support the development of JTX-8064 as a novel immunotherapy to reprogram immune-suppressive macrophages and enhance anti-tumor immunity. A Phase 1 clinical trial named INNATE (NCT04669899) of JTX-8064 as a monotherapy and in combination with Jounce’s internal anti-PD-1 inhibitor, pimivalimab (formerly JTX-4014) is currently enrolling patients with advanced solid tumors into tumor-specific expansion cohorts.

About Pimivalimab
Pimivalimab (formerly JTX-4014) is a well-characterized fully human IgG4 monoclonal antibody designed to block binding to PD-L1 and PD-L2. Pimivalimab demonstrated a 17% durable overall response rate in a Phase 1 trial of 18 heavily pre-treated PD-(L)1 inhibitor naïve patients, which excluded all tumor types for which PD-(L)1 inhibitors were approved. In this Phase 1 trial, pimivalimab was shown to have an acceptable safety profile. Pimivalimab is currently being assessed in the INNATE Phase 1 trial (NCT04669899) in combination with JTX-8064, a LILRB2 (ILT4) inhibitor. Pimivalimab is also being assessed in the SELECT Phase 2 clinical trial (NCT04549025) in combination with vopratelimab, a clinical-stage monoclonal antibody that binds to and activates ICOS, the Inducible T cell CO-Stimulator, a protein on the surface of certain T cells commonly found in many solid tumors.