On April 13, 2021 Galectin Therapeutics Inc. (NASDAQ:GALT), the leading developer of therapeutics that target galectin proteins, reported that a paper published in the peer-reviewed Journal for ImmunoTherapy of Cancer (JITC), the highest ranked fully open access immunology journal, provides further clinical evidence that using belapectin, a potent galectin-3 inhibitor, in combination with pembrolizumab (KEYTRUDA), a PD-1 inhibitor, significantly enhances tumor response to immunotherapy in patients with advanced metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC) (Press release, Galectin Therapeutics, APR 13, 2021, View Source [SID1234578044]).

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The paper, titled "Enhancing Clinical and Immunological Effects of anti-PD-1 with Belapectin, a Galectin-3 Inhibitor" (doi:10.1136/jitc-2021-002371) describes results from an ongoing Phase 1 clinical study, a collaboration between Galectin Therapeutics and Providence Cancer Institute in Portland, Oregon.

Following the recent publication of positive preclinical results that showed the inhibition of galectin-3 in combination with an agonist anti-OX40 monoclonal antibody reprograms the tumor microenvironment to favor anti-tumor activity, the current study tests the clinical hypothesis that galectin-3 blockade with belapectin in combination with pembrolizumab enhances tumor response for patients with advanced MM or HNSCC.

In the study, as previously disclosed, an objective response was observed in 50% of MM (7/14) and 33% of HNSCC (2/6) patients. This compares favorably to published response rates on pembrolizumab alone. The authors noted that the combination was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab alone. In addition, the analysis of patients’ tumor tissue revealed reduced monocytic myeloid-derived suppressor cells and increased effector memory T-cell activation in responders compared with non-responders. Also, an increased baseline expression of galectin-3 positive tumor cells correlated with clinical response.

"Immunotherapy is a significant breakthrough in the treatment of many cancers, but tumor-induced immune suppression contributes to treatment resistance. Galectin-3 is an important driver of this tumor-induced immunosuppression, and this clinical study constitutes proof-of-concept that the addition of belapectin, a galectin-3 inhibitor, to a PD-1 inhibitor can benefit cancer patients," said Dr. Brendan Curti, M.D., Earle A. Chiles Research Institute, a division of Providence, and the first author of the paper.

"The analysis of patients’ tumor tissues is consistent with previously published pre-clinical data with belapectin and confirms the ability of belapectin to modulate the tumor microenvironment to favor anti-tumor activity. The possibility to improve the tolerance and safety of immunotherapy is also very exciting," commented Pol F. Boudes, M.D., Chief Medical Officer of Galectin Therapeutics. "These proof-of-concept clinical data provide a strong rationale to initiate a randomized placebo-controlled phase 2 clinical trial to evaluate the efficacy and safety of belapectin in combination with a PD-1 inhibitor compared to a PD-1 inhibitor alone in this cancer patient population. We look forward to continuing our work with Providence Cancer Institute, and we anticipate the upcoming release of additional data from the expansion cohort in this study."

About Belapectin (GR-MD-02)

Belapectin (GR-MD-02) is a complex carbohydrate drug that targets galectin-3, a critical protein in the pathogenesis of NASH and fibrosis. Galectin-3 plays a major role in diseases that involve scarring of organs including fibrotic disorders of the liver, lung, kidney, heart and vascular system. Belapectin binds to galectin-3 and disrupts its function. Preclinical data in animals have shown that belapectin has robust treatment effects in reversing liver fibrosis and cirrhosis. A Phase 2 study showed belapectin may prevent the development of esophageal varices in NASH cirrhosis; these results provide the basis for the conduct of the NAVIGATE trial. The NAVIGATE trial (NAVIGATEnash.com), entitled "A Seamless Adaptive Phase 2b/3, Double-Blind, Randomized, Placebo-controlled Multicenter, International Study Evaluating the Efficacy and Safety of Belapectin (GR-MD-02) for the Prevention of Esophageal Varices in NASH Cirrhosis" began enrolling patients in June 2020 and is posted on www.clinicaltrials.gov (NCT04365868). Galectin-3 also has a significant role in cancer, and the Company is supporting a Phase 1 study in combined immunotherapy of belapectin and KEYTRUDA in treatment of advanced melanoma and in head and neck cancer.

On April 13, 2021 BridgeBio Pharma, Inc. (NASDAQ: BBIO) reported a collaboration with Oregon Health & Science University (OHSU) in Portland, Oregon, to advance research and the development of investigational medicines for patients with genetically driven conditions (Press release, BridgeBio, APR 13, 2021, View Source [SID1234577967]).

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"We feel privileged to have the opportunity to work with OHSU to focus on developing potential therapies for diseases with clear genetic drivers and severe unmet need," said BridgeBio founder and CEO Neil Kumar, Ph.D. "OHSU was one of the first research institutions we connected with in the early days of BridgeBio, and we look forward to deepening our relationship through close collaboration with their scientists as we strive to help patients together."

This arrangement builds on five years of informal collaborations between the two organizations. Under the agreement, the BridgeBio team will work closely with OHSU scientists and investigators to advance potential medicines for patients with genetically driven conditions, including cancers.

"BridgeBio’s approach to identifying and developing novel therapies allows them to interact with multiple investigators at OHSU who are studying a wide variety of diseases," said OHSU Chief Research Officer and Executive Vice President Peter Barr-Gillespie, Ph.D. "We believe their expertise and infrastructure will help lead to the rapid development of new drugs. We see this collaboration as an important part of our efforts to bring OHSU innovations to clinical significance."

BridgeBio collaborates with stand-out academic institutions, including OHSU, to support research around genetically driven conditions and is focused on rapidly translating findings into meaningful treatments for patients. Today BridgeBio also announced formal partnerships with Brown University, GlycoNet, The Lundquist Institute, Roswell Park Comprehensive Cancer Center, University of California, Davis and University of California, San Diego – for a total of 20 partnerships between BridgeBio and leading academic and research institutions to date. For a list of some of the institutions BridgeBio partners with, please visit Our Partners page.

With a diverse pipeline encompassing investigational therapies for rare diseases and genetically validated cancers, BridgeBio provides the insights and support needed to rapidly progress therapeutic research from labs to clinical development. BridgeBio intends to develop similar long-term partnerships based on trust, engagement, science and respect to support its mission of developing life-changing medicines for patients with genetically driven conditions as quickly and safely as possible.

On April 13, 2021 Purple Biotech Ltd. ("Purple Biotech" ", or the "Company") (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class, effective and durable therapies by overcoming tumor immune evasion and drug resistance, reported that additional preclinical data supporting the mechanism of action of NT219, a dual inhibitor, novel small molecule that simultaneously targets IRS1/2 and STAT3, were presented in a poster entitled "Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2," at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) 2021 Annual Meeting (Press release, Purple Biotech, APR 13, 2021, View Source [SID1234577984]). These data update and expand on the results previously reported by the Company from its collaboration with Professor Ido Wolf, Head of the Oncology Division at Tel Aviv Sourasky Medical Center.

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Colorectal cancer (CRC) represents the fourth most frequent cause of brain metastasis, which is the most common brain tumor. The study included an analysis of more than 16,000 human CRC local and metastasis samples, and revealed increased amplification of IRS2 in brain metastases.

In an in vitro system mimicking the brain microenvironment, IRS2-overexpressed CRC cells showed prolonged survival. Importantly, transcriptomic analysis demonstrated significant enrichment of the oxidative phosphorylation (OXPHOS) pathway by IRS2. CRC cells expressing IRS2 showed increased mitochondrial activity and glycolysis-independent viability. Inhibition of IRS2 using NT219 dose-dependently inhibited IRS2-expressing cells viability and OXPHOS genes expression.

The Wnt/β-catenin pathway was among the most significantly enriched pathways in the brain metastasis, as IRS2-expressing cells showed increased transcriptional activity of the β-catenin. In addition, NT219 decreased the transcriptional activity of β-catenin in IRS2-expressing CRC cells to a greater extent than AKT and PI3K inhibitors, and most significantly suggested relevance of IRS2 in activating β-catenin. It was further shown that 5-FU, a chemotherapy approved for treating CRC, elevated β-catenin expression, and that NT219 diminished both 5FU-induced and the basal level of the β-catenin expression. Utilizing an intracranial animal model, it was also demonstrated that while 5-FU alone had no significant effect, the combination of 5-FU and NT219 significantly inhibited the formation of brain metastasis and extended survival rates of the study mice.

"We are excited about these highly encouraging study results," said Bertrand Liang, M.D., Ph.D., Chief Medical Officer of Purple Biotech. "These compelling data provide important insights regarding the role of IRS2 in promoting CRC brain metastasis, and suggest that novel agents such as NT219 have the potential to effectively inhibit the development of brain metastasis. Our ongoing Phase 1/2 clinical trial of NT219 as monotherapy for the treatment of solid tumors, followed by a dose escalation of NT219 in combination with cetuximab, an epithelial growth factor receptor (EGFR) blocking monoclonal antibody, for the treatment of recurrent and/or metastatic solid tumors and squamous cell carcinoma of the head and neck cancer, is proceeding with enrollment as planned and we continue to expect the availability of top-line data from the first part of this study in the second half of this year."

The poster presentation is available at View Source

On April 12, 2021 Greenwich LifeSciences, Inc. (Nasdaq: GLSI) (the "Company"), a clinical-stage biopharmaceutical company focused on the development of GP2, an immunotherapy to prevent breast cancer recurrences in patients who have previously undergone surgery, reported a poster of the final 5 year GP2 Phase IIb clinical trial immune response data on April 10th at the 2021 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Greenwich LifeSciences, APR 12, 2021, View Source [SID1234577894]). Immune response is the primary mechanism of action for GP2 and is critical to developing dosing and booster treatment strategies that are designed to achieve and sustain peak immunity, as well as to prevent metastatic breast cancer recurrences.

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It has been previously reported that the completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients who had received a standard course of trastuzumab after surgery. The abstract and poster present the final immune response results over the 5 year follow-up period, assessing peak immunity compared to baseline and between patients treated with GP2+GM-CSF versus GM-CSF alone, including by HER2 status.

Summary of the Final 5 Year Immune Response Data as Previously Presented:

Potent immune response data supports the previously reported clinical outcome of 0% metastatic breast cancer recurrences over 5 years of follow up, if a patient completes the Primary Immunization Series over the first 6 months of GP2 treatment.
Statistically significant peak immunity was reached after 6 months of GP2 treatment as measured in both the Dimer Binding Assay and the DTH skin test.
HER2 3+ population immune response was similar to the HER2 1-2+ population immune response, suggesting the potential to treat the HER2 1-2+ population (including triple negative breast cancer) with GP2 immunotherapy in combination with trastuzumab (Herceptin) based products and other clinically active agents.
Broad based immune response suggests that GP2 immunotherapy and Herceptin based products may also have the potential to treat other HER2 1-3+ expressing cancers.
Dr. Thompson commented, "The analysis of the immune response data in the Phase IIb trial provides mechanistic confirmation of treatment effect correlated with the clinical response previously reported. GP2 treated patients, independent of their HER2 status, experienced a potent immune response to GP2, far greater than patients treated with placebo. In addition, this data has provided us with insight that will guide the upcoming Phase III trial. We believe that monitoring immune response will be an important aspect of the Phase III trial."

Excerpts from the AACR (Free AACR Whitepaper) Poster CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Each GP2 treated patient was scheduled to receive 6 intradermal injections with GP2+GM-CSF over the first 6 months of treatment as part of the Primary Immunization Series and 4 boosters every 6 months thereafter. Placebo patients received intradermal injections with GM-CSF alone.

Immune responses to GP2 were measured over time using a CD8 T cell dimer binding assay (Dimer Binding Assay) and delayed-type-hypersensitivity (DTH) skin tests. The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters 48-72 hours after injection of GP2 without GM-CSF.

Figure 1 of the poster shows that GP2 immunity peaked at 6 months in HER2 3+ patients after they completed their first 6 immunizations, as measured by the Dimer Binding Assay. The data also shows that for the 2.5 years that the immune response was measured, the immunity was sustained and remained above baseline, resulting in 100% disease free survival (0% recurrence rate) over 5 years. In the placebo arm, the immune response was not as robust, resulting in 89% disease free survival (11% recurrence rate). Immune response in GP2-treated patients increased quickly during the Primary Immunization Series and remained statistically significantly above baseline for 6 months after the completion of the Primary Immunization Series. Some patients received boosters beginning at 12 months and the immune response was assessed one month after the receiving the booster.

Dimer Binding Assay: The Dimer Binding Assay detects the percentage of GP2 specific killer T cells that can kill recurring cancer cells. Ex vivo immune response was assessed over 2.5 years with blood draws at baseline, then after the 3rd and 6th immunizations in the Primary Immunization Series, and then after each booster. Immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=113). GP2-specific CTLs were quantified in patients treated with GP2 using the Ig:A2 Dimer Assay and demonstrated an expansion over time, showing an increase over baseline after the 3rd immunization and remaining elevated for the entire course of follow-up.

Figure 2 of the poster shows the same Dimer Binding Assay data for HER2 3+ patients as in Figure 1, where the GP2 treated patients showed statistically significant dimer readings versus baseline (pre-vaccination) at 3, 6, and 12-13 months.

DTH Skin Test: The DTH skin test measures the diameter of the skin immune response to GP2 in millimeters, 48-72 hours after intradermal injection of GP2 without GM-CSF. A DTH reaction was used to assess in vivo immune responses in patients (n=150). The DTH orthogonal mean of the skin wheal was measured 48-72 hours after injection using the sensitive ballpoint-pen method and is compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions.

Figure 3A shows that after completion of the 6th immunization after 6 months, GP2 treated patients showed a robust immune response using the DTH skin test, while the placebo did not (p = 0.009). Within GP2 treated patients, the change from baseline after 6 months was a median of 4.8 mm (mean of 11.6 mm), which was a statistically significant increase over baseline (p < 0.0001). The change from baseline in DTH at 6 months was more robust in the GP2 treated patients. Those patients had an 11.6 mm mean increase in DTH after 6 months of exposure while patients treated with GM-CSF alone had a 5.2 mm mean increase (p = 0.023). This DTH data supports the Dimer Binding Assay data that shows a peak immune response after 6 months.

Figure 3B shows that the DTH immune response for GP2 treated patients was similarly robust in HER2 3+ patients and HER2 1-2+ patients, independent of prior trastuzumab treatment and HER2 expression levels. Thus, GP2’s robust immune response in the HER2 1-2+ population suggests the potential to apply GP2 immunotherapy to HER2 low to intermediate expressing breast cancers, as well as to other HER2 1-3+ expressing cancers.

AACR Abstract CT183:

Title: Final five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating a time series of immune responses using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Snehal S Patel, David B McWilliams, Mira S Patel, Christine T Fischette, Jaye Thompson and F Joseph Daugherty.

Greenwich LifeSciences, Stafford, TX

Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial (NCT00524277) investigating GP2+GM-CSF versus GM-CSF alone in HLA-A02 patients administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with HER2 status (IHC 1-3+) is now complete with 5 year follow-up. It has been previously reported that completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients, who received a standard course of trastuzumab after surgery. Here we present the final immune response results, assessing peak immunity compared to baseline and between GP2 treated patients versus placebo, including by HER2 status. Interim analyses for this trial have been previously reported by Mittendorf et al.

Methods: Each GP2-treated patient was scheduled to receive 6 GP2+GM-CSF intradermal injections over the first 6 months as part of the PIS and 4 GP2+GM-CSF booster intradermal injections every 6 months thereafter. Placebo patients received GM-CSF only intradermal injections. Immune responses to GP2 were measured over time using delayed-type-hypersensitivity (DTH) skin tests and CD8 Tcell dimer binding assays.

Results: This basket trial explored HER2 3+ patients, who received a standard course of trastuzumab after surgery, and HER2 1-2+ patients, who did not receive trastuzumab after surgery. A DTH reaction was used to assess in vivo immune responses in patients (n=145). The DTH orthogonal mean was measured 48-72 hours after injection using the sensitive ballpoint-pen method and are compared using a Wilcoxon Rank-Sum. For GP2 treated patients, there was a significant increase in DTH reactions after the PIS compared to baseline DTH reactions. The DTH orthogonal mean in GP2 treated patients at baseline had a median 0.0mm versus 10.8mm after the PIS. For patients receiving GM-CSF alone, the DTH orthogonal mean prior to and after the PIS had a median of 0.0mm. In addition, the DTH reactions after the PIS were significantly greater in GP2 treated patients than in placebo patients (10.8mm vs. 0.0mm, p=0.009) and the DTH immune response in GP2 treated patients was similar between HER2 3+ and HER2 1-2+ patients. Ex vivo immune responses were assessed by phenotypic clonal expansion assays in the majority of patients (n=114). GP2-specific CTLs were quantified using the Ig:A2 dimer assay and demonstrated a gradual expansion over time reaching statistical significance approximately 6 months after the PIS compared to baseline in the GP2 treated patients (n=53, p=0.010) but not in the control patients (n=39, p=0.165).

Conclusions: Immunological data comparing peak immunity to baseline and GP2 treated patients to placebo showed that GP2 treated patients, independent of HER2 status, experienced a significant increase in their immune response while those receiving GM-CSF only did not. Future studies may explore the use of immune responses to assess: immunogenicity of GP2 by HLA type, timing of boosters to sustain immunity, clinical site performance, and the discontinuation of treatment for non-responders.

About the AACR (Free AACR Whitepaper) Annual Meeting 2021

The AACR (Free AACR Whitepaper) is the first and largest cancer research organization dedicated to accelerating the conquest of cancer and has more than 48,000 members residing in 127 countries and territories. The AACR (Free AACR Whitepaper) Annual Meeting program covers the latest discoveries across the spectrum of cancer research — from population science and prevention; to cancer biology, translational, and clinical studies; to survivorship and advocacy — and highlights the work of the best minds in research and medicine from institutions all over the world.

About Breast Cancer and HER2/neu Positivity

One in eight U.S. women will develop invasive breast cancer over her lifetime, with approximately 266,000 new breast cancer patients and 3.1 million breast cancer survivors in 2018. HER2/neu (human epidermal growth factor receptor 2) protein is a cell surface receptor protein that is expressed in a variety of common cancers, including in 75% of breast cancers at low (1+), intermediate (2+), and high (3+ or over-expressor) levels.

On April 12, 2021 NuCana plc (NASDAQ: NCNA) reported the presentation of five posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 being held virtually April 9 to 14, 2021 (Press release, Nucana BioPharmaceuticals, APR 12, 2021, View Source [SID1234577911]). Data from all three of NuCana’s ProTides in clinical development were presented. Summaries of the posters are described below.

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NUC-3373

NuCana presented two posters on NUC-3373, its ProTide transformation of the active anti-cancer metabolite of 5-fluorouracil (5-FU), a very widely used anti-cancer drug. NUC-3373 has been designed to overcome the main challenges associated with 5-FU and capecitabine, including cancer-resistance mechanisms, the generation of toxic metabolites and unfavorable pharmacokinetic profile.

Poster Title: NUC-3373, a targeted inhibitor of thymidylate synthase, in patients with advanced colorectal cancer

This poster describes further encouraging interim data from 38 patients with metastatic colorectal cancer. In this difficult-to-treat group, who had received a median of four prior lines of therapy, NUC-3373, with or without leucovorin, demonstrated a 62% disease control rate (defined as stable disease lasting more than 8 weeks) in the efficacy-evaluable population. Three patients experienced reductions in their target lesions of 40%, 28% and 15% and several patients achieved a longer progression-free survival on NUC-3373 than they had on their prior therapy. NUC-3373 also continues to demonstrate a favorable safety profile with no FBAL or FUTP-associated Grade 3 or 4 toxicities, such as hand-foot syndrome, GI or hematological adverse events.

Poster Title: NUC-3373-induced DAMPs release in CRC cells promotes natural killer cell activation

The second NUC-3373 poster showed that NUC-3373-treated colon cancer cells are able to activate a natural killer (NK) cell response. NUC-3373 was shown to induce the release of damage associated molecular patterns (DAMPs) which may restore NK cell-mediated immune responses by reducing inhibitory signals. Thus, NUC-3373 has the potential to evoke immunogenic cell death and may enhance the clinical utility of immunotherapy agents.

NUC-7738

NuCana presented two posters on NUC-7738, a ProTide transformation of a novel nucleoside analog, 3’-deoxyadenosine or 3’-dA. NUC-7738, which has several potential anti-cancer mechanisms of action, is being evaluated in a Phase I study in patients with advanced solid tumors who have exhausted all standard therapies.

Poster Title: NUC-7738, a novel ProTide transformation of 3’-deoxyadenosine, in patients with advanced solid tumors

The first poster describes additional interim data from the ongoing Phase I study. These data demonstrate NUC-7738’s encouraging anti-cancer activity and favorable tolerability profile. Three case studies were described detailing patients who achieved tumor reductions and prolonged stable disease on NUC-7738.

Poster Title: From bench to bedside: Using ProTide chemistry to transform 3’-deoxyadenosine into the novel anti-cancer agent NUC-7738

The second poster describes how NUC-7738 was designed to overcome the key cancer resistance mechanisms which have prevented the clinical development of 3’-dA. NUC-7738 was shown to efficiently generate high and prolonged intracellular levels of the active anti-cancer metabolite, 3’-dATP, and to cause cell death by activation of apoptotic pathways, as well as through inhibition of NFkB nuclear translocation.

Acelarin

Poster Title: NUC-1031 causes incorporation of fluorinated deoxycytidine into DNA, inducing persistent damage in biliary tract cancer cells

NuCana presented a poster that further demonstrated Acelarin’s activity in biliary tract cancer cells. Specifically, the poster described how Acelarin (NUC-1031) is converted to the active anti-cancer metabolite (dFdCTP) and demonstrated that it is incorporated into DNA, inducing persistent double-strand breaks. This leads to cell cycle arrest and DNA damage resulting in apoptosis in biliary tract cancer cells.

Abstracts and full session details can be found at www.aacr.org