On April 10, 2021 Bayer reported Results from the randomized, double-blind, placebo-controlled Phase III trial CHRONOS-3 show a significant improvement in progression-free survival (PFS) with the investigational combination of Aliqopa (copanlisib) and rituximab given intravenously in patients with relapsed indolent non-Hodgkin’s Lymphoma (iNHL) compared to the combination of rituximab and placebo (Press release, Bayer, APR 10, 2021, View Source [SID1234577867]). After a median follow-up of 19.2 months, patients treated with this combination had a median PFS of 21.5 months (95% CI 17.9, 33.0) versus 13.8 months in patients treated with rituximab and placebo (95% CI 10.2, 17.5), (HR=0.52, p=0.000002). No new safety signals were identified for Aliqopa in the combination arm of the study.1 The data will be presented in a Clinical Trials Plenary Session on April 10 at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 and simultaneously published in The Lancet Oncology.

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CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled trial with the objective to evaluate whether Aliqopa in combination with rituximab is superior to placebo plus rituximab in extending PFS in patients with relapsed iNHL following at least one prior rituximab-containing therapy. Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included.2

In 2017, Aliqopa was approved for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies based on the results of a single-arm, multicenter, Phase II clinical trial (CHRONOS-1).3 Accelerated approval was granted for this indication based on overall response rate (ORR). Continued approval for this indication is contingent upon verification and description of clinical benefit in a confirmatory trial.

"In clinical practice, we have seen an overall improvement in the prognosis of iNHL patients, yet relapsed disease is still a prominent treatment challenge," said Matthew J. Matasar, M.D., Medical Oncologist, Regional Care Network Medical Site Director, Memorial Sloan Kettering Cancer Center (MSK) Bergen. "The results reported with the combination of copanlisib and rituximab suggest a potential advancement for patients with these diverse types of cancers."

"Bayer is committed to putting patients’ needs first and delivering innovative treatment options that address areas of high unmet need, and clinical research is the first step in that process," said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer. "These data highlight the potential of Aliqopa and rituximab as a new strategy for treating these patients and we look forward to advancing regulatory discussions."

Bayer is in discussions with health authorities worldwide regarding the data from CHRONOS-3.

Additional CHRONOS-3 Data Being Presented at AACR (Free AACR Whitepaper)
In addition to the primary endpoint of PFS, data on the secondary endpoints of ORR and complete response rate (CRR) will also be presented. Best ORR for the combination of Aliqopa and rituximab was 80.8% (95% CI 76, 85) versus 47.7% (95% CI 40, 56) for rituximab and placebo (p<0.0001), with 33.9% and 14.6% of patients achieving CR, respectively. Of the relapsed iNHL patients included in the trial, 60% had FL, 20.7% marginal zone lymphoma (MZL), 10.9% small lymphocytic lymphoma (SLL) and 8.3% lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). Analysis of the subtypes will be presented at AACR (Free AACR Whitepaper) and published in The Lancet Oncology.1

All-grade treatment-emergent adverse events (TEAEs) observed with the Aliqopa and rituximab combination that occurred in more than 20% of the patients included hyperglycemia (69.4%), hypertension (49.2%), diarrhea (33.6%), neutropenia (20.8%), nausea (22.5%) and pyrexia (20.5%). Discontinuation due to all-grade TEAEs in CHRONOS-3 for Aliqopa and rituximab was 32% versus 8% for rituximab and placebo.1

Aliqopa is an intravenous phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant activity against alpha and delta isoforms the PI3K-alpha and PI3K-delta isoforms expressed in malignant B cells.4 Aliqopa is approved in the U.S. under the accelerated approval pathway for the treatment of adult patients with relapsed FL who have received at least two prior systemic therapies. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Accelerated approval was granted for this indication based on an ORR of 59% (n=61/104; 95% CI 49, 68), including 14% (15/104) of CRs from the open-label, single-arm multicenter, Phase II clinical trial (CHRONOS-1), in a total of 142 subjects, which included 104 subjects with follicular B-cell non-Hodgkin’s Lymphoma who had relapsed disease following at least two prior treatments. In the updated two-year follow-up analysis conducted on data until 16 weeks after the last patients eligible for full analysis started treatment, Aliqopa ORR was 59% (n=61; 95% CI 49, 68), including 20% CR (n=21).5 Tumor response was assessed according to the International Working Group response criteria for malignant lymphoma. Efficacy based on ORR was assessed by an Independent Review Committee.

Disclosure: This study was sponsored by Bayer AG. Dr. Matasar has received honoraria from Bayer AG and subsidiaries of Bayer AG for advising and related activities. Bayer AG also provides research funding for Dr. Matasar through Memorial Sloan Kettering Cancer Center (MSK). In addition, Dr. Matasar has received honoraria from Roche/Genentech for advising and related activities, and the company also provides research funding for him through MSK.

About Aliqopa (copanlisib) Injection3
Aliqopa (copanlisib) is indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Aliqopa is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. Aliqopa has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. Aliqopa inhibits several key cell-signaling pathways, including B-cell receptor signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines.

IMPORTANT SAFETY INFORMATION FOR ALIQOPA (copanlisib)

Infections: Serious, including fatal, infections occurred in 19% of 317 patients treated with ALIQOPA monotherapy. The most common serious infection was pneumonia. Monitor patients for signs and symptoms of infection and withhold ALIQOPA for Grade 3 and higher infection.

Serious pneumocystis jiroveci pneumonia (PJP) infection occurred in 0.6% of 317 patients treated with ALIQOPA monotherapy. Before initiating treatment with ALIQOPA, consider PJP prophylaxis for populations at risk. Withhold ALIQOPA in patients with suspected PJP infection of any grade. If confirmed, treat infection until resolution, then resume ALIQOPA at previous dose with concomitant PJP prophylaxis.

Hyperglycemia: Grade 3 or 4 hyperglycemia (blood glucose 250 mg/dL or greater) occurred in 41% of 317 patients treated with ALIQOPA monotherapy. Serious hyperglycemic events occurred in 2.8% of patients. Treatment with ALIQOPA may result in infusion-related hyperglycemia. Blood glucose levels typically peaked 5 to 8 hours post-infusion and subsequently declined to baseline levels for a majority of patients; blood glucose levels remained elevated in 17.7% of patients one day after ALIQOPA infusion. Of 155 patients with baseline HbA1c <5.7%, 16 (10%) patients had HbA1c >6.5% at the end of treatment.

Of the twenty patients with diabetes mellitus treated in CHRONOS-1, seven developed Grade 4 hyperglycemia and two discontinued treatment. Patients with diabetes mellitus should only be treated with ALIQOPA following adequate glucose control and should be monitored closely.

Achieve optimal blood glucose control before starting each ALIQOPA infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hyperglycemia.

Hypertension: Grade 3 hypertension (systolic 160 mmHg or greater or diastolic 100 mmHg or greater) occurred in 26% of 317 patients treated with ALIQOPA monotherapy. Serious hypertensive events occurred in 0.9% of 317 patients. Treatment with ALIQOPA may result in infusion-related hypertension. The mean change of systolic and diastolic BP from baseline to 2 hours post-infusion on Cycle 1 Day 1 was 16.8 mmHg and 7.8 mmHg, respectively. The mean BP started decreasing approximately 2 hours post-infusion; BP remained elevated for 6 to 8 hours after the start of the ALIQOPA infusion. Optimal BP control should be achieved before starting each ALIQOPA infusion. Monitor BP pre- and post-infusion. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of hypertension.

Non-infectious Pneumonitis: Non-infectious pneumonitis occurred in 5% of 317 patients treated with ALIQOPA monotherapy. Withhold ALIQOPA and conduct a diagnostic examination of a patient who is experiencing pulmonary symptoms such as cough, dyspnea, hypoxia, or interstitial infiltrates on radiologic exam. Patients with pneumonitis thought to be caused by ALIQOPA have been managed by withholding ALIQOPA and administration of systemic corticosteroids. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of non-infectious pneumonitis.

Neutropenia: Grade 3 or 4 neutropenia occurred in 24% of 317 patients treated with ALIQOPA monotherapy. Serious neutropenic events occurred in 1.3%. Monitor blood counts at least weekly during treatment with ALIQOPA. Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of neutropenia.

Severe Cutaneous Reaction: Grade 3 and 4 cutaneous reactions occurred in 2.8% and 0.6% of 317 patients treated with ALIQOPA monotherapy respectively. Serious cutaneous reaction events were reported in 0.9%. The reported events included dermatitis exfoliative, exfoliative rash, pruritus, and rash (including maculo-papular rash). Withhold, reduce dose, or discontinue ALIQOPA depending on the severity and persistence of severe cutaneous reactions.

Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ALIQOPA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of copanlisib to pregnant rats during organogenesis caused embryo-fetal death and fetal abnormalities in rats at maternal doses as low as 0.75 mg/kg/day (4.5 mg/m2/day body surface area) corresponding to approximately 12% the recommended dose for patients. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least one month after the last dose.

Adverse Drug Reactions: Serious adverse reactions were reported in 44 (26%) patients. The most frequent serious adverse reactions that occurred were pneumonia (8%), pneumonitis (5%) and hyperglycemia (5%). Adverse reactions resulted in dose reduction in 36 (21%) and discontinuation in 27 (16%) patients. The most frequently observed adverse drug reactions (≥20%) in ALIQOPA-treated patients were: hyperglycemia (54%), leukopenia (36%), diarrhea (36%), decreased general strength and energy (36%), hypertension (35%), neutropenia (32%), nausea (26%), thrombocytopenia (22%), and lower respiratory tract infections (21%).

Drug Interactions: Avoid concomitant use with strong CYP3A inducers. Reduce the ALIQOPA dose to 45 mg when concomitantly administered with strong CYP3A inhibitors.

Lactation: Advise women not to breastfeed. Advise a lactating woman not to breastfeed during treatment with ALIQOPA and for at least 1 month after the last dose.

For important risk and use information about Aliqopa, please see the full Prescribing Information.

About CHRONOS-3
CHRONOS-3 is a Phase III randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Aliqopa in combination with rituximab versus placebo in combination with rituximab in patients with relapsed indolent NHL who have received at least one or more lines of prior rituximab-containing therapy. Histological subtypes included in the trial were follicular lymphoma (FL), small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and marginal zone lymphoma (MZL). Patients who had a progression-free and treatment-free interval of at least 12 months after completion of the last rituximab-containing regimen or patients unwilling/unfit or for who chemotherapy was contraindicated by reason of age, co-morbidities and/or residual toxicity were included (NCT02367040). The study enrolled 458 participants.2

About non-Hodgkin’s Lymphoma
Non-Hodgkin’s Lymphoma (NHL) comprises a highly heterogeneous group of chronic diseases with poor prognosis. NHL is the most common hematologic malignancy and the eleventh most common cancer worldwide, with nearly 510,000 new cases diagnosed in 2018. It accounted for nearly 249,000 deaths worldwide in 2018.6,7

Indolent NHL consists of multiple subtypes, including follicular lymphoma (FL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), and lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM). While the disease is typically slowly growing, it can become more aggressive over time. Despite treatment advances, there remains a need for improved treatment options for the relapsed or refractory stage of the disease. After response to initial therapy, response rates and duration of response decline with subsequent lines of therapy, underscoring the need for patients whose disease has already progressed.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now expands to six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On April 10, 2021 Mersana Therapeutics, Inc. (NASDAQ:MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, reported preclinical data from XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate (ADC), and XMT-2056, an Immunosynthen-based STING-agonist ADC at the Virtual 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held from April 10-15th (Press release, Mersana Therapeutics, APR 10, 2021, View Source [SID1234577819]).

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"The ability of Immunosynthen-based ADCs to activate the innate immune system via STING in tumor cells in addition to tumor-resident immune cells in a targeted manner could offer a significant therapeutic advantage over ADCs that modulate other immune activating pathways. These data demonstrate that XMT-2056 is highly differentiated from other innate immune activating approaches and has the anti-tumor activity and tolerability to support continued development of this novel STING-agonist ADC candidate," said Timothy B. Lowinger, Ph.D., Chief Science and Technology Officer of Mersana Therapeutics. "Additionally, we presented data showing that XMT-1660 outperformed other B7-H4 ADCs in vivo. The inversely correlated expression of B7-H4 and PD-L1 in breast tumors suggests an opportunity for a B7-H4 Dolasynthen ADC to address patients poorly served by checkpoint inhibitors. We expect to complete IND-enabling studies and advance both XMT-1660 and XMT-2056 into the clinic in early 2022."

"These encouraging data for both the Dolasynthen and Immunosynthen platforms demonstrate the scientific prowess of the Mersana research team and our commitment to discover and develop life-changing antibody-drug conjugates for patients fighting cancer," said Anna Protopapas, President and Chief Executive Officer of Mersana Therapeutics.

Details of the posters are as follows:

Poster Title: XMT-1660, a B7-H4-targeted Dolasynthen antibody-drug conjugate for the treatment of breast cancer
Poster Number: 907
Session Category: Experimental and Molecular Therapeutics
Session Title: Antibody Technologies

These data show that B7-H4 is a promising target for a Dolasynthen ADC due to its expression and function. B7-H4 is expressed across multiple different tumor types with high unmet medical need, including breast, endometrial and ovarian. XMT-1660 demonstrated robust in vivo activity against multiple triple-negative breast cancer models, as well as an ER+/HER2- breast cancer model, all of which express B7-H4.

In the MX-1 triple-negative breast model, XMT-1660 showed complete, durable regressions of tumors at a DolaLock payload dose of 0.15 mg/kg. In contrast, the DAR-2 and DAR-12 ADCs required twice the payload dose for comparable efficacy. XMT-1660 also showed superior efficacy at matched payload doses in the TNBC patient-derived xenograft model HBCx-24, and in the ER+/HER2- breast cancer PDX model HBCx-19 versus comparators.
Pharmacokinetics of XMT-1660 as well as the Dolasynthen DAR-2 and Dolaflexin DAR-12 comparator ADCs were evaluated in tumor-bearing mice and all were shown to be highly stable in vivo. Pharmacokinetics and tolerability of XMT-1660 and the Dolasynthen DAR-2 ADC were evaluated in non-human primates at equivalent payload doses. The PK and tolerability profiles were comparable and both ADCs exhibited high stability. These results, together with the superior efficacy of XMT-1660, support the selection of XMT-1660 for further development and for clinical study for the treatment of B7-H4-expressing tumors, such as breast, endometrial and ovarian.
Poster Title: XMT-2056, a well-tolerated, Immunosynthen-based STING-agonist antibody-drug conjugate which induces anti-tumor immune activity
Poster Number: 1738
Session Category: Immunology
Session Title: Immunomodulatory Agents and Interventions

These data suggest that XMT-2056, an Immunosynthen STING-agonist ADC, can overcome the limitations of the current therapeutic approaches, enabling tumor-targeted delivery of a STING agonist with improved efficacy and tolerability over a free IV STING agonist. Anti-tumor activity of Immunosynthen STING-agonist ADCs involves targeted activation of the STING pathway in both tumor-resident immune cells and tumor cells, delivering a one-two punch with the potential to increase the therapeutic index.

In vitro studies show that XMT-2056 has potent STING activity with >100-fold improvement in activity in comparison to the free STING-agonist payload.
XMT-2056 shows excellent in vivo efficacy even after a single IV dose, while having minimal effect on systemic cytokines. A single, low dose administration of XMT-2056 led to sustained tumor regressions in mice in comparison to the IV STING agonist which showed modest activity even at a dose approximately 100 times higher than that of the ADC. In contrast, when comparing the effect on systemic cytokine levels, the IV STING agonist had significantly higher levels compared to the STING-agonist ADC, which supports the hypothesis that a STING-agonist ADC can target STING activation to the tumor microenvironment, leading to improved anti-tumor activity and a significantly greater therapeutic index.
In vitro and in vivo studies demonstrate that STING agonist ADCs are able to activate the STING pathway in both tumor-resident immune cells and tumor cells, offering a potential advantage over other innate immune activating pathways.
To evaluate the safety profile, XMT-2056 was administered intravenously to non-human primates (NHP) in single and repeat-dose studies at multiple dose levels. XMT-2056 shows favorable pharmacokinetics in NHPs and is well tolerated at a dose level >10-fold higher than required for sustained tumor regression in mice models. Together these data support the clinical development of XMT-2056.
Poster Title: Tumor cell-intrinsic STING pathway activation leads to robust induction of Type III Interferons and contributes to the anti-tumor activity elicited by STING agonism
Poster Number: 1773
Session Category: Immunology
Session Title: Innate Immunity to Tumors

STING pathway agonism induces anti-tumor immunity by upregulating a Type I interferon response within the tumor microenvironment. While systemically or intra-tumorally administered free STING agonists are currently being evaluated in the clinic, these data suggest that a STING-agonist ADC, in which the STING agonist is conjugated to an antibody directed to a tumor antigen, can overcome the limitations of the current therapeutic approaches.

In vitro studies show that while most cancer cell lines do not respond to STING agonism in standard monoculture conditions, Immunosynthen STING-agonist ADCs do activate STING in the same cancer cells in the presence of immune cell-conditioned media, suggesting that the tumor cell-intrinsic STING pathway can be activated in the presence of cues from immune cells.
Nanostring analysis of human tumor xenografts reveal tumor cell specific induction of type III interferons (IFNs) by tumor cell-targeting Immunosynthen STING-agonist ADCs. In vitro studies confirmed the Type III interferon induction at the mRNA and cytokine level. Type III interferon production was markedly reduced in STING knock out cancer cell and immune cell co-cultures, suggesting that the tumor intrinsic STING activation is required for a robust Type III interferon induction in response to STING agonism. In addition, these data show that blocking Type III IFNs with neutralizing antibodies in cancer cell:immune cell co-cultures inhibits the production of key cytokines and cancer cell killing induced by STING-agonist ADC treatment, pointing to a potentially important role for Type III IFNs in anti-tumor immune responses downstream of STING pathway activation in tumor cells.
Together these data demonstrate that tumor cell intrinsic STING activation leads to a robust type III interferon induction, which contributes to the anti-tumor activity of tumor cell-targeted STING-agonist ADCs. This study supports the further development of Immunosynthen STING-agonist ADC candidates.

On April 10, 2021 Vincerx Pharma, Inc. (Nasdaq: VINC) is a biopharmaceutical company reported that aspiring to address the unmet medical needs of cancer patients through paradigm-shifting therapeutics (Press release, Vincerx Pharma, APR 10, 2021, View Source [SID1234577836]). Today, Vincerx presented preclinical data characterizing VIP236, a novel small molecule drug conjugate (SMDC) at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 . The SMDC is comprised of an αvβ3 integrin antagonist linked to a cytotoxic camptothecin (CPT) derivative, designed to selectively release its payload via neutrophil elastase in the tumor microenvironment (TME).

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"These preclinical data demonstrate that VIP236 has enhanced tumor specificity via tumor specific binding through αvβ3 integrin and targeted drug release in the TME with our neutrophil elastase cleavable linker," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "The payload is a modified camptothecin derivative which has been optimized for high cell permeability and a low efflux ratio. When VIP236 is administered to tumor bearing mice, an over 10-fold higher tumor-to-plasma ratio of the CPT payload was observed, when compared to delivery of the payload alone. Importantly, these properties translate into potent antitumor activity across multiple xenograft models, with tumor regression in all models tested and complete tumor responses in 100% across all dose levels of mice in a triple negative breast cancer model. These compelling data, combined with a favorable tolerability profile, suggest that VIP236 has the potential to provide potent, highly targeted antitumor activity to address the needs of patients with advanced and aggressive cancers. We look forward to continued progress as we advance VIP236 towards the clinic, with first-in-human studies expected in the first half of 2022."

Key Presentation Highlights:

Poster presentation, titled, "A novel small molecule drug conjugate – αvβ3 integrin antagonist linked to a cytotoxic camptothecin derivative – for the treatment of multiple cancer types" presented by Hans-Georg Lerchen, Ph.D., Chief Scientific Officer of Vincerx.

VIP236 is a novel SMDC targeted by an αvβ3 integrin antagonist with a neutrophil elastase cleavable linker linked to a modified CPT payload derived from SN38, a well-known cytotoxic drug and active metabolite of irinotecan.
Efficient anti-tumor targeting and greater cytotoxicity is achieved by multiple mechanisms associated with aggressive tumor cells and its microenvironment.
VIP236 targets αvβ3 integrin which is overexpressed by invasive cancer and stromal cells in the TME such as endothelial cells undergoing neovascularization. Efficient tumor homing with the αvβ3 integrin antagonist is demonstrated by the imaging studies.
Neutrophil elastase (NE) is overexpressed in the invasive TME associated with advanced cancers. The abundance of NE in the TME promotes linker cleavage, release of the active modified CPT payload and enhances VIP236 cytotoxicity.
Drug resistant cancer cells often have greater drug efflux capabilities. The CPT payload is modified to improve cellular permeability and lower cell efflux properties resulting in better cytotoxicity in cancer cells overexpressing drug efflux pumps when compared to SN38.
The combination of these properties results in a 10.8-fold higher tumor-to-plasma ratio of the targeted and modified CPT payload compared to administration of the payload alone.
In vivo, VIP236 demonstrates higher antitumor efficacy in comparison to reference chemotherapy drugs across multiple mouse xenograft models.
Complete tumor responses were observed in 100% of mice across all dose levels in the MX-1 triple negative breast cancer model.
Partial responses were observed in 100% of mice in both the NCI-H69 small cell lung cancer and SW480 colorectal cancer mouse models at a VIP236 dose of 40mg/kg.
Across mouse models, VIP236 showed good tolerability as evidenced by less than 5% mean body weight loss.
The poster can be accessed on the presentations section of the Vincerx website.

On April 10, 2021 Molecular Partners AG (SIX: MOLN), a clinical-stage biotech company that is developing a new class of custom-built protein drugs known as DARPin therapeutics, reported the presentation of four posters highlighting research across its immuno-oncology programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual Annual Meeting (Press release, Molecular Partners, APR 10, 2021, View Source [SID1234577852]). The preclinical data shared include results from the Company’s acute myeloid leukemia (AML) CD3 T-cell engager program, new data from the MP0317 (FAP x CD40) tumor localized immune activator, and initial results from the Company’s CD3 prodrug programs.

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"With our new technologies designed for localized immune activation, targeting of cell surface-displayed peptides derived from intracellular proteins, and T-cell engagement, we believe we have a solid strategy for our new immune-oncology product candidates, and novel design capabilities that have the potential to greatly benefit our own and partnered immuno-oncology programs," said Daniel Steiner, Ph.D., SVP Research of Molecular Partners. "Our first T-cell engager program is focused on AML, where statistically about half of people diagnosed relapse after treatment and die from the disease. Despite the existence of approved therapies, patients are often unable to benefit from these treatments due to intolerable toxicity. We believe we have made significant progress toward finding a way to avoid this trade-off and widen the therapeutic window for T-cell engagers in AML, aiming to deliver deeper and broader anti-tumor effect and reduce the impact on patients’ healthy cells."

In preclinical studies, the Company’s AML candidates demonstrated substantial activity against different populations of AML cells in vitro, without significant damage to healthy cells. As shown in the poster titled Novel multi-specific DARPin T-cell engager with an improved therapeutic window to overcome dose limiting toxicities in AML therapies, Molecular Partners is building on the strength of the DARPin platform to create a single product designed to target three different cancer antigens simultaneously (CD70, CD33, and CD123). The multi-specific DARPin T-cell engager candidate is designed to deliver highly potent and specific activity on AML cells, with a reduced effect on healthy normal cells, and with the potential to counteract target escape mechanisms expected due to tumor heterogeneity. In an ex vivo assay using fresh blood from healthy donors, the candidate induced profoundly less inflammatory cytokine production and reduction in platelet counts, unlike simultaneously tested T-cell engager candidates in development by other parties. We believe these data support the designed capability of this candidate to kill a broader population of AML cells while decreasing risk of toxicity.

The T-cell engager research presented today also displays the Company’s prodrug DARPin technology for tumor-localized release of immune stimulation, through incorporation of a protease cleavable blocker DARPin molecule. As CD3-binding T-cell engagers are highly potent and can lead to systemic toxicities, Molecular Partners has developed a DARPin domain designed to mask the CD3 engager from interacting with T cells systemically/outside of the tumor. This technology is aimed at focusing the power of the effector function and reduce toxicities by controlling the location of activation to the tumor microenvironment. In a poster titled A solution to T-cell engager toxicity: An anti-CD3 Prodrug DARPin (CD3-PDD) shows no toxicity, but potent anti-tumor activity in a humanized mouse model, Molecular Partners presents an anti-CD3 Prodrug DARPin molecule, CD3-PDD, consisting of an EGFR-binder and a CD3-binder, linked via a protease-cleavable linker to a DARPin domain masking the CD3 effector function. This-anti EGFR x anti-CD3 – Blocker Prodrug is shown to be unable to bind and recruit T-cells in its non-cleaved state in circulation, and is designed to become activated in the tumor microenvironment upon cleavage of the linker by tumor-associated proteases.

With respect to MP0317, a multi-specific DARPin product candidate targeting both FAP and CD40 to enable tumor-localized immune activation, new preclinical data demonstrated a localized activation of immune cells in vitro, as well as ex vivo in human tumor samples, dependent on the presence of the FAP protein, which is highly expressed in the stroma of a broad range of solid tumors. The data presented in the poster titled MP0317, a FAPxCD40 targeting multi-specific DARPin therapeutic, drives immune activation and leads to macrophage repolarization in vitro and ex vivo shows that MP0317 led to macrophage repolarization and reversion of T cell suppression: MP0317 led to upregulation of CD80, an M1 marker, and downregulation of CD163, an M2 marker, only in the presence of FAP, indicating macrophage repolarization towards an M1 phenotype. Furthermore, when these repolarized macrophages were co-cultured with T cells, T cell suppression was shown to revert and CD8 T-cell activation was observed, as shown by the increase of CD25. In both assays the killing effect was comparable to that achieved by an anti-CD40 antibody. We believe these data support MP0317’s potential to deliver tumor-localized CD40-mediated immune cell activation while avoiding systemic toxicity seen in other agents. MP0317 is anticipated to begin clinical trials in the second half of 2021.

Finally, with respect to the Company’s peptide-MHC targeting program, the Company presents preclinical results from a proof of concept study targeting a peptide derived from the NY-ESO-1 protein displayed in the context of a HLA-A2 molecule (a human MHC protein). The poster, Application of the DARPin technology for specific targeting of tumor-associated MHC class I: peptide complexes, highlights results demonstrating rapid and reliable generation of DARPin proteins against pMHC which were then formatted into bispecific T-cell engagers, and engineered to enable potent and specific activation of T cells. Further, the results show that the pMHC-targeting DARPin candidate was able to achieve systemic half-life extension with limited impact on potency.

The posters presented at AACR (Free AACR Whitepaper) are available to view in the Scientific Presentations section of Molecular Partners’ corporate website.

About Molecular Partners’ Immuno-oncology Product Candidates
Molecular Partners is developing several candidates designed to activate the immune system to fight cancer while reducing damage to healthy cells. These candidates use multiple novel DARPin technologies potentially applicable against a wide range of tumor types, including DARPin candidates with the ability to restrict immune activation to the tumor microenvironment, the ability to target intracellular disease-associated proteins, and multiple novel control mechanisms for immune activation designed to direct immune attack to the right cells, at the right place, and at the right time. These capabilities can be combined during candidate design through the inherent modularity of the DARPin platform, to provide precise control over immune activation and potentially enable more effective cancer immunotherapies.

On April 10, 2021 Guardant Health, Inc. (Nasdaq: GH), along with leading academic institutions and pharmaceutical companies, reported new data at the AACR (Free AACR Whitepaper) Virtual Annual Meeting I, April 10-15, 2021, highlighting the use of the company’s proprietary blood tests to advance precision oncology (Press release, Guardant Health, APR 10, 2021, View Source [SID1234577868]).

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Key findings demonstrate the value of Guardant360, Guardant360 CDx, and GuardantOMNI liquid biopsy tests to detect clinically actionable mutations, inform treatment for patients as their cancer progresses, and reveal tumor evolution and resistance in response to interventional therapies, including immunotherapies.

"At this year’s AACR (Free AACR Whitepaper), we highlight the growing clinical utility of our liquid biopsy tests, from revealing critical genomic and molecular insights that contribute to vitally important drug development efforts, to further informing treatment decisions as patients with advanced disease progress," said Helmy Eltoukhy, Guardant Health CEO. "As we exit the pandemic, the ability to effectively treat advanced cancers that may have remained undetected during the past year will be critical, and there is no room for error or further delays in finding the right treatment or clinical trial. Now more than ever, our liquid biopsies are needed to accelerate the accessibility of effective treatment options for patients most in need of precise clinical therapies."

Guardant360 CDx validated for use with Amgen’s investigational KRASG12C inhibitor, sotorasib

Data from the phase 2 CodeBreaK 100 trial evaluating investigational sotorasib in patients with advanced non-small cell lung cancer (NSCLC) showed the objective response rate was comparable in patients selected using Guardant360 CDx liquid biopsy or tissue biopsy, with high concordance demonstrated between the two assays.

"The study results highlight that the Guardant360 blood-based companion diagnostic test was effective at selecting patients with KRAS G12C who may benefit from treatment with sotorasib, said Darryl Sleep, senior vice president, global medical and chief medical officer, Amgen. "KRAS G12C can only be detected with a biomarker test and with one in eight patients with NSCLC harboring the KRAS G12C mutation, there is a critical need to improve access to high quality diagnostics and more routine screening."

Title

Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC

Abstract No.

CT181

Session

Phase II Clinical Trials

Date / Time

e-Poster Presentation: April 10, 2021, 8:30 AM – 11:59 PM EDT

Guardant360 CDx delivers results at low inputs, which can potentially increase patient samples for clinical decision-making and clinical studies

Study shows Guardant360 CDx provides comprehensive tumor profiling results with robust analytical performance at demonstrated low inputs (5ng cutoff). These data suggest that Guardant360 CDx has the potential to guide therapy decisions for about 34% more patients compared to some liquid biopsies that use 2 blood collection tubes (BCT) for minimal 30ng of cell-free DNA (cfDNA). The data also show that the ability to process samples below 15ng input from a single BCT increases the yield of EGFR driver mutations by >25%. Furthermore, because retrospective studies are often performed with as little as 2mL of plasma, the study shows that the Guardant360 CDx is expected to return valid results on over 88% of such samples, which may be outside the performance specifications for other assays.

Title

The liquid biopsy Guardant360 CDx has robust performance at low inputs allowing for high rate of returning patient results

Abstract No.

572

Session

Liquid Biopsies: Circulating DNA

Date / Time

April 10, 2021, 8:30 AM – 11:59 PM EDT

Studies show Guardant360 provides early indication of treatment response and resistance mechanisms in the management of advanced cancer

Data presented are consistent with prior studies, across various treatments and indications,1-10 showing Guardant360 provides early indication of treatment response and clinical outcomes by measuring molecular response or changes to circulating tumor DNA from baseline at different time-points. In addition, data presented show that Guardant360 can also reveal tumor evolution and resistance in response to interventional therapies, including immunotherapies.

Title

Reversion patterns in homologous recombination repair genes in metastatic cancer patients profiled by cell-free DNA

Abstract No.

25

Session

Biomarkers

Date / Time

MINISYMPOSIUM PRESENTATION
April 10, 2021, 2:20 PM – 2:30 PM EDT

Title

Comparison of molecular response calculations for prediction of patient outcome

Abstract No.

401

Session

Biomarkers Predictive of Therapeutic Benefit

Date / Time

Poster presentation: April 10, 2021, 8:30 AM – 11:59 PM EDT

Other abstracts and poster presentations

Title

Confirmation of Target Inhibition and Anti-Tumor Activity of the SHP2 Inhibitor RMC-4630 via Longitudinal Analysis of ctDNA in RAS-Addicted Tumors in a Phase 1 Clinical Study

Title

A single institution experience with Guardant360 liquid biopsy for therapeutic decision in advanced solid tumors

Title

NTRK1 fusion detection from clinical cfDNA NGS using a de novo fusion caller

Title

Detection of somatic copy number alterations from on-target and off-target sequencing data