On June 3, 2020 Pierre Fabre reported that the European Commission (EC) has approved BRAFTOVI (encorafenib) in combination with cetuximab (marketed as Erbitux) for the treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) who have received prior systemic therapy (Press release, Pierre Fabre, JUN 3, 2020, View Source [SID1234560804]).1 This approval is based on data from the Phase 3 BEACON CRC trial.1,2 The EC decision is applicable to all 27 EU member states plus Iceland, Liechtenstein, Norway and the United Kingdom.3

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"This approval is truly great news and much needed for patients with BRAFV600E-mutant mCRC and for physicians treating this devastating cancer, as until now, there has been no EC-approved therapies specifically indicated for this high-medical-need population," said Josep Tabernero, MD, PhD, BEACON CRC trial lead investigator and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain. "The new encorafenib and cetuximab combination regimen will now change the way we treat these patients, with the possibility of delaying disease progression and prolonging their lives."

The EC decision, which follows the positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on 30 April 2020, is based on available results from the pivotal Phase 3 BEACON CRC trial,2 the first and only randomised Phase 3 trial designed to test a BRAF combination targeted therapy in BRAFV600E-mutant mCRC. The data showed that BRAFTOVI in combination with cetuximab significantly improved overall survival (OS) in patients with BRAFV600E-mutant mCRC (median 9.3 months vs 5.9 months; hazard ratio: 0.61; 95% confidence interval: 0.48–0.77; p<0.0001) and reduced the risk of death by 40%, compared with the cetuximab plus irinotecan-containing regimen (control) arm. Furthermore, the data also reported an improved objective response rate (ORR; 20% vs 2%; p<0.0001; per assessment by blinded independent central review [BICR]), compared with the control arm. BRAFTOVI plus cetuximab demonstrated a well-tolerated safety profile with no unexpected toxicities in the trial. The most common adverse drug reactions (>25%), observed in the BEACON CRC trial, were fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting.1

"We are extremely pleased that patients will now have access, for the very first time, to a targeted therapy specifically for BRAFV600E-mutant mCRC," said Jean-Luc Lowinski, CEO of Pierre Fabre Medical Care Business Unit. "Today’s approval is a testament to our long-term commitment to advancing care for patients living with difficult-to-treat cancers and to delivering precision medicine. We will now work tirelessly to bring this new treatment option to patients in Europe, as quickly as possible."

BRAF mutations are estimated to occur in approximately 8–12% of patients with mCRC, and V600E is the most common mutation.4–12 Patients with mCRC who have BRAFV600E-mutant tumours generally have a poor prognosis representing a high unmet medical need.13 Currently, there are no other approved targeted treatments in Europe specifically indicated for this patient population.14,15

Important safety information and recommendations for the use of BRAFTOVI in combination with cetuximab will be detailed in the Summary of Product Characteristics (SmPC), published in the European public assessment report (EPAR) and available in all official EU languages. The full SmPC will be found at: View Source

On 8 April 2020, Pierre Fabre’s partner Pfizer, which has exclusive rights to BRAFTOVI in the USA and Canada, announced that BRAFTOVI, in combination with cetuximab, was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with mCRC with a BRAFV600E mutation, as detected by an FDA-approved test, after prior therapy.16 Additional submissions of the BEACON data to health authorities around the world are planned.

About Colorectal Cancer
Worldwide, colorectal cancer (CRC) is the third most common type of cancer in men and the second most common in women, with approximately 1.8 million new diagnoses in 2018. Globally in 2018, approximately 881,000 deaths were attributed to CRC.17 Every year more than 450,000 people in Europe are diagnosed with CRC and approximately 230,000 will die of their disease.18 BRAF mutations are estimated to occur in approximately 8–12% of patients with mCRC and represent a poor prognosis for these patients.4–12 The V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF.18–20

About BEACON CRC
BEACON CRC is a randomised, open-label, global Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) ± binimetinib in combination with cetuximab in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF combination targeted therapy in BRAFV600E-mutant mCRC. A total of 665 patients were randomised 1:1:1 to one of the following treatment arms:

BRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm)
BRAFTOVI 300 mg orally once daily in combination with cetuximab and binimetinib
Irinotecan with cetuximab or FOLFIRI with cetuximab (control arm)
The study was amended to include an interim analysis of endpoints, including ORR. The primary OS endpoint is a comparison of BRAFTOVI+binimetinib in combination with cetuximab with the control arm. Secondary endpoints address the efficacy (OS) of BRAFTOVI in combination with cetuximab, compared with the control arm and compared with BRAFTOVI+binimetinib in combination with cetuximab. Other secondary endpoints include progression-free survival, duration of response, safety and tolerability.

The trial was conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial was conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre, Pfizer and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

About BRAFTOVI (encorafenib)
BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor that targets a key enzyme in the MAPK signalling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma, colorectal cancer and others.

On 20 September 2018, the EC granted marketing authorisations for BRAFTOVI and MEKTOVI to be used in combination for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation.1,21 The EC decision is applicable to all 27 EU member states as well as Iceland, Liechtenstein, Norway and the United Kingdom. BRAFTOVI and MEKTOVI have also received regulatory approvals in the USA, Australia, Japan, Argentina and Switzerland. On 27 June 2018, the combination of BRAFTOVI and MEKTOVI was approved by the FDA for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.22,23 BRAFTOVI and MEKTOVI are not indicated for treatment of patients with wild-type BRAF melanoma.

On 8 April 2020, the US FDA granted the approval for BRAFTOVI, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAFV600E mutation, as detected by an FDA-approved test, after prior therapy. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC.16

Pfizer has exclusive rights to BRAFTOVI in the USA and Canada. Pfizer has granted Ono Pharmaceutical Co. Ltd. exclusive rights to commercialise BRAFTOVI in Japan and South Korea; Medison exclusive rights to commercialise BRAFTOVI in Israel; and Pierre Fabre exclusive rights to commercialise BRAFTOVI in all other countries in Africa, Asia (excluding Japan and South Korea), Europe, and Latin America.

On June 3, 2020 BostonGene Corporation, a biomedical software company focused on defining optimal precision medicine-based therapies for cancer patients, reported that three abstracts were selected for poster presentations at the 2020 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Virtual Annual Meeting II, which will be conducted from June 22 – 24, 2020 (Press release, BostonGene, JUN 3, 2020, View Source [SID1234560803]).

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The presentations describe findings obtained by using BostonGene’s technologies and analytical tools designed to improve diagnosis and treatment decisions for cancer patients. Results include validation of bulk RNAseq utility for accurate reconstruction of tumor microenvironment and identification of four prominent microenvironment types conserved among solid tumors. Application of BostonGene computational tools lead to better understanding of the role of microenvironment compartments in tumor pathogenesis and supporting clinical decision making for the treatment of cancer.

"We are excited to present at the 2020 AACR (Free AACR Whitepaper) Virtual Annual Meeting to share the clinical utility of the BostonGene solution and demonstrate how it improves diagnosis and treatment decisions for cancer patients," said Andrew Feinberg, President and CEO of BostonGene.

Details of the poster presentations are as follows:

Abstract Number: 6168
Title: Integrated whole exome and transcriptome analyses of the tumor and microenvironment provide new opportunities for rational design of cancer therapy
Session: Tumor Heterogeneity and Microenvironment: Next-Generation Sequencing, Single Cell, and Imaging
Poster: 4418
Presenter: Alexander Bagaev, BostonGene

BostonGene developed and validated a new analytic platform for multi-parametric analyses of malignant and nonmalignant tumor compartments using genomic and transcriptomic sequencing data. Application of BostonGene platform to more than 8,500 patient data sets revealed four types of tumor microenvironment (TME) that are conserved across cancer types and demonstrate high prognostic significance and differential response to immunotherapy. This novel Molecular-Functional (MF) portrait platform, involving analytic and visualization methods, provides a robust tool for prediction of response to immunotherapy and for future tailoring of personalized therapeutic combinations.

Abstract Number: 6997
Title: Novel machine learning based deconvolution algorithm results in accurate description of tumor microenvironment from bulk RNAseq
Session: Machine Learning and Artificial Intelligence for Omics, Imaging, and Diagnostics
Poster: 853
Presenter: Alexander Bagaev, BostonGene

BostonGene developed a novel machine learning-based algorithm for cellular deconvolution of tumor microenvironment (TME) from bulk RNAseq data. This tool accurately reconstructs proportions of major immune and stromal cell populations, as well as T cell subtypes and M1 and M2 macrophages. Validation of BostonGene algorithm performance by comparison of flow cytometry, single cell RNAseq and bulk RNAseq analysis performed on samples from different tissues will be presented. The result demonstrates utility of bulk RNAseq for accurate and robust reconstruction of TME composition and paves the road for application of the BostonGene computational tool for support of clinical decision making for the treatment of cancer.

Research conducted with Massachusetts General Hospital

Abstract Number: 7544
Title: HER2 expression and M2-like tumor infiltrating macrophages associated with Cabazitaxel activity in gastric cancer
Session: Predictive Biomarkers for Treatment Efficacy 1
Poster: 2011
Presenter: Sandipto Sarkar, Weill Cornell Medicine

In the clinical study of cabazitaxel efficacy in gastric cancer, comprehensive whole exome sequencing (WES) and RNAseq data analysis identified genetic aberrations and tumor microenvironment signatures associated with favorable response. In particular, this analysis resulted in identification of two novel biomarkers, HER2 overexpression and M2-high tumor macrophage signature, both of which associated with improved outcomes. RNAseq-based deconvolution demonstrating M2 macrophages enrichment in patients with improved PFS, was further validated by immunohistochemistry using M1 and M2 macrophage-specific markers.

Research conducted with Weill Cornell Medicine

The e-poster website will be launched June 22, 2020, the first day of the AACR (Free AACR Whitepaper) Virtual Annual Meeting II. All e-posters will be made available for browsing on this date.

Additionally the abstracts will be published in an online-only Proceedings supplement to the AACR (Free AACR Whitepaper) journal Cancer Research after the completion of the AACR (Free AACR Whitepaper) Virtual Annual Meeting II.

On June 3, 2020 Maverick Therapeutics, Inc., a private biopharmaceutical company pioneering conditionally active bispecific T cell targeted immunotherapies, reported pipeline updates for its robust set of Conditional Bispecific Redirected Activation (COBRATM) programs at the Jefferies Virtual Healthcare Conference taking place June 2-4, 2020 (Press release, Maverick Therapeutics, JUN 3, 2020, View Source [SID1234560802]).

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By nature of its elegant and innovative design, the COBRATM platform is the most mature bispecific T cell engaging platform in its class that can safely target solid tumors with highly specific and potent activity. COBRA molecules are prodrugs selected to bind to specific targets, which may be expressed in both tumor and healthy tissue. However, COBRAs are engineered to take advantage of the tumor’s unique microenvironment for T cell activation; triggering T cell mediated killing only at the site of the tumor while sparing damage to patients’ healthy tissues.

"As we continue to advance our pipeline, we look forward to initiating the clinical development of our lead first-in-class COBRA programs, MVC-101 and MVC-280, both of which have generated promising pre-clinical data designed to validate the COBRA mechanism of action and be predictive of translation to patients. Our pipeline reflects our single focus on developing potent and conditionally active T cell engaging therapies for solid tumor cancers. Beyond our two lead programs, we have also generated compelling in vivo data for two additional COBRA molecules," said Jim Scibetta, Chief Executive Officer, Maverick Therapeutics. "The first patient who is safely and effectively treated for a solid tumor cancer with any form of T cell therapy, whether CAR T cell therapy or redirected T cell engagers like our COBRAs, will serve as a major breakthrough in the field of cancer immunotherapy. For us at Maverick, this is an incredibly important and humbling mission."

"Although evidence of anti-tumor activity has been observed in patients with solid cancers, the full potential of T cell engaging therapies against solid tumor cancers continues to be hindered by unacceptable toxicity," said Jim Vasselli, M.D., Senior Vice President, Clinical Development, Maverick Therapeutics. "Underpinning the pre-clinical development of COBRA technology is Maverick’s commitment to using gold standard in vivo and in vitro models to maximize our understanding of the molecules. We are encouraged by the early results generated by these first two programs and are excited to continue development towards the clinic."

MVC-101 Is a Highly Potent COBRA Targeting Tumors that Express EGFR

Maverick Therapeutics’ lead program candidate, MVC-101, is a proprietary COBRA molecule designed to target Epidermal Growth Factor Receptor (EGFR), a protein expressed on both malignant and healthy tissues. MVC-101 regressed established human tumors in several preclinical models. Exposures of MVC-101 at efficacious relative to tolerated doses in safety studies demonstrates an increased therapeutic index compared to standard T cell engagers. MVC-101 is designed to be a universal solution for patients with EGFR expressing solid tumor cancers. EGFR is expressed on a wide range of solid tumor cancers, including but not limited to colorectal, head & neck, renal, pancreatic, cervical and non small cell lung cancers. Maverick expects to initiate a Phase 1 trial in Q1 2021.

MVC-280 Is a Highly Potent COBRA Targeting Tumors that Express B7H3

Maverick Therapeutics’ second program candidate, MVC-280, is a proprietary COBRA molecule designed to target B7H3 (CD276). B7H3 is expressed in a broad range of malignant and healthy tissues, similar to EGFR. MVC-280 regressed established tumors in several preclinical models. It is cross-reactive to its target protein expressed on mouse tissues, creating an opportunity to measure both efficacy and relative safety in the same preclinical model and use that data to calculate a therapeutic index. MVC-280 is designed to be a universal solution for patients with B7H3 expressing solid tumor cancers. B7H3 is expressed on a wide range of solid tumor cancers, including but not limited to prostate, renal, triple negative breast, head & neck, ovarian and urothelial cancers. Maverick expects to initiate a Phase 1 trial in H2 2021.

About the COBRATM Therapeutics Platform

Maverick Therapeutics’ COBRATM platform is the most mature conditionally active bispecific T cell engaging platform designed to safely target a broad range of solid tumors with highly specific and potent activity while limiting on-target toxicities in normal tissues. By nature of its highly innovative design, the COBRA platform reflects a novel approach to T cell engaging immunotherapies where T cell activation and resulting cell killing only take place where it is needed – in tumors. This unique design delivers the long sought after trifecta in cancer care; high specificity, high potency and reduced toxicity.

On June 3, 2020 Aldeyra Therapeutics, Inc. (Nasdaq: ALDX) (Aldeyra) reported that Todd C. Brady, M.D., Ph.D., President and Chief Executive Officer, will present at the Jefferies Virtual Healthcare Conference at 1:00 p.m. ET Thursday, June 4, 2020 (Press release, Aldeyra Therapeutics, JUN 3, 2020, View Source [SID1234560801]).

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A live webcast of the presentation will be available on the investor relations page of the company’s corporate website at View Source After the live webcast, the even will remain archived on the Aldeyra Therapeutics website for 90 days.

On June 3, 2020 Horizon Therapeutics plc (Nasdaq: HZNP) reported that it issued a notice of redemption for all $400 million of its 2.50% exchangeable senior notes due 2022 (Press release, Horizon Therapeutics, JUN 3, 2020, View Source [SID1234560800]). The redemption date is August 3, 2020. The exchangeable senior notes may be exchanged by holders at any time before 5 p.m. (Eastern time) on July 30, 2020. Each $1,000 principal amount of the notes is exchangeable into 34.8979 ordinary shares of the Company, plus cash in lieu of fractional shares.

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"The redemption of our $400 million in exchangeable senior notes is an additional step in successfully executing our strategy to improve our capital structure to be in line with that of our biopharma peers," said Paul Hoelscher, executive vice president, chief financial officer, Horizon. "We began to execute on this strategy about a year ago, and inclusive of this redemption, we will have reduced our gross debt by about $1 billion, while maintaining a strong cash balance. In addition, through our refinancing and debt reduction initiatives, we have lowered our annualized cash interest expense by more than 40 percent versus a year ago and extended the maturity of our senior secured term loans and senior notes out to 2026 and 2027, respectively."

As of March 31, 2020, the Company had cash and cash equivalents of $754.6 million. In addition, the total principal amount of debt outstanding was $1.418 billion, consisting of $418 million in senior secured term loans due 2026, $600 million of senior notes due 2027 and $400 million of exchangeable senior notes due 2022. Following the exchange or redemption of the exchangeable senior notes, the total principal amount of debt outstanding will be $1.018 billion. The Company has no maintenance covenants on its debt.