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US Food and Drug Administration (FDA) grants priority review of belantamab mafodotin for patients with relapsed or refractory multiple myeloma

On January 21, 2020 GlaxoSmithKline plc (LSE/NYSE: GSK) reported the US Food and Drug Administration (FDA) granted a priority review for the company’s Biologics License Application (BLA) seeking approval of belantamab mafodotin (GSK2857916) for the treatment of patients with relapsed or refractory multiple myeloma whose prior therapy included an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody (Press release, GlaxoSmithKline, JAN 21, 2020, View Source [SID1234553362]).

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The BLA is based on data from the pivotal DREAMM-2 (DRiving Excellence in Approaches to Multiple Myeloma) study, recently published in The Lancet Oncology, which enrolled heavily pre-treated patients who had actively progressing multiple myeloma that had worsened despite current standard of care.[1]

In 2017, belantamab mafodotin was granted Breakthrough Therapy designation by the FDA, which is intended to facilitate the development of investigational medicines that have shown clinical promise for conditions where there is significant unmet need.

About B-cell maturation antigen (BCMA)
The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway has been shown to be important for myeloma cell growth and survival. BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients and BCMA membrane expression is universally detected in myeloma cell lines.[2]

About multiple myeloma
Multiple myeloma is the second most common blood cancer and is generally considered treatable, but not curable.[3] In the US, more than 32,000 people were diagnosed with multiple myeloma last year and nearly 13,000 people died from the disease.[4] Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments.[5]

About the DREAMM clinical trial programme for belantamab mafodotin (GSK2857916)
Belantamab mafodotin is an investigational immunoconjugate comprising a humanised anti-B cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent auristatin F via non-cleavable linker. The drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa.

Belantamab mafodotin is not currently approved for use anywhere in the world.

Trial Name

GSK ID/NCT ID

Status

Design

DREAMM-1

117159/ NCT02064387

Completed

A Phase I Open-label Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, Immunogenicity and Clinical Activity of Belantamab Mafodotin (GSK2857916) in Subjects with Relapsed/Refractory Multiple Myeloma and Other Advanced Hematologic Malignancies Expressing BCMA

DREAMM-2

205678/ NCT03525678

Active, not recruiting

A Phase II Study to Investigate the Efficacy and Safety of Two Doses of Belantamab Mafodotin (GSK2857916) in Subjects with Relapsed/Refractory Multiple Myeloma Who are Refractory to a Proteasome Inhibitor and an Immunomodulatory Agent and Have Failed Prior Treatment with an Anti-CD38 Antibody

DREAMM-3

207495/ NCT04162210

Planned

A Phase III Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Compared to Pomalidomide plus low-dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma

DREAMM-4

205207/ NCT03848845

Recruiting

A Phase I/II Single Arm Open-Label Study to Explore Safety and Clinical Activity of Belantamab Mafodotin (GSK2857916) Administered in Combination with Pembrolizumab in Subjects with Relapsed/Refractory Multiple Myeloma

DREAMM-5

208887/

NCT04126200

Recruiting

A Phase I/II, Randomized, Open-label Platform Study of Belantamab Mafodotin (GSK2857916) with Innovative Combination Anti-Cancer Treatments in Participants with Relapsed/Refractory Multiple Myeloma

DREAMM-6

207497/ NCT03544281

Recruiting

A Phase I/II Randomized Study to Evaluate Safety, Tolerability and Clinical Activity of Belantamab Mafodotin (GSK2857916) Administered in Combination with Lenalidomide plus Dexamethasone (Arm A), or in Combination with Bortezomib plus Dexamethasone (Arm B) in Subjects with Relapsed/Refractory Multiple Myeloma

DREAMM-7

207503

Planned

A Phase III Study of Belantamab Mafodotin (GSK2857916) Administered in Combination with Bortezomib plus Dexamethasone versus Daratumumab, Bortezomib, and Dexamethasone in Participants with Relapsed/Refractory Multiple Myeloma

DREAMM-8

207499

Planned

A Phase III, Multicentre, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) in Combination with Pomalidomide plus Low-Dose Dexamethasone (BPd) versus Pomalidomide plus Bortezomib and Low-Dose Dexamethasone (PVd) in Participants with Relapsed/Refractory Multiple Myeloma

DREAMM-9

209664/ NCT04091126

Recruiting

A Phase III Study of Belantamab Mafodotin (GSK2857916) Administered in Combination with Bortezomib plus Lenalidomide and Low-Dose Dexamethasone (VRd) vs. VRd in Participants with Newly Diagnosed Multiple Myeloma who are Ineligible for Transplant

DREAMM-10

207500

Planned

A Phase III Study of Belantamab Mafodotin (GSK2857916) Administered in Combination with a Novel Agent versus SoC

ISS / GSK Co-Sponsored Study

209418/ NCT03715478

Recruiting

A Phase I/II Dose-escalation and Dose-expansion Study of Belantamab Mafodotin (GSK2857916) Administered in Combination with Pomalidomide plus Low-dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma Who Have Received Two or More Prior Lines of Therapy That Must Have Included Lenalidomide and a Proteasome Inhibitor

GSK in Oncology
GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, cancer epigenetics, and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody drug conjugates and cells, either alone or in combination.

Scientists study zebrafish in search of melanoma-fighting drugs

On January 21, 2020 Northern Arizona University reported that melanoma is the most lethal type of skin cancer and unusually common in Arizona, where residents are exposed to higher-than-average amounts of ultraviolet radiation (Press release, Northern Arizona University, JAN 21, 2020, View Source [SID1234553361]). However, Northern Arizona University scientists believe the formula for a combination of melanoma-fighting drugs is within reach.

Matthew Salanga, an assistant professor in NAU’s Department of Biological Sciences, is leading an 18-month project funded through a Flinn Foundation grant of $100,000. His team, which includes experts in experimental biology, computational systems biology and translational medicine, will study melanoma tumors on zebrafish, a small minnow-sized fish that has 70 percent of the same genes that are found in humans. Physiologically, zebrafish also have pigment cells in their skin, called melanocytes, which give them their stripes and their name. In humans, these cells are responsible for creating a tan when exposed to the sun, and if dysregulated can give rise to melanoma.

The majority of melanoma skin cancers are the result of a specific mutation in the BRAF gene (BRAF V600E). BRAF is a type of enzyme known as a protein kinase that adds a phosphate group to other proteins in cell signaling pathways. For this project, zebrafish that express the human form of mutated BRAF are employed to test strategies for treating melanoma.

"Fish don’t often get cancer," said Salanga, an expert in cell and developmental biology, "but in the lab, we can engineer fish to contain human genes that we know are associated with cancer. Essentially, it’s a way to use non-human vertebrates as though they were human. We call this humanization."

Currently there are around 30 zebrafish carrying the BRAF V600E human oncogene in Salanga’s lab that have visible melanoma tumors, and that number will grow as the study progresses. Activated BRAF acts to promote cell growth and proliferation. Salanga explains that the V600E mutation of BRAF leaves it stuck in the "on" position. This can result in unrestricted cell growth and proliferation. Drugs have been developed that specifically target and suppress tumor cells that have aberrant BRAF kinase activity. These drugs are in a class of drug called protein kinase inhibitors (PKIs), and are currently used clinically. However, not all patients respond and many relapse after a few months of therapy.

Researchers try to predict best drug combinations for inhibiting kinase activity

Salanga believes that there is a combination and dosage of PKIs recognizing distinct conformations of the BRAF kinase that can shut down the misfiring proteins and kill tumor cells dependent on oncogenic BRAF activity.

"The crux of the project is trying to predict which set of currently available drugs will work the best at inhibiting BRAF’s ability to turn things on inappropriately," he said. "Molecular profiling of tumor cells might be used to guide the drug selection for individual patients."

Critical to the NAU-based pilot project team is Richard Posner, a professor in NAU’s Department of Biological Sciences and William Hlavacek, a scientist at Los Alamos National Laboratory. Posner and Hlavacek are computational systems biologists who have developed mathematical models for predicting optimal strategies to target mutations in BRAF. In recent work, they and their collaborators predicted that two-drug combinations will be able to effectively suppress mutant BRAF (V600E) signaling. These predictions were validated in melanoma cell lines. The researchers are leveraging this computation pipeline to predict therapeutic responses to novel combinations of U.S. Food and Drug Administration-approved drugs in humanized zebrafish harboring melanoma skin cancer.

Also involved in the project is Haiyong Han, a scientist in the Molecular Medicine Division at the Translational Genomics Research Institute (TGen). His specialty is pancreatic cancer, which could potentially be treated using similar therapeutic strategies that are being proposed for melanoma.

The researchers, including undergraduate and graduate students, will be adding various combinations of inhibitors to see if they can find combinations that are most effective in targeting mutated RAF proteins.

Salanga says taking the melanoma-fighting research from the lab to medical facilities could happen quickly, as 150 PKIs are already in various stages of safety testing, and many are approved by the FDA.

"TGen and its partners can carry out these PKI clinical trials fairly routinely through its patient network and its scientists, who assist in these human studies. We could see humans receiving treatments like this within the next year or two," he said.

Although early detection of melanoma contributes to an 89 percent, five-year survival rate, metastatic melanoma is often lethal, with less than a 20 percent survival rate.

NAU’s grant for the project was awarded by the Flinn Foundation under its Seed Grants to Promote Translational Research initiative.

Blueprint Medicines Announces Proposed Public Offering of Shares of Common Stock

On January 21, 2020 Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, reported that it has commenced an underwritten public offering of $325,000,000 in shares of its common stock (Press release, Blueprint Medicines, JAN 21, 2020, View Source [SID1234553360]). In addition, Blueprint Medicines expects to grant the underwriters a 30-day option to purchase up to an additional $48,750,000 in shares of its common stock in connection with the public offering. All shares of common stock will be offered by Blueprint Medicines.

Blueprint Medicines expects to use the net proceeds of the offering to further build its global commercial infrastructure to support additional planned regulatory filings and commercial launches for AYVAKIT and pralsetinib, if approved, in the U.S. and Europe; to fund clinical trials for avapritinib in systemic mastocytosis (SM), including its ongoing registration-enabling Phase 2 PIONEER clinical trial for indolent and smoldering SM, as well as future indication expansion clinical trials; to fund clinical trials for pralsetinib in RET-driven cancers, including its Phase 3 AcceleRET Lung clinical trial for pralsetinib in first-line RET-altered NSCLC and its planned Phase 3 clinical trial for pralsetinib in first-line RET-mutant MTC, as well as future indication expansion clinical trials; to fund its planned Phase 1 trial for BLU-263 in healthy volunteers and future clinical trials for BLU-263 and other future drug candidates; to fund manufacturing costs for AYVAKIT and for ongoing and anticipated drug development efforts for its most advanced drug candidates; and the balance, if any, to fund additional discovery research efforts, its other ongoing and planned clinical trials, working capital requirements and other general corporate purposes.

Goldman Sachs & Co. LLC and Cowen and Company, LLC are acting as joint book-running managers for the offering. Canaccord Genuity LLC, JMP Securities LLC, and Raymond James & Associates, Inc. are acting as co-lead managers for the offering. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed or as to the actual size or terms of the offering.

A registration statement on Form S-3 (File No. 333-216573) relating to these securities has been previously filed with the Securities and Exchange Commission (SEC) and has become effective. This press release shall not constitute an offer to sell or a solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

The offering will be made only by means of a prospectus. A copy of the prospectus supplement relating to the offering will be filed with the SEC and may be obtained, when available, from Goldman Sachs & Co. LLC by mail at Prospectus Department, 200 West Street, New York, NY 10282, by telephone at (866) 471-2526, by fax at (212) 902-9316, or by email at [email protected], or from Cowen and Company, LLC, c/o Broadridge Financial Services, 1155 Long Island Avenue, Edgewood, NY 11717, Attention: Prospectus Department, or by telephone at (833) 297-2926.

BeiGene Announces that the Phase 3 Clinical Trial of its Anti-PD-1 Antibody Tislelizumab in Patients with First-Line Squamous Non-Small Cell Lung Cancer Met the Primary Endpoint of Progression-Free Survival at Interim Analysis

On January 21, 2020 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported that the pivotal Phase 3 trial evaluating its anti-PD-1 antibody tislelizumab in combination with two chemotherapy regimens for the first-line treatment of patients with squamous non-small cell lung cancer (NSCLC), met the primary endpoint of improved progression-free survival (PFS) at the planned interim analysis, as assessed by independent review committee (IRC) (Press release, BeiGene, JAN 21, 2020, View Source [SID1234553359]). In this study, patients with previously untreated advanced squamous NSCLC were randomized to receive either tislelizumab in combination with paclitaxel and carboplatin, tislelizumab in combination with nanoparticle albumin-bound (nab) paclitaxel (ABRAXANE) and carboplatin, or paclitaxel and carboplatin alone. Based on the pre-planned interim analysis, both tislelizumab treatment arms crossed the pre-specified efficacy boundary compared to chemotherapy alone. The safety profile of tislelizumab in both combinations in this trial was consistent with the known risks of each study treatment, and no new safety signals were identified.
"Tislelizumab was recently approved in China for patients with relapsed or refractory classical Hodgkin’s lymphoma, and we have a broad development program with more than 5,000 patients enrolled in over 25 tislelizumab studies, including 15 potentially registration-enabling trials," commented Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. "We are extremely excited about the compelling results that tislelizumab demonstrated in this Phase 3 trial and for its potential use as a first-line treatment for patients in China with advanced squamous NSCLC. We look forward to continuing the development program for tislelizumab in lung cancer, which includes three other Phase 3 trials, and reporting additional data."
The company plans to discuss its plans for filing a supplemental new drug application (sNDA) for tislelizumab as a first-line treatment for squamous NSCLC with the Center for Drug Evaluation (CDE) at the National Medical Products Administration (NMPA) in China and to present these data at an upcoming medical meeting.
This trial (NCT 03594747, known as BGB-A317-307) is a Phase 3, randomized, open-label, multi-center trial investigating tislelizumab combined with either paclitaxel and carboplatin or nab-paclitaxel (ABRAXANE, which is commercialized by BeiGene in China) and carboplatin compared with paclitaxel and carboplatin alone in patients with

a317307readoutenimage1.jpg

untreated stage IIIB or IV squamous NSCLC from mainland China, regardless of PD-L1 expression. The primary endpoint is PFS per IRC. Key secondary endpoints include overall survival and safety. The study began enrolling patients in July 2018, and 360 patients were randomized 1:1:1 to receive tislelizumab (200mg every three weeks) in combination with each of the chemotherapy regimens or chemotherapy only, until disease progression, unacceptable toxicity, physician decision or consent withdrawal. Patients on the chemotherapy-only control arm who experienced disease progression, verified by central independent review, were eligible to cross over to receive tislelizumab monotherapy.
"Squamous NSCLC remains a significant unmet need, representing approximately 30 percent of patients with NSCLC in China. This Phase 3 study was designed to assess the impact of tislelizumab given in combination with chemotherapy as a potential treatment to improve outcomes in patients with advanced squamous NSCLC, for whom prognoses are typically quite poor. These results give us hope that we could have a new treatment option for these patients," commented Jie Wang, M.D., Professor at the Cancer Hospital Chinese Academy of Medical Sciences, in Beijing, China and lead investigator for the trial.
About Non-Small Cell Lung Cancer
In contrast to most Western countries where lung cancer death rates are decreasing, lung cancer incidence rate is still increasing in China.12 There were approximately 770,000 new cases of lung cancer in China in 2018 and it is the leading cause of cancer-related death in both men and women, with approximately 690,500 deaths in China in 2018.3 Non-small cell lung cancer (NSCLC) comprises the most common form of lung cancer in China.4
About Tislelizumab
Tislelizumab (BGB-A317) is a humanized IgG4 anti–PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.
Tislelizumab is approved by the China National Medical Products Administration (NMPA) as a treatment for patients with classical Hodgkin’s lymphoma who received at

a317307readoutenimage1.jpg

least two prior therapies. A supplemental new drug application (sNDA) for tislelizumab in patients with previously treated locally advanced or metastatic urothelial carcinoma has been granted priority review by the Center for Drug Evaluation at the NMPA and is currently under review.
Tislelizumab is being studied in a broad clinical program as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. Currently, 15 potentially registration-enabling clinical trials are being conducted in China and globally, including 11 Phase 3 trials and four pivotal Phase 2 trials.
Tislelizumab is not approved for use outside of China.

OBI Pharma Granted U.S. FDA Orphan Drug Designation for the Treatment of Gastric Cancer for Its Antibody-Drug Conjugate (ADC) Targeted Cancer Therapy, OBI-999

On January 21, 2020 OBI Pharma, Inc., a Taiwan biopharma company (TPEx: 4174), reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for OBI-999 for the treatment of Gastric Cancer (Press release, OBI Pharma, JAN 21, 2020, View Source [SID1234553356]). OBI-999 is a first-in-class antibody drug conjugate targeting Globo H, a glycolipid antigen. On December 26, 2019 OBI-999 was granted Orphan Drug Designation for Pancreatic Cancer.

A Phase 1/2 clinical trial of OBI-999 has commenced enrollment at the University of Texas M.D. Anderson Cancer Center, with Dr. Apostolia M Tsimberidou as the Principal Investigator, in patients with locally advanced or metastatic solid tumors, including Gastric, Pancreatic, Colorectal and Esophageal Cancers (ClinicalTrials.gov Identifier: NCT04084366). The objective of the trial is to verify the safety and preliminary efficacy profile of OBI-999 in these patient populations.

Tillman Pearce, MD, CMO, OBI Pharma noted, "Advanced gastric cancer is an orphan disease where targeted therapies are lacking for the majority of patients. OBI-999 is an antibody-drug conjugate therapeutic targeting the cancer-associated glycolipid antigen, Globo H. OBI-999 incorporates a validated payload, MMAE, with a proprietary linker technology. It has demonstrated high effectiveness in xenograft models of metastatic gastric cancer that overexpress Globo H. Clinical development of this agent will be guided by evaluation of patients based on a validated Globo H immunohistochemistry assay, which will allow selection of patients whose tumors overexpress this tumor antigen for clinical investigation."

About Gastric Cancer

Gastric cancer (GC), or stomach cancer, is a disease in which malignant cancer cells form in the lining of the stomach. The majority of GC (90-95%) presents as adenocarcinomas arising from the mucosa layer. Some of the potential risk factors associated with GC include Helicobacter pylori infection, high intake of salt, low consumption of fruits and vegetables, obesity, heavy alcohol consumption, chronic atrophic gastritis and cigarette smoking.

GC is a deadly disease and an estimated prevalence in 2019 at 100,189 individuals in the US, with a low 5-year survivability of 31.0%. Current standard treatment options for patients with advanced or recurrent GC are associated with limited efficacy and unfavorable toxicity profile, especially for extended use or maintenance treatment in a patient population which is often already frail and cachectic.

About Orphan Drug Designation (ODD)

The orphan drug designation provides OBI Pharma with potential benefits, including market exclusivity upon regulatory approval is received, exemption of FDA application fees, and tax credits for qualified clinical trials. The FDA’s Office of Orphan Drug Products grants orphan status to support development of medicines for rare diseases or conditions that affect fewer than 200,000 people in the U.S.

About OBI-999

OBI-999 is a novel first-in-class Antibody Drug Conjugate (ADC) with a proprietary linker technology that provides a consistent Drug-to-Antibody ratio (DAR) for cancer treatment that is based on Globo H, an antigen expressed in up to 15 epithelial cancers. OBI-999 uses a Globo H antibody to target cancer cells of high Globo H expression. By releasing a small molecule chemotherapeutic drug through the specificity of the antibody, it directly deploys cytotoxic therapy at the targeted cancer cells. OBI-999 is currently in a Phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT04084366) to test its safety and efficacy as an oncology ADC therapy. In pre-clinical xenograft animal models in multiple tumor types (gastric, pancreatic, lung and breast), OBI-999 has demonstrated profound tumor shrinkage at various doses. In pre-clinical single and repeated dose toxicology studies, OBI-999 was well-tolerated, and achieved a favorable safety margin which warrants further clinical development. OBI Pharma owns global rights to OBI-999.