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neurovive out-licenses targeted lhon therapy to bridgebio pharma’s new subsidiary fortify therapeutics

On June 18, 2018 NeuroVive Pharmaceutical AB and BridgeBio Pharma reported that BridgeBio has entered into an exclusive licensing agreement for a subset of succinate prodrug chemistry under NeuroVive’s NVP015 program (Press release, BridgeBio, JUN 18, 2018, View Source [SID1234576278]). BridgeBio also announced that it has launched a subsidiary company Fortify Therapeutics to further develop this chemistry for local treatment of Leber’s Hereditary Optic Neuropathy (LHON), with an initial financial commitment of $20 million USD. NeuroVive’s NVP015 program for other mitochondrial disorders will continue without any changes in focus or timelines.

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LHON is caused by mitochondrial DNA mutations in subunits of NADH dehydrogenase (complex I), leading to reduced oxidative phosphorylation and energy production in retinal cells. The disease predominantly affects young adults, and results in sudden onset of progressive and severe vision loss. The licensed succinate prodrugs have the potential to overcome the disease by bypassing the dysfunctional metabolic pathway, providing an alternate source of energy to the retinal cells.

"As a targeted treatment for a genetic disease, the LHON program is a clear fit with the BridgeBio model," said Neil Kumar, Ph.D., CEO of BridgeBio. "We have been impressed with the ability of these compounds to rescue specific genetic mitochondrial deficiencies, and we have assembled a team of international experts to further develop a subset of the NVP015 chemistry to address this devastating disease."

Fortify Therapeutics will develop selected lead compounds derived from NeuroVive’s novel NVP015 succinate prodrug program into drug candidates for the localized treatment of LHON. These compounds have been selected because they have properties that make them suitable for delivery to the eye.

The licensing agreement for this particular subset of the NVP015 program has a total deal value of approximately $60 million USD, which includes limited initial funding for research, and later milestone payments and a single digit royalty stream, that are dependent on successful development and market approval.

"The agreement with BridgeBio is important to both NeuroVive and our innovative NVP015 program, as it validates the quality of the program, our business development model and potential in a variety of mitochondrial disorders," commented NeuroVive CEO Erik Kinnman, M.D., Ph.D. "We will work closely with BridgeBio to further develop this chemistry subset and make the LHON program successful. It is important to note that our intentions for the NVP015 program are unchanged, and we are progressing towards experimental proof-of-principle during 2018."

This information is information that NeuroVive Pharmaceutical AB (publ) is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person set out below, at 08:30 a.m. CET on 18 June 2018.

About LHON
Leber’s Hereditary Optic Neuropathy (LHON) is a disease caused by mitochondrial DNA mutations in subunits of NADH dehydrogenase (complex I), a component of the electron transport chain. This results in dysfunctional oxidative phosphorylation and ATP production, leading to degeneration of the retinal ganglion cells and loss of central vision. LHON most commonly affects males in their second or third decade of life. The prevalence of LHON in Europe is between 1:30,000-1:50,000.

About NVP015
One of the most common causes of mitochondrial diseases relates to Complex I dysfunction, i.e. when energy conversion in the first of the five protein complexes in the mitochondrion that are essential for effective energy conversion does not function normally. This is apparent in disorders including Leigh’s Syndrome and MELAS, both of which are very serious diseases with symptoms such as muscle weakness, epileptic fits and other severe neurological manifestations. The NVP015 project is based on a NeuroVive innovation in which the body’s own energy substrate, succinate, is made available in the cell via a prodrug technology. A prodrug is an inactive drug that is activated first when it enters the body by the transformation of its chemical structure. Results from the NVP015 project were published in the prestigious Nature Communications journal in August 2016.

ARRAY BIOPHARMA TO PRESENT OVERALL SURVIVAL RESULTS FROM THE PHASE 3 BEACON CRC SAFETY LEAD-IN OF THE COMBINATION OF ENCORAFENIB, BINIMETINIB AND CETUXIMAB IN BRAF-MUTANT COLORECTAL CANCER AT THE ESMO 20TH WORLD CONGRESS ON GASTROINTESTINAL CANCER

On June 18, 2018 Array BioPharma Inc. (Nasdaq: ARRY) reported that it will present updated safety and efficacy results, including overall survival (OS) data, from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of encorafenib, a BRAF inhibitor, binimetinib, a MEK inhibitor and cetuximab, an anti-EGFR antibody, in patients with BRAF-mutant colorectal cancer (CRC) (Press release, Array BioPharma, JUN 18, 2018, View Source [SID1234527431]). These data will be featured in an oral presentation on Saturday, June 23, at the ESMO (Free ESMO Whitepaper) 20thWorld Congress on Gastrointestinal Cancer in Barcelona, Spain.

Oral Presentation BEACON CRC Safety Lead-In

Title:

BEACON CRC Study Safety Lead-in: Assessment of the BRAF Inhibitor Encorafenib + MEK Inhibitor Binimetinib + Anti–Epidermal Growth Factor Receptor Antibody Cetuximab for BRAFV600E Metastatic Colorectal Cancer

Presenter:

Eric Van Cutsem, M.D., Professor, Internal Medicine, Head, Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven

Abstract:

O-027

Session:

Session XX

Date:

Saturday, June 23

Session Time:

11:40 a.m. – 12:20 p.m. CET (5:40 – 6:20 a.m. ET)

Location:

Auditorium A

Following the presentation, the slides will be available as a PDF on Array’s website at www.arraybiopharma.com.

Array will host an encore webcast presentation of the BEACON CRC safety lead-in trial data.

Encore Investor Webcast:

Presenter:

Axel Grothey, M.D., Division of Hematology/Oncology, Mayo Clinic

Date:

Saturday, June 23

Time:

4:30 pm CET (10:30 am ET)

Toll-Free:

(844) 464-3927

Toll:

(765) 507-2598

Pass Code:

8588348

Webcast, including replay and conference call slides:View Source

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer. [1] In the U.S. alone, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease. [2] In the U.S., BRAF mutations are estimated to occur in 10% to 15% of patients with colorectal cancer and represent a poor prognosis for these patients. [3, 4, 5, 6] The risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [7] Several approved standard of care benchmarks for this population range between 4% to 8% ORR, 1.8 and 2.5 months mPFS and 4 and 6 months mOS. [8, 9, 10, 11, 12, 13, 14] Based on recent prospective historical data, the prevalence of MSI-H in tumors from patients with metastatic BRAF-mutant CRC ranged from 14% in a recent Phase 1b/2 trial (NCT01719380) (Array, data on file) to 18% in a recent Southwestern Oncology Group (SWOG) randomized phase 2 trial. [8]

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of encorafenib, binimetinib and cetuximab in patients with BRAF-mutant metastatic CRC 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/MEK combo targeted therapy in BRAF-mutant advanced CRC. Thirty patients were treated in the safety lead-in and received the triplet combination (encorafenib 300 mg daily, binimetinib 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAFV600E mutation. Microsatellite instability-high (MSI-H), resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial.

The randomized portion of the BEACON CRC trial is designed to assess the efficacy of encorafenib in combination with cetuximab with or without binimetinib compared to cetuximab and irinotecan-based therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet combination, doublet combination (encorafenib and cetuximab) or the control arm (irinotecan-based therapy and cetuximab). The primary endpoint of the trial is overall survival of the triplet combination compared to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, ORR, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.

About Encorafenib and Binimetinib
BRAF and MEK are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma and colorectal cancer. Encorafenib is a late-stage small molecule BRAF inhibitor and binimetinib is a late-stage small molecule MEK inhibitor, both of which target key enzymes in this pathway. Encorafenib and binimetinib are being studied in clinical trials in advanced cancer patients, including the Phase 3 BEACON CRC trial and the Phase 3 COLUMBUS trial.

The U.S. Food and Drug Administration (FDA) is currently reviewing the New Drug Applications (NDAs) to support use of the combination of encorafenib and binimetinib for the treatment of patients with BRAFV600E or K-mutant advanced, unresectable or metastatic melanoma. The FDA set a target action date under the Prescription Drug User Fee Act (PDUFA) of June 30, 2018 for both applications. The European Medicines Agency (EMA), as well as the Swiss Medicines Agency (Swissmedic) and the Australian Therapeutic Goods Administration (TGA), are reviewing the Marketing Authorization Applications (MAAs) submitted by Pierre Fabre and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) has accepted the Manufacturing and Marketing Approval (MMA) applications submitted by Ono Pharmaceutical Co, Ltd.

Encorafenib and binimetinib are investigational medicines and are not currently approved in any country.

Array BioPharma has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array has granted Ono Pharmaceutical exclusive rights to commercialize both products in Japan and South Korea and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Asia and Latin America. The BEACON CRC trial is being conducted with support from Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

Ziopharm Oncology Reports on Status of Investigational New Drug Application for Phase 1 Trial to Evaluate CD19-targeted CAR T Therapy

On June 18, 2018 Ziopharm Oncology, Inc. (Nasdaq:ZIOP) reported the U.S. Food and Drug Administration (FDA) placed on clinical hold a Phase 1 trial to evaluate CD19-specific CAR-T therapies manufactured under point-of-care and requested additional information in support of the investigational new drug (IND) application for the trial (Press release, Ziopharm, JUN 18, 2018, View Source [SID1234527386]).

Ziopharm, Precigen, Inc., a wholly-owned subsidiary of Intrexon Corporation (NYSE: XON) and The University of Texas MD Anderson Cancer Center, the IND sponsor, are seeking to conduct a clinical trial to evaluate CAR+ T cells manufactured with Sleeping Beauty technology as an investigational treatment for patients with relapsed or refractory, CD19+ leukemias and lymphomas. CAR+ T cells very-rapidly manufactured with the Sleeping Beauty platform for this third-generation trial are designed to co-express CD19-specific chimeric antigen receptor, or CAR, membrane-bound interleukin 15 and a safety switch. The FDA has requested additional information relative to Chemistry, Manufacturing and Controls. Ziopharm and its partners will address the FDA’s requests, and the initiation of this trial may be delayed.

"We know what is needed to address the hold issues and are looking forward to responding to the agency in a timely manner," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of Ziopharm. "We are undertaking cutting-edge science and are on the verge of a paradigm shift based on our approach to very-rapidly manufacture CD19-specific T cells within two days using our non-viral approach to CAR-T therapy based on the Sleeping Beauty platform."

Ziopharm believes this feedback from the FDA does not affect timelines for the Company’s planned trial at the National Cancer Institute using the Sleeping Beauty platform to target solid tumors infusing TCR-modified T cells. The second-generation clinical trial evaluating Sleeping Beauty-manufactured CD19-specific CAR-T cells continues enrolling and infusing patients at MD Anderson.

Gamida Cell to Present Preliminary Data from Ongoing Phase I NAM-NK Study at AACR International Meeting on Advances in Malignant Lymphoma

On June 18, 2018 Gamida Cell, a leading cellular and immune therapeutics company, reported that preliminary data from an ongoing phase I study from the nicotinamide-based natural killer cell expansion, or NAM-NK, program will be presented during the Inaugural AACR (Free AACR Whitepaper) International Meeting on Advances in Malignant Lymphoma, held June 22 – 26 in Boston, Massachusetts (Press release, Gamida Cell, 18 18, 2018, View Source [SID1234527379]).

Veronika Bachanova, M.D., Ph.D., hematologist/oncologist at the Blood and Marrow Transplantation and Cellular Therapy Program of the University of Minnesota, and lead investigator of the investigator-sponsored phase I NAM-NK clinical study at the Masonic Cancer Center, will present a poster of early patient outcomes from the study in patients with refractory non-Hodgkin lymphoma and multiple myeloma.

Title: Phase I study of nicotinamide-expanded related donor Natural Killer (NK) cells for the treatment of relapsed/refractory CD20+ non-Hodgkin lymphoma (Abstract: B05)
Session: Poster Session B: Therapeutics and Clinical Trials in Lymphoma 2
Location: Salon F, Boston Marriott Copley Place
Date: Sunday June 24, 2018 11:45 AM – 1:45 PM

About NAM-NK
Gamida Cell applied the capabilities of its NAM-based cell expansion technology to highly functional NK cells to develop NAM-NK, an innate immunotherapy for the treatment of hematologic and solid tumors in combination with SoC antibody therapies. NAM-NK addresses key limitations of NK cells by increasing the cytotoxicity and in vivo retention and proliferation in the bone marrow and lymphoid organs of NK cells expanded in culture. NAM-NK is in phase I development (NCT03019666) through an investigator-sponsored trial in patients with refractory non-Hodgkin lymphoma and multiple myeloma.

TG Therapeutics, Inc. Presents Phase 2 Data Evaluating Umbralisib in CLL Patients Intolerant to Prior BTK or PI3K Delta Inhibitor Therapy at the 23rd Congress of the European Hematology Association (EHA)

On June 18, 2018 TG Therapeutics, Inc. (NASDAQ: TGTX), reported an oral presentation of clinical data from its ongoing Phase 2 study evaluating umbralisib (TGR-1202), the Company’s PI3K delta inhibitor, in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) who are intolerant to prior BTK or PI3K delta inhibitor therapy (Press release, TG Therapeutics, JUN 18, 2018, View Source [SID1234527378]). Data from this trial were presented over the weekend during an oral session at the 23rd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper).

Michael S. Weiss, the Company’s Executive Chairman and Chief Executive Officer, stated, "We are pleased to present data evaluating umbralisib in patients intolerant to currently approved BTK or PI3K therapies during the EHA (Free EHA Whitepaper) annual congress. While there have been great advancements in recent years in the treatment of CLL, this study confirms that there are many patients still in need of an alternative treatment option and that umbralisib can be used safely and effectively in those patients who were not able to tolerate a prior BTK or PI3K therapy. The rate of patients withdrawing from kinase treatment for CLL in real world settings has been estimated to reach upwards of 40%, representing a significant unmet medical need." Mr. Weiss continued, "We are extremely pleased with the data presented at ASCO (Free ASCO Whitepaper) and EHA (Free EHA Whitepaper) this month and we look forward to presenting the topline response rate data from the UNITY- CLL Phase 3 trial by the end of summer 2018."

Highlights from the oral presentation include the following:

Oral Presentation: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) In Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-delta Inhibitor Therapy (Abstract Number S808)

This presentation includes data from patients with CLL who are intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent umbralisib (TGR-1202). To be eligible for the study patients had to have received prior treatment with a BTK inhibitor (ibrutinib, acalabrutinib) or a PI3K delta inhibitor (idelalisib, duvelisib) and discontinued therapy due to intolerance within 12 months of starting treatment on this study. Forty-seven patients were evaluable for safety of which 46 were evaluable for Progression Free Survival (PFS), (1 patient had a confirmed Richter’s Transformation (RT) at enrollment which did not meet eligibility criteria).

Highlights from this presentation include:

●Umbralisib demonstrated a favorable safety profile in patients intolerant to prior BTK or PI3K therapy

●Only 13% discontinued due to an adverse event, of which only one patient discontinued due to a recurrent adverse event (AE) also experienced with prior kinase inhibitor therapy

●Median progression free survival (PFS) and overall survival has not been reached with a median follow-up of 9.5 months

●In this relapsed/refractory CLL population, of which 77% required treatment within 6 months of prior KI discontinuation, 64% had a high-risk molecular / genetic marker and 6% had an ibrutinib resistance mutation, significant clinical activity has been observed

PRESENTATION DETAILS
The above referenced presentation is now available on the Publications page, located within the Pipeline section, of the Company’s website at www.tgtherapeutics.com/publications.cfm.