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Efficacy, Durability of Response and Safety of Onvansertib Demonstrated in Completed Phase 1b Trial in AML Patients Presented in Oral Session at ASH

On December 9, 2019 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage, Precision Cancer Medicine oncology therapeutics company developing drugs that target cell division (mitosis), for the treatment of various cancers including leukemia, prostate and colorectal, reported the presentation of final results from the Company’s Phase 1b study of onvansertib in patients with relapsed/refractory acute myeloid leukemia (AML) in an oral session at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual conference in Orlando, FL, on Saturday, December 7th (Press release, Trovagene, DEC 9, 2019, View Source [SID1234552131]). The presentation highlighted the efficacy, durability of response, favorable safety and tolerability profile, as well as correlative biomarker data from the recently completed Phase 1b trial.
The oral presentation at ASH (Free ASH Whitepaper) is available for download from the Scientific Presentations page on the Trovagene website at View Source

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"I am encouraged by the preliminary efficacy and safety/tolerability demonstrated in the dose escalation part 1b of our trial," said Dr. Amer Zeidan, lead investigator and associate professor of Medicine at the Yale School of Medicine, and Hematology expert at Yale Cancer Center. "As we continue with enrollment and assessment of efficacy in the Phase 2 portion of the trial, I look forward to seeing additional clinical benefit of onvansertib in combination with decitabine in our relapsed and refractory AML patients."

Oral Presentation Highlights
Background:

Onvansertib is an oral, highly-selective Polo-like Kinase 1 (PLK1) inhibitor with a half-life of ~24 hours
PLK1 inhibition by onvansertib, assessed via a simple blood test and shown as changes in the phosphorylation of its direct substrate, the translational controlled tumor protein, TCTP, is a biomarker for identifying patients most likely to respond to treatment

Patients eligible for enrollment in the Phase 1b trial were treatment naïve and not candidates for induction therapy or had relapsed/refractory disease to up to 3 prior regimens (Phase 1b)

Trovagene Inc. | 11055 Flintkote Avenue | San Diego | CA 92121 | Tel.: USA [+1] 888-391-7992

Treatment Summary as of October 31, 2019
Safety and Tolerability:

Treatment was well tolerated through the first 5 dose escalation cohorts (onvansertib 12 – 60 mg/m2)

9 of the 71 SAEs (13%) were considered as possibly related to onvansertib and occurred at the higher dose levels: 40 mg/m2 (1), 60 mg/m2 (1) and 90 mg/m2

The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) was established at 60 mg/m2
Preliminary Efficacy:

6 (17%) patients had a complete response (CR, CRi); 9 (25%) had an ORR (CR, CRi, MLFS, PR) across LDAC and decitabine arms and doses

At the 4 higher dose levels (27 to 90 mg/m2), CR/CRi was observed in:
o
5 (31%) of the 16 patients in the decitabine Arm
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1 (11%) of the 9 patients in the LDAC Arm

Median time to achieve CR/CRi was 4 cycles (range 1-7)

Median duration of response was 5 months (range 0-11.5)

4 of 6 patients remain on treatment and in remission; duration of CR/CRi is respectively 1.5, 7, 8 and 11.5 months
Biomarker Analysis:

Of the 24 evaluable patients, 8 (33%) were biomarker positive across both arms
•
Among patients with at least 1 BM biopsy (n=17), biomarker positivity was associated with higher response to treatment:
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67% of biomarker positive patients (4/6) had a ≥20% decrease in blasts versus 18% in biomarker negative patients (1/11)
o
CR/CRi was achieved in 2 biomarker positive patients but in none of the biomarker negative patients

About the Phase 2 Clinical Trial of Onvansertib in AML
The Phase 2 AML trial (NCT03303339) of onvansertib in combination with decitabine will enroll 32 patients who are either treatment naïve and not candidates for induction therapy or who have relapsed disease after treatment with one prior regimen. Patients will receive onvansertib,

administered orally, on days 1 through 5 of each 21-28-day cycle in combination with decitabine. The primary efficacy endpoint of objective response (CR + CRi) will be assessed in patients who complete at least 1 cycle of treatment.
About Onvansertib
Onvansertib is a first-in-class, third-generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK1) enzyme, which is over-expressed in multiple cancers including leukemias, lymphomas and solid tumors. Onvansertib targets the PLK1 isoform only (not PLK2 or PLK3), is orally administered and has a 24-hour half-life with only mild-to-moderate side effects reported. Trovagene believes that targeting only PLK1 and having a favorable safety and tolerability profile, along with an improved dose/scheduling regimen will significantly improve on the outcome observed in previous studies with a former panPLK inhibitor in AML.
Onvansertib has demonstrated synergy in preclinical studies with numerous chemotherapies and targeted therapeutics used to treat leukemias, lymphomas and solid tumor cancers, including irinotecan, FLT3 and HDAC inhibitors, taxanes and cytotoxins. Trovagene believes the combination of onvansertib with other compounds has the potential to improve clinical efficacy in acute myeloid leukemia (AML), metastatic castration-resistant prostate cancer (mCRPC), non-Hodgkin lymphoma (NHL), colorectal cancer and triple-negative breast cancer (TNBC), as well as other types of cancer.
Trovagene has three ongoing clinical trials of onvansertib: A Phase 2 trial of onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with mCRPC who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving Zytiga (NCT03414034); a Phase 1b/2 Study of onvansertib in combination with FOLFIRI and Avastin for second-line treatment in patients with mCRC with a KRAS mutation (NCT03829410); and a Phase 1b/2 clinical trial of onvansertib in combination with low-dose cytarabine or decitabine in patients with relapsed or refractory AML (NCT03303339). Onvansertib has been granted orphan drug designation by the FDA in the U.S. and by the EC in the European Union for the treatment of patients with AML.
Trovagene licensed onvansertib (also known as NMS-1286937 and PCM-075) from Nerviano Medical Sciences (NMS), the largest oncology-focused research and development company in Italy, and a leader in protein kinase drug development. NMS has an excellent track record of licensing innovative drugs to pharma/biotech companies, including Array (recently acquired by Pfizer), Ignyta (acquired by Roche) and Genentech.

TG Therapeutics Announces Phase I Data Presentation for TG-1701, a Once-Daily BTK Inhibitor, as a Single Agent and in Triple Combination with Ublituximab and Umbralisib (U2), at the 61st American Society of Hematology Annual Meeting and Exposition

On December 9, 2019 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the first clinical data from the Company’s once daily, oral, BTK inhibitor, TG-1701, as a single agent and as a triple therapy in combination with ublituximab (TG-1101), the Company’s novel glycoengineered anti-CD20 monoclonal antibody, and umbralisib (TGR-1202), the Company’s oral, dual inhibitor of PI3K delta and CK1 epsilon, in patients with relapsed/refractory non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) (Press release, TG Therapeutics, DEC 9, 2019, View Source [SID1234552130]). Data from this Phase I trial are being presented this evening during a poster session at the 61stAmerican Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition.

Michael S. Weiss, Executive Chairman and Chief Executive Officer, stated, "We are highly encouraged by the first clinical data presented from our once daily, BTK inhibitor, TG-1701, which has demonstrated superior selectivity for BTK compared to ibrutinib in an in vitro whole kinome screening. The data presented today show that TG-1701 is an active BTK inhibitor as a single agent and that the combination of U2 plus TG-1701 has been generally well tolerated and active with 6 of 7 patients responding to the triple therapy at 100 mg QD, the lowest dose of TG-1701 tested. We look forward to continuing dose escalation of TG-1701 in the combination arm and identifying the optimal dose for this therapy." Mr. Weiss continued, "Our goal has always been to develop the best possible combination treatment options for patients, and we are excited to present the first data from a triple combination study in which all of the agents are being developed by TG. We believe this proprietary combination has the potential to enhance the results of BTK inhibitor therapy alone and offer patients early and deep responses with a tolerable safety profile."

Below are highlights from today’s poster presentation.

Poster Presentation: Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton’s Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies

This presentation includes safety information from 30 patients, 21 patients treated with single agent TG-1701, and 9 patients treated with the triple combination of TG-1701 plus U2.

TG-1701, a once daily BTK inhibitor, demonstrates an encouraging safety profile to date, with clinical and pharmacodynamic activity at all dose levels evaluated
30 patients have been treated with TG-1701 at doses that ranged from 100mg to 400mg once daily for TG-1701 monotherapy; dose escalation continues in the triple combination arm
Single agent TG-1701 produced partial responses at multiple dose levels (including the lowest dose tested) across multiple B-cell diseases, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), and small lymphocytic lymphoma (SLL)
86% (6/7) of patients treated with 100 mg TG-1701 plus U2 have achieved a response
• 4 patients with follicular lymphoma (FL): 2 Complete Responses (CR), 1 Partial Response (PR) and 1 Stable Disease (SD)
• 1 PR in marginal zone lymphoma (MZL); 1 PR in Waldenström’s macroglobulinemia (WM); and 1 PR in diffuse large B-cell lymphoma (DLBCL)
All patients treated with the triple combination of TG-1701 plus U2 remain on study
ASH Poster Presentation Details

Title: Phase 1 Study of TG-1701, a Selective Irreversible Inhibitor of Bruton’s Tyrosine Kinase (BTK), in Patients with Relapsed/Refractory B-Cell Malignancies
• Publication Number: 4001
• Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster III
• Date and Time: Monday, December 9, 2019; 6:00 PM – 8:00 PM ET
• Location: Orange County Convention Center, Hall B
• Presenter: Chan Cheah, MD, Sir Charles Gairdner Hospital, Hollywood Private Hospital, University of Western Australia, Blood Cancer Research Western Australia
Below recaps highlights from yesterday’s oral presentation of U2 plus venetoclax.

Title: A Phase 1/2 Study of Umbralisib, Ublituximab and Venetoclax in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

This oral presentation includes data from patients with relapsed or refractory CLL treated with the triple combination of ublituximab, umbralisib, and venetoclax. Twenty-seven patients were evaluable for safety and 23 were evaluable for efficacy. Data highlights include:

Regimen was administered with 3 cycles of U2 induction/debulking to reduce the risk of tumor lysis syndrome (TLS), followed by the combination of umbralisib and venetoclax starting in cycle 4. Patients who were bone marrow MRD negative after cycle 12 stopped all therapy.
Overall response rate (ORR) of 87% (20/23) after U2 induction period at cycle 3, prior to introduction of venetoclax, in relapsed/refractory CLL patients, including patients refractory to ibrutinib
U2 induction appeared to reduce venetoclax TLS risk, with no patients remaining as TLS high-risk following 3 cycles of U2
13 patients treated for >7 cycles and 9 patients for > 12 cycles:
• 100% ORR (13/13) after cycle 7 for the triple combination
• 100% ORR (9/9) including 44% Complete Response (CR) after cycle 12 for the combination
• 100% (9/9) of patients had undetectable minimal residual disease (MRD) (<0.01%) in peripheral blood after 12 cycles of therapy; and
• 78% (7/9) of patients who completed 12 cycles of therapy had undetectable MRD in bone marrow and have stopped therapy
No patients (n=27) have progressed to date with a median follow-up of 6.4 months
Triple combination was generally well tolerated with no events of TLS observed
An open-label, multicenter, Phase 2 study evaluating U2 plus venetoclax (ULTRA-V) in treatment naïve and previously treated CLL is now open for enrollment.

All data presented is available on the Publications page of the Company’s website at View Source

Syndax Announces Preclinical Results Supporting Development of its Portfolio of Menin Inhibitors In Mixed Lineage Leukemias

On December 9, 2019 Syndax Pharmaceuticals, Inc. ("Syndax," the "Company" or "we") (Nasdaq: SNDX), a clinical stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported the publication of a preclinical report demonstrating that selective inhibition of the Menin-MLL interaction, provides consistent anti-proliferative and anti-leukemic activity across multiple mixed lineage leukemia rearranged (MLLr) samples (Press release, Syndax, DEC 9, 2019, View Source [SID1234552129]). The article, "A Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia," was published in the December 9 issue of Cancer Cell; the article is also available online.

This study, which was led by researchers at Dana-Farber Cancer Institute and Children’s Cancer Institute, Sydney, Australia, examined the activity of VTP-50469, a close analog of the clinical lead SNDX-5613, against a range of MLLr harboring cell lines and patient-derived xenograft (PDX) models. Cell lines carrying MLL rearrangements were selectively responsive to VTP-50469, triggering disruption of menin containing transcription complexes and causing changes to gene expression that induced terminal differentiation and cell death. In PDX models, of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) subtypes of MLLr, single agent treatment with the Menin-MLL interaction inhibitor significantly reduced leukemia burden and led to profound survival benefit, with many mice remaining disease free more than one year after treatment.

"The newly developed Menin-MLL inhibitor demonstrated remarkable single-agent activity in PDX models of human MLL-rearranged leukemia including disease eradication," said Scott A. Armstrong, M.D., Ph.D., President, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and Chairman, Department of Pediatric Oncology, Dana-Farber Cancer Institute and senior author of the study. "This level of activity is unusual for single agent treatments in leukemia models."

"For patients with genetically-defined acute leukemias, there exists a dire unmet need for novel and effective therapeutic options," said Briggs W. Morrison, M.D., Chief Executive Officer of Syndax. "We are encouraged by these preclinical data, which continue to support our belief that SNDX-5613, our lead Menin inhibitor, has the potential to overcome the limitations of currently approved regimens, many of which do not yield a durable benefit. We are hopeful that these findings will translate positively in our ongoing Phase 1/2 AUGMENT-101 trial, for which we continue to expect initial data in 2020."

About SNDX-5613

SNDX-5613 is a potent, selective, small molecule inhibitor of the Menin-MLL binding interaction that is being developed for the treatment of MLL-rearranged (MLL-r) acute leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). MLL rearrangements occur in approximately 80% of acute leukemia cases in infants and up to 10% of all leukemias. In preclinical models of MLL-r acute leukemias, SNDX-5613 demonstrated robust, dose-dependent inhibition of tumor growth, resulting in a marked survival benefit. Menin-MLL interaction inhibitors have also demonstrated robust treatment benefit in multiple preclinical models of NPM1 mutant AML, which represents the most frequent genetic abnormality in adult AML. SNDX-5613 is currently being evaluated in the Company’s AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory acute leukemias.

About Mixed Lineage Leukemia Rearranged (MLL-r)

Rearrangements of the MLL gene give rise to MLL-r acute leukemias, known to have a poor prognosis, with less than 55% of patients surviving past 5 years. MLL rearrangements produce fusion proteins that require interaction with the protein called Menin to drive leukemic cancer growth. Disruption of the Menin-MLL-r interaction has been shown to halt the growth of MLL-r leukemic cells. MLL-r leukemias, which are routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques, occur in approximately 80% of infant acute leukemias and up to 10% of all acute leukemias. There are currently no approved therapies indicated for MLL-r leukemias.

Sesen Bio Initiates Rolling Submission of BLA for Vicinium to FDA

On December 9, 2019 Sesen Bio (Nasdaq: SESN), a late-stage clinical company developing targeted fusion protein therapeutics for the treatment of patients with cancer, reported that on December 6, 2019, the Company initiated the submission of its Biologics License Application (BLA) for Vicinium for the treatment of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) under Rolling Review to the U.S. Food and Drug Administration (FDA) (Press release, Sesen Bio, DEC 9, 2019, View Source [SID1234552128]). Vicinium was granted Fast-Track Designation by the FDA in 2018.

"There remains a significant unmet medical need in NMIBC that has also been further complicated by the ongoing BCG shortage," said Dr. Thomas Cannell, president and chief executive officer of Sesen Bio. "The initiation of the rolling BLA for Vicinium marks a tremendous achievement for Sesen Bio and an important step forward in our efforts to help save and renew the lives of patients with cancer."

The Company has submitted completed non-clinical and clinical modules, and a partially completed Chemistry, Manufacturing and Controls (CMC) module. The Company anticipates completing the BLA submission with the finalization of the CMC module in 2020. If the FDA accepts the BLA filing, the Company plans to request a Priority Review.

In addition, Dr. Cannell will host a conference call and webcast on Monday, December 16th at 8 AM ET to provide a regulatory update for Vicinium.

To participate in the conference call, please dial (844) 831-3025 (domestic) or (315) 625-6887 (international) and refer to conference ID 5285284. The webcast can be accessed from the Investor Relations section of the Company’s website at www.sesenbio.com. The replay of the webcast will be available in the Investor Relations section of the Company’s website at www.sesenbio.com for 60 days following the call.

About Vicinium

Vicinium, a locally-administered fusion protein, is Sesen Bio’s lead product candidate being developed for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC). Vicinium is comprised of a recombinant fusion protein that targets epithelial cell adhesion molecule (EpCAM) antigens on the surface of tumor cells to deliver a potent protein payload, Pseudomonas Exotoxin A. Vicinium is constructed with a stable, genetically engineered peptide tether to ensure the payload remains attached until it is internalized by the cancer cell, which is believed to decrease the risk of toxicity to healthy tissues, thereby improving its safety. In prior clinical trials conducted by Sesen Bio, EpCAM has been shown to be overexpressed in NMIBC cells with minimal to no EpCAM expression observed on normal bladder cells. Sesen Bio is currently conducting the Phase 3 VISTA trial, designed to support the registration of Vicinium for the treatment of high-risk NMIBC in patients who have previously received a minimum of two courses of bacillus Calmette-Guérin (BCG) and whose disease is now BCG-unresponsive. Additionally, Sesen Bio believes that cancer cell-killing properties of Vicinium promote an anti-tumor immune response that may potentially combine well with immuno-oncology drugs, such as checkpoint inhibitors. The activity of Vicinium in BCG-unresponsive NMIBC is also being explored at the US National Cancer Institute in combination with AstraZeneca’s immune checkpoint inhibitor durvalumab.

Quest Diagnostics Prices $800 Million of Senior Notes

On December 9, 2019 Quest Diagnostics Incorporated (NYSE: DGX), the world’s leading provider of diagnostic information services, reported the pricing of a public offering of $800 million aggregate principal amount of its 2.950% senior notes due 2030 under the Quest Diagnostics’ shelf registration statement (Press release, Quest Diagnostics, DEC 9, 2019, View Source [SID1234552127]).

Quest Diagnostics expects to receive the net offering proceeds upon closing on December 16, 2019, subject to customary closing conditions. The company intends to use the net proceeds from the offering to repay at maturity or redeem its 4.750% senior notes due 2020 and 2.500% senior notes due 2020 and for general corporate purposes. This press release is not a notice of redemption. Any notice of redemption will be made in accordance with the applicable provisions of the indenture governing such notes.

This press release shall not constitute an offer to sell or a solicitation of an offer to purchase any of these securities and shall not constitute an offer, solicitation or sale in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful. This offering may be made only by means of a prospectus supplement and accompanying base prospectus, copies of which or information concerning this offering may be obtained by calling J.P. Morgan Securities LLC, collect at (212) 834-4533, Morgan Stanley & Co. LLC, toll-free at (866) 718-1649 or Wells Fargo Securities, LLC, toll-free at (800) 645-3751.