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SpringWorks Therapeutics Completes $125 Million Series B Financing

On April 1, 2019 SpringWorks Therapeutics, Inc. (the "Company"), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported the closing of a $125 million Series B preferred stock financing led by Perceptive Advisors (Press release, SpringWorks Therapeutics, APR 1, 2019, View Source [SID1234534840]). New investors participating in this financing include Boxer Capital of Tavistock Group, HBM Healthcare Investments, BVF Partners, Surveyor Capital (a Citadel company), Samsara BioCapital, ArrowMark Partners, GlaxoSmithKline (NYSE: GSK), and Laurion Capital Management, as well as several other long-term institutional investors. All of the Company’s existing investors – OrbiMed, Bain Capital, Pfizer (NYSE: PFE), via Pfizer Ventures, and LifeArc – also participated in the offering.

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Proceeds from the financing will be used to advance the Company’s two late-stage rare disease oncology programs towards potential regulatory approval and commercialization: nirogacestat, a gamma secretase inhibitor for the treatment of desmoid tumors, and PD-0325901, a MEK inhibitor for the treatment of neurofibromatosis type 1-associated plexiform neurofibromas. The proceeds will also support the continued expansion of the Company’s emerging targeted oncology programs, as well as future in-licensing opportunities and clinical collaborations in rare diseases and cancer.

"This financing from a committed, knowledgeable and distinguished investor syndicate, which includes new and existing investors as well as key industry partners, underscores the progress we’ve made to advance our late-stage clinical programs towards pivotal studies, execute on our initial business development strategy, and build upon our leading drug development operations," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "We are well positioned to continue to execute on our strategy to build a leading rare disease and targeted oncology company that brings promising science to underserved patient communities."

"We are excited to partner with SpringWorks Therapeutics as they build a differentiated rare disease and targeted oncology company, and we look forward to supporting the team as they work towards achieving product approvals over the coming years," said Adam Stone, Chief Investment Officer of Perceptive Advisors, LLC.

Celldex Presents Promising Data from CDX-527 Bispecific and TAM Receptor Programs at American Association for Cancer Research (AACR) Annual Meeting 2019

On April 1, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported promising data from the Company’s growing bispecific and TAM (Tyro3, Axl, MerTK) receptor programs during poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 1, 2019, View Source [SID1234534839]).

"Our research and discovery efforts have yielded multiple promising candidates that address important needs in cancer immunotherapy and complement our pipeline," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "CDX-527 joins two powerful pathways in the immune system, PD-1 blockade and CD27 costimulation. The data we presented at AACR (Free AACR Whitepaper) demonstrate that this bispecific antibody candidate has greater activity than the combination of the two individual antibodies and support advancing the program into IND-enabling studies. In addition, we also presented data on our lead candidate antibodies targeting the TAM receptors, which act as checkpoints on myeloid cells. We have uncovered a unique mechanism for antibody-mediated activation of dendritic cells and macrophages and demonstrated that a surrogate MerTK mAb promotes anti-tumor immunity alone and enhances the activity of PD-1 blockade. We look forward to continuing to progress both CDX-527 and our TAM program over the course of the year," concluded Keler.

Presentation Highlights:

Poster #2392: CDX-527: A novel bispecific immune-modulating antibody targeting CD27 and PD-L1 (Vitale, et. al)

The use of bispecific antibodies provides opportunities to engage two independent pathways involved in controlling immune responses to tumors. Preclinical and clinical studies support the safety and benefit of combining PD-1 blockade with a CD27 agonist.
The bispecific CDX-527 combines a novel and potent PD-L1 antibody for blocking the PD-1 checkpoint pathway with the binding domains of a CD27 agonist antibody for CD27-mediated costimulation of T cells.
CDX-527 demonstrated potent inhibition of PD-1 signaling and T cell activation using in vitro models with reporter cell lines and human primary cell cultures.
Anti-tumor activity was tested with a surrogate bispecific molecule that binds mouse PD-L1 and human CD27 in human CD27-expressing transgenic mice. The bispecific demonstrated potent anti-tumor activity in a BCL1 lymphoma model and was significantly more effective than the combination of the CD27 and PD-L1 monoclonal antibodies (mAbs).
A pilot study in non-human primates suggests that CDX-527 demonstrates good pharmacokinetic properties and no toxicities were observed.
Based on the promising data observed to date and the PK/PD profiles, Celldex has initiated manufacturing activities and investigational new drug (IND) enabling studies to support clinical studies of CDX-527.
Poster #1555: Monoclonal antibodies targeting the TAM family of receptor tyrosine kinases (Alvarado, et al)

TAM receptors (Tyro3, Axl, MerTK) are receptor tyrosine kinases (RTKs) expressed in innate immune cells. These receptors have been gaining importance in the immunotherapy field due to their role as checkpoint molecules on macrophages, dendritic cells, and other immune cells, where they can negatively regulate anti-tumor immunity.
Celldex presented data showing that lead candidate mAbs targeting MerTK, Axl or Tyro-3 activate myeloid cells, including monocytes, macrophages and dendritic cells, enhancing pro-inflammatory cytokine release, increasing expression of costimulatory molecules and enhancing T cell activation in mixed lymphocyte reaction (MLR) assays.
Celldex demonstrated that the potent activity of the TAM-specific antibodies are dependent on a unique coupling of the TAM receptors with Fc receptors.
Celldex’s most advanced program targets MerTK, where the Company has demonstrated that antibody targeting of MerTK in mice elicits an inflammatory cytokine response similar to that observed in the human cells and in MerTK deficient mice and has anti-tumor activity when dosed alone or in combination with a PD-1 inhibitor in a colon cancer model.
These data support development of anti-TAM mAbs as therapies to activate innate immune responses with a potential for systemic dosing. The Company intends to advance potential candidates into development activities this year.

Dynavax’s SD-101 and 4SC’s Domatinostat Demonstrate Synergy and Induce a Systemic Anti-tumor Response in Preclinical Models

On April 1, 2019 Dynavax Technologies Corporation (NASDAQ: DVAX) and 4SC AG (FSE Prime Standard: VSC) reported the combination of 4SC’s orally available class I selective HDAC inhibitor domatinostat (4SC-202) with Dynavax’s intratumoral TLR9 agonist SD-101 induced a systemic anti-tumoral immune response in tumor mouse models, resulting in the significant decrease in tumor size of both target tumors and distant site metastases (Press release, Dynavax Technologies, APR 1, 2019, View Source [SID1234534838]).

Combination of SD-101 with domatinostat showed better results than combinations of SD-101 with competing HDAC inhibitors. The triple combination of both compounds with PD-1 blockade (checkpoint inhibition) demonstrated even higher efficacy.

Émilie Degagné, PhD, scientist at Dynavax will present the data in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting, which takes place from 29 March to 3 April 2019 in Atlanta, USA.

Combined mode of actions of SD-101 plus checkpoint inhibitor plus domatinostat

SD-101 is a TLR9 agonist, which was specifically developed for cancer based upon its ability to stimulate both IFN-α production and the maturation of plasmacytoid dendritic cells into tumor antigen presenting cells. This results in increased activation and proliferation of tumor-specific CD8+ T cells which attack distant site non-injected tumors. Domatinostat, acting via epigenetic regulation, renders tumor cells more visible to the immune system and promotes a general immune response against tumor tissue as well as infiltration of T cells into the tumor tissue.

Preclinical data demonstrate that the combination of intra-tumoral SD-101 and systemic domatinostat strongly synergize to induce substantial regression of the primary (injected) tumor, as well as distant site non-injected tumors, including lung metastases. Checkpoint inhibitors, such as anti-PD-1 antibodies further boost the anti-tumor T-cell response, leading to rejection in mice with high metastatic burden. These data indicate that the combination of these three different treatment classes result in induction of a more potent tumor-specific immune response and better recognition and elimination of tumors by immune cells, especially in cancer patients refractory to anti-PD-1 treatment.

"We believe the induction of innate immunity will be instrumental in the future treatment of cancer and are pleased to work with 4SC as they develop differentiated drug candidates to modulate the immune system," said Eddie Gray, CEO of Dynavax. "SD-101 has demonstrated significant antitumor effects by direct enhancement of innate immunity and adds meaningful clinical benefit to anti-PD-1 therapy. The addition of domatinostat to this combination shows encouraging results and we look forward to continuing to assess the potential of this combination."

Jason Loveridge, Ph.D., CEO of 4SC, added: "We thank Eddie Gray and his team at Dynavax for performing these highly promising experiments. We are very impressed by the data on the triple-combination of SD-101, domatinostat and PD-1 blockade and believe there is significant potential for novel combinations based on immunotherapeutics such as these to fight cancer, especially in patients who are resistant to or progressing on treatment with prior immunotherapies. Of particular importance to us was the clear demonstration of domatinostat’s superiority as compared to competing HDAC inhibitors."

Abstract ID 2259: Tumor abscopal responses induced by the TLR9 agonist, SD-101, are strongly potentiated by a HDAC class I inhibitor, domatinostat.

Date: 1 April 2019
Time: 1:00 PM – 5:00 PM EDT
Session: PO.CL06.05 – Combination Immunotherapies 1
Location: Exhibit Hall B, Section 19, Poster Board Number 18

Further information

About SD-101

SD-101, the Company’s lead clinical candidate, is a proprietary, second-generation, Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide. Dynavax is evaluating this intratumoral TLR9 agonist in several clinical studies to assess its safety and activity, including a Phase 2 study in combination with KEYTRUDA (pembrolizumab), an anti-PD-1 therapy, in patients with advanced melanoma and in patients with head and neck squamous cell cancer, in a clinical collaboration with Merck. Dynavax maintains all commercial rights to SD-101.

About domatinostat (4SC-202)

Domatinostat is an orally administered small molecule Class I selective HDAC inhibitor with a unique mode of action that was designed to strengthen the body’s own anti-tumor immune response. Domatinostat also influences the tumor microenvironment facilitating infiltration of immune cells into the tumor and making it more visible to the immune system.

Domatinostat has been investigated in a Phase I study with 24 heavily pretreated patients with several types of advanced hematologic cancers and was well tolerated. Positive signs of anti-tumor efficacy were also observed; with one complete remission (28 months) and one partial responder (8 months).

In addition to its therapeutic potential in cancer monotherapy, 4SC is evaluating domatinostat’s capacity as a partner in combination therapies, specifically in the immuno-oncology area. In this respect, 4SC initiated a Phase Ib/II study of domatinostat in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in patients with advanced-stage melanoma. A second Phase II study of domatinostat in combination with the anti-PD-L1 checkpoint inhibitor avelumab in patients with advanced-stage microsatellite-stable gastrointestinal cancer is conducted by Prof. David Cunningham of The Royal Marsden NHS Foundation Trust (London, UK).

As soon as results from the aforementioned trials will be available, 4SC plans to advance domatinostat into a potentially pivotal study in combination with a checkpoint inhibitor in PD-(L)1 refractory patients with advanced Merkel-cell carcinoma (MCC).

Phase 1b/2 Dose Escalation Trial of Onvansertib in Relapsed/Refractory AML Demonstrates Safety, Tolerability and Relative Durability with Complete Responses at Highest Dose Levels

On April 1, 2019 Trovagene, Inc. (Nasdaq: TROV), a clinical-stage oncology therapeutics company, taking a precision medicine approach to develop drugs that target cell division (mitosis) for the treatment of leukemias, lymphomas and solid tumor cancers, reported its new data from its ongoing Phase 1b/2 study evaluating onvansertib in combination with standard-of-care chemotherapy in Acute Myeloid Leukemia (AML) (Press release, Trovagene, APR 1, 2019, View Source [SID1234534837]).

The data, featured at the American Association for Cancer Research (AACR) (Free AACR Whitepaper), demonstrates the safety, tolerability, preliminary efficacy and relative durability of response in patients treated with onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine, in patients with relapsed/refractory acute myeloid leukemia (AML). The prognosis for these patients is poor with short survival time and limited treatment options. Onvansertib is a first-in-class, 3rd generation, highly-selective oral Polo-like Kinase 1 (PLK1) Inhibitor that is being evaluated in an ongoing Phase 1b/2 clinical trial at nine sites in the U.S.

Presentation Highlights

Anti-Leukemic Activity:

Objective response rate (anti-leukemic activity) has been observed at last 3 highest dose levels of onvansertib with 5 of 19 evaluable patients achieving a complete response (CR and CRi, 2 patients); a morphologic leukemic-free state (MLFS, 2 patients); and a partial response (PR, patient). Furthermore, stable disease (SD) was observed in 12 patients
The greatest anti-leukemic activity has been observed in the onvansertib + decitabine arm, with 2 of 4 (50%) evaluable patients from the two highest dose levels tested to-date (27mg/m2 and 40mg/m2) achieving a complete response (CR and CRi)
Early indication of safety, tolerability and durability of response has been demonstrated by 16 of 24 patients who have completed ≥2 cycles of treatment, including 2 patients who have been on treatment for 11.5 months (patient with PR) and 5.4 months (patient with CRi)
Biomarker Analysis:

Positive biomarker status to-date (the phosphorylation of translational control tumor protein (pTCTP), which is a specific marker for PLK1 activity, has been observed in 8 out of 22 patients (33%) and has been associated with a statistically significant greater response to treatment (p=0.019)
Safety/Tolerability:

There have been no dose-limiting toxicities through the completed dose level of 40mg/m2
No serious adverse events (SAEs) reported to-date have been considered related to onvansertib
"While we are still in the dose escalation part of the trial, the preliminary efficacy data is encouraging, in particular that we are seeing some complete and relatively durable responses," said Dr. Amer Zeidan, lead investigator and assistant professor of Medicine at Yale School of Medicine, and Hematology expert at Yale Cancer Center. "AML patients with relapsed or refractory disease have short survival time and very limited treatment options. As we continue to dose escalate through the Phase 1b trial, we are not only encouraged by how safe and well-tolerated onvansertib appears to be thus far in this patient population, but also by the evidence of clinical activity we are seeing especially with the decitabine-based combination at the higher doses of onvansertib. For example, one of my patients, who responded to treatment, is nearly one year out from the time of enrollment in this trial and continues to do quite well. We hope, as we continue in the trial and reach the recommended Phase 2 dose, that we will see additional evidence of clinical efficacy."

Details of the poster presentation are provided below:

Title: Phase 1b Safety, Preliminary Anti-Leukemic Activity and Biomarker Analyses of the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Low-Dose Cytarabine (LDAC) or Decitabine in Patients with Relapsed/Refractory Acute Myeloid

Session Title: Phase I-III Trials in Progress: Part 1

Date and Time: Monday, April 1, 2019; 1:00 PM – 5:00 PM EDT

Session Location: Georgia World Congress Center, Exhibit Hall B, Poster Section 17

About the Ongoing Onvansertib Phase 1b/2 Acute Myeloid Leukemia Trial

The Phase 1b/2 trial (NCT03303339) is a multi-center, open-label trial to evaluate the safety and efficacy of Onvansertib in combination with standard-of-care chemotherapy in AML patients who are ineligible for intensive induction therapy or whose disease is relapsed or refractory. In Phase 1b dose-escalation segment of the trial, the primary objective is to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), using a traditional 3+3 design. In Phase 2 the MTD or RP2D will be administered to 32 patients to evaluate preliminary antitumor activity and to continue to evaluate the safety and tolerability of Onvansertib in combination with standard-of-care chemotherapy. This trial is being led by Amer Zeidan, MBBS, MHS, assistant professor of Medicine at Yale School of Medicine, and Hematology expert at Yale Cancer Center, and Jorge Cortes, M.D., Deputy Department Chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. The trial is being conducted at nine sites in the U.S.

About Onvansertib

Onvansertib is a first-in-class, 3rd generation, oral and highly-selective adenosine triphosphate (ATP) competitive inhibitor of the serine/threonine polo-like-kinase 1 (PLK 1) enzyme, which is over-expressed in multiple cancers, including leukemias, lymphomas and solid tumors. Separate studies with other PLK inhibitors have shown that inhibition of polo-like-kinases can lead to tumor cell death, including a Phase 2 study in Acute Myeloid Leukemia (AML) where response rates of up to 31% were observed when combined with a standard therapy for AML (low-dose cytarabine-LDAC) versus treatment with LDAC alone with a 13.3% response rate. A Phase 1 open-label, dose escalation safety study of Onvansertib has been completed in patients with advanced metastatic solid tumor cancers and published in Investigational New Drugs. The maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) in this trial was 24 mg/m2. Trovagene has an ongoing Phase 1b/2 clinical trial with onvansertib in AML that was accepted by the National Library of Medicine (NLM) and is now publicly viewable on www.clinicaltrials.gov. The NCT number assigned by clinicaltrials.gov for this study is NCT03303339. Onvansertib has been granted Orphan Drug Designation by the FDA in the U.S. and by the EC in the European Union (EU) for the treatment of patients with AML.

Onvansertib targets the PLK1 isoform, only (not PLK2 or PLK3), is orally administered, has a 24-hour drug 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 FLT3 and HDAC inhibitors, taxanes, and cytotoxins. Trovagene believes the combination of its targeted PLK1 inhibitor, 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, Triple Negative Breast Cancer (TNBC), as well as other types of cancer.

Syndax Pharmaceuticals Presents Updated Phase 2 Data from ENCORE 601 Trial of Entinostat in Combination with KEYTRUDA® (pembrolizumab) at the American Association for Cancer Research 2019 Annual Meeting

On April 1, 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 presentation of updated findings from the melanoma and non-small cell lung cancer (NSCLC) cohorts of ENCORE 601, the Company’s Phase 1b/2 trial evaluating the efficacy and safety of entinostat, its once-weekly, oral, small molecule, class I HDAC inhibitor, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 (programmed death receptor-1) therapy (Press release, Syndax, APR 1, 2019, View Source [SID1234534836]). The data were presented during oral presentations at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held March 29 – April 3, 2019 in Atlanta, Georgia. A copy of each presentation is available via the Syndax website at View Source

"We are very pleased to report that updated findings announced today continue to support our prior observation that the addition of entinostat to pembrolizumab may overcome resistance in a subset of melanoma and NSCLC patients who are refractory to anti-PD-1 therapy," said Briggs W. Morrison, M.D., Chief Executive Officer of Syndax. "Both indications represent areas of high unmet need and we believe that available data warrant consideration to move the entinostat-pembrolizumab combination into one or more registration trials. As previously communicated, we look forward to determining next steps for the combination program following availability of overall survival results from E2112, our Phase 3 registration trial of entinostat plus exemestane in HR+, HER2- breast cancer, the next interim readout of which is expected in the second quarter of this year."

Melanoma Update

During an oral presentation today titled, "Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy", Ryan J. Sullivan M.D., Assistant Professor, Hematology/Oncology, Massachusetts General Hospital, presented results from the ENCORE 601 melanoma cohort that enrolled patients whose disease had progressed on or after anti-PD-1 therapy. Of 53 patients treated, a confirmed objective response was observed in 19% of patients per irRECIST criteria (1 complete response (CR), 9 partial responses (PR); 95% CI: 9-32%), with a clinical benefit rate of 36% (CR, PR, stable disease (SD) > 6 months; 95% CI: 23%-50%). Median duration of response is 13 months (range 3-20 months). Four responders, all of whom have been on study therapy for over a year, currently remain on treatment. Efficacy results in patients who also received prior YERVOY (ipilimumab) therapy (n=37, 70%) were consistent with the overall population. The entinostat-pembrolizumab combination was well tolerated with a manageable toxicity profile.

Correlative analyses consistent with entinostat’s hypothesized mechanism of action indicate a trend in decreased circulating myeloid derived suppressor cells (MDSCs) and increased CD8+ T cells in responding patients. Gene expression changes in post-treatment tumor biopsy samples in responders versus non-responders support up-regulated immune response signatures and down-regulation of immune resistance pathways.

NSCLC Update

During an oral presentation on Sunday titled, "Identification of gene signatures associated with response in a Phase 2 trial of entinostat (ENT) plus pembrolizumab (PEMBRO) in non-small cell lung cancer (NSCLC) patients whose disease has progressed on or after anti-PD-(L)1 therapy", Suresh S. Ramalingam, M.D., Assistant Dean for Cancer Research and Deputy Director of the Winship Cancer Institute at Emory University, presented updated clinical results and findings from gene expression analyses of pre-treatment tumor samples conducted in a subset of patients. Updated results continue to support the association of high baseline classical monocytes with improved clinical outcome to entinostat plus pembrolizumab in anti-PD-1 pre-treated NSCLC patients and with extended follow up, the median duration of response is 8 months (range 3-18 months).

Results from gene set analyses revealed a significantly enriched Myc regulated gene signature in responders versus non-responders. Multiple studies have implicated elevated Myc signaling as a resistance factor to anti-PD-(L)1 therapy1-3, and separately have shown that entinostat can downregulate Myc activity4,5. These findings provide further insight into the potential mechanistic basis for response to the entinostat-pembrolizumab combination treatment in PD-(L)1 pretreated patients.

About Entinostat

Entinostat, Syndax’s selective, oral, once-weekly inhibitor of class I histone deacetylases (HDACs), has been shown to resensitize Hormone Receptor positive (HR+) advanced breast cancer to endocrine therapy, and is currently being evaluated in a pivotal Phase 3 clinical trial in combination with exemestane for advanced HR+ breast cancer, an indication for which it has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration. Entinostat has also been shown to block the function of immune suppressive cells in the tumor microenvironment, and in a Phase 2 clinical trial in combination with KEYTRUDA (pembrolizumab) from Merck & Co., Inc, demonstrated evidence of clinical benefit in patients with melanoma and non-small cell lung cancer.