On April 2, 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 early data from its ongoing Phase 2 study evaluating Onvansertib in combination with Zytiga (abiraterone acetate)/prednisone in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC) (Press release, Trovagene, APR 2, 2019, View Source [SID1234534897]).

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The data, featured at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) shows clinical activity as measured by prostate specific antigen (PSA) response when onvansertib is added to Zytiga in patients showing early signs of resistance to Zytiga.

Presentation Highlights

Preliminary Efficacy:

Early PSA response was observed with the addition of onvansertib to daily abiraterone in 2 of 6 patients, with 1 patient achieving the efficacy endpoint of disease control and a 30% decrease in tumor size by RECIST criteria (unconfirmed Partial Response to be confirmed with subsequent CT scan in May 2019)
PSA trajectory in the patient achieving the primary efficacy endpoint changed from 100% increase (16.05ng/ml to 34.23 ng/ml) in the 60 days prior to study to 8.4% increase during 84 days on study, indicating alteration of the natural history of early abiraterone resistance
Both patients that showed an early response (at C1D8) with decreases in PSA levels, also tested positive for AR-V7, a highly aggressive androgen receptor variant (AR-V7) which is resistant to Zytiga because it no longer needs androgen for tumor growth
Safety and Tolerability:

The combination of onvansertib and Zytiga is safe and well tolerated as demonstrated in the safety lead-in segment of the trial
No unexpected, off-target toxicities have been reported in patients treated to-date
"We are encouraged by the signs of clinical activity observed to-date and intrigued by the potential to be able to effectively treat patients who are AR-V7 positive," said Dr. Mark Erlander, Chief Scientific Officer of Trovagene. "There are limited options, other than intensive chemotherapy which has a poor prognosis, in patients who are showing initial signs of resistance to treatment with Zytiga and those that harbor the highly aggressive androgen receptor variant (AR-V7). We believe the combination regimen may provide a much-needed new therapeutic option for these patients."

Details of the poster presentation are provided below:

Title: A Phase 2 Study of the Polo-like Kinase 1 (PLK1) Inhibitor Onvansertib in Combination with Abiraterone (Abi) and Prednisone in Patients with Metastatic Castration-Resistant Prostate Cancer

Session Title: Phase I-III Trials in Progress: Part 2

Session Date and Time: Tuesday, April 2, 2019; 8:00 AM – 12:00 PM EDT

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

About the Ongoing Onvansertib Phase 2 Trial in mCRPC

In this multi-center, open-label, Phase 2 trial, Onvansertib in combination with the standard dose of Zytiga (abiraterone acetate) and prednisone, all administered orally, is being evaluated for safety and efficacy. The trial will enroll up to 45 patients with mCRPC showing early signs of disease progression demonstrated by two rising PSA values separated by at least one week, while on Zytiga/prednisone therapy. The primary efficacy endpoint is the proportion of patients achieving disease control after 12 weeks of study treatment, as defined by lack of prostate specific antigen (PSA) progression in patients who are showing signs of early progressive disease (rise in PSA but minimally symptomatic or asymptomatic) while currently receiving abiraterone acetate and prednisone (NCT03414034). The trial is being conducted at Beth Israel Deaconess Medical Center (BIDMC), Dana Farber Cancer Institute (DFCI) and Massachusetts General Hospital (MGH).

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.

On April 2, 2019 Inovio Pharmaceuticals, Inc. (NASDAQ: INO) reported the company’s novel DNA-Encoded Bi-specific T Cell Engagers (dBiTEs) generated potent anti-tumor activities in a preclinical study (Press release, Inovio, APR 2, 2019, View Source [SID1234534896]). Results were presented as a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Atlanta. For this study, Inovio, with its collaborators at The Wistar Institute, developed a novel dBiTE targeting the HER2 molecule which was tested in therapeutic models for the treatment of ovarian and breast cancers. Importantly, just a single dose of Inovio’s HER2 dBiTE resulted in high levels of corresponding BiTE in mice for four months, far exceeding what is typically displayed with conventional BiTE’s short half-life of only a few hours. The HER2 dBiTE effectively generated T cell cytotoxicity against HER2-expressing tumor cells resulting in a near-complete tumor clearance. Also presented was Inovio’s CD19 dBiTE which can kill B cell cancers by targeting B cell specific marker CD19.

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Dr. J. Joseph Kim, Inovio’s President and CEO, said, "In layman’s terms, dBiTEs are like a double-sided tape that binds to a tumor and to a cancer-killing T cell. By allowing the products be expressed directly and efficiently in the patient, our dBiTEs could finally fulfill the therapeutic promise of BiTEs. Based on these promising preclinical results, we are rapidly preparing for the clinical development of our dBiTE candidates, as well as constructing more cancer tumor targeting dBiTE candidates using our transformative dBiTE platform."

Dr. Kim added, "Leveraging Inovio’s in vivo synthetic nucleic expression platform, we have shown that just one dose of Inovio’s dBiTE could generate corresponding BiTEs at high levels in mice for several months, demonstrating a dramatic advantage over conventional BiTEs. Our CD19 dBiTE has the potential to treat multiple B cell cancers and to compete favorably with CD19 CAR-T products with potentially improved tolerability and safety profiles. Similarly, the HER2 dBiTE could be used to treat multiple solid tumors which express HER2 such as breast, ovarian, and gastric cancers."

BiTEs are a class of artificial bi-specific monoclonal antibodies that has the potential to transform the immunotherapy landscape for cancer. They direct a host’s immune system, more specifically the T cells’ cytotoxic activity, against cancer cells. BiTEs have two binding domains. One domain binds to the targeted tumor (like HER2 or CD19 expressing cells) while the other engages the immune system by binding directly to CD3 molecules on T cells. This double-binding activity drives T cell activation directly at the tumor resulting in a killing function and tumor destruction.

The biggest drawback of conventional protein-based BiTEs is the delivery and expression. The BiTEs have a half-life of only about two hours, which requires patients to undergo continuous intravenous infusion for several weeks to maintain therapeutic levels, making treatment adherence more difficult and resulting in high levels of infusion-associated adverse events. In addition, just like other traditional monoclonal antibodies, conventional BiTEs are also manufactured in bioreactors, typically requiring costly large-scale manufacturing facility development and laborious production as well as having to deal with improper product folding and stability. They must also be kept and distributed frozen at all times. These difficulties collectively have limited the development and commercialization of conventional BiTEs as only one licensed product is currently on the market (BLINCYTO (blinatumomab)).

Inovio’s dBiTE is a new transformative application of Inovio’s dMAb platform. The dBiTEs share many advantages of Inovio’s dMAbs as they both are composed of engineered DNA sequences which encode two antibody fragments. When administered by Inovio’s CELLECTRA delivery device, the patient’s own cells become the factory to manufacture functional BiTES encoded by the delivered dBiTE sequences.

Inovio’s dBiTEs provide major potential advantages over a conventional protein-based BiTE therapy because of dBiTEs’ better product expression and availability as well as simplicity in administration and manufacturing. Inovio has demonstrated that a single dose of dBiTE construct delivered with CELLECTRA expressed the product at high levels in mice for four months. Inovio’s dBiTEs are developed with simplified design using novel plasmid vectors and unique formulations allowing for rapidity of development, long-term product stability at refrigeration, ease of validated and scalable manufacturing and deployability.

Earlier this year, Inovio initiated the first clinical trial for a dMAb. Funded fully by the Bill & Melinda Gates Foundation, this trial’s focus is on evaluating the dMAb’s (INO-A002) ability to prevent or treat Zika virus infection. The clinical results will help to broadly advance Inovio’s dMAb and dBiTE programs in infectious diseases and cancer.

About Inovio’s dBiTE program

Inovio’s dBiTEs are able to target the cytotoxic T cells to tumors by engaging proteins expressed in the tumor surface. The current preclinical models have shown proof that DNA technologies are in an advantageous position to launch a more ambitious BiTE program. The tumor-binding domain can be modified to engage multiple targets, of which preclinical data targeting HER2 and CD19 will be presented. Of these, the CD19dBiTE can be used to target B cell cancers and the HER2dBiTE can be used to treat advanced breast, ovarian, gastric, esophageal and endometrioid cancers.

On April 2, 2019 Conatus Pharmaceuticals Inc. (NASDAQ:CNAT) reported has accepted an invitation to participate in the H.C. Wainwright Global Life Sciences Conference (April 7-9 in London) (Press release, Conatus Pharmaceuticals, APR 2, 2019, View Source [SID1234534895]). Conatus senior management will conduct a series of scheduled meetings with investment professionals and present a company overview on Tuesday, April 9, 2019, from 10:30 a.m. to 10:50 a.m. BST (5:30 a.m. to 5:50 a.m. EDT). A webcast of the presentation will be available live and archived in the Investors section of the Conatus website at www.conatuspharma.com.

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On April 2, 2019 Pacira Pharmaceuticals, Inc. (NASDAQ: PCRX) reported that it will present at the 18th Annual Needham Healthcare Conference at 3:30 PM ET on Tuesday, April 9, 2019 (Press release, Pacira Pharmaceuticals, APR 2, 2019, View Source;p=irol-newsArticle&ID=2393147 [SID1234534894]). Live audio of the presentation can be accessed by visiting the "Events" page of the company’s website at investor.pacira.com. A replay of the webcast will also be available for two weeks following the event.

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On April 2, 2019 Onconova Therapeutics, Inc. (NASDAQ: ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with a primary focus on myelodysplastic syndromes (MDS), reported that the Company will be presenting at the 2019 HCW Global Life Sciences Conference at the Grosvenor House/JW Marriott Hotel in Mayfair, London (Press release, Onconova, APR 2, 2019, View Source [SID1234534893]). Dr. Steven Fruchtman, President & CEO, will present at the conference and meet with investors.

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Presentation details
Date/Time:
Venue:
Presenter:
Webcast link: Monday, April 8th at 10:10 a.m. BST
Grosvenor House/JW Marriott Hotel – Spencer Suite
Steven M. Fruchtman, President & CEO
View Source
About Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are conditions that can occur when the blood-forming cells in the bone marrow become dysfunctional and thus produce an inadequate number of circulating blood cells. It is frequently associated with the presence of blasts or leukemic cells in the marrow. This leads to low numbers of one or more types of circulating blood cells, and to the need for blood transfusions. In MDS, some of the cells in the bone marrow are abnormal (dysplastic) and may have genetic abnormalities associated with them. Different cell types can be affected, although the most common finding in MDS is a shortage of red blood cells (anemia). Patients with higher-risk MDS may progress to the development of acute leukemia.