On October 24, 2019 Syros Pharmaceuticals (NASDAQ: SYRS), a leader in the development of medicines that control the expression of genes, reported that updated clinical data from its ongoing Phase 2 trial evaluating SY-1425, its first-in-class selective retinoic acid receptor alpha (RARα) agonist, in combination with azacitidine, continue to demonstrate high complete response rates, rapid onset of action and a favorable tolerability profile in a genomically defined subset of newly diagnosed acute myeloid leukemia (AML) patients who are not suitable candidates for standard intensive chemotherapy (Press release, Syros Pharmaceuticals, OCT 24, 2019, View Source [SID1234542486]). These data are being presented at the European School of Haematology (ESH) 5th International Conference Acute Myeloid Leukemia "Molecular and Translational": Advances in Biology and Treatment in Estoril, Portugal.

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"I am very encouraged by these data. AML patients continue to need new treatment options, despite recent advances in the field, that are well-tolerated and can be used in combination to extend survival and improve quality of life," said Stéphane de Botton, M.D., Head of Acute Myeloid Malignancies at Institut Gustave Roussy and a clinical investigator in the Phase 2 trial of SY-1425. "These data show that SY-1425, a targeted therapy, in combination with azacitidine is highly active in a subset of patients that can be readily identified and that the combination is generally well-tolerated even in very sick AML patients. I believe SY-1425 is a promising combination agent with the potential to provide a meaningful benefit for a subset of AML patients, and I look forward to its continued development."

"These data mark an important milestone in the development of SY-1425," said David A. Roth, M.D., Chief Medical Officer of Syros. "SY-1425 in combination with azacitidine continues to demonstrate high complete response rates, rapid onset of action and a favorable tolerability profile in RARA-positive AML patients. As we study the combination in more patients, we are also seeing a high rate of transfusion independence and early evidence of durable responses. We are gratified to see our discovery of this novel patient subset, as defined by our RARA biomarker, translating into clinical benefit. These results demonstrate the power of our gene control platform to identify which genes to modulate in which patients to maximize the chances of providing them with a profound benefit. We look forward to continuing to evaluate SY-1425 in our ongoing study and to reporting potential proof-of-concept data next year in RARA-positive relapsed or refractory AML patients."

Updated Clinical Data on SY-1425 in Combination with Azacitidine in Newly Diagnosed, Unfit AML Patients

Syros presented updated data from its Phase 2 trial of SY-1425 in combination with azacitidine, a standard-of-care hypomethylating agent, in newly diagnosed unfit AML patients. The trial evaluated the safety and efficacy of the combination in patients with either the RARA or IRF8 biomarker, as well as in patients without the biomarkers. All patients were treated with azacitidine administered at standard daily doses of 75 mg/m2 intravenously or subcutaneously for seven days, followed by SY-1425 administered at 6 mg/m2/day orally, divided in two doses, for the remainder of each 28-day cycle.

As of Aug. 22, 2019, 40 newly diagnosed unfit AML patients had been enrolled in the trial and were eligible for the safety analysis. The median age of patients enrolled in the study was 76. Of the 17 biomarker-positive patients evaluable for response, 13 were RARA-positive and four were IRF8-positive. Enrollment in the newly diagnosed unfit cohorts of the ongoing Phase 2 trial is nearly complete. Syros will continue to follow patients enrolled in the trial to further characterize the overall profile of the combination, including safety, efficacy and durability of response.

Clinical Activity Data

62% complete response (CR) and complete response with incomplete blood count recovery (CRi) rate, as defined by Revised International Working Group, IWG, criteria), in RARA-positive patients.

54% CR rate in RARA-positive patients, consisting of seven CRs, including three molecular CRs and three cytogenetic CRs.

Most initial responses were seen at the first response assessment.

Duration of these responses in RARA-positive patients was up to 344 days, with three of the eight responding patients having responses lasting beyond seven months at the time of the data cutoff.

82% of RARA-positive patients achieved or maintained transfusion independence.

Responses were seen in RARA-positive patients across AML risk groups, including patients with mutations that are typically associated with poor outcomes.

In patients with only the IRF8-biomarker, the CR/CRi rate was 0%, supporting Syros’ decision to use RARA as the sole biomarker for patient selection in SY-1425 clinical trials going forward. Based on data from 112 newly diagnosed patients screened for its clinical trial, Syros believes that approximately 30% of newly diagnosed AML patients are RARA-positive.

In the 22 response-evaluable RARA-negative patients, the CR/CRi rate was 27%, which is consistent with the published response rates of 18-29% observed in newly diagnosed unfit AML patients treated with single-agent azacitidine.

Safety Data

SY-1425 in combination with azacitidine was generally well-tolerated with no evidence of increased toxicities beyond what is seen with either SY-1425 or azacitidine alone.

Rates of myelosuppression, including neutropenia, were comparable to reports of single-agent azacitidine in this AML population.

The majority of non-hematologic AEs were low grade.

Across all grades and causalities, the most commonly reported AEs were nausea (38%), decreased appetite (38%), constipation (33%), fatigue (33%) and peripheral edema (30%).

The most commonly reported Grade 3 or higher AEs (all causality) were thrombocytopenia (25%), anemia (23%), and febrile neutropenia (23%).

The poster presented at ESH is now available on the Publications and Abstracts section of the Syros website at www.syros.com.

The ongoing Phase 2 trial is actively enrolling patients with relapsed or refractory AML patients who are positive for the RARA biomarker. Syros expects to report potential proof-of-concept from the cohort in relapsed or refractory AML patients in 2020. Additional details about the Phase 2 trial of SY-1425 can be found using the identifier NCT02807558 at www.clinicaltrials.gov.

On October 24, 2019 Replimune Group Inc. (NASDAQ: REPL), a biotechnology company developing oncolytic immuno-gene therapies derived from its Immulytic platform, reported that the company has enrolled the first patient in its Phase 1 clinical trial of RP2 (Press release, Replimune, OCT 24, 2019, View Source [SID1234542485]). RP2 expresses a genetically encoded anti-CTLA-4 antibody-like molecule, in addition to GALV-GP-R- and GM-CSF, both of which are expressed in Replimune’s first product candidate, RP1. This is intended to block the inhibition of the initiation of immune responses caused by CTLA-4.

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"We are excited to be advancing RP2, our second novel Immulytic product candidate, into clinical studies," said Robert Coffin, Ph.D., co-founder, President and CEO of Replimune. "CTLA-4 inhibition is an established mechanism of action for cancer treatment, including proven synergy with anti-PD1 therapy. By combining the expression of anti-CTLA-4 with oncolytic tumor destruction and antigen release directly in the tumor and draining lymph nodes, we believe that the efficacy of CTLA-4 inhibition can be enhanced with RP2, while reducing toxicity as compared to systemic administration."

The Phase 1 clinical trial will study RP2 as a single agent and in combination with Opdivo (nivolumab) in patients with advanced solid tumors. The Phase 1 clinical trial is designed to assess the safety, tolerability and to determine the optimal dose of RP2 alone and in combination with anti-PD1 therapy and is being conducted as a collaboration with Bristol-Myers Squibb Company (BMS). BMS has granted Replimune a nonexclusive, non-transferable, royalty-free license to, and will supply at no cost, Opdivo, for use in combination with RP2. BMS has no further development-related obligations under this collaboration.

About RP2

RP2 is Replimune’s second Immulytic product candidate and like RP1, is based on a proprietary new strain of herpes simplex virus which expresses GM-CSF and the fusogenic protein GALV-GP R-. In addition to the properties of RP1, RP2 expresses an anti-CTLA-4 antibody-like protein in order to block the inhibition of the immune response otherwise caused by CTLA-4. In preclinical studies comparing RP1 to RP2 to determine the effect of expressing anti-CTLA-4, RP2 demonstrated enhanced efficacy both alone and in combination with anti-PD1 therapy both in tumors which were injected with RP1 or RP2 and in tumors which were left uninjected

On October 24, 2019 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology both in vivo and ex vivo, reported that it will present third quarter 2019 results and operational highlights in a conference call on October 31, 2019 at 8 a.m. ET (Press release, Intellia Therapeutics, OCT 24, 2019, View Source [SID1234542484]).

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To join the call:

U.S. callers should dial 888-208-1711 and use conference ID# 7693636, approximately five minutes before the call.
International callers should dial +1 856-344-9299 and use conference ID# 7693636, approximately five minutes before the call.
A replay of the call will be available through the Events and Presentations page of the Investor Relations section of the company’s website at www.intelliatx.com, beginning on October 31, 2019 at 12 p.m. ET.

On October 24, 2019 Onconova Therapeutics, Inc. (NASDAQ:ONTX), a Phase 3-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, with a focus on myelodysplastic syndromes (MDS), reported that the Company believes it remains on target to report top-line data from the global Phase 3 INSPIRE Trial with intravenous (IV) rigosertib in second-line, higher-risk MDS patients in the first half of 2020 following full enrollment and 288 death events (Press release, Onconova, OCT 24, 2019, View Source [SID1234542483]). The Company anticipates completion of the INSPIRE Trial in the first half of 2020 based on approaching 90 percent or 324 randomized patients of the required 360 randomized patients, and the number of confirmed death events reached to date.

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Steven M. Fruchtman, M.D., President and Chief Executive Officer, stated, "Enrollment in our global Phase 3 INSPIRE Trial with IV rigosertib in second-line, higher-risk MDS patients is progressing. We are approaching 90 percent of planned enrollment. Based on enrollment and the number of reported events reached, which exceeded 75% of the required 288 events at end of September 2019, we continue to anticipate reporting top-line data in the first half of 2020 following full enrollment and 288 death events. Enrollment in Brazil is expected to begin in November, and we look forward to the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy Congress in Rio de Janeiro, November 6-9."

Dr. Richard Woodman, Chief Medical Officer of Onconova, continued, "Prior to readout of the INSPIRE trial, the Company plans to focus Onconova’s research and development activities on completing the INSPIRE trial. After completion of the INSPIRE trial, based on recent feedback from the FDA, we plan to conduct a randomized Phase 2 Trial with a control arm of single agent azacitidine for the continued development of oral rigosertib plus azacitidine in first-line higher-risk MDS patients. We also plan to consult with key opinion leaders on the design of a Phase 2 controlled study for submission to the FDA as the next step in the development of oral rigosertib. The proposed Phase 2 Study does not require a Special Protocol Assessment (SPA)."

In addition to the pivotal Phase 3 INSPIRE study, a Phase 1 study of rigosertib in combination with a PD-1 inhibitor for patients with progressive K-Ras mutated non-small cell lung cancer is expected to commence by early 2020 as an investigator-initiated study. Ras-mutated cancers represent about a third of all human cancers. We recently participated in the RAS Drug Discovery Summit in Boston and plan to participate in the next RAS Drug Discovery Summit in Vienna, Austria in February 2020. We are also working toward filing an IND for a Phase 1 trial of ON 123300, our investigational dual inhibitor of CDK4/6 + ARK5, which we believe has the potential to treat various cancers including refractory metastatic breast cancer. The IND has been submitted in China by our corporate partner Han X.

On October 24, 2019 TG Therapeutics, Inc. (NASDAQ: TGTX) reported that final long-term results from the Phase 3 GENUINE study demonstrated that ublituximab in combination with ibrutinib improved progression-free survival (PFS), as determined by Independent Review Committee (IRC) (Press release, TG Therapeutics, OCT 24, 2019, View Source [SID1234542482]). The GENUINE Phase 3 study evaluated ublituximab, the Company’s novel, glycoengineered anti-CD20 monoclonal antibody, in combination with ibrutinib, compared to ibrutinib monotherapy in patients with relapsed/refractory high-risk chronic lymphocytic leukemia (CLL). As previously reported, the GENUINE study met its primary endpoint of improved IRC-assessed overall response rate (ORR), as well as increased centrally-assessed rate of minimal residual disease (MRD). The combination of ublituximab and ibrutinib was well tolerated with no new safety signals identified at a median follow-up of >4 years.

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The Company plans to present these final data at a future medical conference, as well as share the results with the U.S. Food and Drug Administration (FDA).

Michael S. Weiss, Executive Chairman and Chief Executive Officer of TG Therapeutics stated, "We are pleased with the final results from the Phase 3 GENUINE trial with median follow-up of over 4 years. The improvement in PFS observed in these high-risk CLL patients is extremely encouraging, and we look forward to presenting the full data at a future medical conference."

ABOUT THE PHASE 3 GENUINE STUDY

The Phase 3 GENUINE study is a randomized, open label, multicenter clinical trial to evaluate the safety and efficacy of ublituximab in combination with ibrutinib compared to ibrutinib monotherapy in adult patients with high-risk chronic lymphocytic leukemia (CLL) who received at least one prior therapy for their disease. In this study, high-risk was defined as having any one or more of the following: 17p deletion, 11q deletion or p53 mutation.

The study was conducted at 160 clinical trial sites in the US and Israel and randomized 126 patients. Patients received ibrutinib orally at 420 mg once daily in both arms and in the treatment arm those patients also received intravenous infusions of ublituximab at 900 mg dosed on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6. Patients in the treatment arm who had not progressed received quarterly infusions of ubltuximab maintenance at 900 mg.