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FORMA Therapeutics Announces Positive Preliminary Phase 1/2 IDH1m Inhibitor Olutasidenib Results Demonstrating Rapid Clinical Remissions and Mutation Clearance in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

On December 9, 2019 FORMA Therapeutics, Inc., a clinical stage biopharmaceutical company focused on rare hematologic diseases and cancers, reported positive preliminary Phase 1/2 results from an ongoing study of olutasidenib, a next-generation inhibitor of mutated IDH1 (IDH1m), in patients with IDH1m acute myeloid leukemia (AML) and IDH1m myelodysplastic syndrome (MDS) (Press release, Forma Therapeutics, DEC 9, 2019, View Source [SID1234552117]). The data, presented at the 2019 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper), demonstrate the potential of olutasidenib to induce rapid remissions and mutation clearance in a percentage of patients with IDH1m AML and MDS.

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"We are very pleased with the safety and clinical activity observed in this study of high-risk patients," said Patrick Kelly, M.D., chief medical officer of FORMA Therapeutics. "As we continue our Phase 2 evaluation, the therapeutic potential of olutasidenib to restore normal cellular differentiation in IDH1m malignancies, as well as to become a best-in-class treatment option, remains promising."

"In the U.S. alone, more than 20,000 new cases of AML are diagnosed each year, with about one-third of those evolving from patients with MDS," said Frank Lee, chief executive officer of FORMA Therapeutics. "Despite recent advances in the field, the low median five-year survival rate for AML patients is only 28%, so the need for a new therapy to transform patient outcomes remains significant."

FORMA is conducting a Phase 1/2 study evaluating the safety, efficacy and pharmacokinetics/pharmacodynamics (PK/PD) of olutasidenib for patients with AML or MDS with an IDH1 mutation. Phase 1 of the trial, 2102-HEM-101, was an open-label, dose-escalation and expansion study of olutasidenib alone and in combination with azacitidine (AZA). Phase 2 is an ongoing, open-label, fixed dose study of olutasidenib as a monotherapy and in combination with AZA in multiple IDH1m AML/MDS populations. Phase 2 includes a pivotal arm with olutasidenib as a monotherapy in relapsed and refractory (R/R) AML.

Presentation Overviews

Olutasidenib (FT-2102), an IDH1m Inhibitor as a Single Agent or in Combination with Azacitidine, Induces Deep Clinical Responses with Mutation Clearance in Patients with Acute Myeloid Leukemia Treated in a Phase 1 Dose Escalation and Expansion Study

Oral presentation by Justin Watts, MD, Assistant, Professor University of Miami, Sylvester Comprehensive Cancer Center

Results announced today are based on continuous oral treatment of olutasidenib for 28-day cycles, either alone (n=32) or in combination with AZA (n=46), in patients with IDH1m AML, with a dose evaluation of 300 mg once daily for olutasidenib alone and 150 mg once daily or twice daily for olutasidenib in combination with AZA. The findings indicate:

Olutasidenib is well tolerated as monotherapy and in combination with AZA;
No dose-limiting toxicities in dose escalation; 150 mg BID is the RP2D based on optimal exposure and robust 2-HG response;
Olutasidenib demonstrates clinical activity in a high-risk Phase 1 AML population; and
Olutasidenib induces IDH1 mutation clearance in a percentage of patients with TN and R/R AML regardless of IWG response.
FORMA’s Phase 2 study is ongoing with olutasidenib 150 mg BID as monotherapy and in combination with AZA in multiple IDH1m AML and MDS populations.

Olutasidenib (FT-2102) Induces Rapid Remissions in Patients with IDH1-Mutant Myelodysplastic Syndrome: Results of Phase 1/2 Single Agent Treatment and Combination with Azacitidine

Oral presentation by Jorge E. Cortes, MD, Professor, Augusta University, Director of the Georgia Cancer Center

Results presented today are based on continuous oral treatment of olutasidenib for 28-day cycles, either alone (n=6) or in combination with AZA (n=17) in 23 patients (16 relapsed/refractory, 7 treatment naïve) with IDH1m MDS. The findings indicate:

Olutasidenib is well-tolerated as a single agent and in combination with AZA;
Olutasidenib demonstrates preliminary clinical activity as a single agent and in combination with AZA in treatment-naive and relapsed/refractory patients with MDS;
Mutation clearance was observed in a percentage of evaluable patients; and
Rapid and sustained reduction of 2-HG was seen by the end of the first cycle.
About Olutasidenib (FT-2102)

FORMA Therapeutics’ most advanced clinical asset, olutasidenib, is designed to be a potent and selective next generation inhibitor of mutated isocitrate dehydrogenase 1 (IDH1m) to treat patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), as well as patients with glioma and other solid tumors with an IDH1 mutation. IDH1 is a natural enzyme that is part of the normal metabolism in all cells; when mutated, its activity can promote blood malignancies and solid tumors. IDH1 mutations are present in 7-14% of patients with AML, 3-4% of patients with MDS, and more than 70% of patients with gliomas. In AML, hypermethylation driven by IDH mutations inhibits normal differentiation of progenitor cells leading to accumulation of immature blasts. Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed disease remain an unmet need. In MDS, often a precursor to AML, epigenetic changes from aberrant DNA methylation contribute to the formation of blast cells and the progression of MDS to AML.

Zentalis Pharmaceuticals Raises $85 Million in Oversubscribed Series C Financing to Accelerate Internally-Developed Clinical-Stage Oncology Pipeline

On December 9, 2019 Zentalis Pharmaceuticals (the "Company" or "Zentalis"), a clinical-stage biopharmaceutical company focused on developing clinically differentiated, novel small molecule therapeutics that target fundamental pathways in cancer, reported the completion of an $85 million Series C financing (Press release, Zentalis Pharmaceuticals, DEC 9, 2019, View Source [SID1234552116]). The Company has raised a total of $147 million in gross proceeds from private financings since its founding in December 2014.

Leading investors participating in this Series C financing include Matrix Capital, Viking Global Investors, Redmile Group, Farallon Capital, Perceptive Advisors, Surveyor Capital (a Citadel company) and Eventide Asset Management.

The proceeds from the Series C financing will be used to advance the Company’s lead clinical candidates towards pivotal trials and to broaden the scope of Zentalis’ ongoing clinical programs. The Company’s product pipeline is being developed to address unmet medical needs in large patient populations in both solid and liquid tumors and to make potential significant clinical advances over standard of care therapies.

The Company’s lead clinical product candidate, ZN-c5, is currently in Phase 1/2 trials. ZN-c5 is a potential best-in-class oral Selective Estrogen Receptor Degrader (SERD) for estrogen receptor-positive, HER2-negative (ER+/ HER2-) breast cancer, which affects approximately 70% of all breast cancer patients. ZN-c5 is being developed for use as monotherapy or in combination therapy. In May 2018, Zentalis entered into a clinical development collaboration agreement with Pfizer Inc. to enable trials of its ZN-c5 in combination with Pfizer’s Ibrance (palbociclib), a CDK4/6 inhibitor which is approved for ER+/HER2- advanced breast cancer patients in combination with hormonal therapies. The Company recently initiated dosing ZN-c5 in combination with Ibrance in a Phase 1/2 clinical trial targeting safety, efficacy and pharmacokinetics readouts in 2020, in addition to its ongoing monotherapy cohort.

Zentalis is also developing ZN-c3, a next-generation DNA Damage Response (DDR) drug candidate targeting the WEE1 kinase for solid tumors. ZN-c3 is currently in a Phase 1 trial. The Company’s additional pipeline compounds target other fundamental cancer pathways.

"Zentalis is delighted to partner with its outstanding group of leading healthcare investors to drive forward best-in-class chemistry for cancer patients. In my career, I have never seen a company progress at this pace with three INDs accepted in the first five years since inception. I am very proud of our team for these remarkable accomplishments. This financing reflects strong support for our capabilities, people and pipeline," said Anthony Sun, M.D., Chief Executive Officer, Zentalis Pharmaceuticals. "The investment positions us to implement our clinical and partnering strategies around our current pipeline and to accelerate expansion of our team."

"We were attracted to Zentalis by the excellent science, integrated discovery engine, broad therapeutic applicability and market potential with a strong pipeline across a broad range of oncology indications. There are significant advantages with a small molecule approach in cancer, such as oral delivery and ease of manufacturing compared to biologics or immunotherapy, and the ability to reach a large number of potential intracellular targets. We see tremendous opportunity for Zentalis’ pipeline candidates to be potential best-in-class agents for use as monotherapy or in combination. Their approach to targeting fundamental cancer pathways has the potential to address major unmet medical needs in large patient populations," said Karan Takhar, Managing Director at Matrix Capital Management.

Eagle Pharmaceuticals Commences Dosing in Pilot Study for Novel Estrogen Receptor Antagonist Product Candidate

On December 9, 2019 Eagle Pharmaceuticals, Inc. (Nasdaq: EGRX) ("Eagle" or the "Company") reported that the Company has commenced dosing in a pilot clinical study to assess the unique characteristics of its fulvestrant product candidate, which has the potential to enhance estrogen receptor ("ER") inhibition and improve patient outcomes (Press release, Eagle Pharmaceuticals, DEC 9, 2019, View Source [SID1234552114]). The results of the pilot study will inform the design of the Company’s pivotal trial, which Eagle expects to commence in 2020.

"We are pleased that dosing is underway in our pilot study, and look forward to gathering data to determine the design of our future pivotal study in estrogen receptor positive breast cancer patients. We believe there is a sizable patient population who could benefit from our product’s differentiated characteristics, and we look forward to expanding our portfolio of oncology assets," stated Scott Tarriff, Chief Executive Officer of Eagle Pharmaceuticals.

About Fulvestrant

Fulvestrant, an estrogen receptor antagonist with no agonist properties, is approved by the U.S. Food and Drug Administration for the treatment of advanced hormone-related breast cancers. The therapeutic effect of fulvestrant relies on its ability to inhibit ERs in cancer cells by binding to and downregulating, or blocking, the ER in breast cancer cells. Recent studies have shown that higher residual ER availability is associated with early disease progression.

Fulvestrant is indicated as a monotherapy treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, or HR-positive advanced breast cancer in postmenopausal women with disease progression following endocrine therapy, or as a combination therapy for the treatment of: (1) HR-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women, in combination with ribociclib, as initial endocrine based therapy or following disease progression on endocrine therapy, or (2) HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with palbociclib or abemaciclib, in women with disease progression after endocrine therapy.

About Breast Cancer

Breast cancer is the most commonly diagnosed cancer in women, with approximately 290,000 women diagnosed in the U.S. annually and more than 2.8 million breast cancer survivors in the U.S. today. Hormone receptor-positive (HR+) breast cancer is the most common clinical subtype, with the ER being expressed in approximately 75% of those diagnosed.

Daiichi Sankyo Initiates Pivotal Phase 2 Trial in Japan with Valemetostat in Patients with Adult T-Cell Leukemia-Lymphoma

On December 10, 2019 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that the first patient has been dosed in a pivotal phase 2 study in Japan evaluating valemetostat (DS-3201), an investigational EZH1/2 dual inhibitor, in patients with relapsed/refractory adult T-cell leukemia-lymphoma (ATL) (Press release, Daiichi Sankyo, DEC 10, 2019, View Source [SID1234552113]).

ATL is one of the most aggressive forms of non-Hodgkin’s lymphoma (NHL) and although rare, occurs with greater frequency in certain regions including Japan. Treatments for ATL, a complex and heterogeneous disease, are largely limited to systemic chemotherapy combinations, and patients often face a difficult prognosis, especially for relapsed disease.[1]

"Valemetostat is a novel targeted therapy that has demonstrated preliminary potential in several types of NHL including ATL, which represents one of the greatest areas of need among lymphoma patients, particularly in Japan," said Kaszushi Araki, DVM, PhD, Valemetostat Global Team Leader, Oncology Clinical Development Department, Oncology Function, Daiichi Sankyo. "Valemetostat is the only EZH1/2 dual inhibitor in clinical development, and our program includes translational research to improve understanding of underlying disease mechanisms and treatment response."

The pivotal phase 2 trial with valemetostat was initiated based on preliminary findings from an ongoing phase 1 study in patients with several types of NHL, which were presented on December 9th at the 2019 annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper).[2]

About the Study

The pivotal, open-label, multi-center, single-arm phase 2 study will evaluate efficacy and safety of valemetostat as monotherapy in patients with relapsed/refractory ATL previously treated with mogamulizumab or at least one systemic chemotherapy.

The primary efficacy endpoint is overall response rate (ORR). Secondary efficacy endpoints include investigator-assessed ORR, complete remission rate, time to response, duration of response, progression-free survival and overall survival. The study will evaluate safety endpoints including adverse events and a number of pharmacokinetic, pharmacodynamic and biomarker endpoints. Approximately 25 patients are expected to be enrolled in the study in Japan. For more information, please visit ClinicalTrials.gov.

About Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma (ATL), an often fast-growing form of T-cell lymphoma, is associated with human T-cell lymphotropic virus type 1 (HTLV-1).[3] While ATL is rare in most parts of the world, it is endemic in several regions of the world with Japan having the highest prevalence of both HTLV-1 and ATL. Although the majority of an estimated one million people in Japan that are carriers of the HTLV-1 virus remain asymptomatic during their lifetime, it is estimated that the annual incidence of developing ATL is approximately 60 per 100,000 carriers resulting in 1,000 deaths annually.[4] The lifetime risk of ATL for HTLV-1 carriers is approximately 5 percent for men and 3 percent for women in Japan.[4]

Treatment options for ATL vary based on the subtype of the disease. Since there are no optimal standard treatments to manage this type of cancer, enrollment in a clinical trial is a recommended treatment option for all patients with ATL.[5]

About Valemetostat

Valemetostat (DS-3201) is an investigational and potential first-in-class EZH1/2 dual inhibitor that targets epigenetic regulation by inhibiting both the EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2) enzymes, which act through histone methylation to regulate gene expression.[6]

Research has shown that EZH1 and EZH2 are recurrently highly expressed or mutated in many hematologic cancers and are involved in suppression of genes that control tumor cell growth and proliferation.[7] Valemetostat has displayed preliminary activity in various hematological malignancies in preclinical models.[8], [9]

In addition to the pivotal phase 2 trial in relapsed/refractory ATL, valemetostat is in phase 1 clinical development for several types of NHLs including ATL, peripheral T-cell lymphoma (PTCL) and B-cell lymphomas, and the trial is now enrolling patients in the U.S. as well as Japan (ClinicalTrials.gov). A phase 1 study is also underway with valemetostat in other hematologic cancers including acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) (ClinicalTrials.gov). Valemetostat has received SAKIGAKE Designation for the treatment of adult patients with relapsed/refractory PTCL by the Ministry of Health, Labour and Welfare (MHLW) in Japan.

There are no dual EZH1/2 targeting treatments approved for treatment of any cancer. Valemetostat is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.

About Daiichi Sankyo Cancer Enterprise

The mission of Daiichi Sankyo Cancer Enterprise is to leverage our world-class, innovative science and push beyond traditional thinking to create meaningful treatments for patients with cancer. We are dedicated to transforming science into value for patients, and this sense of obligation informs everything we do. Anchored by three pillars including our investigational Antibody Drug Conjugate Franchise, Acute Myeloid Leukemia Franchise and Breakthrough Science, we aim to deliver seven distinct new molecular entities over eight years during 2018 to 2025. Our powerful research engines include two laboratories for biologic/immuno-oncology and small molecules in Japan, and Plexxikon Inc., our small molecule structure-guided R&D center in Berkeley, CA. For more information, please visit: www.DSCancerEnterprise.com.

Corvus Pharmaceuticals Presents Preclinical and Initial Clinical Data from the Phase 1/1b Trial of CPI-818 at the American Society of Hematology (ASH) Annual Meeting

On December 9, 2019 Corvus Pharmaceuticals, Inc. (Nasdaq: CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of precisely targeted oncology therapies with biomarker patient enrichment selection, reported that initial results from its Phase 1/1b trial of CPI-818, the Company’s ITK-inhibitor (Press release, Corvus Pharmaceuticals, DEC 9, 2019, View Source [SID1234552112]). The early clinical data from the study demonstrated specific target engagement by CPI-818. The results were presented in a poster at the American Society of Hematology (ASH) (Free ASH Whitepaper) 61st Annual Meeting 2019 in Orlando, Florida, taking place December 7-10, 2019.

"We are excited to report the first clinical experience with CPI-818, our selective covalent ITK inhibitor designed to address T-cell lymphomas, a category of hematologic cancers with great need for novel therapeutic options," said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. "The results show that CPI-818 achieved specific and sustained target occupancy and we look forward to continuing the dose escalation portion of the study to identify an optimum dose. In addition to T-cell lymphomas, we believe CPI-818 may have applications in other immune mediated diseases. Overall, our team is now advancing three candidates in clinical trials for a wide range of cancers, and each of our programs remains on track with enrollment and progress towards next data milestones."

The CPI-818 Phase 1/1b study is currently enrolling patients with several types of advanced, refractory T-cell lymphomas, including peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), cutaneous T-cell lymphoma (CTCL) and other T-cell lymphomas. The study employs an adaptive, expansion cohort design to select the dose and evaluate the safety, pharmacokinetics (PK), target occupancy, immune-related biomarkers and efficacy of CPI-818. The initial phase of the trial is evaluating escalating doses in successive cohorts of patients in order to determine the optimum dose. A second phase will evaluate safety and tumor response to this optimum dose of CPI-818 in disease-specific patient cohorts that may be expanded based on early signs of efficacy. The study is enrolling patients at major medical centers in the United States, Australia and South Korea.

CPI-818 Phase 1/1b Results at ASH (Free ASH Whitepaper) 2019
The preclinical and early clinical data from the Phase 1/1b trial of CPI-818 was presented by Patrick Ng, PhD, Corvus Senior Scientist, in a poster session at the ASH (Free ASH Whitepaper) Annual Meeting. The key highlights from the poster, which is titled "Preliminary Clinical Data from a Phase 1 Trial with CPI-818, A Selective ITK Inhibitor that Preferentially Blocks the Growth of T Lymphoma Cells," include:

Seven patients have been enrolled in the first two dose cohorts in the initial phase of the trial, receiving a 100 mg or 200 mg oral dose of CPI-818 two times per day, with no dose limiting toxicities and no grade 3 or 4 adverse events observed.
The results from the pharmacokinetic and occupancy studies for the first seven patients have been in-line with expectations. The Company anticipates that a dose that achieves maximum target occupancy will be achieved in the next one or two dose cohorts.
CPI-818 has been shown to bind covalently to ITK at low nanomolar concentrations without reacting with other kinases.
In vitro studies demonstrated selective cytotoxicity to Sezary cells (malignant cells from patients with CTCL), while sparing normal T-cells, in three subjects not enrolled in the study.
Preclinical murine models of lymphoproliferative and autoimmune disease showed CPI-818 inhibited the development of lymph node and spleen enlargement by preventing proliferation of abnormal T-cells. Treatment with CPI-818 led to regression of lymphadenopathy and splenomegaly in animals with established disease.