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.

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"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.

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]).

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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.

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.

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"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.

On December 9, 2019 Constellation Pharmaceuticals, Inc., (Nasdaq: CNST) a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported that it has commenced an underwritten public offering of 4.75 million shares of its common stock (Press release, Constellation Pharmaceuticals, DEC 9, 2019, View Source [SID1234552111]). All of the shares are being offered by Constellation. In addition, Constellation expects to grant the underwriters a 30-day option to purchase up to an additional 15% of the shares of its common stock sold in the public offering.

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J.P. Morgan, Jefferies and Cowen are acting as joint book-running managers for the offering. RBC Capital Markets is acting as a bookrunner, and SunTrust Robinson Humphrey is acting as lead manager for the offering. The offering is subject to market and other conditions, and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering.

The shares are being offered by Constellation pursuant to an automatically effective shelf registration statement that was filed with the Securities and Exchange Commission ("SEC") on December 9, 2019.

This offering is being made only by means of a prospectus and prospectus supplement that form a part of the registration statement. A preliminary prospectus supplement relating to and describing the terms of the offering is expected to be filed with the SEC and, if and when filed, copies of the preliminary prospectus supplement relating to the offering may be obtained for free by visiting the SEC’s website at www.sec.gov. Copies of the preliminary prospectus supplement and the accompanying prospectus may also be obtained by contacting: J.P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, telephone: (866) 803-9204; Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, by telephone at 877-821-7388 or by email at [email protected]; or Cowen and Company, LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, Attn: Prospectus Department, by email at [email protected] or by telephone at (833) 297-2926. The final terms of the offering will be disclosed in a final prospectus supplement to be filed with the SEC.

This press release shall not constitute an offer to sell, or a solicitation of an offer to buy these securities, nor shall there be any sale of, these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

On December 9, 2019 Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported an update of preliminary data from the MANIFEST clinical trial in oral and poster presentations at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando (Press release, Constellation Pharmaceuticals, DEC 9, 2019, View Source [SID1234552110]).

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MANIFEST is an open-label Phase 2 clinical trial of the Company’s bromodomain and extra-terminal domain (BET) protein inhibitor CPI-0610 in patients with myelofibrosis (MF). Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in ruxolitinib-resistant or -intolerant MF patients.

The updated preliminary data presented at ASH (Free ASH Whitepaper) showed signs of clinical activity for CPI-0610 similar to that previously reported at the annual meetings of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the European Hematology Association (EHA) (Free EHA Whitepaper) and in the ASH (Free ASH Whitepaper) abstracts. The preliminary data included data on additional patients and showed evidence of activity across a broad range of myelofibrosis parameters in both JAK-inhibitor-naïve and ruxolitinib-resistant or -intolerant patients.

"If trends in preliminary data from MANIFEST in JAK-inhibitor-naïve patients are confirmed with further study, CPI-0610 has the potential to transform the standard of care in these patients," said Claire Harrison, D.M., Professor of Haematology, and Clinical Director, Guy’s and St Thomas’ NHS Foundation Trust, and a MANIFEST investigator.

"Preliminary data from MANIFEST in ruxolitinib-resistant or -intolerant patients are encouraging, suggesting the potential opportunity for a differentiated treatment option in such patients," said John Mascarenhas, M.D., Associate Professor, the Icahn School of Medicine at Mount Sinai, and a MANIFEST investigator.

The presentations at ASH (Free ASH Whitepaper) reflect data as of an October 17, 2019, data cutoff, updating preliminary data presented in ASH (Free ASH Whitepaper) abstracts published on November 6, 2019, as of a June 27, 2019, data cutoff.

Below are highlights of the presentations at ASH (Free ASH Whitepaper):

JAK-Inhibitor-Naïve Patients (Arm 3)

SVR35: Twelve out of 15 (80%) evaluable JAK-inhibitor-naïve patients experienced SVR35 at 12 weeks. The median percent change in spleen volume reduction was -49.7%.
TSS50: Ten out of 14 (71%) evaluable patients achieved at least a 50% improvement in Total Symptom Score (TSS50) at 12 weeks. The median percent change in TSS at 12 weeks was -60.3%.
Ruxolitinib-Resistant or -Intolerant Patients (Arms 1 and 2)

CPI-0610 Add-on to Ruxolitinib in Transfusion-Dependent Patients (Cohort 2A)

SVR35: At 24 weeks, SVR35 was achieved in 3 out of 12 (25%) evaluable patients, with a median percent change of -24.9%. An SVR35 at any time (best response) was achieved in 5 out of 17 (29%) evaluable patients, with a best median percent change of -21.2%.
SVR: At 24 weeks, 11 out of 12 (92%) evaluable patients had a spleen volume reduction.
TSS50: At 24 weeks, TSS50 was achieved in 7 out of 13 (54%) evaluable patients, with a median percent change of -58.8%. A TSS50 at any time (best response) was achieved in 13 out of 17 (76.5%) evaluable patients, with a median best change of -71.0%.
TD to TI: Conversion from transfusion dependence (TD) to transfusion independence (TI) occurred in 6 out of 14 (43%) evaluable patients with at least 24 weeks of treatment.
Other Ruxolitinib-Resistant or -Intolerant Patients (Cohorts 1A, 1B, and 2B)

SVR35: None of the patients in these cohorts achieved SVR35 at 24 weeks. An SVR35 at any time (best response) was achieved in 1 out of 4 evaluable patients in cohort 1A.
SVR: Nine out of 13 (69%) evaluable patients in Cohort 2B, 1 out of 2 (50%) evaluable patients in Cohort 1A, and 5 out of 7 (71%) evaluable patients in Cohort 1B achieved a spleen volume reduction at 24 weeks. The median reductions were -10.9%, -3.2%, and -26.0%, respectively.
TSS50: Five out of 13 (38%) evaluable patients in Cohort 2B, 0 out of 1 evaluable patient in Cohort 1A, and 3 out of 5 (60%) evaluable patients in Cohort 1B achieved a TSS50 at 24 weeks. Median reductions were -44.1%, -18.4%, and -53.5%, respectively.
TD to TI: Zero out of 2 TD patients in cohort 1A with at least 24 weeks of treatment converted to TI.
Additional Data Supporting Possible Disease Modification

Hemoglobin Improvement: Six out of 11 (55%) evaluable patients treated with CPI-0610 monotherapy and 2 out of 15 (13%) evaluable patients treated with CPI-0610 + ruxolitinib achieved at least a 1.5 g/dL improvement in hemoglobin without receiving a blood transfusion in the 12 weeks prior to assessment.
Bone Marrow Fibrosis Score Improvement: Twelve out of 32 (38%) evaluable patients in Arms 1 and 2, including 7 out 11 (63%) evaluable patients in Cohort 2A, achieved at least a one-grade improvement in bone marrow fibrosis score. Ten out of 12 improvements occurred within the first six months of treatment.
Safety

CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve patients (Arm 3) was generally well tolerated. No adverse events led to study discontinuation. Three patients (10%) had ≥ Grade 3 anemia. One patient (3.3%) had Grade 4 thrombocytopenia, which was reversible. The most common non-hematologic adverse events were diarrhea, nausea, dizziness, and muscle spasms, which were primarily Grade 1/2.
CPI-0610 as monotherapy or in combination with ruxolitinib in ruxolitinib-refractory or -intolerant patients (Arms 1 and 2) was generally well tolerated. The most common hematologic adverse event was thrombocytopenia. Nine patients (10%) had ≥ Grade 3 thrombocytopenia, none of which were serious adverse events. These nine patients included two (5.6%) in Arm 1 and seven (12.9%) in Arm 2. The most common non-hematologic adverse events, primarily Grade 1/2, were diarrhea, nausea, cough, fatigue, vomiting, and upper respiratory tract infection. Eight out of 90 (8.9%) patients reported Grade 4 adverse events, all of which resolved. Of these eight, four (11.1%) occurred in Arm 1, of which three required dose interruption and one (rash) was considered related to CPI-0610, and four (7.4%) occurred in Arm 2, none required dose reduction and one (anemia) was considered related to the combination therapy. One ruxolitinib-resistant or -intolerant patient (1.1%) discontinued due to serious adverse event(s), which were reported as unlikely to have been related to CPI-0610. Three out of 90 (3.3%) ruxolitinib-resistant or -intolerant patients, all in Arm 2, reported Grade 5 adverse events—acute kidney injury, traumatic subdural hematoma (fall due to tripping), and brain stem hemorrhage (no concomitant thrombocytopenia)—none of which were considered by Constellation to be related to CPI-0610.
Orphan Drug Designation

The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to CPI-0610 for the treatment of MF on November 20, 2019.
The FDA Orphan Drug Designation program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. Under specified conditions, this designation may provide companies a seven-year marketing exclusivity period, as well as certain incentives, including federal grants, tax credits, and a waiver of Prescription Drug User Fee Act (PDUFA) filing fees.
Future Plans

Constellation continues to enroll patients in MANIFEST. As a result of encouraging preliminary data, Constellation expanded Arm 3 of MANIFEST for JAK-inhibitor-naïve patients from 43 to up to 101 patients. The Company also expanded Cohort 2A, for TD ruxolitinib-resistant or -intolerant patients adding CPI-0610 to ruxolitinib, from 16 to up to 60 patients.
Constellation has started planning for a randomized, active-controlled, pivotal Phase 3 clinical trial studying the combination of CPI-0610 and ruxolitinib versus ruxolitinib and placebo in JAK-inhibitor-naïve patients with MF. The Company expects this clinical trial to start in 2020.
Investor Event

Constellation will host an analyst/investor event and webcast today at 12:30 PM EST in Salon 2 at the Rosen Centre Hotel in Orlando in conjunction with the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper). The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source Analysts and investors may also access the event and participate in the live question-and-answer session by dialing (877) 473-2077 (domestic) or (661) 378-9662 (international) and referring to conference ID 7892044. A replay of the call will be available at (855) 859-2056, (404) 537-3406, or (800) 585-8367.
About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment. Constellation is also evaluating CPI-0610, either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to TI for 12 consecutive weeks. The primary endpoint for the patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.