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Salarius Pharmaceuticals Enrolls First Patient in a Phase 1 Clinical Study of its Novel Inhibitor Targeting Epigenetics in Patients with Advanced Solid Tumors

On July 22, 2019 Salarius Pharmaceuticals, Inc. (Nasdaq: SLRX), a clinical-stage oncology company targeting the epigenetic causes of cancers, reported it has enrolled the first patient in a Phase 1 clinical study of the company’s lead compound, Seclidemstat, in patients with advanced solid tumors resistant to standard-of-care therapies. Seclidemstat is a differentiated reversible inhibitor of the widely studied epigenetic enzyme lysine-specific demethylase 1 (LSD1) (Press release, Flex Pharma, JUL 22, 2019, View Source [SID1234537641]). This is Salarius’ second Phase 1 clinical study for Seclidemstat, which is also the subject of an ongoing clinical study focused on Ewing sarcoma, a devastating bone and soft tissue cancer for which Seclidemstat has Orphan Drug Designation and Rare Pediatric Disease Designation from the U.S. Food and Drug Administration (FDA). Salarius expects to report early cohort data from both Phase 1 clinical studies in 2020.

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David Arthur, President and CEO of Salarius Pharmaceuticals, stated, "We are excited to expand our clinical pipeline for Seclidemstat to include patients with advanced solid tumors and we believe addressing the epigenetic dysregulation underlying certain cancers represents a potentially powerful approach to providing a therapeutic benefit for patients with limited or no other treatment options. With potential data readouts from both clinical programs expected next year, we hope to further establish Salarius in this exciting and growing field."

Seclidemstat is an oral small molecule inhibitor of LSD1, a validated drug target for clinical development. LSD1 is known to associate with more than 60 different gene regulatory proteins to drive a variety of cancer types. High levels of LSD1 expression are often correlated with poor patient prognosis. The open-label, dose escalation/dose expansion Phase 1 clinical study in advanced solid tumor cancers is designed to evaluate the safety, pharmacokinetics and pharmacodynamics of Seclidemstat, as well as establish a recommended dose for Phase 2 studies. The study is enrolling patients with advanced (non-Ewing’s) solid tumors, with a focus on prostate, breast, ovarian, melanoma, colorectal, non-Ewing’s sarcomas and other cancers where Seclidemstat demonstrated single-agent preclinical activity. The study will also use established and exploratory biomarkers to assess sensitivity and early signs of therapeutic activity in these patients.

Michael Gordon, M.D., Medical Director of Oncology Clinical Trials at the HonorHealth Research Institute and principal investigator of the advanced solid tumor Phase 1 study, commented, "Epigenetics is a rapidly growing field within oncology, and selective yet reversible inhibitors such as Seclidemstat represent the cutting-edge progress being made in this space. We know that epigenetic modulation by LSD1 occurs not only through its enzymatic activity as a demethylase, but also via its scaffolding properties. If clinical studies prove Seclidemstat is able to safely and effectively inhibit both mechanisms of gene regulation by LSD1, which is supported by substantial preclinical work, Seclidemstat will have a highly differentiated profile that could translate into improved outcomes for patients."

Salarius Pharmaceuticals Announces Closing of Strategic Merger with Flex Pharma

On July 22, 2019 Salarius Pharmaceuticals, Inc. (Nasdaq: SLRX), a clinical-stage oncology company targeting the epigenetic causes of cancers, reported that Salarius Pharmaceuticals, LLC, has closed its merger with Flex Pharma, Inc.’s wholly owned subsidiary on July 19, 2019 (Press release, Flex Pharma, JUL 22, 2019, View Source [SID1234537640]). Flex Pharma, Inc. has been renamed and will operate as Salarius Pharmaceuticals, Inc. The newly combined company will focus on the continued development of Salarius’ clinical pipeline, which targets rare, orphan cancers for which no approved targeted treatments are currently available and cancers with a high unmet need. The company will be led by Salarius’ current management team under the leadership of President and CEO, David Arthur. Former Flex Pharma President and CEO, William McVicar, Ph.D., will join Salarius’ Board of Directors. The company’s common stock will trade on the Nasdaq Capital Market under the new ticker symbol "SLRX" beginning on July 22, 2019 and will reflect the previously announced 25:1 reverse stock split that occurred effective as of the close of business on July 19, 2019.

David Arthur, President and CEO of Salarius Pharmaceuticals, stated, "We believe this strategic merger and Nasdaq listing establishes a foundation for future growth. The enhanced visibility and exposure to institutional investors will allow Salarius to showcase the potential of our lead asset, Seclidemstat, and showcase our clinical pipeline. We look forward to sharing important updates with our investors as we advance our clinical programs."

Salarius’ lead compound, Seclidemstat, targets the epigenetic dysregulation underlying Ewing sarcoma, a devastating pediatric, adolescent, and young adult bone and soft-tissue cancer for which no approved targeted therapies are currently available. Seclidemstat is a differentiated, reversible inhibitor of lysine-specific demethylase 1, or LSD1, which is a widely studied epigenetic enzyme and a validated drug target for clinical development. Salarius is currently enrolling refractory and relapsed Ewing sarcoma patients in an open-label Phase 1 dose escalation/dose expansion study, with potential early cohort data readouts in 2020. Salarius is also conducting a Phase 1 clinical study of Seclidemstat in patients with advanced solid tumors including, but not limited to, prostate, breast, and ovarian cancers.

Healthios Capital Markets served as financial advisor in the transaction to Salarius Pharmaceuticals and Flex Pharma’s strategic advisor was Wedbush PacGrow. Pillsbury Winthrop Shaw Pittman LLP is serving as legal counsel to Salarius Pharmaceuticals and Dentons is serving as legal counsel to Flex Pharma.

CStone receives approval in China to initiate ivosidenib Phase I bridging registrational study for the treatment of IDH1 mutant relapsed or refractory AML

On July 22, 2019 CStone Pharmaceuticals ("CStone"; HKEX: 2616) reported that it has received approval from China National Medical Products Administration (NMPA) to initiate a Phase I bridging registrational study of ivosidenib (TIBSOVO) for the treatment of relapsed or refractory acute myeloid leukemia (R/R AML) with an IDH1 mutation (Press release, CStone Pharmaceauticals, JUL 22, 2019, View Source [SID1234537637]). This stand-alone trial is designed to evaluate the efficacy, safety and pharmacokinetics of ivosidenib in Chinese patients with IDH1 mutant R/R AML.

AML is the most common type of acute leukemia in adults and is characterized by rapid disease progression. There are approximately 20,000 new cases of AML in the U.S. each year, with a five-year survival rate of approximately 27%, as compared to 30,000 new cases in China annually and a five-year survival rate of below 20%. The majority of AML patients develop tolerance to treatments or eventually relapse, leading to R/R AML which has a poor prognosis. With an increasing life expectancy and aging population in China, the incidence of AML may rise significantly in the country. Interruption to the differentiation of hematopoietic stem cells due to IDH1 mutation is associated with around 6%-10% of all AML cases. Among the currently approved treatments for AML in China, there is no effective therapy for this patient population.

Discovered and developed by CStone’s partner Agios Pharmaceuticals, ivosidenib was approved by the U.S. FDA in July 2018 for the treatment of adult R/R AML patients with an IDH1 mutation as detected by an FDA-approved test.

"Ivosidenib is the first and only approved precision therapy in the U.S. that targets IDH1 mutation in R/R AML and the only asset in CStone’s pipeline that has obtained a marketing authorization. This approval for the registrational study in China marks a big milestone for us," commented Dr. Frank Jiang, Chairman and CEO of CStone. "Through precision therapies, patients can potentially benefit from treatments targeting the specific genetic mutations that drive the cancer. CStone remains committed to advancing precision therapies and bringing more targeted treatment options to patients."

"Ivosidenib was first approved as a treatment for IDH1 mutant R/R AML. The U.S. FDA recently approved a supplemental NDA for ivosidenib to include newly diagnosed AML patients with an IDH1 mutation who are ≥ 75 years old or have comorbidities that preclude the use of intensive induction chemotherapy. In March 2019, the U.S. FDA granted Breakthrough Therapy designation for ivosidenib in combination with azacitidine for the treatment of the same newly diagnosed AML patients. These milestones demonstrate ivosidenib’s promising clinical utility. We are poised to rapidly roll out this trial for ivosidenib as a monotherapy for R/R AML in China. We hope the study will generate favorable clinical data, paving the way for the drug to quickly enter the China market," noted Dr. Jason Yang, CStone’s Chief Medical Officer.

About TIBSOVO (ivosidenib)

In the United States, TIBSOVO is indicated for the treatment of acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in:

Adult patients with newly-diagnosed AML who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.
Adult patients with relapsed or refractory AML.
IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME

Patients treated with TIBSOVO have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, hypoxia, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, hypotension, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome, and creatinine increased. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe.

QTc Interval Prolongation: Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias. One patient developed ventricular fibrillation attributed to TIBSOVO. Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Conduct monitoring of electrocardiograms (ECGs) and electrolytes. In patients with congenital long QTc syndrome, congestive heart failure, or electrolyte abnormalities, or in those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Guillain-Barré Syndrome: Guillain-Barré syndrome occurred in <1% (2/258) of patients treated with TIBSOVO in the clinical study. Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome.

ADVERSE REACTIONS

The most common adverse reactions including laboratory abnormalities (≥20%) were hemoglobin decreased (60%), fatigue (43%), arthralgia (39%), calcium decreased (39%), sodium decreased (39%), leukocytosis (38%), diarrhea (37%), magnesium decreased (36%), edema (34%), nausea (33%), dyspnea (32%), uric acid increased (32%), potassium decreased (32%), alkaline phosphatase increased (30%), mucositis (28%), aspartate aminotransferase increased (27%), phosphatase decreased (25%), electrocardiogram QT prolonged (24%), rash (24%), creatinine increased (24%), cough (23%), decreased appetite (22%), myalgia (21%), constipation (20%), and pyrexia (20%).
In patients with newly diagnosed AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were fatigue (14%), differentiation syndrome (11%), electrocardiogram QT prolonged (11%), diarrhea (7%), nausea (7%), and leukocytosis (7%). Serious adverse reactions (≥5%) were differentiation syndrome (18%), electrocardiogram QT prolonged (7%), and fatigue (7%). There was one case of posterior reversible encephalopathy syndrome (PRES).
In patients with relapsed or refractory AML, the most frequently reported Grade ≥3 adverse reactions (≥5%) were differentiation syndrome (13%), electrocardiogram QT prolonged (10%), dyspnea (9%), leukocytosis (8%), and tumor lysis syndrome (6%). Serious adverse reactions (≥5%) were differentiation syndrome (10%), leukocytosis (10%), and electrocardiogram QT prolonged (7%). There was one case of progressive multifocal leukoencephalopathy (PML).
DRUG INTERACTIONS

Strong or Moderate CYP3A4 Inhibitors: Reduce TIBSOVO dose with strong CYP3A4 inhibitors. Monitor patients for increased risk of QTc interval prolongation.

Strong CYP3A4 Inducers: Avoid concomitant use with TIBSOVO.

Sensitive CYP3A4 Substrates: Avoid concomitant use with TIBSOVO.

QTc Prolonging Drugs: Avoid concomitant use with TIBSOVO. If co-administration is unavoidable, monitor patients for increased risk of QTc interval prolongation.

LACTATION

Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with TIBSOVO and for at least 1 month after the last dose.

Ascentage Pharma to Initiate Phase Ib Study of HQP1351 in Tyrosine Kinase Inhibitors -resistant Chronic Myeloid Leukemia Patients in the US

On July 21, 2019 Ascentage Pharma, a globally-focused, clinical-stage biotechnology company engaged in developing novel therapies for cancers, hepatitis B virus and age-related diseases, reported that the company was notified by the U.S. Food & Drug Administration (FDA) on the clearance of the Investigational New Drug (IND) application which allows the company to initiate its Phase Ib clinical trial of HQP1351, a novel drug candidate developed by Ascentage Pharma, for the treatment of patients with tyrosine kinase inhibitors (TKI)-resistant chronic myeloid leukemia (CML) in the United States (Press release, Ascentage Pharma, JUL 21, 2019, View Source;resistant-chronic-myeloid-leukemia-patients-in-the-us-300888373.html [SID1234537658]).

HQP1351 is the sixth molecule to receive clearance of IND from the FDA for Ascentage Pharma. The Company submitted data generated from over 100 subjects in the Phase I clinical trial in China to the FDA to support the IND application.

This clinical study is a bridging Phase Ib clinical trial with three dose cohorts (30mg, 40mg and 50mg), which is more efficient than the traditional 3+3 dose-escalation study and is expected to accelerate the progress of this clinical trial. It is designed to evaluate the safety, tolerability, and pharmacokinetic (PK) of HQP1351 in CML patients who are resistant or intolerant to at least second-line TKIs and to confirm the recommended Phase II dose (RP2D). This clinical study will be led by Hagop Kantarjian, M.D., Chair of Department of Leukemia at MD Anderson Cancer Center, and other prominent US research centers and hospitals will also participate.

HQP1351 is designed to address the acquired drug resistance from the treatment using Imatinib. Such resistance is developed in 20-30% of patients treated with the drug develop acquired drug resistance, thus representing a major challenge to the treatment of CML. HQP1351 is an oral, third-generation BCR-ABL TKI targeting a broad spectrum of BCR-ABL mutants, including those with the T315I mutation, to treat drug-resistant CML patients. The agent is currently in pivotal Phase II clinical trial and is the first third-generation BCR-ABL inhibitor targeting drug-resistant CML in China. A New Drug Application (NDA) submission is planned upon the successful completion of the pivotal Phase II clinical studies in China.

As previously announced, the updated data from HQP1351 Phase I study in China was accepted as an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting last December. The preliminary data showed that HQP1351 was effective in the treatment of first and second generation TKI-resistant CML, especially the highly resistant CML with T315I mutation, with improved safety profile compared to other agents in the same class. This result demonstrates HQP1351’s best-in-class potential for treating TKI-resistant CML.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, commented: "Ascentage Pharma used the clinical data from its HQP1351 Phase1 clinical trial in China to support the US IND application. This FDA agreed Phase Ib clinical trial design could significantly accelerate HQP1351’s global clinical development program. Drug-resistant CML represents significant unmet clinical need and we hope that HQP1351 will soon benefit patients worldwide."

About HQP1351
HQP1351 is a novel kinase inhibitor developed by Ascentage Pharma. It is an oral third-generation BCR-ABL inhibitor targeting a broad spectrum of BCR-ABL mutants, including those with the T315I mutation, to treat drug-resistant CML patients. A Phase I clinical trial for patients with TKI-resistant CML has been completed and a pivotal Phase II clinical trial was initiated in China. It also entered a Phase I trial in patients with GIST in China.

Personalized gene-edited immune cell therapy for patients with solid cancers: New data establishes approach for verifying patient-specific cancer mutation targets

On July 21, 2019 PACT Pharma, a leader in the fields of cancer immunology and cell therapy in collaboration with a team at UCLA, reported new data demonstrating for the first time the ability to identify mutation targets unique to each person’s cancer and verify the cancer specificity of multiple cloned T cell receptors (Press release, PACT Pharma, JUL 21, 2019, View Source [SID1234537638]). Each patient’s cancer has a private signature of mutations, creating an opportunity to develop fully personalized immune therapies that have the potential to eradicate tumor cells. Defining these cancer mutation targets for each person, known as neoantigens, enables the company to use its proprietary gene engineering technologies to manufacture an immune cell therapy product for each person with cancer. The presentation was at the AACR (Free AACR Whitepaper)’s Special Conference on Immune Cell Therapies for Cancer. The company has begun enrolling patients with advanced solid tumors in its Phase 1 dose escalation study of NeoTCR-P1, an autologous gene-edited TCR T cell product that targets personalized neoantigens (View Source).

"These exciting results open a bold new frontier for directing a person’s own immune system to treat patients with solid cancers, an area that hasn’t yet seen the successes of immune cell therapies that we have seen for blood cancers," said PACT’s Chief Executive Officer Alex Franzusoff, Ph.D. "While it is early, the results demonstrate the possibility for PACT’s approach to ignite a patient’s immune response directly against their unique tumor mutation signature, within a clinically relevant timeframe, with potential applicability to most cancers and all ethnicities across the globe."

Today’s data is relevant because they show that mutations that build up in tumors, creating the unique tumor mutation "signature" that drives each patient’s cancer, have already triggered each person’s immune system to target those unique mutations, but at a very low level. Now those low-level targeted immune responses can be analyzed with greater accuracy, used to manufacture a truly personalized treatment that is tailored for each patient with cancer, and evaluated in clinical trials.

The company’s approach is designed to select and confirm tumor-exclusive mutations to empower a patient’s immune system to target their specific cancer. PACT utilizes bioinformatics to identify the mutation blueprint of each person’s tumor, and then uses its barcoded snare technologies to capture pre-existing T cells from the blood that already recognize and target the unique mutations. From that group, a proprietary selection platform is used to identify the ideal T cell receptors for specific mutations. Once the target is authenticated, the company uses non-viral gene editing to engineer the ideal mutation-targeted T cell receptors into T cells from the same patient. When reinfused back to the patient, these T cells have the potential to eliminate tumor cells that express these unique mutations.

"The results presented today show that PACT’s approach of neoantigen-specific T cell capture and non-viral precision genome engineering is indeed groundbreaking and promising for a new chapter in personalized immune cell therapies for patients with solid cancers," said Antoni Ribas, a professor of medicine at the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who is a co-author of the study and also a co-founder of PACT. "The demonstration that T cell receptor-engineered T cells using the PACT approach can specifically kill that same person’s cancer cells is based on the analysis of immune cells captured from the blood of a patient with a long-lasting response to anti-PD-1 therapy."

The evolution of personalized immune-oncology treatments
Recently, a new generation of personalized cellular therapies for cancer has emerged. Rapid sequencing technologies, bioinformatics, and genetic/cellular engineering — in addition to a deeper understanding of clinical immunology and a renaissance in immunotherapy — have made these advancements possible. Designer immune-oncology treatments have been developed, including CAR-T cell therapies, cancer vaccines and tumor-infiltrating lymphocyte therapies.

While transformative, these therapeutic approaches face limitations. CAR-T cells only recognize shared cancer targets expressed on the cell surface, which, while effective for blood cancers, have not been applied successfully to patients with solid cancers, and cancer vaccines are often too slow to address a rapidly growing tumor burden. Further, tumor-infiltrating lymphocytes can be impractical—and at times even impossible—to generate for every patient due to the difficulty of isolating limited numbers of specific tumor-targeting immune cells and then needing to greatly expand their numbers for patient dosing. In the case of expanded immune cells in particular, they often become exhausted before reinfusion, which may limit their value for eliminating the cancer throughout the body.

In order to truly tailor cancer treatments to individuals, the therapy must target each patient’s unique cancer signature–including different tissue compatibility receptors of the immune system, or HLA, in each person. These HLA receptors are key to immune recognition, which is what limits organ sharing between people. PACT’s approach captures this nuance. Custom tailored, yet for a global population, PACT’s approach is designed to select and authenticate tumor-exclusive mutations to empower the patient’s immune system to target their specific cancer for a lasting effect. PACT plans to further investigate the safety and effectiveness of this technology in a series of clinical trials, starting with a first-in-human Phase 1 clinical trial at clinical sites in California.