Yeliva: a selective inhibitor of sphingosine kinase-2.

Biotechnology Clinical Study: An Early-Phase Clinical Trial Evaluating ABC294640 in Patients With Refractory/Relapsed Diffuse Large B-cell Lymphoma

Dr. Ananda Kumar Kondepati, M.D. andDr. Shalini D. Pasumarthi, M.D.

Canada, 2015

Clinical Research Program Supervisor:Pr. Peivand Pirouzi, Ph.D., M.B.A., C.C.P.E.

Product Details

Company -- Apogee Biotechnology Corp.Description -- Small molecule inhibitor of sphingosine kinase 2 (SPHK2)Molecular Target -- Sphingosine kinase 2 (SPHK2)Mechanism of Action -- Sphingosine kinase inhibitorTherapeutic Modality -- Small molecule

Pharmacology and antitumor activity of ABC294640(yeliva)

Sphingolipid-metabolizing enzymes control the dynamic balance of the cellular levels of important bioactive lipids, including the apoptotic compound ceramide and the proliferative compound sphingosine 1-phosphate (S1P). Many growth factors and inflammatory cytokines promote the cleavage of sphingomyelin and ceramide leading to rapid elevation of S1P levels through the action of sphingosine kinases (SK1 and SK2).

Pharmacology and antitumor activity of ABC294640

SK1 and SK2 are overexpressed in a variety of human cancers, making these enzymes potential molecular targets for cancer therapy.We have identified an aryladamantane compound, termed ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], that selectively inhibits SK2 activity in vitro, acting as a competitive inhibitor with respect to sphingosine and attenuates S1P formation in intact cells.

Pharmacology and antitumor activity of ABC294640

In tissue culture, ABC294640 suppresses the proliferation of a broad panel of tumor cell lines, and inhibits tumor cell migration concomitant with loss of microfilaments. In vivo, ABC294640 has excellent oral bioavailability. Acute and chronic toxicology studies indicate that ABC294640 induces a transient minor decrease in the hematocrit however, this normalizes by 28 days of treatment.

Pharmacology and antitumor activity of ABC294640

No other changes in hematology parameters, or gross or microscopic tissue pathology, result from treatment with ABC294640. Oral administration of ABC294640 bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases.

Besides that, ABC294640 is also found to have greater anti-proliferation effects in ER(estrogen receptor)-positive than ER-negative breast cancer cells. The effect of E2 signaling caused by ABC294640 is expected to be a therapeutic in endocrine-related diseases [1, 2].

Chemical Properties of ABC294640

Chemical Name (7S)-3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide

Canonical SMILES C1C2CC3(CC1CC(C2)(C3)C(=O)NCC4=CC=NC=C4)C5=CC=C(C=C5)Cl

Formula C23H25ClN2O M.Wt 380.91

Solubility Soluble in DMSO Storage Store at -20°C

General tips For obtaining a higher solubility , please warm the tube at 37 and shake it in the ultrasonic ℃bath for a while.Stock solution can be stored below -20 for several months. ℃

Shipping Condition Evaluation sample solution : ship with blue iceAll other available size: ship with RT , or blue ice upon request

Chemical structure of ABC294640

Because of its targeting of the sphingosine binding site of SK2, ABC294640 shows no inhibition activity against other 20 kinases.

Apogee completed enrollment on the initial safety trial for ABC294640 in advanced solid tumor cancer patients. Results showed that the ABC294640 safety profile correlated well to that observed in preclinical toxicology studies and that ABC294640 had an excellent pharmacokinetic profile that modulated the pharmacodynamic marker of circulating spingosine-1-phosphate as expected.

The results from this trial support additional clinical trials in cancer focused more on efficacy of this promising drug. Information regarding this trial can be found at https://clinicaltrials.gov/ct2/show/NCT01488513?term=abc294640&rank=1 .

Description of ABC294640:

ABC294640 is an orally available, aryladamantane compound and selective inhibitor of sphingosine kinase-2 (SK2) with potential antineoplastic activity. Upon administration, ABC294640 competitively binds to and inhibits SK2, thereby preventing the phosphorylation of the pro-apoptotic amino alcohol sphingosine to sphingosine 1-phosphate (S1P), the lipid mediator that is pro-survival and critical for immunomodulation.

This may eventually lead to the induction of apoptosis and may result in an inhibition of cell proliferation in cancer cells overexpressing SK2. SK2 and its isoenzyme SK1 are overexpressed in numerous cancer cell types

YELIVA™ (ABC294640) is a first-in-class, proprietary sphingosine kinase-2 (SK2) selective inhibitor, administered orally, with anti-cancer and anti-inflammatory activities, targeting a number of potential inflammatory, oncology and gastrointestinal indications.YELIVA™ (ABC294640) inhibits SK2, a lipid kinase that catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P).

S1P promotes cancer growth, and proliferation and pathological inflammation, including TNFα signaling and other inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, YELIVA™ (ABC294640) blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells..

Sphingosine 1 Phosphate

Sphingosine-1-phosphate signaling

Preliminary evidence suggests that because of its specificity for targeting SK2, rather than SK1, YELIVA™ (ABC294640) may have a better therapeutic ratio than nonspecific sphingosine kinase inhibitors or those targeting only SK1.

Red Hill Biopharma Ltd. (Tel Aviv ,Israel) acquired the rights to Yeliva in March 2015 from US based Apogee Biotech corp. Apogee previously completed numerous successful pre-clinical studies with YELIVA™ (ABC294640) in GI-inflammation, radioprotection and oncology models, as well as a successful Phase I clinical study in cancer patients with advanced solid tumors. The open-label, dose-escalation Phase I clinical study demonstrated the drug’s safety and assessed its pharmacokinetics and pharmacodynamics in cancer patients with advanced solid tumors.A Phase I/II clinical study evaluating YELIVA™ (ABC294640) in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) was initiated in June 2015 in the U.S.

The Phase I/II study is intended to evaluate the safety and tolerability of YELIVA™ (ABC294640), as well as provide a preliminary evaluation of efficacy of the drug in patients with refractory/relapsed DLBCL, primarily patients with HIV-related DLBCL. Up to 33 patients are expected to be enrolled in the study, which will be conducted at the Louisiana State University Health Sciences Center (LSUHSC) in New Orleans.

The study is funded primarily by a grant awarded by the National Cancer Institute (NCI) Small Business Technology Transfer (STTR) program. Dr. Chris Parsons, MD, an associate professor in the Departments of Medicine and Microbiology, Immunology & Parasitology at LSUHSC, is the lead investigator for the study.

The National Cancer Institute (NCI) $2 million grant is intended to support the Phase II study with YELIVA™ (ABC294640) for refractory or relapsed multiple myeloma, planned to be initiated by RedHill at Duke University Medical Center by the end of 2015YELIVA™ (ABC294640) is a proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications.

A Phase I/II study with YELIVA™ (ABC294640), also supported by a grant from the NCI, was recently initiated in the U.S. in patients with refractory/relapsed diffuse large B-cell lymphoma (DLBCL) Sponsor:RedHill Biopharma Limited Collaborators:Louisiana State University Health Sciences Center in New OrleansApogee Biotechnology CorporationInformation provided by (Responsible Party):RedHill Biopharma Limited

An Early-Phase Clinical Trial Evaluating ABC294640 in Patients With Refractory/Relapsed Diffuse Large B-cell Lymphoma

Sponsor: RedHill Biopharma Limited Collaborators: Louisiana State University Health Sciences Center in New Orleans

Apogee Biotechnology CorporationInformation provided by (Responsible Party):

RedHill Biopharma Limited

ClinicalTrials.gov Identifier: NCT02229981First received: August 28, 2014Last updated: July 19, 2015Last verified: July 2015

Purpose:

The investigators are conducting sequential Phase 1 and IIa trials to identify the maximum tolerated dose and to evaluate safety, tolerability, toxicity, pharmacokinetics and pharmacodynamics of the oral anti-cancer agent ABC294640 specifically in patients with diffuse large B-cell lymphoma, including patients with virus-induced (e.g., KSHV- or EBV-associated) lymphoma.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Inclusion Criteria:

Pathologically confirmed DLBCL which is radiographically refractory to standard therapy, or which has relapsed following standard therapy (one or more tumors measurable on PET-CT scan; see caveats for antineoplastic therapies in Exclusion criteria below)Tumor progression after receiving standard/approved chemotherapy, or lack of candidacy for standard therapyOne or more tumors measurable on MRI and PET scan

Inclusion criteria

Life expectancy of at least 3 monthsAge greater than or equal to 18 yearsSigned, written IRB-approved informed consentA negative pregnancy test (if female)Acceptable liver function:Bilirubin ≤ 3 times upper limit of normal (CTCAE Grade 2 baseline)AST (SGOT), ALT (SGPT) ≤3 x ULN (CTCAE Grade 1 baseline)

Inclusion CriteriaSerum creatinine ≤ 1.5 X ULN (CTCAE Grade 1 baseline)Acceptable hematologic status:Absolute neutrophil count ≥ 1000 cells/mm3Platelet ≥75,000 (plt/mm3) (CTCAE Grade 1 baseline)Hemoglobin ≥ 8 g/dLUrinalysis: No clinically significant abnormalities.PT and PTT ≤ 1.5 X ULN after correction of nutritional deficiencies that may contribute to prolonged PT/PTT.

Exclusion Criteria:New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree to use barrier methods (preferably condoms) or other methods of birth control at your doctor's discretion, or abstain from sexual activity, prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Exclusion CriteriaPatients with active, life-threatening bacterial or fungal infectionsTreatment with radiation therapy, surgery, chemotherapy, or investigational therapy within one month prior to study entryUnwillingness or inability to comply with procedures required in this protocol.Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor

Exclusion CriteriaPatients who are currently receiving any other investigational agentPatients who are currently taking coumadin or coumadin derivatives.Patients who have received any antineoplastic therapy within 1 month of starting treatment with ABC294640 or who have not adequately recovered from side effects and toxicities of previous antineoplastic therapyPatients who are currently participating in any other clinical trial of an investigational productAllergy to radiographic contrast.

A third Phase II study is planned to evaluate YELIVA™ (ABC294640) as a radioprotectant in cancer patients undergoing therapeutic radiotherapy.

Top-line results from the Phase I study with YELIVA™ (ABC294640) for the treatment of advanced solid tumors are expected early in the fourth quarter of 2015, and a full analysis and final Clinical Study Report (CSR) are expected by the end of this year or early 2016

References:www.ncbi.nlm.nih.gov/pubmed/20061445https://clinicaltrials.gov/ct2/show/NCT01488513www.apexbt.com/abc294640.htmlwww.apogee-biotech.com/.../apogee-successfully-completes-enrollment-in-the...YELIVA™ (ABC294640) Phase I/II study on ClinicalTrials.gov www.redhillbio.com/abc294640www.redhillbio.com/RedHill/Templates/showpage.asp?..