Recent Progress in the Development of Opaganib for the Treatment of Covid-19

Figures & data

Figure 1 Multitargeting of sphingolipid metabolism by opaganib. Opaganib (aka ABC294640; Yeliva^®; 3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)-1-adamantanecarboxamide, hydrochloride salt) inhibits SK2 decreasing S1P synthesis, DES1 elevating dihydroceramides, and GCS reducing hexosylceramides.

Table 1 Clinical Studies of Opaganib

Study Code and Title	Country	Subjects Treated with Opaganib	Primary Objective
ABC-101: A Phase I, Open-Label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of ABC294640 in Patients with Advanced Solid Tumors [NCT01488513]^Citation32	USA	21	To assess safety and determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of opaganib in patients with solid organ tumors.
ABC-103: A Phase Ib/II Safety and Efficacy Study of ABC294640 in Patients with Refractory or Relapsed Multiple Myeloma Who Have Previously Been Treated with Proteasome Inhibitors and Immunomodulatory Drugs [NCT02757326]	USA	13	Assess overall treatment response rate and overall survival in patients with relapsed or refractory multiple myeloma treated with single-agent opaganib.
ABC-107: A Phase II Study of the Addition of Opaganib to Androgen Antagonists in Patients with Prostate Cancer Progression on Enzalutamide or Abiraterone [NCT04207255]	USA	61	To measure the proportion of patients with disease control during opaganib (plus abiraterone or enzalutamide) therapy, using a composite metric based on PSA, bone scan, and RECIST measurements per Prostate Cancer Working Group 3 (PCWG3) criteria. For purposes of this study, disease control is defined as stable disease or better after four cycles (16 weeks) of treatment.
ABC-108: A Phase I/IIA Study of ABC294640 Alone and in Combination with Hydroxychloroquine Sulfate in the Treatment of Patients with Advanced, Unresectable Intra-hepatic, Perihilar and Extra-Hepatic Cholangiocarcinoma [NCT03377179]	USA	65	Part 1: determine the Response Rate (RR) of cholangiocarcinoma defined as objective responses, ie complete and partial responses plus stable disease (SD) of at least 4 months to treatment with opaganib. Part 2: determine Durable Disease Control Rate (DCCR) of cholangiocarcinoma, defined as a DCR of at least a period of ≥4 4 months of treatment with opaganib and HCQ.
ABC-109: A Phase 1, Single-Dose, Open-Label, Randomized, Three-Period Crossover Study to Evaluate the Effect of Food and Nasogastric Administration on the Pharmacokinetics of ABC294640 in Healthy Subjects [RedHill Biopharma unpublished data]	USA	23 healthy subjects	Assessment of the effect of a standardized meal on the absorption and bioavailability of opaganib.
ABC-110: Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, Placebo-Controlled Phase 2a Study, in Adult Subjects Hospitalized With SARS-CoV-2 Positive Pneumonia [NCT04414618]^Citation39	USA	22	Phase 2a Proof of concept study. To assess the safety and tolerability of opaganib administered orally at 500 mg Q 12 hours, for up to 14 days, in patients with COVID-19 pneumonia and to assess to evaluate the total oxygen requirement (area under the curve) using daily supplemental oxygen flow (L/min) over 14 days (Day 1 to Day 14) as primary efficacy.
ABC-201: Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, Placebo-Controlled Phase 2/3 Study, in Adult Subjects Hospitalized With Severe SARS-CoV-2 Positive Pneumonia [NCT04467840]^Citation40	Italy, Poland, Russia, Brazil, Mexico, Israel, Colombia	230	A phase 2/3 multi-center randomized, double-blind, parallel arm, placebo- controlled study in Adult Subjects Hospitalized with Severe SARS-CoV-2 Positive Pneumonia to determine the potential of opaganib to improve and/or stabilize the clinical status of the patient.

Table 2 Nonclinical Studies of Opaganib Relating to Covid-19

Pathology	Model	Key Findings		Reference
Inflammation (in vivo studies only)
Ulcerative colitis	Dextran sulfate sodium		Opaganib reduced colon damage and markers of inflammation including neutrophil infiltration and cytokine induction	[^Citation29]
Crohn’s Disease	Trinitrobenzene sulfonic acid		Opaganib reduced colon damage and markers of inflammation including neutrophil infiltration and cytokine induction	[^Citation30]
Colitis-driven colon cancer	Azoxymethane + dextran sulfate sodium		Opaganib decreased the incidence and multiplicity of colon tumors	[^Citation24]
Vascular permeability	Intradermal VEGF or Streptozotocin		Opaganib reduced vascular leakage in skin and retinas	[^Citation31]
Rheumatoid arthritis	Subcutaneous collagen or Intradermal adjuvant		Opaganib reduced disease severity and degradation of bone and cartilage	[^Citation28]
Osteoarthritis	Monosodium iodoacetate		Opaganib attenuated knee joint histological damage and pain	[^Citation27]
Liver transplantation failure	Cold storage of donor liver		Opaganib in organ storage solution improved survival following surgery and decreased damage and markers of inflammation in the transplanted liver	[^Citation94]
Hepatic ischemia-reperfusion injury	Liver ischemia-reperfusion surgery		Opaganib reduced hepatic necrosis and markers of inflammation including iNOS, TNFα and neutrophil infiltration, resulting in protection against death	[^Citation96]
Bacterial pneumonia	Pseudomonas aeruginosa		Opaganib reduced lung damage and markers of inflammation including cell infiltration and cytokine induction	[^Citation118]
Lupus nephritis	MRL/lpr transgenic mice		Opaganib attenuated glomerular pathology but not vascular or interstitial pathology	[^Citation127]
Psoriasis	Imiquimod		Opaganib reduced psoriatic markers including erythema, scaling and epidermal thickness, as well as the sizes of the inguinal lymph nodes and spleen	[^Citation128]
Renal fibrosis	Unilateral ureteral obstruction		Opaganib reduced renal fibrosis	^Citation62 and RedHill Biopharma unpublished data
Acute Kidney Injury	Ischemia-reperfusion or lipopolysaccharide injection		Opaganib reduced kidney damage and inflammation in both models	Apogee Biotechnology manuscript submitted
Atherosclerosis	ApoE knockout mice		Opaganib reduced the number of aortic plaques and increased survival duration	Apogee Biotechnology unpublished data
Gastrointestinal acute radiation syndrome	Ionizing radiation		Opaganib reduced colon damage and improved survival following exposure to X-rays	Apogee Biotechnology unpublished data
Pulmonary fibrosis	Ionizing radiation		Opaganib reduced lung fibrosis and increased survival duration following exposure to X-rays	Apogee Biotechnology unpublished data
Viral (in vivo and in vitro studies)
Kaposi Sarcoma Herpes Virus associated lymphoma	Primary effusion lymphoma (PEL) cells/xenografts	Opaganib induced tumor regression and promoted viral lytic gene expression in PEL cells		[^Citation13,Citation34,Citation35]
Arthralgic febrile illness	Chikungunya virus (CHIKV) in cells and mice	Opaganib inhibited CHIKV replication in HepG2 cells		[^Citation36]
Influenza	Influenza A virus (IAV) in cells and mice	Opaganib improved viability of mice following IAV infection and attenuated viral replication in vitro		[^Citation37]
Covid-19	SARS-CoV-2 in EpiAirway model	Opaganib inhibited the replication of multiple SARS-CoV-2 variants (alpha (Washington), beta (South African), gamma (Brazilian), delta (Indian) and omicron)		RedHill Biopharma unpublished data

Figure 2 Model for the therapeutic activity of opaganib against Covid-19. Sphingolipids regulate the ability of SARS-CoV-2 to replicate and thereby cause Covid-19. Firstly, pro-autophagic dihydroceramide levels are normally maintained at low levels by DES1. Inhibition of DES1 by opaganib elevates dihydroceramides and promotes autophagy which suppresses viral replication. Secondly, hexosylceramides are necessary for the endocytosis of virus bound to ACE2. Inhibition of GCS by opaganib reduces hexosylceramides thereby impairing the ability of the virus to enter target cells. Thirdly, SK2 regulates several signaling pathways, as well as the viral replication complex, that are required for viral replication. Inhibition of SK2 by opaganib therefore has multifaceted suppressive effects on viral infection and replication. Furthermore, opaganib suppression of inflammation and thrombosis mediated by SK2 may protect against multi-organ dysfunction in Covid-19 patients.

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