Table 3.
Completed multicenter randomized double-blind placebo-controlled trials to prevent or treat sickle painful crises that failed, discontinued or terminated.
| Compound | Company | Mechanism of Action | Indication | Stage of Development | Reference |
|---|---|---|---|---|---|
| Acetylsalicylic acid | Takeda | Benzoic acid, 2-(acetyloxy)- | General pain and thrombosis, SCD | Phase I and II study for SCD completed | [1] |
| AES-103 | AesRx | Anti-sickling agent | Anemia; SCD | Phase I study for SCD completed. Phase II study for SCD terminated by the Sponsor due to unbinding between study drug and placebo groups at the subject, site and Sponsor levels | [2,3] |
| Dipyridamole | Boehringer Ingelheim Pharmaceuticals, Inc | RBC hydration | Thrombosis; SCD | Phase II study withdrawn | [4] |
| Eptifibatide | Millennium and Schering Plough | Antiplatelet agent Use as therapeutic agent for VOC | Acute myocardial infarction, unstable angina, abrupt closure following coronary angioplasty, stroke and other diseases associated with arterial thrombosis; treat VOC | Phase II for SCD terminated due to slow accrual and no cost extension not approved by NHLBI | [5] |
| HQK 1001 | HemaQuest | γ globin gene promoter | SCA and β-Thalassemia | Phase II for SCD terminated | [6] |
| Inhaled Nitric Oxide (NO) | Ikaria | Vasodilator | Therapeutic for VOC | Phase III for SCD; Failure | [7] |
| L-citrulline | Asklepion | Vasodilator | Pediatric pulmonary hypertension, post-cardiopulmonary bypass surgery; SCD | Ceased; Phase I for SCD | [8] |
| Magnesium Sulfate (MgSO4) | Numerous companies produce magnesium as magnesium oxide, magnesium citrate, magnesium sulfate, magnesium gluconate and magnesium pidolate | RBC hydration Therapeutic agent | Vitamin supplement; Treat VOC | Phase II and III for SCD; Failure | [9] |
| MP4CO | Sangart | Prevents microvascular stasis; Therapeutic agent | Anemia; Treat SCD | Discontinued; Phase I completed. Phase II withdrawn prior to enrollment for SCD | [10,11] |
| Nonionic polyoxyethylene-polyoxypropylene; Poloxamer 188 (Flocor) | CytRx | Oxirane, methyl-, polymer with oxirane, block, Therapeutic agent | Surfactant | Treat VOCs and ACS in SCD and acute myocardial infarction | [12–13] |
| Omega-3-acid ethyl esters | Glaxo Smith Kline | Anti-inflammatory agent | Improves several cardiovascular risk factors: lowers serum triglyceride concentration, lowers blood pressure, reduces resting heart rate, improves endothelial dysfunction; SCD | Phase II for SCD terminated due to manufacturing problem with study drug | [15,16] |
| Prasugrel (DOVE Trial) | Eli Lilly | Inhibition of platelet activation and aggregation | Prevention of VOC | Failure | [17] |
| Senicapoc | Pfizer | Gardos channel blocker, Preventive agent | Prevention of VOC | Phase II completed for SCD; Drug increased red cell survival and hematocrit and blood viscosity; Phase III trial failed | [18,19] |
| Sildenafil | Preventive agent | Prevention of VOC | Failure | [20, 21] | |
| Sodium nitrite | Hope | Used to treat cyanide poisoning, Therapeutic agent for leg ulcers | Vasodilator; treat SCD leg ulcers | Phase I and II study for SCD terminated due to low enrollment | [22] |
| TRF-1101 | TRF Pharma | Anti-sickling agent | SCD | Phase I study completed and successfully demonstrated improved microvascular blood flow in patients with SCD and revealed no drug-related side effects. Phase II study terminated due to perceived futility because the baseline pain score in first 40 patients was too low to be able demonstrate improvement. | [23] |
| Varespladib sodium | Shionogi | Inhibitor of secretory phospholipases A2 (sPLA2) | Therapy for acute chest syndrome in SCA | Discontinued; no current studies being conducted in relation to SCD | [24] |
| Vepoloxamer 18 (EPIC) | Mast Therapeutics | Similar to Poloxamer 188 | Therapeutic for VOC | Failure | [25] |
| Vorintostat | Merck & Co. | Hb F induction | Cutaneous T-cell lymphoma; SCD | Phase II terminated due to slow accrual | [26] |
| Sevuparin | Modus therapeutics | Polysaccharide- based drug that is designed to retain the anti- adhesive properties of heparin. Therapeutic agent | Treatment of VOCs | Underwent Phase I and II Trials. Failed to Show Clinically Meaningful Improvements in Managing VOCs, | [27] |
| Rivipansel sodium; GMI-1070 | GlycoMimetics | 1,3,6-Naphthalenetrisulfonic acid, 8-[[13-[(1R,3R,4R,5S)-3-[[2-O-benzoyl-3-O-[(1S)-1-carboxy-2-cyclohexylethyl]-β-D-galactopyranosyl]oxy]-4-[(6-deoxya-L-galactopyranosyl)oxy]-5-[[(1,2,3,6-tetrahydro-2,6-dioxo-4 pyrimidinyl) carbonyl] amino] cyclohexyl]- | Inflammation and VOCs in SCD. Therapeutic agent | Phase III to treat VOC failed | [28,29] |
| Sanguinate | Prolong Pharmaceutical | Sanguinate is PEGylated Bovine Carboxyhemoglobin | Designed to prevent clumping of RBC and maintain blood flow. Therapeutic agent | Phase II trial to treat VOC failed | [30] |
NHLBI: National Heart, Lung, and Blood Institute; RBC = Red blood cell; SCA = Sickle cell anemia; SCD = Sickle cell disease; VOC: Vaso-occlusive crisis.