N-acetylmannosamine (ManNAc), a hexosamine monosaccharide, is the first committed biological precursor of Neu5Ac. N-acetylmannosamine is being investigated as a potential treatment for GNE myopathy. N-acetylmannosamine has being reported to improve the cognitive function in aged animals. It has potential therapeutic application for cognitive dysfunction. N-acetylmannosamine is under investigation for GNE myopathy.

Somatoprim (DG3173) is a heptapeptide somatostatin analog (SSA) that binds with high affinity to sstr2, sstr4 and sstr5 and shows a very low insulin suppression in contrast to other SSA. Initially developed by Ipsen, it is under active development by licensee Aspireo Pharmaceuticals, an Israeli company. In vitro as well as in vivo testing showed a dose-dependent GH lowering effect. Somatoprim has demonstrated a unique receptor binding and pharmacological profile which is differentiated from SSAs that are currently marketed or in clinical development. In particular, Somatoprim has shown an improved side effect profile with reduced adverse effects on the gastrointestinal tract and glucose metabolism. Furthermore, assessment of growth hormone secretion in cultured human somatotroph adenoma tissue treated with Somatoprim indicates that it has the potential to increase the response rate of acromegalic patients to SSA therapy. Somatoprim is currently in phase I/II of clinical development.

DS-3032 (Milademetan) is an orally available, potent and selective inhibitor of the p53-MDM2 (murine double minute 2) interaction. Milademetan binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. Milademetan is 10-fold more potent than the first-generation inhibitor nutlin-3a. By preventing this MDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis. DS-3032 is currently being evaluated in three phase 1 clinical trials for solid and hematological malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma and myelodysplastic syndrome (MDS).

PBT-1033, also known as PBT-2, is a neural protective agent potentially for the treatment of Alzheimer's disease and Huntington's Disease. PBT-1033 is a moderate-affinity 8-hydroxyquinoline transition metal-ligand that acts as a synthetic chaperone, re distributing copper, zinc, and iron from locations where they are abundant to subcellular locations where they might be deficient. Delivery of copper and zinc by PBT-1033 into the cytoplasm deactivates the kinase glycogen synthase kinase 3β and the phosphatase calcineurin, both potential targets for Huntington’s disease. In aged wild-type mice, PBT-1033 improves cognitive ability and markers of neuronal plasticity and function. In Alzheimer’s disease mouse models, PBT-1033 inhibits the accumulation of amyloid β, attenuates neuropathological effects of amyloid β, including amyloid-β-induced hyperphosphorylation of tau, and improves cognition. In a 12-week, phase 2a, randomized, double-blind, placebo-controlled trial in 78 individuals with mild Alzheimer’s dementia, PBT-1033 was safe and well tolerated and significantly reduced concentrations of amyloid β42 in CSF.

Sephin1 is a guanabenz derivative that binds to and inhibits a regulatory subunit of the stress-induced protein phosphatase 1 (PPP1R15A), but not the constitutive PPP1R15B, and lacks beta2-adrenergic activity. Phosphorylation of eIF2α, α subunit of eukaryotic translation initiation factor 2, reduces protein synthesis and prevents the accumulation of misfolded protein in the endoplasmic reticulum (ER). PPP1R15A recruits the serine/threonine-protein phosphatase PP1 to dephosphorylate eIF2α, so inhibiting PPP1R15A activity prolongs the phosphorylation of eIF2α and aids in its prevention of the accumulation of misfolded protein. In vitro, Sephin1 protected cells from lethal protein misfolding and cytotoxic ER stress. In vivo Sephin1 prevented Charcot-Marie-Tooth 1B and ALS diseases in mice.

ABTL 0812 is a autophagy inducer that acts via PI3K/Akt/mTOR pathway and has a dual mechanism of action. ABTL-0812 is a first-in-class small molecule, orally administered that binds to the nuclear receptors PPARα/γ inducing TRIB3 overexpression which blocks Akt activation, the central kinase of the PI3K/Akt/mTOR pathway, and inducing PPAR-dependent Endoplasmic Reticular Stress (ER-stress). The combination of TRIB3-mediated inhibition of the PI3K/Akt/mTOR pathway and the ER-Stress induction results in an autophagy-mediated cancer cell death. In animal cancer models ABTL0812 is efficacious as single agent with an excellent safety profile in a broad spectrum of cancer types: lung, endometrial and pancreatic cancer and neuroblastoma. ABTL0812 is also active on cells resistant to other targeted therapies, on tumor stem cells and inhibits metastasis formation. Preliminary results show promising immunomodulatory effects. ABTL0812 is currently in phase 2 clinical trials in Europe in patients with endometrial cancer or squamous cell lung cancer, as a first-line treatment in combination with chemotherapy and as a maintenance treatment after the chemotherapy cycles. The study is being conducted in leading cancer hospitals in Spain and France. This same phase 2 study was also approved by the US FDA in December 2017. In addition, the FDA approved the protocol for a phase 2 study in pancreatic cancer in January 2018. ABTL-0812 has also received Orphan Drug Designations (ODD) for pancreatic cancer, biliary cancer and the pediatric cancer neuroblastoma by the FDA in the USA and by the EMA in Europe.