Tafamidis meglumine (Vyndaqel®, Pfizer) is a novel, first-in-class drug for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP), a rare neurodegenerative disorder characterized by progressive sensory, motor and autonomic impairment that is ultimately fatal. Pathogenic mutations in the transthyretin (TTR) protein lead to destabilization of its tetrameric structure and subsequent formation of amyloid aggregates. Tafamidis is a small-molecule inhibitor that binds selectively to TTR in human plasma and kinetically stabilizes the tetrameric structure of both wild-type TTR and a number of different mutants. Clinical trials indicate that tafamidis slows disease progression in patients with TTR-FAP and reduces the burden of disease, demonstrating improvement in small and large nerve fiber function, modified body mass index and lower extremity neurological examination. Tafamidis meglumine has been launched for TTR FAP in the EU, Japan, Argentina, Malta and Mexico, and is preregistration in the US for this indication.

ODM-201 (also known as BAY-1841788) is a non-steroidal antiandrogen, specifically, a full and high-affinity antagonist of the androgen receptor (AR), that is under development by Orion and Bayer HealthCare for the treatment of advanced, castration-resistant prostate cancer (CRPC). ODM-201 appears to negligibly cross the blood-brain-barrier. This is beneficial due to the reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition that tends to occur in non-steroidal antiandrogens that are structurally similar to enzalutamide. Moreover, in accordance with its lack of central penetration, ODM-201 does not seem to increase testosterone levels in mice or humans, unlike other non-steroidal antiandrogens. Another advantage is that ODM-201 has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently-identified clinically-relevant F876L mutation. ODM-201 has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated, with the most commonly reported side effects including fatigue, nausea, and diarrhea. No seizures have been observed.

Lumateperone (ITI-722/ITI-007) is a dual 5HT2A receptor antagonist/dopamine phosphoprotein modulator (DPPM) for the treatment of schizophrenia. It is an orally available compound which combines potent 5HT2A receptor antagonism with cell-type-specific modulation of phosphoprotein pathways downstream of dopamine receptors. Lumateperone was developed by Intra-Cellular Therapies, Inc., and is being evaluated for the treatment of schizophrenia and bipolar depression. In 3 efficacy studies in patients with acute schizophrenia, lumateperone was well-tolerated with a favorable safety profile, and in 2 studies of 3 demonstrated significantly superior efficacy over placebo.

Entrectinib (previously known as RXDX-101, NMS-E628) is an investigational drug, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Entrectinib (RXDX-101) is a selective inhibitor for all three Trk receptor tyrosine kinases encoded by the three NTRK genes, as well as the ROS1 and ALKreceptor tyrosine kinases.This investigational drug is active at low nanomolar concentrations, allowing for once-daily oral administration to patients whose tumors have been shown to have gene rearrangements in NTRK, ROS1, or ALK. Nerviano Medical Sciences, the original sponsor for entrectinib (formerly referred to as NMS-1191372), initiated the first-in-human Phase 1 study ALKA-372-001 in Italy in October 2012. The study is currently ongoing in Italy. Entrectinib is currently being tested in a global phase 2 basket clinical trial called STARTRK-2. In the U.S., entrectinib has orphan drug designation and rare pediatric disease designation for the treatment of neuroblastoma and orphan drug designation for treatment of TrkA-, TrkB-, TrkC-, ROS1- and ALK-positive non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC).

Cenobamate (also known as YKP3089) is a small molecule sodium channel blocker in development for the treatment of partial-onset seizures in adult patients. In mice and rats, Cenobamate displayed an anticonvulsant activity in the maximal electroshock test and prevented seizures induced by chemical convulsants such as pentylenetetrazol and picrotoxin. In addition, Cenobamate was reported to be effective in two models of focal seizure, the hippocampal kindled rat and the mouse 6 Hz psychomotor seizure models. Two completed adequate and well-controlled clinical studies demonstrated a significant reduction in focal seizures with Cenobamate in patients with epilepsy, and a long-term open-label phase 3 safety clinical trial is currently ongoing. Cenobamate is considered a new generation antiepileptic therapy and clinical trials have shown that it may be more effective and safer than existing drugs. If licensed, Cenobamate will offer a new adjunctive treatment option for patients with partial focal epilepsy.

Pexidartinib (PLX3397) is a small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Pexidartinib binds to and inhibits phosphorylation of stem cell factor receptor (KIT), colony-stimulating factor-1 receptor (CSF1R) and FMS-like tyrosine kinase 3 (FLT3), which may result in the inhibition of tumor cell proliferation and down-modulation of macrophages, osteoclasts and mast cells involved in the osteolytic metastatic disease. FDA has granted Breakthrough Therapy Designation to pexidartinib (PLX3397) for the treatment of tenosynovial giant cell tumor (TGCT) where surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. In addition to Breakthrough Therapy Designation, pexidartinib (PLX3397) has been granted Orphan Drug Designation by FDA for the treatment of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCT-TS). It also has received Orphan Designation from the European Commission for the treatment of TGCT.

Cannabidiol is the major nonpsychoactive ingredient in cannabis. Cannabidiol demonstrates a range of effects that may be therapeutically useful, including anti-seizure, antioxidant, neuroprotective, anti-inflammatory, analgesic, anti-tumor, anti-psychotic, and anti-anxiety properties. Exact mechanism of action of cannabidiol is not known, but may include effects on the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 glycine receptors. GW Pharmaceuticals successfully developed the world’s first prescription medicine derived from the cannabis plant, Sativex® (buccal spray containing delta-9-tetrahydrocannabinol and cannabidiol) now approved in over 29 countries outside of the United States for the treatment of spasticity due to Multiple Sclerosis. GW Pharmaceuticals is developing Epidiolex® (a liquid formulation of pure plant-derived cannabidiol) for certain rare and severe early-onset, drug-resistant epilepsy syndromes.

Binimetinib (MEK162) is an oral small-molecule with potential antineoplastic activity. It is a selective mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, a key protein kinase in the RAS/RAF/MEK/ERK pathway, which regulates several key cellular activities including proliferation, differentiation, migration, survival and angiogenesis. Inappropriate activation of this pathway has been shown to occur in many cancers, in particular through mutations in BRAF, KRAS and NRAS. MEK162 at 6 mg/kg, BID combined with BEZ235 (dual PI3K/mTOR inhibitor) resulted in a significant reduction of tumor growth in immunodeficient mice injected with MCF7 cells. There are three ongoing Phase 3 trials with binimetinib in advanced cancer patients: NEMO (NRAS-mutant melanoma), COLUMBUS (encorafenib in combination with binimetinib in BRAF-mutant melanoma) and BEACON CRC (encorafenib, binimetinib and cetuximab in BRAF-mutant colorectal cancer).

Lorlatinib is an investigational medicine that inhibits the anaplastic lymphoma kinase (ALK) and ROS1 proto-oncogene. Lorlatinib was specifically designed to inhibit tumor mutations that drive resistance to other ALK inhibitors. Lorlatinib has in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on a) the prior use of crizotinib and at least one other ALK inhibitor for metastatic disease, or b) the prior use of alectinib as the first ALK inhibitor therapy for metastatic disease, or c) the prior use of certinib as the first ALK inhibitor therapy for metastatic disease.

PF-04449913 is a potent and selective inhibitor of the Hh signaling pathway through binding to the target, smoothened. PF-04449913 inhibits Hh signaling in vitro and has demonstrated significant antitumor activity in vivo. In the clinic, PF-04449913 is being evaluated both in hematological and solid malignancies, with a phase II trial currently underway in both fit and unfit patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Treatment-related adverse-events were nausea, dizziness, somnolence, QT prolongation and pruritus. Based on pre-clinical assessments, CYP3A4 is believed to be primarily involved in the metabolism of PF-04449913 that is why PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole (CYP3A4 inhibitor).