Our innovative know-how enables us to undertake the design of novel synthetic fatty acid molecules that modulate specific signalling pathways at cell membrane level. This structure-function based drug design is the foundation of a prolific discovery engine that has allowed us to develop a dynamic and promising pipeline of novel products proposing alternative and innovative therapeutic strategies for a number of important conditions such as Cancer, CNS diseases or metabolic disorders.
LP561A1 is an orally bioavailable synthetic derivative of oleic acid that crosses de Blood Brain Barrier and activates SMS1 expression, a key enzyme that regulates phospholipid, particularly sphingolipid, concentrations at the plasma membrane. Membrane lipid composition and organization is known to be significantly altered in cancer cells and it has been observed that these changes are enabling increased recruitment to the cell membrane of central proliferation signaling proteins, such as K-Ras. Aberrant activity of Ras-associated proliferative signalling pathways is found in at least one third of all human cancers.
LP561 induces translocation of K-Ras from its active domain in the plasma membrane to the cytosolic membranes and inhibits its nanoclustering and signalling, inactivating key Ras-dependent proliferation pathways (like Ras/MAPK, Pi3K/AKT/mTOR or PKC/Cyclin CDK), causing endoplasmic reticulum stress, cell cycle arrest and eventually selective death of cancer cells.
LP561 increases SMS1 expression, a phospholipid/sphingolipid enzyme which is critical for glioma (and other cancers) patients’ survival. In fact, high SMS1 levels are associated with ca. 43% of survival 5 years after diagnosis, whereas the 5-year survival of patients with low SMS1 can be as low as 4%. This effect justifies the important therapeutic effects found for LP561 in a phase I/IIA clinical trial, with about a half of the patients, who were refractory to other therapies, obtaining therapeutic benefit from LP561 as single therapy.
The main mechanism of action is explained in the publications below. Basically, regulation of the plasma membrane lipid fraction induces translocation of relevant cancer cell growth signaling proteins from the plasma membrane to the cytoplasm and internal membranes. This produces a shutdown of growth signals and the initiation of ER stress, cell cycle arrest, cancer cell differentiation and death in approximately 50% of the human cancer cell lines we have studied and a similar proportion of patients treated with LP561. These facts, along with its oral administration and lack of relevant side effects at therapeutic doses, suggest that this compound is a serious candidate to be approved as standard-of-care drug for the treatment of glioma.
The European Medicines Agency designated 2OHOA as an orphan medicinal product for the treatment of glioma in October 2011 (EU/3/11/916). Current clinical investigations have found the product to be safe and well-tolerated in adult patients, even at doses well above the expected therapeutic range.
A phase I/IIA clinical trial with 2OHOA in Adult Patients with Advanced Solid Tumors including Malignant Glioma (MIN-001-1203) has already been completed with very encouraging results: no relevant drug-related toxicities found (other than anticipated reversible gastrointestinal effects at very high doses) and very promising clinical activity confirmed in several patients, including recurrent glioblastoma patients.
A poster with a summary of the final results of the MIN-001-1203 study with 2OHOA was presented at ASCO 2017. ::> Download the poster here
Further clinical trials with LP561A1 in pediatric population with malignant glioma and other advanced solid tumors (MIN-001P-1501), and in adult patients with newly-diagnosed glioblastoma (MIN-002-1801 and MIN-003-1806) are currently on the way in the USA and in Europe.
For more detailed information, visit the Clinical Trials section
LP226A1 is a modified natural fatty acid (DHA derivative) with highly specific incorporation into neurons due to the specific omega-3 transporters present in neuronal membranes. LP226A1 is a potent dose-dependent inhibitor of Tau phosphorylation (both in vitro and in vivo) as determined in differentiated SH-SY5Y cells and in brain samples of transgenic 5xFAD mice with Familiar Alzheimer´s Disease).
Treatment of 5xFAD mice with LP226A1 (15 mg/kg daily for 3 months) demonstrated a recovery of cognitive abilities as determined by a computer-assisted-radial maze exercise. This positive behavioural effect correlated with recovery of healthy brain biomarkers and restoration of synaptic protein expression (synaptophysin and SNAP25) in the hippocampus.
Concomitant with these effects a loss of the total brain Aβ amyloid load was observed. In addition, in vitro studies demonstrated the capacity of LP226A1 in restoring the viability of SH-SY5Y cells in cell culture intoxicated with Aβamyloid peptide together with significant increases in markers of protective autophagy.
LP204A1 is a PUFA derivative that produces a remarkable anti-inflammatory effect in a LPS-challenged mouse model of inflammation acting through COX1 and COX2. Its efficacy is similar to that of steroid compounds, albeit its non-steroid structure suggests a lower toxicity, aspect that has been initially assessed in preliminary studies in zebra fish, flies and mice.
LP204A1 inhibits both COX-1 and COX-2, although it only induces proteaseome-associated degradation of COX-2, the inducible isoform involved in the inflammatory response.
A collaboration with an external research group (at the University of Leon, Spain) is currently ongoing to explore potential effect of LP2014A1 in an animal model of ischaemic lesion following brain stroke.
Laminar Pharma currently investigates the therapeutic applications of new compounds based on our innovative Membrane Lipid Content Modification approach.
LP30171 is a new fatty acid derivative currently being investigated as a potential treatment for cancer and metabolic disorders.