Lipid Research

 

From fundamental science to clinical trials

Melitherapy

A new pharmaceutical perspective

Melitherapy (short for Membrane-Lipid Therapy) is an innovative scientific platform based on the discovery and rational design of drugs which specifically target lipids of the cell membrane. This contrasts with the usual approach to drug design, which targets proteins to elucidate their structure and then uses molecules (chemicals, antibodies, etc.) that directly regulate their activity.

 

In melitherapy, we use synthetic fatty acids that modify the composition and fluidity of the cell membrane to interfere with the activity of membrane-associated proteins responsible for disease processes, such as tumor growth.

Next-generation medicines

Thanks to this disruptive innovation, we will develop new medicines with an exceptional safety/efficacy combination for serious pathologies where other treatments fail, such as cancer, neurodegenerative or metabolic diseases.

 

Through different clinical trials, we are evaluating the potential translation of significant clinical benefit to patients who receive melitherapy drugs. Study MIN-001-1203 is the first clinical trial with 2-hydroxyoleic (LAM561A1) in patients with advanced solid tumors, including malignant glioma, and it has already been completed with very promising results.

Pathologies

We work on severe diseases with limited treatment options

Our most advanced line of research is for therapies in oncology. Several of our late-stage clinical trials focus on the very promising antitumoral effects of 2-hydroxyoleic acid (LAM561A1) in glioma, brain tumor, in adults and in children.

 

Since our origins in 2006, we have focused on rare, pediatric and geriatric diseases, especially those with unmet medical needs. We are also developing melitherapy drugs for Alzheimer’s disease, and for metabolic, cardiovascular and inflammatory diseases.

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Clinical Trials

MIN-001-1203

A Phase 1/2a Dose Escalation Study of 2-Hydroxyoleic Acid (2-OHOA) in Adult Patients with Advanced Solid Tumours Including Malignant Glioma.

 

EudraCT  #2012-001527-13 – clinicaltrials.gov #NCT01792310

More information

This trial is an open label, non-randomized study in patients with advanced solid tumours including malignant glioma and consists of two phases: (1) a dose-escalation phase following a standard “3+3” design to establish dose-limiting toxicity (DLT) and a safe dose of 2-OHOA and (2) an expansion phase with two expanded safety cohorts (approximately 10 of whom have malignant glioma and approximately 10 of whom have other advanced solid tumours that are suitable for biopsy) treated at the maximum tolerated dose (MTD). MIN-001-1203 trial has been conducted in leading investigational sites in London, Newcastle, Barcelona, San Sebastian and Bilbao.

Recruitment and treatment of patients in MIN-001-1203 study have completed. A total of 54 patients have been treated, of which 46 are evaluable for safety assessment. 32 patients were recruited in 7 cohorts in the Dose-Escalation Phase and 22 patients in two safety expansion cohorts in the expanded phase. Results of the study are currently being evaluated and have confirmed an excellent safety profile, while promising clinical activity (by RANO / RECIST v1.1) has been reported in several cases, including patients with recurrent malignant glioma.

MIN-002-1801

A Phase 1b Dose Finding Study of the Safety of 2-Hydroxyoleic Acid Sodium Salt (2-OHOA) Administered Orally in Combination with Temozolomide and Radiation Therapy (Concurrent Phase) or Temozolomide Alone (Maintenance Phase) in the First Line Treatment of Subjects with Glioblastoma.

 

EudraCT #2018-000317-21 – clinicaltrials.gov #NCT03867123

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First-line treatment for patients with GBM consists of a concurrent phase (one 6-week cycle with daily administration of temozolomide (TMZ)) during which TMZ is given with Radiation Therapy (RT), followed by a rest phase (4 weeks in duration;), and a maintenance phase, during which patients receive TMZ for up to six 28-day cycles. The purpose of this study is to determine the highest safe dose of 2-OHOA administered orally in combination with temozolomide (TMZ) and radiation therapy (RT) during the concurrent phase, and in combination with TMZ alone during the maintenance phase. This study is currently recruiting participants in 3 hospitals in Spain.

MIN-001P-1501

A Phase 1 Study of 2-Hydroxyoleic Acid in Pediatric Patients with Malignant Glioma and Other Advanced Solid Tumors.

 

EudraCT #2018‐000365‐37 – clinicaltrials.gov: information to be validated by the server

More information

An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors. The study will be performed in two phases – a dose escalation phase in up to 18 patients following a standard “3+3” design to establish dose limiting toxicity (DLT) and a “safe” dose of 2-OHOA followed by an expanded safety cohort of up to 10 patients treated at the MTD. If the MTD is well tolerated in the expanded safety cohort, that dose becomes the RP2D.

IND approved. Patient recruitment to open in Q2 2019 in four leading paediatric clinical research institutions in the USA lead by Hackensack UMC, NJ.

MIN-003-1806

A Phase 2b, Randomized, Double-Blind, Adaptive, Placebo-Controlled Adjuvant Trial in Newly Diagnosed Glioblastoma (NDGBM) Patients to Assess the Efficacy and Safety of 2-Hydroxyoleic Acid (LAM561) in Combination with Radiotherapy and Temozolomide Standard of Care Treatment.

clinicaltrials.gov: information to be validated by the server

More information

This is a randomized, double-blind, placebo-controlled, 3 parallel arms (1:1:1 ratio), adjuvant trial to assess the efficacy and safety of two doses of 2-hydroxyoleic acid (LAM561) versus placebo in patients with newly diagnosed GBM IDH wildtype. In all arms, patients will receive the SoC and will be randomized to receive either placebo (Arm A), low-dose of LAM561 (Arm B) or high-dose of 2-OHOA (Arm C).

PIIB Protocol design and regulatory strategy agreed with EMA (Sep. 2018) CTA process ongoing in IL, SP, FR, UK, IT & NL. Up to 25 sites planned to recruit patients as of Q1 2019.

Collaborations

Scientific partnerships with leading research institutions and hospitals

We currently head a consortium of 12 leading clinical and research institutions from across Europe in the CLINGLIO project, designed to test the efficacy and safety of our most promising anticancer drug, LAM561 (2OHOA). Our goal is to execute “A Clinical Phase IIB trial with 2OHOA in patients with newly-diagnosed malignant glioma”, and to this end we have been awarded a 6,15 million euro grant by the European Commission. Find out more at the CLINGLIO project website. We are also working with the Fundación Rioja Salud, in Spain.

Current Public Funding

This research is supported by:

  • European Commission H2020 Framework Programme (agreement number 755179)

  • Spanish Ministerio de Economía y Competitividad and European Regional Development Fund (grant numbers RTC-2015- 3542 and RTC-2015-4094)

  • Spanish research agency (Grants DI-14-06701 and DI-17-09187)

  • Balearic Island Government and European Regional Development Fund (grants number ES01/TCAI/53_2016; PROCOE/5/2017; ES01/TCAI/21_2017 and ES01/BT/21)

  • Balearic Island Government and European Social Fund (grants number PD/036/2016; FPI/1981/2016; FPI/2063/2017; FPI/2177/2018)

Papers

Read our published research

2019 – Massalha W, et al. Minerval (2-hydroxyoleic acid) causes cancer cell selective toxicity by uncoupling oxidative phosphorylation and compromising bioenergetic compensation capacity. Biosci Rep. 2019 Jan 18;39(1). pii: BSR20181661. doi: 10.1042/BSR20181661

2019 – Paula Fernández-García, Catalina A. Rosselló, Raquel Rodríguez-Lorca, Roberto Beteta-Göbel, Javier Fernández-Díaz, Victoria Lladó, Xavier Busquets and Pablo V. Escribá. Cancers 201911, 88

2017 – Ugidos IF et al. A role for lipids as agents to alleviate stroke damage: the neuroprotective effect of 2-hydroxy arachidonic acid. Neural Regen Res. 2017 Aug;12(8):1273-1275. doi: 10.4103

2017 – Ugidos IF et al. A role for lipids as agents to alleviate stroke damage: the neuroprotective effect of 2-hydroxy arachidonic acid. Neural Regen Res. 2017 Aug;12(8):1273-1275. doi: 10.4103

2017 – Mohaibes RJ, et al. The hydroxylated form of docosahexaenoic acid (DHA-H) modifies the brain lipid composition in a model of Alzheimer’s disease, improving behavioral motor function and survival. Biochim Biophys Acta Biomembr. 2017 Sep;1859(9 Pt B):1596-1603. doi: 10.1016

2017 – Casas J et al. G protein-membrane interactions II: Effect of G protein-linked lipids on membrane structure and G protein-membrane interactions. Biochim Biophys Acta. 2017 Sep;1859(9 Pt B):1526-1535.

2017 – Noguera-Salvà MA et al. Biochim Biophys Acta. 2017 Sep;1859(9 Pt B):1536-1547 (PRE)

2017 – Álvarez R et al. G protein-membrane interactions I: Gαi1 myristoyl and palmitoyl modifications in protein-lipid interactions and its implications in membrane microdomain localization. Biochim Biophys Acta. 2015 Nov;1851(11):1511-20

MORE DOCUMENTS

2016 – Manuel Torres et al. Update on Dementia. Chapter 7. Dr. Davide Moretti (Ed.) Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease. InTech, DOI: 10.5772/64757

2017 – Escriba PV. Membrane-lipid therapy: A historical perspective of membrane-targeted therapies – From lipid bilayer structure to the pathophysiological regulation of cells.Biochim Biophys Acta Biomembr. 2017 Sep;1859(9 Pt B):1493-1506. doi: 10.1016

2015 – Escribá PV, Busquets X, Inokuchi JI, Balogh G, Török Z, Horváth I, Harwood JL, Vígh L.Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment. . Prog Lipid Res. 2015 May 9;59:38-53. Review.

2015 – Torres M, Marcilla-Etxenike A, Fiol-deRoque MA, Escribá PV, Busquets X. Apoptosis. 2015 May; 20(5):712-24

2015 – G. Avila-Martin, I. Galan-Arriero, A. Ferrer-Donato, X. Busquets, J. Gomez-Soriano, P.V. Escribá, J. Taylor. Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury. Eur J Pain. 2015 Jan;19(1):111-22.

2014 – Fernández R, Lage S, Abad-García B, Barceló-Coblijn G, Terés S, López DH, Guardiola-Serrano F, Martín ML, Escribá PV, Fernández JA. Analysis of the lipidome of xenografts using MALDI-IMS and UHPLC-ESI-QTOF. J Am Soc Mass Spectrom. 2014 Jul;25(7):1237-46

2014 – Escribá PV, Nicolson GL. Membrane structure and function: relevance of lipid and protein structures in cellular physiology, pathology and therapy. Biochim Biophys Acta. 2014 Jun;1838(6):1449-50.

2017 – Lladó V, López DJ, Ibarguren M, Alonso M, Soriano JB, Escribá PV, Busquets X. Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma.  Biochim Biophys Acta. 2014 Jun;1838(6):1619-27

Study posters

Resources

Science communication materials for everyone

Do you want to know how melitherapy works? We have made an animation video and a series of infographics with clear illustrations and straightforward explanations of this fascinating science.

Feel free to download and share these educational materials, or even republish them — without alteration and with appropriate credit to Laminar Pharma, please!