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Minerval:Minerval:a novel clinical-stage, lipid regulator with game-a novel clinical-stage, lipid regulator with game-

changing potential inchanging potential in glioma gliomaVicenç Tur. Vicenç Tur. CEO, Co-FounderCEO, Co-Founder

Barcelona, 11Barcelona, 11thth April 2014 April 2014

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Lipopharma [2007] is an pioneering clinical-stage biopharmaceutical

company based in Palma de Mallorca (Spain) that focuses on the

discovery, rational design and development of next generation medicinesnext generation medicines

associated with a novel breakthrough therapeutic approach:

the Membrane Lipid TherapyMembrane Lipid Therapy (MLT)

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1. Based on an disruptive Technology platform: Membrane Lipid TherapyMembrane Lipid Therapy ((MLTMLT))

2. Game-changing novel MOAnovel MOA: SMS activation → regulation of membrane lipids

→ Multi-pathway modulation

3. Highly specific to cancer cells; very high efficacy in glioma (in cells & animals).

Non Toxic. Crosses the BBB.

4. ORAL formulation. Simple Chemistry. Stable at ambient for +24 months

5. Clinical stage compound: MIN-001-1203 PI/IIa study on-going since May 2013

6. 5M€ sought for PIIb study in glioma (2014-2015)

Minerval for the treatment of glioma

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Effect of SMS1 genetic alterations on glioma patients’ survival(Differential SGMS1 Gene Expression & Copy Number Analysis for SGMS1)

National Cancer Institute. 2005. REMBRANDT <http://rembrandt.nci.nih.gov>. Accessed October 2012

SGSM1 up-regulated (n = 1) SGMS1 Intermediate (n = 258) All Glioma average (n=454) SGSM1 down-regulated (n = 84)

Left panel: down-regulation of SGMS1 (green line) is associated with a marked and significant (P = 2 x 10-10) reduction in the life-span of glioma patients.

SGSM1 Amplified (n = 73) All Glioma average (n=454) SGSM1 Deleted (n = 278)

Right panel: deletion of the SGMS1 gene (green line) occurs in about 61% of all glioma patients and is associated with a significant reduction in their life-span, whereas patients with more than 2 copies of the SGMS1 gene (red line) have an

increased life span and ca. 25% probability to live over 20 years.

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Minerval vs. other targeted therapies in glioma

Mercer et al. BioDrugs 2010

Minerval

SMS

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Minerval vs. other targeted therapies in glioma

Mercer et al. BioDrugs 2010

Minerval

SMS

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Minerval, a new class of orally bioavailable lipid regulator multi-targetlipid regulator multi-target anticancer drugfor tumors with sphingomyelin metabolism alterationssphingomyelin metabolism alterations

Specific activator of sphingomyelin synthase (SMS)sphingomyelin synthase (SMS) [1]

SelectiveSelective regulation of lipid compositionlipid composition in cancer cell membranes: membranes: ▲▲SMSM; ▲▲DAGDAG; ▼▼PEPE; ▼PCPC [2]

K-RasK-Ras localization↓↓

MAPK – PI3K/AktMAPK – PI3K/Aktpathway normalization [3]

CellCell cyclecycle arrest arrest [▼▼DHFRDHFR]& differentiationdifferentiation [4]

PKC/Cyclin CDKPKC/Cyclin CDKRegulation [4]

selective AutophagyAutophagy [5]

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Minerval on membrane lipids in human glioma cells (U118)

Time-dependent changes in sphingomyelin (SM) content in U118 Cells after treatment with

Minerval

Increase induced on diacylglycerol (DAG) levels after Minerval treatments for 72 hours

Levels of SM, phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylinositol (PI) and phosphatidylethanolamine (PE) after

72-h treatments with Minerval (2OHOA)

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Minerval regulates Ras localization in GLIOMA (SF767) cells

Translocation of K-Ras (green) from the membrane to the cytosol and inner membranes after incubations of 10 minutes (1) or 24 hours (2). Ph. C.: phase contrast micrography. Increase in green fluorescence (K-Ras) after 10-minute incubations in the presence of Minerval does not correspond to increases in the expression of this protein. Proteins in the MAPK signalling pathway present a reduction in their activity, as measured by its phosphorilation status, while the expression of this proteins is not altered.

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Effect of Minerval in animal models of human brain tumours (GLIOMA) compared with temozolomide and control group

Anti-cancer effect of Minerval in animal models of cancer

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PI/II Clinical Study with Minerval

MIN-001-1203: “A phase I/IIa open-label dose escalation study of Minerval in subjects with advanced solid tumors including malignant glioma”

Top leading European KOL and investigational sites involved: Johann de Bono (Royal Marsden Hospital, London), Roger Stupp (University Hospital, Zurich), Jordi Rodon (Vall d'Hebron Institute of Oncology, Barcelona), Ruth Plummer (NCCC, Freeman Hospital, Newcastle)

Part A. Dose escalating study. Up to 30 patients. 21-day treatments. Glioma and other solid tumors (lung, pancreas…)

Part B. Exploratory study. Up to 20 patients in two groups. 21-day treatments. 1st group with glioma patients. 2nd group with biopsiable solid-tumors patients for biomarker evaluation.

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BiomarkersBiomarkers in MIN-001-1203 PI/II study in cancer

1) membrane lipids: SMSM → MOA/response [All cancers] >>> in tumor samples

2) GFAPGFAP → cancer cell differentiation [glioma] >>> in plasma samples

3) DHFRDHFR → cell proliferation [All cancers] >>> in tumor samples

4) miRNAmiRNA → diagnostic, response, pt segmentation [glioma, solid tumours]

>>> in plasma samples

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Marked and significant reduction in several miRNA have been observed after analysis of plasma samples from nude mice inoculated with human lung cancer (A549) and glioma (SF767) cells. Treatment with

Minerval (4 weeks) induced a significant recovery of miRNA levels.MiRNA identification not shown for confidentiality reasons (a patent filing is being considered)

[ * → p=0,05 | ** → p=0,01 | *** → p=0,001 ]

miRNA in Lung Cancer (A549)

miR

NA

exp

ress

ion

(arb

itra

ry u

nits

)

1 2 3 4 5 60

2

4

6

8

10

12

control with tumor

control without tumor

treated 400 mg/Kg

* *** *

** **** **** **

*** *

miRNA in glioma (SF767)

miR

NA

expre

ssio

n(a

rbit

rary

un

its)

8 11 12 13 200

10

20

30

40control with tumor

control with tumor

treated 400 mg/Kg

** *

* **** **

****

** **

miR

NA

expre

ssio

n(a

rbit

rary

un

its)

8 11 12 13 200

10

20

30

40control with tumor

control with tumor

treated 400 mg/Kg

** *

* **** **

****

** **

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MIN-001-1203. Minerval in cancer patients. Update:MIN-001-1203. Minerval in cancer patients. Update:

►3 cohorts completed: 0.5, 1 & 2g/day (BID)

►10 pt have received at least 1 cycle of treatment with Minerval (3-week) (6 GBM, 2 mesothelioma, 1 pancreas, 1 SCLC )

►no safety, tolerability, DLT or compliance issues

►pt #0102 (mesothelioma)pt #0102 (mesothelioma) on treatment since 02JUL13. Stable Disease (SD) so far. Dose escalated to 1g/day from cycle 7 (12NOV13) & to 2g/day from cycle 12 (24FEB14)

►pt #0202 (GBM)pt #0202 (GBM) on treatment since 03SEP13. Partial Response (PR) on RANO criteria.

►3 pt enroled in cohort #04 (4g/day, BID) On treatment since 11FEB14. No issues so far

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Lipopharma & Minerval today:

• PI/II trials in glioma & solid tumors (MIN-001-1203) on-going since May 2013

• Orphan Drug status granted in EU (glioma) in Oct. 2011

• Subsidiary in the US (Lipopharma Inc.) established in 2011

• 10+ M Euro already raised in equity / grants (2007-2013)

• World class strategic partners & collaborators' network

• Looking for additional collaborations/investment (5M Euro in 2014) for PII

studies in glioma & other solid tumors (2014-2015)

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Lipopharma Ctra. Valldemossa, Km. 7,4. ParcBIT. Edif. Disset. 2º C-8. E07121 – Palma de Mallorca. Spain

+34 971 439 886 |34 971439974 | info@lipopharma.com | www.lipopharma.com

Thank you!