Date: 2012-08-03
Type of information:
Compound: Apo E mimetic peptides including Apo E Mimetic Molecule — AEM-28
Company: Capstone Therapeutics (USA) LipimetiX (UK)
Therapeutic area: Rare diseases - Genetic diseases - Cardiovascular diseases
Type agreement: joint-venture (JV)
Action mechanism: Apolipoprotein E is a 299 amino acid protein that plays an important role in lipoprotein metabolism. AEM-28 is a 28 amino acid mimetic of Apo E that contains a domain that anchors into a lipoprotein surface while also providing the Apo E binding domain that is avidly removed by heparin sulfate receptors in the liver. AEM-28 replicates the function of Apo E, and due to its small size, extends that function to LDL, which does not normally bind to the Apo E receptors on the liver. As a result, when AEM-28 is injected into the plasma, it associates with Apo B containing lipoproteins to facilitate their clearance into the liver by receptors specific for Apo E. Apo B lipoproteins (chylomicron remnants, VLDL, IDL and LDL) are proatherogenic and if elevated are associated with a significantly increased risk for cardiovascular disease. Since Apo B lipoproteins are the main substrates for the pathogenesis of atherosclerosis, lowering these lipoproteins is a major therapeutic strategy to prevent cardiovascular events. The Apo E receptor mediated uptake of AEM-28 enriched lipoproteins has enhanced capacity to remove the Apo B lipoproteins compared to the LDL/Apo B receptors in the liver and is the principal receptor mediated mechanism for the removal of post-prandial lipoproteins. By attaching to LDL, AEM-28 may provide an alternative pathway for clearance of these lipoproteins beyond the traditional LDL/Apo B receptor. AEM-28 as an Apo E mimetic has the potential to restore the ability of these atherogenic lipoproteins to be cleared from the plasma, completing the reverse cholesterol transport pathway, and thereby reducing cardiovascular risk. This is an important mechanism of action for AEM-28 that is not shared by other biological therapies presently in clinical development. For patients that lack LDL receptors (homozygous familial hypercholesterolemia or HoFH), AEM-28 may provide a therapeutic solution. This potential beneficial effect of AEM-28 for patients suffering from HoHF, which is a fatal disease, provides an opportunity for rapid regulatory approval for an orphan indication. For patients that have a deficiency of LDL-receptors due to heterozygous familial hypercholesterolemia (HeFH), many of these patients cannot achieve adequate LDL-c goals on existing therapy. In summary, AEM-28 has a unique mechanism of action that may provide substantial reductions of all the atherogenic Apo B containing lipoproteins (VLDL, VLDL-R, IDL and LDL). This profile may provide a significant clinical advantage over other therapies nearing regulatory approval for HoFH such as mipomersen (anti-sense Apo B) or lomitapide (MTP inhibitor).
Disease: Homozygous Familial Hypercholesterolemia
Details: Capstone Therapeutics and LipimetiX, a privately-held biopharmaceutical company, have entered into a joint venture to develop a class of drugs targeted for indications related to lowering blood cholesterol levels. The joint venture, LipimetiX Development LLC, will develop a family of Apo E mimetic peptides licensed from The University of Alabama at Birmingham Research Foundation (\"UABRF\").
LipimetiX LLC principals Dennis Goldberg, Ph.D., Phillip M. Friden, Ph.D. and Eric M. Morrel, Ph.D. will be joined on the JV\'s five member Joint Development Committee by Capstone consultant Randy Steer, MD, Ph.D. and Jock Holliman, Executive Chairman of Capstone. The JV intends to implement an initial development plan to file an IND and pursue FDA approval under Orphan Drug designation of AEM-28 as treatment for Homozygous Familial Hypercholesterolemia (HoFH), a genetic condition associated with extremely abnormal regulation of lipid levels in blood.
The initial funded development plan will extend through Phase 1a and 1b/2a clinical trials over an expected twenty-seven month period with a biomarker endpoint test targeting reduction of LDL. The JV may also fund research or studies to investigate Apo E mimetic peptides, including AEM-28 and analogs, for treatment of acute coronary syndrome.
Financial terms: Under terms of the JV agreement, Capstone will contribute $6 million: $1 million for voting common ownership units representing 60% ownership in JV; and $5 million for non-voting preferred ownership units, which have preferential distribution rights. Initial funding of $3.3 million will be advanced at closing with funding of the remaining $2.7 million (held in escrow) upon milestone achievement of IND allowance by FDA.
LipimetiX LLC will contribute to JV its existing license agreement with UABRF related to Apo E mimetic peptides AEM-28 and analogs, in return for voting common ownership units representing 40% ownership in JV.
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