Therapeutic inhibition of LPA expression

Abstract

The present invention relates to therapeutic inhibition of LPA gene expression, and in particular to effective doses and administration regimes for the therapeutic use of SLN360 molecules in the prevention or treatment of conditions associated with elevated levels of Lp(a), including stroke, atherosclerosis, thrombosis, and cardiovascular diseases such as coronary heart disease and aortic stenosis.

Description

[Technical field]

[0001] The present invention relates to therapeutic inhibition of LPA gene expression, and in particular to effective doses and administration regimes for the therapeutic use of SLN360 molecules in the prevention or treatment of conditions associated with elevated levels of Lp(a), including stroke, atherosclerosis, thrombosis, and cardiovascular diseases such as coronary heart disease and aortic stenosis. [Background technology]

[0002] Lipoprotein(a) [Lp(a)] has long been recognized as an independent, genetically determined risk factor for atherothrombotic cardiovascular disease. 1 Mendelian randomization studies have consistently demonstrated a causal relationship between plasma concentrations of Lp(a) and the risk of myocardial infarction, stroke, peripheral arterial disease, and cardiovascular mortality. 2 Patients with Lp(a) concentrations in the highest decile (approximately 350 nmol / L) have a lifetime risk of cardiovascular disease similar to that of those with familial hypercholesterolemia. 3~4 Elevated levels of Lp(a) are also associated with aortic valve calcification, the development and more rapid progression of aortic valve stenosis, and higher rates of aortic valve replacement. 5~6 Although some treatments, such as administration of niacin or PCSK9 inhibitors, have modest Lp(a)-lowering effects, there are currently no drug treatments approved by regulatory agencies for elevated Lp(a) levels.

[0003] The LPA gene encodes apolipoprotein(a), [apo(a)], the major and rate-limiting component in the hepatic synthesis of Lp(a) particles. 7 Efforts have been made for several years to develop RNA-targeted therapies that would reduce hepatic production of apo(a) and thus reduce plasma concentrations of Lp(a). Previous phase 1 and 2 studies have demonstrated that peracarsen, an antisense oligonucleotide (ASO), can reduce Lp(a) plasma concentrations by up to 80% with weekly administration. 8 .

[0004] SLN360 is a small interfering RNA (siRNA) that targets LPA messenger RNA. SLN360 is a 19-mer siRNA covalently linked to a triantennary N-acetyl-galactosamine (GalNAc) moiety. The GalNAc conjugate binds to the asialoglycoprotein receptor, which is expressed almost exclusively in hepatocytes. This approach results in selective uptake and concentration of SLN360 in hepatocytes, allowing the drug to bind to and degrade messenger RNA encoding apo(a) (described in WO2020 / 099476). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2020 / 099476 [Non-patent literature]

[0006] [Non-Patent Document 1] "Remington's Pharmaceutical Sciences", 17th edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, PA, USA, 1985 [Non-Patent Document 2] "Encyclopaedia of Pharmaceutical Technology", 3rd edition, James Swarbrick (ed.), Informa Healthcare USA (Inc.), NY, USA, 2007 [Non-Patent Document 3] J. Pharm. Sci. 66:2 (1977) Summary of the Invention [Means for solving the problem]

[0007] In a first aspect, the present invention provides SLN360 for use in the prevention or treatment of a condition associated with elevated levels of Lp(a), the SLN360 being for administration in individual doses of between 100 mg and 600 mg.

[0008] In a further aspect, the present invention provides a method for the prevention or treatment of a condition associated with elevated levels of Lp(a) in a subject in need thereof, wherein said SLN360 is administered in individual doses of 100 mg to 600 mg.

[0009] In a further aspect, the present invention provides the use of SLN360 in the preparation of a medicament or pharmaceutical composition for the prevention or treatment of a condition associated with elevated levels of Lp(a), wherein said SLN360 is for administration in individual doses of between 100 mg and 600 mg.

[0010] Thus, in all embodiments, individual doses of SLN360 may be administered, for example, 100-600mg, 125-600mg, 150-600mg, 175-600mg, 200-600mg, 225-600mg, 250-600mg, 275-600mg, 300-600mg, 325-600mg, 350-600mg, 375-600mg, 400-600mg, 425-600mg, 450-600mg, 475-600mg, 500-600mg, 525-600mg, 550-600mg or 575-600mg; 100~575mg, 125~575mg, 150~575mg, 175~575mg, 200~575mg, 225~575mg, 250~575mg, 275~575mg, 300~575mg, 325~5 75mg, 350~575mg, 375~575mg, 400~575mg, 425~575mg, 450~575mg, 475~575mg, 500~575mg, 525~575mg or 550~575mg; 100~550mg, 125~550mg, 150~550mg, 175~550mg, 200~550mg, 225~550mg, 250~550mg, 275~550mg, 300~550mg, 325~550mg, 350~550mg, 375~550mg, 400~550mg, 425~550mg, 450~550mg, 475~550mg, 500~550mg or 525~550mg; 100~525mg, 125~525mg, 150~525mg, 175~525mg, 200~525mg, 225~525mg, 250~525mg, 275~525mg, 300~5 25mg, 325~525mg, 350~525mg, 375~525mg, 400~525mg, 425~525mg, 450~525mg, 475~525mg or 500~525mg; 100-500mg, 125-500mg, 150-500mg, 175-500mg, 200-500mg, 225-500mg, 250-500mg, 275-500mg, 300-500mg, 325-500mg, 350-500mg, 375-500mg, 400-500mg, 425-500mg, 450-500mg or 475-500mg; 100~475mg, 125~475mg, 150~475mg, 175~475mg, 200~475mg, 225~475mg, 250~475mg, 275~4 75mg, 300~475mg, 325~475mg, 350~475mg, 375~475mg, 400~475mg, 425~475mg or 450~475mg; 100-450mg, 125-450mg, 150-450mg, 175-450mg, 200-450mg, 225-450mg, 250-450mg, 275-450mg, 300-450mg, 325-450mg, 350-450mg, 375-450mg, 400-450mg or 425-450mg; 100-425mg, 125-425mg, 150-425mg, 175-425mg, 200-425mg, 225-425mg, 250-425mg, 275-425mg, 300-425mg, 325-425mg, 350-425mg, 375-425mg or 400-425mg; 100-400mg, 125-400mg, 150-400mg, 175-400mg, 200-400mg, 225-400mg, 250-400mg, 275-400mg, 300-400mg, 325-400mg, 350-400mg or 375-400mg; 100-375mg, 125-375mg, 150-375mg, 175-375mg, 200-375mg, 225-375mg, 250-375mg, 275-375mg, 300-375mg, 325-375mg or 350-375mg; 100-350mg, 125-350mg, 150-350mg, 175-350mg, 200-350mg, 225-350mg, 250-350mg, 275-350mg, 300-350mg or 325-350mg; 100~325mg, 125~325mg, 150~325mg, 175~325mg, 200~325mg, 225~325mg, 250~325mg, 275~325mg or 300~325mg; 100-300mg, 125-300mg, 150-300mg, 175-300mg, 200-300mg, 225-300mg, 250-300mg or 275-300mg; 100-275mg, 125-275mg, 150-275mg, 175-275mg, 200-275mg, 225-275mg or 250-275mg; 100-250mg, 125-250mg, 150-250mg, 175-250mg, 200-250mg or 225-250mg; 100-225mg, 125-225mg, 150-225mg, 175-225mg or 200-225mg; 100-200mg, 125-200mg, 150-200mg or 175-200mg; 100-175mg, 125-175mg or 150-175mg; 100-150 mg or 125-150 mg; or 100-125mg may be provided in an amount of

[0011] Individual doses range from 300 mg to 600 mg of SLN360, for example. 300-600mg, 325-600mg, 350-600mg, 375-600mg, 400-600mg, 425-600mg, 450-600mg, 475-600mg, 500-600mg, 525-600mg, 550-600mg or 575-600mg; 300~575mg, 325~575mg, 350~575mg, 375~575mg, 400~575mg, 425~575mg, 450~575mg, 475~575mg, 500~575mg, 525~575mg or 550~575mg; 300-550mg, 325-550mg, 350-550mg, 375-550mg, 400-550mg, 425-550mg, 450-550mg, 475-550mg, 500-550mg or 525-550mg; 300-525mg, 325-525mg, 350-525mg, 375-525mg, 400-525mg, 425-525mg, 450-525mg, 475-525mg or 500-525mg; 300-500mg, 325-500mg, 350-500mg, 375-500mg, 400-500mg, 425-500mg, 450-500mg or 475-500mg; 300-475mg, 325-475mg, 350-475mg, 375-475mg, 400-475mg, 425-475mg or 450-475mg; 300-450mg, 325-450mg, 350-450mg, 375-450mg, 400-450mg or 425-450mg; 300-425mg, 325-425mg, 350-425mg, 375-425mg or 400-425mg; 300-400mg, 325-400mg, 350-400mg or 375-400mg; 300-375mg, 325-375mg or 350-375mg; 300-350 mg or 325-350 mg; or 300-325mg It may be desirable to provide the

[0012] For example, individual doses can provide SLN360 in an amount of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

[0013] The term "about" in relation to numerical values ​​should be interpreted to mean + / - 10%, for example + / - 5%.

[0014] Thus, individual doses may provide SLN360 in amounts of 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg or 600 mg.

[0015] In certain embodiments, each dose preferably provides SLN360 in an amount of 300 mg or in an amount of 450 mg.

[0016] It will be understood that the amount of SLN360 administered in any individual dose is typically independent of the body weight of the recipient subject.

[0017] It may be desirable to administer SLN360 to a subject in a dosing regime comprising multiple or a series of doses.

[0018] Typically, administration under a dosing regime is once per month, or less frequently, for example, once per 2 months (once every 2 months), once per 3 months (once every 3 months), once per 4 months (once every 4 months), once per 5 months (once every 5 months), once per 6 months (once every 6 months), once per 7 months (once every 7 months), once per 8 months (once every 8 months), once per 9 months (once every 9 months), once per 10 months (once every 10 months), once per 11 months (once every 11 months) or once per 12 months (once every 12 months).

[0019] In certain embodiments, administration under the dosing regime is preferably once every four months or once every six months.

[0020] In certain embodiments, each dose preferably provides SLN360 in an amount of 300 mg, with administration under a dosing regime of once every four months.

[0021] In certain embodiments, each dose preferably provides SLN360 in an amount of 300 mg, with administration under a dosing regime of once every six months.

[0022] In certain embodiments, each dose preferably provides SLN360 in an amount of 450 mg, with administration under a dosing regime of once every six months.

[0023] Thus, the interval between successive doses is typically one month or more. For example, the interval between doses can be at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[0024] In certain embodiments, the interval may preferably be at least 4 months or at least 6 months.

[0025] In certain embodiments, each dose provides SLN360 in an amount of preferably 300 mg, with the interval between successive doses being preferably at least 4 months.

[0026] In certain embodiments, each dose preferably provides SLN360 in an amount of 300 mg, and the interval between successive doses is preferably at least 6 months.

[0027] In certain embodiments, each dose preferably provides SLN360 in an amount of 450 mg, and the interval between successive doses is preferably at least 6 months.

[0028] For example, the interval can be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months.

[0029] In certain embodiments, the interval may be preferably 4 months or 6 months.

[0030] In certain embodiments, each dose preferably provides SLN360 in an amount of 300 mg, and the interval between successive doses is preferably 4 months.

[0031] In certain embodiments, each dose preferably provides SLN360 in an amount of 300 mg, and the interval between successive doses is preferably 6 months.

[0032] In certain embodiments, each dose preferably provides SLN360 in an amount of 450 mg, and the interval between successive doses is preferably 6 months.

[0033] In the context of this disclosure, a month can be a calendar month, or a period of 28-31 days, for example, a period of 30 days. However, it will be understood that exact monthly dosing may not be practical for any individual subject. Thus, consecutive doses may be separated by a reasonable number of months plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day.

[0034] Thus, where monthly dosing is indicated, successive doses may be separated by one calendar month or 30 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where bimonthly dosing is indicated, successive doses may be separated by 2 calendar months or 60 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where quarterly dosing is indicated, successive doses may be separated by 3 calendar months or 90 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every four months is indicated, successive doses may be separated by four calendar months or 120 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 5 months is indicated, successive doses may be separated by 5 calendar months or 150 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every six months is indicated, successive doses may be separated by six calendar months or 180 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 7 months is indicated, successive doses may be separated by 7 calendar months or 210 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 8 months is indicated, successive doses may be separated by 8 calendar months or 240 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 9 months is indicated, successive doses may be separated by 9 calendar months or 270 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 10 months is indicated, successive doses may be separated by 10 calendar months or 300 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 11 months is indicated, successive doses may be separated by 11 calendar months or 330 days, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day; Where dosing once every 12 months is indicated, successive doses may be separated by 365 days or 12 calendar months, plus or minus 7 days, for example, plus or minus 5 days, for example, plus or minus 3 days, for example, plus or minus 2 days, for example, plus or minus 1 day.

[0035] In certain embodiments, SLN360 is administered to a subject by a dosing regimen including, for example, a first dose, a second dose, a third dose, and optionally one or more subsequent doses.

[0036] The interval between the first two doses may be four weeks, while the interval between the second and third doses, and any subsequent doses, may be five weeks.

[0037] The interval between the first two doses may be four weeks, while the interval between the second and third doses, and any subsequent doses, may be six weeks.

[0038] The interval between the first two doses may be three weeks, while the interval between the second and third doses, and any subsequent doses, may be four weeks.

[0039] The interval between the first two doses may be three weeks, while the interval between the second and third doses, and any subsequent doses, may be five weeks.

[0040] The interval between the first two doses may be three weeks, while the interval between the second and third doses, and any subsequent doses, may be six weeks.

[0041] The interval between the first two doses may be two weeks, while the interval between the second and third doses, and any subsequent doses, may be three weeks.

[0042] The interval between the first two doses may be two weeks, while the interval between the second and third doses, and any subsequent doses, may be four weeks.

[0043] The interval between the first two doses may be two weeks, while the interval between the second and third doses, and any subsequent doses, may be five weeks.

[0044] The interval between the first two doses may be two weeks, while the interval between the second and third doses, and any subsequent doses, may be six weeks.

[0045] The interval between the first two doses may be one week, while the interval between the second and third doses, and any subsequent doses, may be three weeks.

[0046] The interval between the first two doses may be one week, while the interval between the second and third doses, and any subsequent doses, may be four weeks.

[0047] The interval between the first two doses may be one week, while the interval between the second and third doses, and any subsequent doses, may be five weeks.

[0048] The interval between the first two doses may be one week, while the interval between the second and third doses, and any subsequent doses, may be six weeks.

[0049] In certain embodiments, the first two doses are spaced apart by four weeks, while the second and third doses, and any subsequent doses, can be spaced apart by six weeks.

[0050] In certain embodiments, the first two doses are spaced apart by three weeks, while the second and third doses, and any subsequent doses, can be spaced apart by four weeks.

[0051] In certain embodiments, the first two doses are spaced apart by three weeks, while the second and third doses, and any subsequent doses, can be spaced apart by six weeks.

[0052] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, can be spaced four weeks apart.

[0053] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, can be spaced six weeks apart.

[0054] The first dose provides SLN360 in an amount between 100 mg and 600 mg, and the second, third and any subsequent doses provide SLN360 in an amount between 200 mg and 600 mg. In certain embodiments, the first dose provides SLN360 in an amount of 200 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 200 mg.

[0055] In certain embodiments, the first dose provides SLN360 in an amount of 200 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 300 mg.

[0056] In certain embodiments, the first dose provides SLN360 in an amount of 200 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 450 mg.

[0057] In certain embodiments, the first dose provides SLN360 in an amount of 300 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 200 mg.

[0058] In certain embodiments, the first dose provides SLN360 in an amount of 300 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 300 mg.

[0059] In certain embodiments, the first dose provides SLN360 in an amount of 300 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 450 mg.

[0060] In certain embodiments, the first dose provides SLN360 in an amount of 450 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 200 mg.

[0061] In certain embodiments, the first dose provides SLN360 in an amount of 450 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 300 mg.

[0062] In certain embodiments, the first dose provides SLN360 in an amount of 450 mg, and the second, third and any subsequent doses provide SLN360 in an amount of 450 mg.

[0063] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0064] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0065] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0066] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0067] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0068] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0069] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0070] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0071] In certain embodiments, the first two doses are spaced apart by 4 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0072] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0073] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0074] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0075] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0076] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0077] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0078] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0079] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0080] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 4 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0081] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0082] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0083] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0084] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0085] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0086] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0087] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0088] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0089] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced four weeks apart, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0090] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0091] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0092] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0093] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0094] In certain embodiments, the first two doses are spaced two weeks apart, but the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0095] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0096] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0097] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0098] In certain embodiments, the first two doses are spaced two weeks apart, while the second and third doses, and any subsequent doses, are spaced six weeks apart, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0099] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0100] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0101] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 200 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0102] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0103] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0104] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 300 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0105] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 200 mg.

[0106] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 300 mg.

[0107] In certain embodiments, the first two doses are spaced apart by 3 weeks, while the second and third doses, and any subsequent doses, are spaced apart by 6 weeks, and the first dose provides SLN360 in an amount of 450 mg, and the second, third, and any subsequent doses provide SLN360 in an amount of 450 mg.

[0108] SLN360 SLN360 is a double-stranded RNA (dsRNA) or siRNA that can inhibit the expression of the human LPA gene. Without wishing to be bound by theory, it is believed that the inhibition occurs by RNA interference.

[0109] The SLN360 is (i) Sequence: mA (ps) fU (ps) mA fA mC fU mC fU mG fU mC fC mA fU mU fA mC (ps) fC (ps) mG and a first (antisense) strand having the following structure: (ii) Sequence: [M]-mC mG mG mU mA mA mA fU fG fG mA mC mA mG mA mG mU mU (ps) mA (ps) mU (wherein [M] is linked to the 5' end of the second strand and has the structure:

[0110] [ka]

[0111] a second (sense) strand having a triantennary ligand moiety having the structure It consists of:

[0112] Thus, the terminal phosphorothioate group of the ligand moiety [M] is directly attached (by a "free" bond indicated by an "*") to the 5' position of the 5'-terminal nucleotide of the second strand (i.e., to the 5'-carbon of the 2'-O-methyl ribose moiety of the mC residue at the 5' end of the second strand).

[0113] In the context of the above formula, the following abbreviations are used:

[0114] [Table 1]

[0115] If no group is specifically shown between adjacent nucleotides, they are linked by conventional phosphodiester bonds. Thus, the first strand contains phosphorothioate bonds between each of the three terminal nucleotides at the 5' end and between each of the three terminal nucleotides at the 3' end (i.e., two phosphorothioate bonds at each end of the strand). The other nucleotides of the first strand are linked by phosphodiester bonds. The second strand contains phosphorothioate bonds between each of the three terminal nucleotides at the 3' end (i.e., two phosphorothioate bonds only at the 3' end of the strand). The other nucleotides of the first strand are linked by phosphodiester bonds.

[0116] Sequences are shown in the conventional 5' to 3' orientation.

[0117] The first and second strands are described by SEQ ID NOs: 165 and 164, respectively, in WO2020 / 099476, which describes SLN360 as "conjugate 21." The ligand moiety [M] (including its phosphorothioate linkage to the second strand) is named in that document as "[ST23 (ps)]3 C6XLT (ps)."

[0118] situation Conditions associated with elevated levels of Lp(a) lipoproteins, eg, elevated levels of Lp(a)-containing particles, include cardiovascular disease and some cancers, including prostate cancer.

[0119] Thus, the condition may be, for example, stroke (e.g., ischemic stroke), atherosclerosis, thrombosis, coronary heart disease, aortic stenosis (e.g., calcific aortic stenosis), hyperlipidemia, dyslipidemia, coronary artery disease, peripheral arterial disease, abdominal aortic aneurysm, heart failure (e.g., heart failure secondary to ischemic cardiomyopathy), or cardiovascular disease such as familial hypercholesterolemia (e.g., atherosclerotic cardiovascular disease or atherosclerotic cerebrovascular disease), all of which are preferred when associated with elevated levels of Lp(a).

[0120] Alternatively, the condition may be cancer, for example prostate cancer.

[0121] The condition is associated with elevated Lp(a) (i.e., lipoprotein A) in a subject, e.g., elevated levels of Lp(a)-containing particles in a subject. The subject can be an adult (age 18 or older) or a child (age under 18).

[0122] It will be understood that the appropriate level of Lp(a) or Lp(a)-containing particles is typically measured in the serum of a subject. The desired level of Lp(a)-containing particles in serum is generally described as a level of less than 14 mg / dL. An elevated level of Lp(a)-containing particles is a level of Lp(a)-containing particles in the serum of a subject of at least 14, preferably at least 20, more preferably at least 30, more preferably at least 40, and most preferably at least 50 mg / dL or at least 60 mg / dL.

[0123] The terms "Lp(a)-containing particles" and "Lp(a) particles" may be used interchangeably.

[0124] Pharmaceutical Compositions SLN360 can be formulated for administration, for example, as part of a pharmaceutical composition, alone or in combination with one or more other agents. Pharmaceutical compositions can include pharmaceutically acceptable excipients, such as stabilizers, preservatives, diluents, buffers, etc. For example, SLN360 molecules can be combined with excipients, such as delivery vehicles (e.g., liposomes) and / or carriers or diluents. Other agents, such as preservatives and stabilizers, can also be added. Methods for delivery of nucleic acids are known in the art and within the knowledge of the skilled artisan.

[0125] The pharmaceutical compositions may be in sterile injectable aqueous suspensions or solutions, or in lyophilized form, or may be attached to, absorbed or contained within any other suitable galenic carrier material such as pellets, tablets, capsules, nanoparticles, gels, pills, beads or similar structures.

[0126] However, simple aqueous solutions may be suitable, for example at physiologically acceptable pH values ​​of 6.4 to 8.4. It may be desirable for the composition to have a pH of 7.6+ / -0.1.

[0127] SLN360 or a pharmaceutical composition may be administered (or formulated for administration) by any suitable route, for example, subcutaneous, intravenous, oral, rectal or intraperitoneal administration. It may be administered (or formulated for administration) by injection. Preferably, administration is by subcutaneous injection, for example, delivered to the abdomen, upper arm or thigh.

[0128] The present invention further provides individual dosage forms of SLN360, providing individual doses of SLN360 as described herein. Preferably, the individual dosage form is for administration by subcutaneous injection. It may be, for example, an aqueous solution as described, having a pH of 6.4 to 8.4, for example, having a pH of 7.6+ / -0.1.

[0129] The terms "patient", "subject" and "individual" may be used interchangeably and may refer to either human or non-human animals. These terms include mammals such as humans, non-human primates (e.g., great apes, Old World monkeys or New World monkeys), livestock animals (e.g., cows, pigs), companion animals (e.g., dogs, cats) and rodents (e.g., mice and rats). However, in the context of the present invention, the subject is typically a human. The subject may be an adult (18 years of age or older) or a child (under 18 years of age). Thus, the terms LPA, LPA, Lp(a), "Lp(a)-containing particles" and "Lp(a) particles" should be construed to refer to typically human proteins (or lipoproteins) and nucleic acids, unless the context requires otherwise.

[0130] As used herein, "treating" or "treatment" and grammatical variations thereof refer to an approach for obtaining beneficial or desired clinical results. The term may refer to slowing the rate of onset or development of a condition, disorder or disease, reducing or alleviating the symptoms associated therewith, causing complete or partial regression of the condition, or some combination of any of the above. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, reduction or alleviation of symptoms, whether detectable or undetectable, attenuation of the extent of the disease, stabilization (i.e., not worsening) of the disease state, delay or slowing of disease progression, improvement or relief of the disease state, and remission (whether partial or complete). "Treatment" may also mean prolonging survival as compared to expected survival in the absence of treatment. Thus, a subject (e.g., a human) in need of treatment may be a subject already suffering from the disease or disorder. The term "treatment" includes inhibition or reduction of the increase in severity of a pathological condition or symptom as compared to the absence of treatment, and is not necessarily intended to imply a complete cessation of the relevant disease, disorder, or condition.

[0131] As used herein, the term "prevention" and grammatical variations thereof refer to an approach to inhibit or prevent the occurrence, progression, or time or probability of onset of a condition, disease, or disorder, and may relate to a pathological condition and / or symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, the prevention, inhibition, or slowing of disease symptoms, progression, or onset, whether detectable or undetectable. Thus, a subject (e.g., a human) in need of prevention may be a subject not yet suffering from the disease or disorder. The term "prevention" includes slowing the onset of disease compared to no treatment, and is not necessarily intended to imply a permanent prevention of the relevant disease, disorder, or condition. Thus, "prevention" of a condition may refer in certain contexts to reducing the risk of the condition occurring, or to preventing, inhibiting, or delaying the onset of symptoms associated with the condition. It will be understood that prevention may be considered a treatment or therapy.

[0132] The pharmaceutical compositions and medicaments of the present invention can be administered to a subject in a therapeutically or prophylactically effective amount, i.e., an effective dose. As used herein, an "effective amount", "prophylactically effective amount", "therapeutically effective amount" or "effective dose" is an amount of a composition (e.g., a therapeutic composition or drug) that produces at least one desired therapeutic effect in a subject, such as preventing or treating a target condition or beneficially alleviating a symptom associated with a condition.

[0133] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is not harmful to the patient or subject to whom the salt is administered. It may be, for example, a salt selected from among acid addition salts and base salts. Examples of acid addition salts include chloride salts, citrate salts, and acetate salts. Examples of base salts include salts in which the cation is an alkali metal cation such as sodium or potassium ion, an alkaline earth metal cation such as calcium or magnesium ion, and a type N(R 1 )(R 2 )(R 3 )(R 4 )+(where R 1 , R 2 , R 3 and R 4are independently typically selected from substituted ammonium ions such as ions of C1-6-alkyl, C2-6-alkenyl, or C1-6-alkyl groups. Examples of suitable C1-6-alkyl groups include methyl, ethyl, 1-propyl, and 2-propyl groups. Examples of suitable C2-6-alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. Other examples of pharma- ceutically acceptable salts are described in "Remington's Pharmaceutical Sciences", 17th Edition, Alfonso R. Gennaro (ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and more recent editions thereof), "Encyclopaedia of Pharmaceutical Technology", 3rd Edition, James Swarbrick (ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and J. Pharm. Sci. 66:2(1977). A "pharmaceutically acceptable salt" retains substantially the desired biological activity of the parent compound without imparting any undesirable effects to the compound. Examples of pharmaceutically acceptable salts include acid addition salts and base addition salts. Acid addition salts include salts derived from non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphorous acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and the like, or non-toxic organic acids, such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include salts derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and the like, and non-toxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like.

[0134] The term "pharmaceutical acceptable carrier" includes any of the standard pharmaceutical carriers. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (edited by AR Gennaro, 1985). For example, sterile saline and phosphate buffered saline at slightly acidic or physiological pH can be used. Exemplary pH buffers include phosphate, citrate, acetate, tris / hydroxymethyl)aminomethane (TRIS), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), ammonium bicarbonate, diethanolamine, the preferred buffers histidine, arginine, lysine, or acetates or mixtures thereof. The term further includes any agent listed in the United States Pharmacopoeia for use in animals, including humans. "Pharmaceutical acceptable carrier" includes any and all physiologically acceptable, i.e. compatible, solvents, dispersion media, coatings, antimicrobial agents, isotonic and absorption delaying agents, and the like. In certain embodiments, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration selected, the nucleic acid may be coated with one or more materials intended to protect the compound from the action of acids and other natural inactivating conditions to which the nucleic acid may be exposed when administered to a subject by a particular route of administration.

[0135] The term "solvate" in the context of the present invention refers to a complex of defined stoichiometry formed between a solute (in this case a nucleic acid compound according to the invention or a pharma- ceutically acceptable salt thereof) and a solvent. The solvent in question may be, for example, water or another pharma- ceutically acceptable, typically low molecular weight organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent in question is water, such a solvate is usually referred to as a hydrate.

[0136] The invention will now be described with reference to the following non-limiting tables, figures and examples. [Brief description of the drawings]

[0137] [Figure 1] FIG. 1 illustrates the flow of patients through the clinical trial. [Figure 2a] Panel A is a graph showing the change in lipoprotein(a) concentration over time for placebo and each SLN360 dose group. Median lipoprotein(a) concentrations are shown as filled circles, and boxes indicate the interquartile range for each of these values. Stars indicate the mean concentration at each time point. [Figure 2b] Panel B is a graph showing the percent change in lipoprotein(a) concentrations over time for placebo and each SLN360 dose group. The median percent change in lipoprotein(a) concentrations is shown as a filled circle, and the boxes show the interquartile range for each of these values. Stars indicate the mean percent change in concentrations at each time point. [Figure 3a] Panel A is a graph showing the mean percent change in low-density lipoprotein-cholesterol over time for placebo and each SLN360 dose group. The mean percent change is shown as a filled circle, and the 95% confidence interval is shown as an error bar. [Figure 3b] Panel B is a graph showing the mean percent change in apolipoprotein B over time for placebo and each SLN360 dose group. The mean percent change is shown as a filled circle, with the 95% confidence intervals shown as error bars. [Figure 4] Study schematic. Cohort 5: 2 doses, 200 mg q4 weeks. Cohort 6: 2 doses, 300 mg q8 weeks. [Diagram 5] Graph showing time-averaged results over 0 to 150 days. [Figure 6]Graphs showing time-averaged results over 30 to 150 days. [Table 1] Baseline characteristics of participants [Table 2] Safety assessments [Table 3] Primary efficacy endpoint: Change in lipoprotein(a) concentration over time [Table 4] Effect of SLN360 on total cholesterol [Table 5] Effect of SLN360 on low-density lipoprotein cholesterol [Table 6] Effect of SLN360 on apolipoprotein(B) [Table 7] Effect of SLN360 on oxidized LDL [Table 8] Pharmacokinetic parameters DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0138] method Study population No known atherosclerotic cardiovascular disease (ASCVD), Lp(a) concentration ≥ 150 nmol / L, and body mass index 18-45 kg / m 2 Adults ≥18 years of age with a history of diabetes were eligible to participate. Women of childbearing potential were required to have a negative serum pregnancy test at screening and a negative urine pregnancy test one day prior to treatment. All participants (male and female) agreed to adhere to contraception requirements from the beginning of the screening period until 3 months after the last dose of study drug. Participants were excluded for moderate or severe liver cirrhosis, positive HIV or hepatitis B or C tests, or other liver disease that may increase the risk of drug-induced liver injury or affect the pharmacology of SLN360. Participants were required to have an HbA1c <6.5% if not previously diagnosed with diabetes, or <8.5% if known to have diabetes.

[0139] Laboratory exclusion criteria included platelet count below the lower limit of normal or alanine transaminase or aspartate aminotransferase >1.5 × upper limit of normal (ULN). Additional laboratory exclusion criteria were total bilirubin >ULN, excluding participants with Gilbert's syndrome, or estimated glomerular filtration rate <60 ml / min / 1.73 m. 2Medications that may affect Lp(a) levels, including antiestrogens or estrogen receptor modulators, PCSK9 inhibitors, prescription dose niacin, fibrates, statins, or ezetimibe, were required to have their doses stable for at least 8 weeks prior to enrollment. Participants were also excluded if they had received any other investigational drug within 90 days (or 10 half-lives, whichever was longer) prior to the first dose of study drug, or other oligonucleotide therapy within 12 months. Participants were excluded for clinically significant illness within 7 days prior to the first dose of study drug, positive nucleic acid test for SARS-CoV-2, or any uncontrolled or severe illness that may interfere with the interpretation of the results.

[0140] Test procedure The study was conducted in accordance with the Declaration of Helsinki and the International Council of Medical Associations International Ethical Guidelines. Using automated response technology, four ascending single dose cohorts were randomized to 30 mg, 100 mg, 300 mg, or 600 mg of SLN360 or placebo (sodium chloride 0.9%) given by subcutaneous injection in the abdomen. Up to two injection sites were used to administer the required dose. For each cohort, two participants were randomized to receive placebo and six subjects were assigned to SLN360, with sentinel dosing for the first two participants in each cohort. A schematic describing the study design is provided in Figure 4. The principal investigator, study participants, and sponsor were blinded to the study drug, but designated site staff, e.g., site pharmacists, were unblinded. Participants were monitored in the Clinical Research Unit (CRU) for 24 hours after dose administration, during which time vital signs, simplified physical examinations, blood and urine samples, and serial electrocardiograms were obtained. CRU staff also assessed participants for adverse effects and injection site adverse events.

[0141] Participants had scheduled visits at 7, 14, 30, 45, 60, 90 and 150 days after drug administration. The presence and severity of any adverse effects of study drug administration was assessed at each visit. At all return visits, blood samples were obtained for lipoprotein(a) levels, other biomarkers, pharmacokinetic analysis and safety laboratory tests, and a focused physical examination was performed if indicated by symptoms. Lp(a) concentrations were measured on a Roche c502 automated analyzer using a particle-enhanced turbidimetric assay. The assay was calibrated by five independent standards with values ​​in nmol / L traceable to the WHO / IFCC reference material for Lp(a) and was demonstrated to be minimally affected by particle size differences of apo(a).

[0142] Study Endpoints As a first-in-human study, safety and tolerability of SLN360 were defined as the primary endpoint of interest. Safety assessments included changes in vital signs, physical examination, ECG, and clinical laboratory assessments of chemistry, hematology, urinalysis, and coagulation parameters. Assessments included treatment-emergent adverse events (TEAEs) and adverse events of special interest, including injection site adverse events or any identified dose-limiting toxicity. Injection site adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 9 Version 5 and FDA recommended scale 10 The test was graded by the examiner using both the

[0143] The primary efficacy assessment was the effect of SLN360 on plasma lipoprotein(a) concentrations from baseline to 150 days after dosing. Secondary objectives included assessment of the pharmacokinetics (PK) of SLN360. Exploratory objectives included assessment of the effects on other lipid parameters (LDL-C, HDL-C, total cholesterol, and triglycerides), apolipoprotein B, oxidized LDL, inflammatory markers, and plasminogen.

[0144] statistical analysis Placebo-allocated subjects from each cohort were pooled to create an overall placebo treatment group. SLN360 treatment groups are presented separately by dose. Safety and Lp(a) changes are summarized by treatment group using descriptive statistics. For categorical variables, summary tables of frequencies and percentages of subjects within each category are presented. For continuous variables, numbers of participants and summary statistics are presented by treatment group. For pharmacokinetic effects, plasma SLN360 concentrations were calculated based on peak plasma concentration (C max) ), time to reach peak plasma concentration (T max ) and the area under the concentration curve to the last measurable concentration (AUC (0-last) ). Missing data were not imputed. No formal statistical tests were performed and therefore no P values ​​are reported. The protocol prespecified that the effect of single ascending doses of SLN360 would be reported separately from the subsequent multiple ascending dose phase of the trial. This report describes the findings of the single ascending dose part.

[0145] result Figure 1 shows the flow of patients through the trial. Table 1 reports the baseline characteristics of the study participants. The mean (SD) age of participants was 50 years (13.5) and 47% were male. None of the participants had known pre-existing clinically evident cardiovascular disease, although hypertension was present in 9% and diabetes in 3%. Baseline characteristics appeared to be broadly similar across all treatment groups. Median (IQR) baseline Lp(a) concentrations were 238 (203, 308), 171 (142, 219), 217 (202, 274), 285 (195, 338), and 231 (179, 276) nmol / L for the placebo, 30 mg, 100 mg, 300 mg, and 600 mg treatment groups, respectively. Mean (SD) LDL-C levels were 99 (48), 113 (38), 121 (46), 100 (25), and 108 (54) mg / dL for the placebo, 30 mg, 100 mg, 300 mg, and 600 mg treatment groups, respectively.

[0146] Figures 2a and 2b show the absolute and percent change in Lp(a) concentrations over time for each treatment group over 150 days post-injection. Table 3 shows the median and IQR for the absolute and percent change at each time point. The maximum median (IQR) change in Lp(a) in nmol / L was -20 (-61, 3), -89 (-119, -61), -185 (-226, -163), -268 (-292, -189), and -227 (-270, -174) for the placebo, 30 mg, 100 mg, 300 mg, and 600 mg doses, respectively. The maximum median percent change (IQR) was -10% (-16, 1%), -46% (-64, -40%), -86% (-92, -82%), -96% (-98, -89%), and -98% (-98, -97%) for the placebo, 30 mg, 100 mg, 300 mg, and 600 mg groups, respectively. The nadir of percent change in Lp(a) levels was achieved between 30 and 60 days post-dosing for all treatment groups (Figure 2). Concentrations rose gradually from the nadir but did not return to baseline values ​​by day 150 for the 100 mg, 300 mg, and 600 mg treatment groups. Median Lp(a) concentrations were >70% and >80% below baseline at 150 days post-dosing for the 300 mg and 600 mg doses, respectively.

[0147] Time-averaged declines were determined to further inform dosing frequency and to more fully evaluate potential clinical benefit. Figures 5 and 6 show time-averaged data including the total observation period up to day 150 (a conservative estimate since it includes the initial baseline before any treatment effect) and the observation period from days 30 to 150 (more reflective of drug effect after the nadir is achieved by the first dose), respectively. Time averaging may be useful to evaluate the cumulative effect of multiple doses and capture the peaks and troughs of drug effect.

[0148] SLN360 produced a moderate dose-dependent reduction in apolipoprotein (B)-containing lipoproteins (Tables 4-7). Mean levels were reduced by up to 18% for total cholesterol and 26% for LDL-C, both after administration of the 600 mg dose (Figure 3a and Tables 4, 5). Smaller reductions were observed at the lower doses. The maximum reduction in mean apolipoprotein B levels was 24% measured after 30 days of the 600 mg dose and 19% measured after 14 days of the 300 mg dose (Figure 3b and Table 6). Mean levels of oxidized LDL were reduced by up to 20% in the 600 mg dose group and 11% in the 300 mg dose group, with similar reductions sustained up to 150 days in the 600 mg group (Table 7). There was no evidence of an effect of SLN360 on triglycerides and HDL-C. Table 8 shows that the plasma pharmacokinetics of SLN360 was roughly dose proportional.

[0149] Table 2 shows the CTCAE scale. 10 Safety findings for each treatment group will be reported, including assessment of injection site adverse events graded by the FDA.

[0150] TEAEs were generally mild, with the most common being low-grade injection site events (grades 1 and 2) and headaches, none of which led to participant withdrawal (Table 2). After receiving the SARS-CoV-2 vaccine on day 38, one participant in the lowest dose group (30 mg) was hospitalized on day 45 for fever and severe headache, which were attributed by the investigator to the SARS-CoV-2 vaccine. A subsequent planned day 45 visit was conducted on day 49, and the participant was found to have >3×ULN values ​​for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and no elevations in bilirubin. AST and ALT returned to normal on routine day 60 laboratory tests.

[0151] A transient, dose-dependent increase in C-reactive protein (CRP) occurred within the first 24 hours after dosing: in the 600 mg dose group, CRP rose from a median of 1.0 mg / L to 16.3 mg / L at 24 hours, then declined rapidly, reaching 1.1 mg / L by day 14 (not shown).

[0152] Neutrophils were also increased during the first 24 hours and returned to normal by the seventh visit.

[0153] After reviewing the data, the SRC recommended extending follow-up of Lp(a) levels from 150 days to 365 days (1 year) for participants in the two highest dose groups. These extension studies included three placebo subjects, five subjects in cohort 3 (300 mg; four subjects completed), and six subjects in cohort 4 (600 mg). At day 365, some subjects in the 300 mg and 600 mg cohorts still showed substantial knockdown of Lp(a) to 50% of baseline, while subjects in the placebo group had all returned to baseline at day 365. No new safety findings or serious adverse effects related to study drug were observed in either of the two highest dose groups at 365 days.

[0154] Consideration Patients with Lp(a) concentrations above 150 nmol / L (approximately 60 mg / dL) constitute approximately 20% of the population and are associated with a substantially increased risk of developing ASCVD and aortic valve stenosis. 4~5The APOLLO trial enrolled participants with plasma Lp(a) concentrations above this threshold. Plasma Lp(a) levels are genetically determined and are not affected by lifestyle interventions such as diet and exercise that lower LDL-C and triglycerides or raise HDL-C. In the absence of an effective Lp(a)-lowering drug therapy, this risk factor has traditionally been considered essentially untreatable. Recent developments using RNA interference have made it possible to selectively and substantially reduce Lp(a). The first of these drugs to reach phase 3, peracarsen, an antisense oligonucleotide (ASO), reduced Lp(a) by 80% with weekly injections in phase 2 trials and is being developed as a monthly treatment thereafter. 8 .

[0155] This clinical trial investigated an alternative approach to prevent Lp(a) particles from assembling in the liver, using siRNA (SLN360) that degrades the messenger RNA that codes for the production of apolipoprotein(a). 11Although SLN360 is still in early development, preliminary results from this Phase 1 study are encouraging, with a median reduction in Lp(a) concentrations of up to 98%, with median reductions that persisted above 70% and 80% at 150 days after administration of the 300 mg and 600 mg doses, respectively (Table 3 and Figure 2). After reviewing the data, the SRC recommended extending follow-up of Lp(a) levels from 150 days to 1 year for participants in the two highest dose groups (cohorts 3 and 4). No new safety findings or serious adverse effects related to the study drug were observed in subjects in these two highest dose groups at 365 days, and there was still evidence of substantial knockdown of Lp(a) in some subjects in each cohort compared with subjects in the placebo group. In Phase 1 studies, evaluation of safety and tolerability is the primary objective. The study was small, including only 32 participants without known cardiovascular disease who were studied for 150 days after a single dose of SLN360. Because the treatment targets Lp(a) production in liver cells, the study measured several markers of liver function to monitor liver toxicity. During the study, one episode of a transient three-fold elevation of liver enzymes (AST and ALT) was observed in one patient who received the lowest dose (30 mg) and was temporally associated with SARS-CoV-2 vaccination. Elevations in liver enzymes have previously been described following COVID vaccinations. 12 No other clinically important perturbations in liver function were observed. Because only a small number of participants were treated for a short period of time, definitive conclusions regarding liver safety are not possible.

[0156] Similar to other RNAi therapies, low-grade injection-site adverse events were observed (Table 2). These adverse events were self-limited with no lasting effects and did not lead to participant withdrawal. Transient dose-dependent increases in inflammatory biomarkers, including CRP and neutrophils, were observed during the first 7 days after dosing. The clinical significance of these short-term increases is unclear. During early development of some previous ASO therapies, thrombocytopenia was observed with higher weekly dosing, but we did not observe any clinically relevant thrombocytopenia in this study with this GalNAc siRNA.13 Future studies treating patients with multiple doses and longer exposure times are needed to more definitively establish the safety of this siRNA therapeutic.

[0157] The study also examined the effect of SLN360 on various lipids and lipoproteins, including LDL-C, apoB, triglycerides, HDL-C, and oxidized LDL. Both LDL-C and apoB were moderately reduced, up to approximately 25%, and most evident at the highest dose (Figures 3a and 3b, Tables 5 and 6). The moderate reductions in LDL-C and apoB were expected, since the assay also measures the portion of LDL-C and apoB contained within Lp(a) particles. 14 Thus, lowering Lp(a) also reduces measured LDL-C and apoB concentrations. Oxidized LDL, present in Lp(a) particles, is proinflammatory and may contribute to the risk of atherothrombotic events. 15 Mean oxidized LDL levels were reduced by up to 20% and remained substantially below baseline for 45 to 60 days in the lower dose groups and for 150 days for the 600 mg dose group (Table 7).

[0158] Inhibiting translation by RNA interference is increasingly being used in therapeutic drug development to block hepatic production of specific target proteins. 11. siRNA is a double-stranded RNA with a guide (antisense) and passenger (sense) strand designed to specifically suppress the translation of target genes whose mRNA contains a sequence complementary to the guide strand. Once siRNA enters the cell, it is incorporated into the RNA-induced silencing complex (RISC). The guide and passenger strands are separated, the passenger strand is cleaved and degraded, and the remaining single-stranded siRNA guide strand binds to the target mRNA and induces cleavage by a catalytic mechanism, leaving the guide strand intact and available to degrade additional copies of the target mRNA. The cleaved mRNA exits the RISC and is recognized as abnormal and degraded by cellular exonucleases. This process prevents the translation of this particular mRNA into protein. In this way, siRNA therapeutics can have a very long duration of effect. A recently published Phase 1 trial of olpaciran, a different siRNA targeting Lp(a), also showed a large, dose-dependent and durable reduction in Lp(a). 16 .

[0159] The siRNA used in this trial was conjugated with GalNAc, a sugar derived from galactose, allowing targeted delivery of SLN360 to the liver. This approach is now used in most liver-directed RNA interference therapeutics currently on the market or in development. GalNAc binds to the asialoglycoprotein receptor, which is highly expressed on the surface of hepatocytes, causing rapid endocytosis of the conjugate. After entering the hepatocyte, acidification during endosomal maturation causes dissociation of the GalNAc ligand that delivered the siRNA to the cell. The selective renewal of SLN360 in hepatocytes reduces the administered dose of this siRNA required to degrade LPA mRNA, which is exclusively expressed in hepatocytes, thus limiting systemic exposure.

[0160] Longer exposure and repeated dosing are needed to assess the duration of the pharmacodynamic effect and to further evaluate drug safety. A multiple ascending dose study of SLN360 is ongoing in subjects with stable ASCVD to further assess its efficacy (NCT04606602). Although this study is small, the magnitude and duration of effect from a single dose is promising and warrants further development.

[0161] All documents referenced herein are incorporated by reference in their entirety. (References) TIFF2025505692000003.tif200158TIFF2025505692000004.tif233159

Claims

1. A medicament comprising SLN360 for use in the prevention or treatment of a condition associated with elevated levels of Lp(a), wherein said SLN360 is administered in individual doses of between 100 mg and 600 mg.

2. The individual doses comprise the SLN360 in the following amounts: 100-600mg, 125-600mg, 150-600mg, 175-600mg, 200-600mg, 225-600mg, 250-600mg, 275-600mg, 300-600mg, 325-600mg, 350-600mg, 375-600mg, 400-600mg, 425-600mg, 450-600mg, 475-600mg, 500-600mg, 525-600mg, 550-600mg or 575-600mg; 100-575mg, 125-575mg, 150-575mg, 175-575mg, 200-575mg, 225-575mg, 250-575mg, 275-575mg, 300-575mg, 325-5 75mg, 350-575mg, 375-575mg, 400-575mg, 425-575mg, 450-575mg, 475-575mg, 500-575mg, 525-575mg or 550-575mg; 100-550mg, 125-550mg, 150-550mg, 175-550mg, 200-550mg, 225-550mg, 250-550mg, 275-550mg, 300-550mg, 325-550mg, 350-550mg, 375-550mg, 400-550mg, 425-550mg, 450-550mg, 475-550mg, 500-550mg or 525-550mg; 100-525mg, 125-525mg, 150-525mg, 175-525mg, 200-525mg, 225-525mg, 250-525mg, 275-525mg, 300-5 25mg, 325-525mg, 350-525mg, 375-525mg, 400-525mg, 425-525mg, 450-525mg, 475-525mg or 500-525mg; 100-500mg, 125-500mg, 150-500mg, 175-500mg, 200-500mg, 225-500mg, 250-500mg, 275-500mg, 300-500mg, 325-500mg, 350-500mg, 375-500mg, 400-500mg, 425-500mg, 450-500mg or 475-500mg; 100-475mg, 125-475mg, 150-475mg, 175-475mg, 200-475mg, 225-475mg, 250-475mg, 275-4 75mg, 300-475mg, 325-475mg, 350-475mg, 375-475mg, 400-475mg, 425-475mg or 450-475mg; 100-450mg, 125-450mg, 150-450mg, 175-450mg, 200-450mg, 225-450mg, 250-450mg, 275-450mg, 300-450mg, 325-450mg, 350-450mg, 375-450mg, 400-450mg or 425-450mg; 100-425mg, 125-425mg, 150-425mg, 175-425mg, 200-425mg, 225-425mg, 250-425mg, 275-425mg, 300-425mg, 325-425mg, 350-425mg, 375-425mg, or 400-425mg; 100-400mg, 125-400mg, 150-400mg, 175-400mg, 200-400mg, 225-400mg, 250-400mg, 275-400mg, 300-400mg, 325-400mg, 350-400mg or 375-400mg; 100-375mg, 125-375mg, 150-375mg, 175-375mg, 200-375mg, 225-375mg, 250-375mg, 275-375mg, 300-375mg, 325-375mg or 350-375mg; 100-350mg, 125-350mg, 150-350mg, 175-350mg, 200-350mg, 225-350mg, 250-350mg, 275-350mg, 300-350mg or 325-350mg; 100-325mg, 125-325mg, 150-325mg, 175-325mg, 200-325mg, 225-325mg, 250-325mg, 275-325mg or 300-325mg; 100-300mg, 125-300mg, 150-300mg, 175-300mg, 200-300mg, 225-300mg, 250-300mg or 275-300mg; 100-275 mg, 125-275 mg, 150-275 mg, 175-275 mg, 200-275 mg, 225-275 mg, or 250-275 mg; 100-250 mg, 125-250 mg, 150-250 mg, 175-250 mg, 200-250 mg, or 225-250 mg; 100-225 mg, 125-225 mg, 150-225 mg, 175-225 mg, or 200-225 mg; 100-200 mg, 125-200 mg, 150-200 mg, or 175-200 mg; 100-175 mg, 125-175 mg, or 150-175 mg; 100-150 mg or 125-150 mg; or 100–125 mg The pharmaceutical composition of claim 1, wherein the composition is provided by

3. 2. The pharmaceutical composition of claim 1, wherein the individual dose provides the SLN360 in an amount of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

4. 2. The method of claim 1, wherein the individual dose provides the SLN360 in an amount of 300 mg.

5. 2. The method of claim 1, wherein the individual dose provides the SLN360 in an amount of 450 mg.

6. 2. The method of claim 1, for administration in individual doses of 300 mg to 600 mg.

7. The individual doses comprise the SLN360 in the following amounts: 300-600mg, 325-600mg, 350-600mg, 375-600mg, 400-600mg, 425-600mg, 450-600mg, 475-600mg, 500-600mg, 525-600mg, 550-600mg or 575-600mg; 300-575mg, 325-575mg, 350-575mg, 375-575mg, 400-575mg, 425-575mg, 450-575mg, 475-575mg, 500-575mg, 525-575mg or 550-575mg; 300-550mg, 325-550mg, 350-550mg, 375-550mg, 400-550mg, 425-550mg, 450-550mg, 475-550mg, 500-550mg or 525-550mg; 300-525mg, 325-525mg, 350-525mg, 375-525mg, 400-525mg, 425-525mg, 450-525mg, 475-525mg or 500-525mg; 300-500mg, 325-500mg, 350-500mg, 375-500mg, 400-500mg, 425-500mg, 450-500mg or 475-500mg; 300-475 mg, 325-475 mg, 350-475 mg, 375-475 mg, 400-475 mg, 425-475 mg, or 450-475 mg; 300-450mg, 325-450mg, 350-450mg, 375-450mg, 400-450mg or 425-450mg; 300-425 mg, 325-425 mg, 350-425 mg, 375-425 mg, or 400-425 mg; 300-400 mg, 325-400 mg, 350-400 mg, or 375-400 mg; 300-375 mg, 325-375 mg, or 350-375 mg; 300-350 mg or 325-350 mg; or 300–325 mg The pharmaceutical composition of claim 6, wherein the composition is

8. 7. The medicament of claim 6, wherein the individual dose provides the SLN360 in an amount of about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, or about 600 mg.

9. 7. The method of claim 6, wherein the individual dose provides the SLN360 in an amount of 300 mg.

10. 7. The method of claim 6, wherein the individual dose provides the SLN360 in an amount of 450 mg.

11. The pharmaceutical composition of claim 1, which is administered to a subject by a dosing regime comprising multiple or a series of doses.

12. 12. The pharmaceutical composition of claim 11, wherein the administration is once every month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, or once every twelve months.

13. The pharmaceutical composition of claim 11, wherein the administration is once every four months.

14. The pharmaceutical composition of claim 11, wherein the administration is once every six months.

15. 12. The method of claim 11, wherein the individual dose provides SLN360 in an amount of 300 mg and the administration is once every four months.

16. 12. The method of claim 11, wherein the individual dose provides SLN360 in an amount of 300 mg, and the administration is once every six months.

17. 12. The method of claim 11, wherein the individual dose provides SLN360 in an amount of 450 mg, and the administration is once every six months.

18. 12. The pharmaceutical composition of claim 11, wherein the interval between successive doses is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

19. The pharmaceutical composition of claim 11, wherein the interval between successive doses is at least 4 months.

20. The pharmaceutical composition of claim 11, wherein the interval between successive doses is at least 6 months.

21. 12. The method of claim 11, wherein the individual dose provides SLN360 in an amount of 300 mg, and the interval between successive doses is at least 4 months.

22. 12. The method of claim 11, wherein the individual dose provides SLN360 in an amount of 300 mg, and the interval between successive doses is at least 6 months.

23. 12. The method of claim 11, wherein the individual doses provide SLN360 in an amount of 450 mg, and the interval between successive doses is at least 6 months.

24. The pharmaceutical composition of claim 1, which is administered by subcutaneous injection.

25. 25. The method of any one of claims 1 to 24, wherein the condition associated with elevated levels of Lp(a) is a cardiovascular disease.

26. 26. The method of claim 25, wherein the condition associated with elevated levels of Lp(a) is atherosclerotic cardiovascular disease or atherosclerotic cerebrovascular disease.

27. 25. The pharmaceutical composition of any one of claims 1 to 24, wherein the condition associated with elevated levels of Lp(a)-containing particles is stroke (e.g., ischemic stroke), atherosclerosis, thrombosis, coronary heart disease, aortic stenosis (e.g., calcific aortic stenosis), hyperlipidemia, dyslipidemia, coronary artery disease, peripheral arterial disease, abdominal aortic aneurysm, heart failure (e.g., heart failure secondary to ischemic cardiomyopathy), or familial hypercholesterolemia.

28. 25. The method of any one of claims 1 to 24, wherein the condition associated with elevated levels of Lp(a) is cancer.

29. The pharmaceutical composition of claim 28, wherein the cancer is prostate cancer.

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