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WO2009156481A1 - Bnp pégylé - Google Patents

Bnp pégylé Download PDF

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Publication number
WO2009156481A1
WO2009156481A1 PCT/EP2009/057993 EP2009057993W WO2009156481A1 WO 2009156481 A1 WO2009156481 A1 WO 2009156481A1 EP 2009057993 W EP2009057993 W EP 2009057993W WO 2009156481 A1 WO2009156481 A1 WO 2009156481A1
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Prior art keywords
bnp
peg
pharmaceutical composition
linker
prodrug
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Inventor
Harald Rau
Silvia Kaden
Ulrich Hersel
Felix Cleemann
Kennett Sprogøe
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Ascendis Pharma AS
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Ascendis Pharma AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising suitable pharmaceutical excipients and also comprising a human in vivo clinical effective amount of a transient PEGylated B-type natriuretic peptide (BNP) prodrug, which may not cause hypotension and controls levels of aldosterone.
  • BNP transient PEGylated B-type natriuretic peptide
  • BNP B-type natriuretic peptide
  • ABP Atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • Uro urodilatin
  • BNP is a 32 amino acid peptide and was originally discovered in extract of porcine brain, leading to the name brain natriuretic peptide. It is present in human brain, but there are significant higher amounts in the cardiac ventricular tissue. BNP is released as response to increased myocardial wall stretch, which is exaggerated in heart failure and is therefore used as a marker for pathology related to high extracellular fluid volumes.
  • BNP binds to the natriuretic peptide receptor A (NPR-A) where it stimulates release of cGMP, that in turn mediates natriuresis, diuresis, inhibition of renin and aldosterone, as well as other effects such as, vasorelaxant, anti-fibrotic, anti-hypertrophic and lusitropic effects.
  • NPR-A natriuretic peptide receptor A
  • hypertension per se is a serious result of an increase in extra-cellular fluid volume and is a major cause of death.
  • BNP is known to have natriuretic, diuretic, and vasorelaxant properties and may have antagonistic effects on the renin-angiotensin (ANG)- aldosterone (Aldo) system. It is understood that these peptides and their analogs (such as Atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) and urodilatin (Uro) are effective in regulating blood pressure by controlling fluid volume and vessel diameter.
  • ADP Atrial natriuretic peptide
  • BNP B-type natriuretic peptide
  • CNP C-type natriuretic peptide
  • Uro urodilatin
  • a number of disease states are characterized by abnormal fluid retention, including congestive heart failure, cirrhosis of the liver and nephrotic syndrome. These diseases are associated with excessive fluid accumulation on the venous side of circulation, and an underperfusion of the kidneys, leading to a fall in glomerular filtration rate (GFR). Since late 1980, BNP was cloned and expressed and a commercial product named Nesiritide has been approved by FDA for clinical indications of management of acute decompressed congestive heart failure (CHF).
  • CHF acute decompressed congestive heart failure
  • BNP product and related medical use of BNP regulating blood pressure by controlling fluid volume and vessel diameter are well described in WO8912069 (Scios) and related patent families (EP418308B1 , US51 14923, US5674710, US65863696).
  • natriuretic peptides are cleared from circulation by several mechanisms.
  • Natriuretic peptides including BNP, bind to Natriuretic Peptide Receptor C, hereafter referred to as NPR-C.
  • BNP binds to NPR-C and is internalized and enzymatically degraded, after which NPR-C returns to the cell surface.
  • Circulating BNP is also degraded by neutral endopeptidases present in the renal tubular cells and vascular cells.
  • BNP is degraded by neutral endopeptidase by initial attack at Met4-Val5. Lastly, a smaller proportion of BNP is excreted through renal filtration.
  • the PEGylated BNP may increase plasma residency duration, decrease clearance rate (hereby achieving reduced dosage), improve stability and decrease antigenicity or a combination thereof.
  • a mechanism for enhancing peptide availability is by conjugation of the peptide with derivatizing compounds, which include, but are not limited to, polyethylene glycol and polypropylene glycol.
  • derivatizing compounds include, but are not limited to, polyethylene glycol and polypropylene glycol.
  • Cataliotti et al. (Trends in Cardiovascular Medicine, VoI 17, Issue 1 , January 2007, Pages 10-14) describes conjugation of BNP to PEG oligomers.
  • Four distinct conjugation sites are described namely serine-1 (the N-terminal), lysine-3, lysine-14 and ly-sine-27.
  • Cataliotti et al. describe that since BNP binding to NPR-A mostly is believed to occur in the loop region, it is expected that activity will be compromised upon conjugation to lysine-14 and perhaps lysin-27. It is shown that conjugation to one or two sites in the loop region results in partial or full loss of activity, respectively. Conjugation to lysine-3 retains the biological activity.
  • Cataliotti's interest was to identify positions to where a conjugate could be attached to without losing the biological activity (page 1 1 of publication "Trends in Cardiovascular Medicine, VoI 17, Issue 1 , January 2007, Pages 10-14"). Cataliotti does not describe anything about cleavable linkers and one may objectively say that this article teaches away from using a cleavable linker using a self hydrolysable (autocleavage) transient linker.
  • WO2006076471 describes orally (transportable through the epithelium) available conjugates of polypeptides, such as BNP.
  • the problem to be solved in WO2006076471 is to provide BNP which is protected against proteolytic enzymes.
  • the solution provided is to conjugate with PEG.
  • the inventors of patent WO2006076471 had no specific interest to inactivate the conjugates and selected actually the most active ones for further evaluation. In this invention, it teaches away from such selection of inactivate conjugates.
  • the main interest in WO2006076471 was to identify conjugates most suitable for transdermal penetration (orally administered).
  • BNP is approved for acute CFH and patients are obliged to get such treatment in a hospital under intensive care. This is therefore an expensive (hospital time) treatment.
  • the chronic treatment of CFH with BNP is not approved by FDA.
  • Hypotension is abnormally low pressure of the blood and called also low blood pressure.
  • One of the adverse effects for administration of BNP is hypotension.
  • Symptomatic hypotension can be defined as a significant decrease in blood pressure (in excess of what would be intended with an intravenous vasodilator) and can be associated with 1 or more of the following symptoms: lightheadedness, dizziness, feeling faint, or having blurred vision.
  • BNP administration may be beneficial in treating conditions relating to high volumes of extracellular fluid because of a direct natriuretic action, increased cardiac output, and/or decreased aldosterone levels.
  • Aldosterone is important in the pathophysiology of heart failure because of its ability to increase sodium retention and potassium loss. Aldosterone production is activated in failing ventricles of humans. Concentration of aldosterone within the heart is reported to greatly exceed circulating concentrations.
  • the problem to be solved by the present invention is to reduce the administration frequency of recombinant BNP.
  • This problem is solved by use of special types of PEG conjugated to BNP as described herein.
  • the herein described BNP PEG conjugate releases sustainably the correct dosage over time and reduces the risk of inducing hypotension.
  • a bolus injection is an injection of a drug (or drugs) in a high quantity (called a bolus) at once.
  • a bolus injection is thought to relate to hypotension.
  • the current invention does not require a bolus injection in order to reach the correct plasma BNP profile. Further in the present invention is claimed the sustained release of relevant lower dosage of BNP to suppress aldosterone hormone as treatment for chronic congestive heart failure.
  • Cataliotti et al. (Trends in Cardiovascular Medicine, VoI 17, Issue 1 , January 2007, Pages 10-14) describes conjugation of BNP to PEG oligomers. Cataliotti's interest was to identify positions to where a conjugate could be attached without losing the biological activity. In current invention, it is the purpose to deactivate BNP and to deliver the optimal sustained release in terms of dosage over the time obtaining virtual no hypotension side effects.
  • WO2006076471 describes orally (transportable through the epithelium) available conjugates of polypeptides, such as BNP.
  • the problem to be solved in WO2006076471 is to provide BNP which is protected against proteolytic enzymes.
  • the solution provided is to conjugate with PEG.
  • class 3 modifying moieties which are full hydrolysable. There are no data provided of this class 3 conjugates.
  • Figure 4 shows several conjugates orally dosed, which have longer half-life than did native BNP (tested trypsin digestion rate).
  • the therein described conjugates BN-002, 021 , BN-022 and BN-024 have an activity closest to native BNP.
  • patent WO2006076471 had thus no specific interest to inactivate the conjugates and selected actually the most active conjugates for further evaluation. In this invention, it teaches away from such selection. Also, the main interest in WO2006076471 was to identify conjugates most suitable for transdermal penetration (orally administered) and the selected candidates are not prodrugs as termed in this invention.
  • the self hydrolysable transient linker PEGylated BNP conjugated prodrug - as described herein - releases the drug in such a way that native BNP is sustainably released and controls a therapeutic effective concentration in the plasma when administered at appropriate intervals.
  • PEG is linked to BNP via a self hydrolysable (autocleavage) transient linker, wherein the linker autohydrolysis rate is such that the in vivo linker half-life is from 50 hours to 500 hours.
  • Feature (1 ) delivers conjugates which are substantially inactive and can be used as useful prodrugs.
  • Feature (2) ensures release the drug in such a way that native BNP is sustainably released and controls a therapeutic effective concentration in the plasma.
  • Feature (1 ) and (2) together delivers the enormous advantage that now the drug can be administered (subcutaneously) for example once weekly.
  • Such administration can be done for example by a nurse visiting the patient or eventually by the patient itself. This saves hospital visits (saving cost), gives the patient comfort and secures that the drug is present in an effective concentration over time without causing risk of hypotension. All this is not possible today with the current way of BNP administration.
  • a first aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising pharmaceutically acceptable excipients and also comprising a PEGylated prodrug capable of releasing an in vivo clinically effective amount of a recombinant human BNP (BNP without PEG), wherein the prodrug is characterized by that:
  • PEG is linked to BNP via a self hydrolysable (autocleavage) transient linker, wherein the linker autohydrolysis rate is such that the in vivo linker half-life is from 50 hours to 500 hours, measured according to the assay to measure autocleavage rate of the transient linker of the prodrug of example 2.
  • Congestive heart failure is reduced ability of the heart to pump blood around the body.
  • the body tries to compensate by retaining water to increase blood volume, but this further weakens the heart.
  • Diuretic drugs reduce water in the body.
  • BNP is approved for acute CHF and therefore patients suffering of decompensated congestive heart failure (CHF) are obliged to get treatment in the hospital (a typical 4 hour infusion once weekly applied in the hospital intensive care). This is therefore an expensive treatment requiring in some cases prolonged hospital time (staying overnight for extra observations).
  • CHF congestive heart failure
  • the present invention overcomes this burden by delivering self hydrolysable transient linker PEGylated BNP conjugated prodrug administered subcutaneously e.g. once weekly.
  • Figure 2 illustrates a typical BNP plasma profile of a continuous infusion of 15 ng/kg/min for 4 hours.
  • BNP blood pressure
  • Figure 3 shows a plasma profile and is a simulation of a plasma profile of a single subcutaneous injection of a sustained release formulation using transiently conjugated nesiritide (BNP).
  • BNP transiently conjugated nesiritide
  • transiently linked BNP prodrug as described in the present invention, it is possible to administer a therapeutic relevant amount of BNP as a subcutaneous injection on e.g. a weekly basis. Due to the slow autohydrolysis of the linker, native BNP is released in a predetermined fashion ensuring a plasma profile free of significant burst effect and with a peak-to-trough ratio of less than 10.
  • the in vivo linker half life can be engineered such that the maximum BNP concentration will be below the concentration inducing symptomatic hypotension. Furthermore, due to the simplicity of subcutaneous administration the need for expensive in hospital intravenous infusion is eliminated.
  • a second aspect of the invention relates to a clinically effective amount of the pharmaceutical composition comprising BNP PEGylated prodrug of the first aspect for use in a method for the treatment of a BNP related disease in a human, wherein the treatment comprises administering the pharmaceutical composition as one administration during a treatment period and wherein the treatment is characterized by that after the one administration of the pharmaceutical composition is the ratio during the treatment period, between the highest concentration of active BNP drug (BNP without PEG) in plasma during the treatment period and the concentration of active BNP drug in the plasma at the end of the treatment period, less than 10, wherein the treatment period is a period of at least three days.
  • This second aspect may alternatively be formulated as a method of treating a BNP related disease in a human which comprises administering the pharmaceutical composition comprising the BNP PEGylated prodrug of the first aspect as one administration during a treatment period characterized by that after one administration of the pharmaceutical composition during the treatment period is the ratio, between the highest concentration of active BNP drug (BNP without PEG) in plasma during the treatment period and the concentration of active BNP drug in the plasma at the end of the treatment period, less than 10, wherein the treatment period is a period of at least three days.
  • Aldosterone is important in the patho-physiology of heart failure because of its ability to increase sodium retention and potassium loss. Aldosterone production is activated in failing ventricles of humans. Concentration of aldosterone within the heart is reported to greatly exceed circulating concentrations. Self hydrolysable transient linker PEGylated BNP conjugated prodrug, releases the drugs in a controlled way and it is an advantage that a specific low concentration of drug is released which can suppress the hormone aldosterone. The suppression of aldoste-rone by sustained release of low concentration of BNP has a therapeutic advantage.
  • activity herein is understood as the ability of BNP or a conjugate thereof, to evoke a clinically relevant biological response when administered to a mammal, e.g. in an in vivo model, or to produce a measureable response in an in vitro model as described in examples.
  • autocleavage herein is understood as spontaneous cleavage of the bond between the transient linker and the drug molecule BNP under physiological conditions, the latter being defined as a pH in the range 7.0 - 7.8 and a temperature of between 35 0 C to 4O 0 C.
  • BNP B-type natriuretic peptide
  • conjugate herein is understood as a PEG molecule covalently bound to the drug herein being BNP.
  • in vivo linker half life is understood as the time interval in which 50% of the initial proportion of BNP is released from the PEGylated BNP conjugate after administration to a mammal and corrected for systemic clearance of the PEGylated BNP conjugate and can be measured as described in Example 2.
  • hypotension refers to an abnormally low blood pressure. This is best understood as a physiologic state, rather than a disease. Hypotension is the opposite of hypertension, which is high blood pressure. Hypotension can be life-threatening. Hypotension can also lead to renal damage due to lack of blood circulating through the kidneys.
  • the therapeutic window is the acceptable range of concentration of the drug in plasma.
  • the window falls between the maximum acceptable dose (as determined by effect vs. tolerability of side effects) and lowest concentration exhibiting therapeutic effect.
  • the risk of hypotension is observed in the higher dose range. Without being limited to theory, the fluctuation of drug concentration in the plasma it is also believed to contribute to side effects.
  • a "pharmaceutical composition comprising "a human in vivo clinically effective amount of a recombinant human BNP PEGylated prodrug" is to be understood as an amount that is sufficiently high to obtain a wanted clinical effect in a human after administration of the pharmaceutical composition to the human - e.g. a wanted clinical effect in relation to treatment of a BNP related disease.
  • the skilled person routinely is able to adjust the amount of recombinant human BNP PEGylated prodrug to be administered in order to get a wanted clinical effect.
  • PEG is also known as Poly(ethylene glycol).
  • Prodrug herein is understood is any compound that undergoes transformation before exhibiting its pharmacological effects. Prodrugs can thus be viewed as drugs containing specialized non-toxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule.
  • transient linker is a linker in which the conjugation of drug to PEG molecule is reversible. This implies that autocleavage of the linker releases the drug in its native and active form. Furthermore, cleavage of the linker proceeds at a predictable manner releasing the unmodified drug over many hours independent of enzyme activity.
  • therapeutic window is herein understood as the window where the active drug has a therapeutic effect and typically has a peak and a trough, where the peak level is the highest allowable concentration in the plasma and is mostly obtained straight after administration and a minimum lower amount of drug (typically after some time circulation in the body) in the plasma still having a therapeutic effect (also termed Trough).
  • Figure 1 Structure and amino acid sequence for BNP.
  • FIG. 1 Plasma profile of a continuous infusion of 15 ng/kg/min for 4 hours. This profile is cited in Scios' Clinical Pharmacology and Bio-pharmaceutics Review: Natrecor (nesiritide) appendix 4.
  • FIG. 3 Simulated plasma profile of a single subcutaneous injection of a sustained release formulation using transiently conjugated nesiritide (BNP) as described herein. Dashed line represents BNP bound in the inactive conjugate. Solid line represents free circulating BNP.
  • BNP transiently conjugated nesiritide
  • composition comprising suitable pharmaceutical excipients
  • composition comprises pharmaceutical acceptable excipients and/or carriers.
  • “Pharmaceutically acceptable” is meant to encompass any excipient and/or carrier, which does not interfere with the effectiveness of the biological activity of the active ingredient and that is not toxic to the host to which it is administered.
  • the pharmaceutical composition is a composition for subcutaneous administration, intramuscular administration or intravenous injection. Most preferred is a subcutaneous administration.
  • the pharmaceutical composition may comprise other active ingredients than a BNP PEGylated prodrug as described herein.
  • Activity BNP with PEG is a BNP PEGylated prodrug as described herein.
  • the BNP PEGylated prodrug as described herein shall have a relatively low activity.
  • a preferred embodiment is the PEG conjugate which has a BNP activity of less than 4% compared to the native BNP without PEG, more preferably less than 3%, even more preferably less than 1 % and most preferably is the PEG-BNP conjugate virtually inactive, measured according to the assay to measure BNP PEGylated prodrug and BNP activity of example 1.
  • a PEGylated-prodrug wherein the drug is for example BNP as described in patent application WO2005099768.
  • the drug is for example BNP as described in patent application WO2005099768.
  • transient linker structures to get a relevant release profile of interest.
  • Other "transient" linker structures are generically/broadly described in e.g. other
  • a conjugate of the invention will possess one or more of the following features and/or advantages over current BNP conjugates or formulations; can easily be syn- thesized in good yields, have half life's falling within preferred range, can be purified to provide homogeneous conjugate compositions, exhibit activity after autocleavage such as in vitro and in vivo activity and have pharmacodynamic effects superior to unmodified BNP and previously described BNP conjugates and do not cause hypotension.
  • conjugates exhibit activity after autocleavage such as in vitro and in vivo activity and have pharmacodynamic effects superior to unmodified BNP and previously described BNP conjugates and suppress aldosterone hormone.
  • a preferred embodiment is a self hydrolysable (autocleavage) transient linker described herein where the linker autohydrolysis rate is such that the in vivo linker half life is from 40 hours to 600 hours; more preferred from 72 hours to 300 hours, more preferred from 96 hours to 192 and most preferred 120 hours to 192 hours.
  • the preferred self hydrolysable transient linker structure is:
  • R2, R3, R4, and R5 are selected independently from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl
  • R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl or
  • n 1 or 2
  • X is selected from C1 to C8 alkyl or C1 to C12 heteroalkyl including heterocycloalkyl
  • BNP is conjugated to the PEG-linker conjugate via a carbamate bond by one of its amino groups.
  • R1 and R2 are selected independently from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cycloalkyl and
  • R1 and R2 may be connected to form a C4 to C8 cycloalkyl and X is selected from C1 to C8 alkyl or C1 to C12 heteroalkyl
  • BNP is linked to the PEG-linker moiety (PEG-linker-BNP structure) via an amide bond by one of its amino groups.
  • PEG structures including linear and branched
  • the PEG structures include linear and branched PEG moieties with molecular weights between 5 kDa and 200 kDa.
  • Preferred PEG structures include linear and branched PEG moieties with molecular weights between 5 kDa and 200 kDa and more preferred PEG molecular weights between 20 and 80 kDa.
  • one to eight BNP molecules are attached to one PEG molecule.
  • one to four BNP molecules are attached to one PEG.
  • PEG-Linker-BNP with one, two or four BNP molecules attached to one PEG molecule include preferred embodiments and can be selected from the group consisting of
  • L is a transient linker and PEG is a polyethylene glycol derivative and are selected from the group consisting of
  • BNP carrier molecule
  • 4 BNP molecules are attached to one 4 armed PEG as shown below.
  • the PEG functions as such especially for a small peptide as BNP, by attaching more BNP molecules per PEG, is maximized.
  • BNP Brain Natriuretic Peptide
  • biopharmaceuticals herein is understood generic forms of biopharmaceuticals; molecules developed using biological processes, usually through modern biotechnology activity.
  • Generic chemical pharmaceuticals can be defined as those molecules which, when compared with the originator product have essentially similar activity, are bioequivalent, achieve market authorization through an abbreviated procedure following patent expiry.
  • BNP a biologies of interest
  • fusion peptides of natriuretic peptides can be of interest herein.
  • the fusion peptides are e.g. produced by combining two or more peptide sequences selected from the group of natriuretic peptides.
  • natriuretic peptides that can be objects of the present inventions are peptides with natriuretic activity, such as ANP, CNP, DNP, Urodilatin and albuBNP, as well as the peptides described in the following patents and patent applications, which are incorporated herein in their entirety; WO2008/021872 A1 ; WO2008/031045 A2;
  • BNP levels in the plasma over time with nesiritide treatment is the topic of ongoing investigation. It is expected that levels could rise to above 3 ng/ml during the infusion and then fall rapidly after discontinuation of therapy to levels below baseline (reflecting the lower ventricular filling pressure achieved).
  • the therapeutic range of BNP in the plasma is in the range of 0.1 ng/ml to 3 ng/ml, more preferred between 0.8 ng/ml and 1.2 ng/ml.
  • Natrecor may cause hypotension.
  • the incidence of symptomatic hypotension in the first 24 hours was similar for Natrecor (4%) and IV nitroglycerin (5%).
  • the herein described conjugated BNP prodrug compounds release active BNP and have a preferred incidence of symptomatic hypotension of maximum 5% and most preferred no symptomatic hypotension. Ratio between the highest and lowest concentration of active BNP drug during treatment period
  • a trough level is generally defined as the lowest plasma concentration and is achieved just prior to re-administration of a drug.
  • the peak value will be outside the therapeutic range and cause side effects and the trough level will be below the therapeutic window and hence not have therapeutic effect.
  • Peak to trough level can also be more simply described as herein is discussed a ratio between the highest concentration of active BNP in plasma and the lowest concentration of active BNP drug in the plasma during treatment.
  • the administration of the PEGylated BNP conjugated pro-drug causes BNP to be present at least 3 days in the plasma, more preferred 5 days and most preferred 7 days and the ratio between highest and lowest plasma concentration within the dosing period is less than 10, more preferred less than 5.
  • the suppression of aldosterone can improve the BNP related disease treatment. It is therefore an advantage which can be delivered by the herein described PEGylated prodrug that a sustained release also helps to suppress aldosterone.
  • the treatment period is a period of at least three days.
  • the treatment period is a period of at least four days, more preferably of at least five days, even more preferably the treatment period is a period of at least six days. Most preferably the treatment period is a period of at least seven days.
  • the BNP-PEG conjugate as described herein is given as a one time administration during the treatment period. After the treatment period has ended, one may start a new treatment by administrating the BNP-PEG conjugate again.
  • This new period may e.g. be started by administrating the BNP-PEG conjugate just after the prior (e.g. first) treatment period has ended. For instance, if the treatment period is three days one may administrate the BNP-PEG conjugate at the end of day three and start a new treatment period of e.g. three extra days. In such a case the complete accumulated treatment period will be 6 days.
  • BNP-PEG conjugate By such regular administration of BNP-PEG conjugate as described herein one may get a very long total accumulated treatment period, wherein the active BNP concentration is constantly within the therapeutic window during the total accumulated treatment period.
  • the patient will have a total accumulated treatment period of 52 weeks, wherein the active BNP concentration is constantly within the therapeutic window.
  • the treatment of the human is done for at least ten continuous treatment periods - with one administration of the BNP PEGy-lated prodrug in each period - wherein the active BNP concentration is constantly within the therapeutic window during the total accumulated treatment period.
  • the therapeutic window may be understood as the ratio of the second aspect herein.
  • BNP relates diseases
  • BNP related disease of second aspect simply herein relates to diseases and conditions where a human could benefit from BNP.
  • CHF Congestive heart failure
  • Congestive heart failure occurs when the heart can no longer meet the metabolic demands of the body at normal physiologic venous pressures.
  • the heart can respond to increased demands by means of one of the following: increasing the heart rate, which is controlled by neural and humoral input, increasing the contractility of the ventricles, secondary to both circulating catecholamines and autonomic input and augmenting the preload, medicated by constriction of the venous capacitance vessels and the renal preservation of intravascular volume.
  • the disease is decompensated congestive heart failure.
  • Example 1 Assay to measure BNP PEGylated prodrug and BNP activity
  • the residual activity of conjugated BNP can be determined using a cell based assay using human aortic smooth muscle cells, for example as described in WO 2006/076471.
  • Human aortic smooth cells are treated with BNP and test materials at varying concentrations.
  • the occurrence of cGMP in the cells were measured and used as indicator for BNP activity.
  • EC50 values can be calculated and compared to that of native BNP.
  • HAEC Human aortic endothelial cells
  • Cambrex Cambrex (Clonetics). Cells were thawed and placed in a T75 flask prior to use in an experiment. Cells were grown for two days until they reached 70-80 % confluence and were then plated into 12 well plates at 2.5 x 104cells/well. The next day the media was removed and cells were pre-incubated for 10 min at 37 0 C with 0.5 mM IBMX to inhibit phosphodieste-rases. Conjugates to be screened were added to the cells for an additional 60 min at 37 0 C. Incubation was stopped by lysing cells using Cell Lysis Solution (Molecular Devices).
  • cGMP was then measured using an ELISA- based cGMP kit.
  • CatchPoint-cyclic GMP Fluorescent Assay Kit catalog #R8074, Molecular Devices Corp, Sunnyvale, CA. This kit measures cGMP via a competitive immunoassay in 96-well format. Lysates were added to the coated microplate followed by the addition of an anti-cGMP antibody and a horseradish peroxidase (HRP)-cGMP conjugate. Plates were incubated for two hours at room temperature, followed by four washes. As known to the skilled person one may identify a kit with essentially the same characteristics as the kit catalog numbers mentioned above.
  • Example 2 Assay to measure autocleavage rate of the transient linker of the BNP prodrug. Determination of in vitro autocleavage rate
  • the compounds are dissolved in buffer at pH 7.4 (e.g. 10 mM sodium phosphate, 140 mM NaCI, 3 mM EDTA) and solution is filtered through a 0.22 ⁇ m filter and incubated at 37 0 C. Samples are taken at time intervals and analyzed by RP-HPLC or size exclusion chromatography at 215 nm. UV-signals correlating to liberated BNP are integrated and plotted against incubation time. Curve fitting software is applied to determine first-order cleavage rates.
  • pH 7.4 e.g. 10 mM sodium phosphate, 140 mM NaCI, 3 mM EDTA
  • Linker cleavage rates in vivo are determined by comparing the pharmacokinetics of permanent PEG-BNP conjugates with the respective transient PEG-linker-BNP conjugate carrying the same PEG moiety after intravenous injection into rat.
  • permanent PEG-BNP is injected intravenously into rats and blood samples are taken at time intervals, plasma prepared, and analyzed for BNP using an ELISA.
  • transient PEG-linker-BNP is injected intravenously in rats, blood samples are taken at time intervals, plasma prepared, and analyzed for BNP using an ELISA.
  • Linker autocleavage half-life is calculated from the ratio of BNP concentration of transient conjugate divided by determined BNP concentration of permanent conjugate at the respective time points and curve fitting. Data are compared to in vitro cleavage rates.
  • Blood pressure in human subjects can be measured with a sphygmomanometer.
  • blood pressure can be monitored by implantation of a blood pressure transducer, for example as described in WO 2007/115182. Rats are induced to a surgical plane of anesthesia with isoflurane and maintained on a heating pad. The abdomen is shaved and scrubbed with 70% alcohol and betadine solution. Using aseptic technique, a midline abdominal incision is made in order to expose the descending aorta and vena cava. The contents of the abdomen are retracted gently using wet sterile gauze and retractors. Based on the manufacturer's instructions (described in Data Sciences International's Multiplus TL Series Device Surgical Manual 2000: pp.
  • the abdominal aorta is carefully dissected from the surrounding fat and connective tissue and the catheter of the blood pressure transducer is inserted.
  • the catheter of the transducer is secured into place using surgical glue and the body of the transducer stabilized by suturing to the abdominal wall (4-0 silk suture). Care is taken to ensure that hemostasis is maintained during the procedure and that blood flow is not compromised (e.g. aorta will not be occluded for more than 3 minutes at a time).
  • Transducer placement is verified using the telemetry radio signal. After transducer placement, the gauze sponges are removed and the abdominal cavity is flushed with sterile saline.
  • Plasma concentration of aldosterone can be measured using commercial kits. Blood samples are drawn from animal or human subjects after a period of rest, transferred to suitable chilled buffer and centrifuged, for example as described by Yamato et al., Circ J 2003 May; 67(5): 384-90. Blood samples are drawn by venipuncture after at least 30 min of rest with the patient in the supine position. Samples were placed immediately in a prechilled tube containing sodium EDTA and centrifuged at 3,000 rpm for 10 min. Plasma concentration of aldosterone (SPAC-S Aldosterone Kit; Dainabot Inc, Tokyo, Japan) were measured by radioimmunoassay using the commercial kits.
  • SPAC-S Aldosterone Kit Dainabot Inc, Tokyo, Japan

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Abstract

La présente invention concerne un BNP humain chimiquement modifié (BNP) préparé par liaison d’un lieur transitoire qui comprend un polyéthylèneglycol. Le peptide chimiquement modifié peut avoir une activité BNP beaucoup plus durable que celle du BNP non modifié, permettant de réduire la dose et offrant des opportunités de planification et le BNP modifié peut ne pas causer d’hypotension. La présente invention concerne en outre des procédés d’utilisation pour le traitement et/ou la prévention de maladies ou troubles dans lesquels l’utilisation de BNP est bénéfique.
PCT/EP2009/057993 2008-06-25 2009-06-25 Bnp pégylé Ceased WO2009156481A1 (fr)

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US9266939B2 (en) 2010-12-27 2016-02-23 Alexion Pharmaceuticals, Inc. Compositions comprising natriuretic peptides and methods of use thereof
US10052366B2 (en) 2012-05-21 2018-08-21 Alexion Pharmaceuticsl, Inc. Compositions comprising alkaline phosphatase and/or natriuretic peptide and methods of use thereof
US10449236B2 (en) 2014-12-05 2019-10-22 Alexion Pharmaceuticals, Inc. Treating seizure with recombinant alkaline phosphatase
US10603361B2 (en) 2015-01-28 2020-03-31 Alexion Pharmaceuticals, Inc. Methods of treating a subject with an alkaline phosphatase deficiency
US10822596B2 (en) 2014-07-11 2020-11-03 Alexion Pharmaceuticals, Inc. Compositions and methods for treating craniosynostosis
CN111978390A (zh) * 2020-08-31 2020-11-24 上海景泽生物技术有限公司 聚乙二醇修饰的rhBNP及其用途
US10898549B2 (en) 2016-04-01 2021-01-26 Alexion Pharmaceuticals, Inc. Methods for treating hypophosphatasia in adolescents and adults
US10988744B2 (en) 2016-06-06 2021-04-27 Alexion Pharmaceuticals, Inc. Method of producing alkaline phosphatase
US11065306B2 (en) 2016-03-08 2021-07-20 Alexion Pharmaceuticals, Inc. Methods for treating hypophosphatasia in children
US11116821B2 (en) 2016-08-18 2021-09-14 Alexion Pharmaceuticals, Inc. Methods for treating tracheobronchomalacia
US11154593B2 (en) 2016-01-08 2021-10-26 Ascendis Pharma Growth Disorders A/S CNP prodrugs with large carrier moieties
US11186832B2 (en) 2016-04-01 2021-11-30 Alexion Pharmaceuticals, Inc. Treating muscle weakness with alkaline phosphatases
US11224637B2 (en) 2017-03-31 2022-01-18 Alexion Pharmaceuticals, Inc. Methods for treating hypophosphatasia (HPP) in adults and adolescents
US11224661B2 (en) 2016-01-08 2022-01-18 Ascendis Pharma Growth Disorders A/S Controlled-release CNP agonists with increased NEP stability
US11229686B2 (en) 2015-09-28 2022-01-25 Alexion Pharmaceuticals, Inc. Reduced frequency dosage regimens for tissue non-specific alkaline phosphatase (TNSALP)-enzyme replacement therapy of hypophosphatasia
US11248021B2 (en) 2004-04-21 2022-02-15 Alexion Pharmaceuticals, Inc. Bone delivery conjugates and method of using same to target proteins to bone
US11311604B2 (en) 2016-01-08 2022-04-26 Ascendis Pharma Growth Disorders A/S Controlled-release CNP agonists with low NPR-C binding
US11352612B2 (en) 2015-08-17 2022-06-07 Alexion Pharmaceuticals, Inc. Manufacturing of alkaline phosphatases
US11389510B2 (en) 2016-01-08 2022-07-19 Ascendis Pharma Growth Disorders A/S Controlled-release CNP agonists with low initial NPR-B activity
US11389511B2 (en) 2016-01-08 2022-07-19 Ascendis Pharma Growth Disorders A/S Controlled-release CNP agonists with reduced side-effects
US11400140B2 (en) 2015-10-30 2022-08-02 Alexion Pharmaceuticals, Inc. Methods for treating craniosynostosis in a patient
US11413351B2 (en) 2016-01-08 2022-08-16 Ascendis Pharma Growth Disorders A/S CNP prodrugs with carrier attachment at the ring moiety
US11564974B2 (en) 2016-09-29 2023-01-31 Ascendis Pharma Growth Disorders A/S Combination therapy with controlled-release CNP agonists
US11590207B2 (en) 2016-09-29 2023-02-28 Ascendis Pharma Bone Diseases A/S Dosage regimen for a controlled-release PTH compound
US11759504B2 (en) 2016-09-29 2023-09-19 Ascendis Pharma Bone Diseases A/S PTH compounds with low peak-to-trough ratios
US11793861B2 (en) 2016-03-01 2023-10-24 Ascendis Pharma Bone Diseases A/S PTH prodrugs
US11913039B2 (en) 2018-03-30 2024-02-27 Alexion Pharmaceuticals, Inc. Method for producing recombinant alkaline phosphatase
US12083169B2 (en) 2021-02-12 2024-09-10 Alexion Pharmaceuticals, Inc. Alkaline phosphatase polypeptides and methods of use thereof
US12268733B2 (en) 2018-08-10 2025-04-08 Alexion Pharmaceuticals, Inc. Methods of treating neurofibromatosis type 1 and related conditions with alkaline phosphatase
US12377133B2 (en) 2019-02-11 2025-08-05 Ascendis Pharma Growth Disorders A/S Dry pharmaceutical formulations of CNP conjugates
US12403182B2 (en) 2019-02-11 2025-09-02 Ascendis Pharma Bone Diseases A/S Liquid pharmaceutical formulations of PTH conjugates
US12433938B2 (en) 2019-12-09 2025-10-07 Alexion Pharmaceuticals, Inc. Alkaline phosphatase polypeptides and methods of use thereof
US12453778B2 (en) 2016-09-29 2025-10-28 Ascendis Pharma Bone Diseases A/S Incremental dose finding in controlled-release PTH compounds

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US9561285B2 (en) 2010-01-22 2017-02-07 Ascendis Pharma As Carrier-linked carbamate prodrug linkers
WO2011089214A1 (fr) * 2010-01-22 2011-07-28 Ascendis Pharma As Lieurs de précurseurs à base de carbamates liés à des supports
US9266939B2 (en) 2010-12-27 2016-02-23 Alexion Pharmaceuticals, Inc. Compositions comprising natriuretic peptides and methods of use thereof
US10052366B2 (en) 2012-05-21 2018-08-21 Alexion Pharmaceuticsl, Inc. Compositions comprising alkaline phosphatase and/or natriuretic peptide and methods of use thereof
US10822596B2 (en) 2014-07-11 2020-11-03 Alexion Pharmaceuticals, Inc. Compositions and methods for treating craniosynostosis
US11224638B2 (en) 2014-12-05 2022-01-18 Alexion Pharmaceuticals, Inc. Treating seizure with recombinant alkaline phosphatase
US10449236B2 (en) 2014-12-05 2019-10-22 Alexion Pharmaceuticals, Inc. Treating seizure with recombinant alkaline phosphatase
US11564978B2 (en) 2015-01-28 2023-01-31 Alexion Pharmaceuticals, Inc. Methods of treating a subject with an alkaline phosphatase deficiency
US10603361B2 (en) 2015-01-28 2020-03-31 Alexion Pharmaceuticals, Inc. Methods of treating a subject with an alkaline phosphatase deficiency
US11352612B2 (en) 2015-08-17 2022-06-07 Alexion Pharmaceuticals, Inc. Manufacturing of alkaline phosphatases
US11229686B2 (en) 2015-09-28 2022-01-25 Alexion Pharmaceuticals, Inc. Reduced frequency dosage regimens for tissue non-specific alkaline phosphatase (TNSALP)-enzyme replacement therapy of hypophosphatasia
US11400140B2 (en) 2015-10-30 2022-08-02 Alexion Pharmaceuticals, Inc. Methods for treating craniosynostosis in a patient
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US11224661B2 (en) 2016-01-08 2022-01-18 Ascendis Pharma Growth Disorders A/S Controlled-release CNP agonists with increased NEP stability
US11154593B2 (en) 2016-01-08 2021-10-26 Ascendis Pharma Growth Disorders A/S CNP prodrugs with large carrier moieties
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US11890326B2 (en) 2016-09-29 2024-02-06 Ascendis Pharma Bone Diseases A/S Controlled-release PTH compound
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US12295989B2 (en) 2016-09-29 2025-05-13 Ascendis Pharma Bone Diseases A/S Controlled-release PTH compound
US11590207B2 (en) 2016-09-29 2023-02-28 Ascendis Pharma Bone Diseases A/S Dosage regimen for a controlled-release PTH compound
US11564974B2 (en) 2016-09-29 2023-01-31 Ascendis Pharma Growth Disorders A/S Combination therapy with controlled-release CNP agonists
US11224637B2 (en) 2017-03-31 2022-01-18 Alexion Pharmaceuticals, Inc. Methods for treating hypophosphatasia (HPP) in adults and adolescents
US11913039B2 (en) 2018-03-30 2024-02-27 Alexion Pharmaceuticals, Inc. Method for producing recombinant alkaline phosphatase
US12268733B2 (en) 2018-08-10 2025-04-08 Alexion Pharmaceuticals, Inc. Methods of treating neurofibromatosis type 1 and related conditions with alkaline phosphatase
US12377133B2 (en) 2019-02-11 2025-08-05 Ascendis Pharma Growth Disorders A/S Dry pharmaceutical formulations of CNP conjugates
US12403182B2 (en) 2019-02-11 2025-09-02 Ascendis Pharma Bone Diseases A/S Liquid pharmaceutical formulations of PTH conjugates
US12433938B2 (en) 2019-12-09 2025-10-07 Alexion Pharmaceuticals, Inc. Alkaline phosphatase polypeptides and methods of use thereof
CN111978390A (zh) * 2020-08-31 2020-11-24 上海景泽生物技术有限公司 聚乙二醇修饰的rhBNP及其用途
US12083169B2 (en) 2021-02-12 2024-09-10 Alexion Pharmaceuticals, Inc. Alkaline phosphatase polypeptides and methods of use thereof

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