OA17297A - Method for treating sepsis in patients with albumin, cholesterol and HDL levels above minimum thresholds. - Google Patents

Abstract

The invention relates to a method for treating sepsis in subjects who exhibit serum albumin levels, and one of total cholesterol or HDL levels, above minimum threshold values. The method involves intravenous administration of an emulsion, which contains a phospholipid, a neutral lipid, and a cholate salt.

Description

loi) This invention relates to treatment of patients sufîering from sepsis. More particularly, it relates to treating defined, subpopulations of patients who suffer from this condition.

BACKGROUND AND PRIOR ART [02] It has been estimated that there are more than 18 million cases of sepsis per year, with the mortality rate in severe cases making it the second leading cause of deaths in noncoronary intensive care units. See, e.g., Dellinger, et al.. Crit. Care Med, 37(11):2929-2938 (2009), incorporated by reference; Dellinger, et al., Crit. Care Med, 36(1):296-327 (2008), also incorporated by reference; Marshall, et al.. J Infect. Diseases, 190:527-534 (2004), also incorporated by reference.

103] Broadly defined, sepsis refers to the presence of a systemic inflammatory response resulting from bacteriai infection. In tum, a systemic inflammatory response is defined as the presence of two or more abnormalities in body température, heart rate, respiratory rate or blood gas, and an abnormal white blood cell count. Severe sepsis” results from dysfunction of one or more organs as a resuit of the response to the above infection, while “septic shock” occurs with the development of cardiovascular instability, including hypotension, also resulting from a response to the above infection. The term “severe septic shock” inciudes both severe sepsis and septic shock.

104] When sepsis is used herein, ail of the above conditions are encompassed thereunder.

[05] Approaches to treating sepsis include, inter alia, administration of intravenous fluids, antibiotics, vasopressors, and steroids. None hâve been very successful and in the case of steroids, therapeutic approaches are controversial. Notwithstanding these approaches, as

Dellinger et al, (2009). supra, reports, mortality remains high, and a large medical need remains unmet. q/· [06] U.S. Patent No. 5,674,855 to Levine, et al., the disclosure of which is incorporated by reference describes émulsions of various materials, which showed efficacy in treatment of endotoxemia. In brief, the émulsions contain a phospholipid (phosphatidylcholine), a neutral lipid (triglycéride), and a cholate sait (sodium cholate). Various ranges of the materials in relationshlp to each other are described. The patent discloses a process for making the émulsion, as well as methods for the intravenous administration thereof.

[07] A product based upon these formulations, referred to as GR270773, was tested for efficacy in dialysis patients with endotoxemia (seewww.clinicaltrials.gov, identifier NCT00506454), and in a very widespread trial reported by Dellinger (2009), supra. The dialysis trial showed no efficacy whatsoever, and the clinical trial reported by Dellinger et al., supra concluded that the émulsion did not show efficacy greater than treatment with a placebo.

[08] It has now been found, however, that émulsions of the type described in the '855 patent do in fact hâve surprising efficacy in a subset of patients, as defined herein. Such a resuit was not to be expected from the literature which concluded that the émulsions were ineffective.

[09] Details of this invention are set forth in the Detailed Description of Preferred Embodiments which foilows.

DETAILEDDESCRIPTION OF PREFERRED EMBODIMENTS [10] The invention relates to a method for treating sepsis, comprising intravenously administering an amount of an émulsion which comprises (i) a phospholipid, (ii) a neutral lipid, and (iii) a cholate sait, to a subject who présents sérum albumin (Alb hereafter) at a level of at least 1.5 g/dL, and one or both of total cholestérol (TC hereafter) of at least 40 mg/dL, and high density lipoprotein (HDL hereafter) of at least 20 mg/dL. Subjects who exhibit these levels of biomarkers exhibit sufficient lipoprotein and hâve sufficient liver function to respond to the émulsion and clear the toxins causing the sepsis. .

[111 While not wishing to be bound to any theory, the parameters used were chosen because they serve as markers for functions key to clearance of sepsis-causing toxins. Albumin is produced by the liver, and its concentration in sérum is impacted by many factors. For example, low levels of albumin in critical illnesses are thought to be related to reduce hepatic synthesïs, increased catabolism, and capillary leakage. Hence albumin Ievels serve as a way to measure hepatic clearance of phospholipids.

[12] With respect to cholestérol and HDL, study of the therapeutic émulsion showed that it functioned via delivery of phospholipid to HDL and other lipoprotéine. Theoretically, then there must be some level of endogenous lipoprotein that is so low that phospholipid from the émulsion, cannot be sufficiently incorporated into those lipoproteins, thus rendering the émulsion ineffective.

[13] Subjects who exhibit sufficient Alb and TC or Alb and HDL to meet the criteria specified above benefit from the administration of émulsions in accordance with the invention, at a much higher level than patients who do not.

[14] The émulsions contain, relative to each other, from about 5% to about 10% by weight of cholate sait, from about 5% to about 10% by weight of neutral lipid, and from about 80% to about 90% by weight of phospholipid. Other ingrédients, e.g., carriers or other inert ingrédients may be added, but the ratios of the 3 ingrédients relative to each other should be as stated. Preferably, the cholate sait is sodium cholate, the neutral lipid is a triglycéride and the phospholipid is phosphatidylcholine. See U.S. Patent No. 5,674,855, incorporated by reference, supra, for information on various formulations.

[15] The émulsions should be administered to subjects intravenously, in amounts ranging from about 500 mg/kg of body weight to about 1500 mg/kg of body weight, and most preferably, a dose of from about 750 mg/kg of body weight, to about 1000 mg/kg of body weight, is preferred, over a three-day period. Other dosing schedules may also be used.

[16] Such dosages can be achieved via an initial high loading dose followed by a Iower maintenance dose. For example, a bolus of 75 mg/kg/hr for 2 hours followed by 10 mg/kg/hr for 70 hours would achieve an 850 mg/kg dose over a 72-hour period.

[17] In the examples which follow, an émulsion was prepared which contained 7.0 wt.% triglycéride, 7.2 wt.% sodium cholate, and 85.8 wt.% phosphatidylcholine. Subjects received an intravenous dose of 850 mg of émulsion per kg of body weight over a 72-hour period. \^/

EXAMPLE 1 [18] It is accepted that a successful médicament for patients suffering from sepsis should reduce overall mortality by at least 5%, and preferably, at least 7% (see “P-E” in Benefit column below). However, to directly equate the number of patients saved with a successful médicament, a Relative Benefit of 15% to 20% is often a better indicator (see “Relative” in Benefit column below).

[19] Analysis was carried out of samples taken from subjects, as reported in Dellinger et al. (2009). supra. This Dellinger study is known as the LIPOS trial, and LIPOS is used hereafter.

[20] Blood samples were assayed for levels of Alb, TC and HDL, using methods well known in the art. Dellinger et al. (2009). did not measure Alb, and failed to obtain measurements of TC and HDL in patients with such values missing from the original LIPOS data.

Table 1. Subjects in Tota	LIPOS Population
Group	N	Mortality % i	Oeaths/Total)	Benefit
Placebo (P)	850 mg/kg of émulsion (E)	P-E	Relative
LIPOS	1197	26.9% (161/599)	25.8% (154/598)	1.1%	4.2%
AlbTC	988	24.5% (120/490)	22.5% (112/498)	2.0%	8.2%
AlbHDL	593	24.1% (72/299)	20.1% (59/294)	4.0%	16.7%

[21] In Table 1, supra, LIPOS refers to the subjects who were studied in the trial reported in Dellinger et al. (2009). AlbTC refers to a subpopulation, where, as noted supra, Alb> 1.5 g/dL and TC > 40 mg/dL. AlbHDL represents a group with Alb levels as described, supra, and HDL > 20 mg/dL.

[22] With respect to Benefit, “P-E” is the mortality réduction, the différence in survival between those who received the émulsion and those who received placebo. The Relative Benefit is 1 - RR, where RR, the relative risk, is the ratio of the probability of death occurring in the émulsion group versus the placebo group.

[23] Although the Relative Benefit was only 4.2% for the entire LIPOS population, it was 8.2% and 16.7% respectively in the AlbTC and AlbHDL groups, clearly within the desired range.

EXAMPLE 2 [24] Further analysis viewed a subpopulation of LIPOS subjects that did not receive the vasopressor cortisol intravenously, in order to détermine how they would respond to the AlbTC and AlbHDL criteria.

[25] Table 2 shows how the AlbTC and AlbHDL criteria select responsive subjects among those that did not receive cortisol. Applying the AlbTC or Alb HDL criteria to this subgroup gives a P-E benefit of 6.2% and 10.8%, respectively, compared to 4.8% without applying the criteria.

Table 2. Subgroup: Subjects that did not receive Intravenous Cortisol
Group	N	Mortality % (Deaths/Total)	Benefit
Placebo (P)	850 mg/kg of émulsion (E)	P-E	Relative
LIPOS	928	27.0% (124/459)	22.2% (104/469)	4.8%	17.9%
AlbTC	796	25.5% (100/392)	19.3% (78/404)	6.2%	24.3%
AlbHDL	474	27.1% (65/240)	16.2% (38/234)	10.8%	40.0%

[26] This subpopulation of subjects surpassed the 5% P-E benefit criteria for both

AlbTC and AlbHDL, with significant Relative Benefits of 24.3% and 40.0% respectively.

EXAMPLE 3 [27] Another analysis took a subpopulation of LIPOS subjects that did not hâve an intra-abdominal infection. These subjects had Gram-negative bacteremia, nosocomial pneumonia or pyelonephritis.

[28] Table 3 shows this subgroup obtained by excluding subjects with intra-abdominal infection, and only containing subjects with Gram-negative bacteremia, nosocomial pneumonia or pyelonephritis. Here, the AlbTC and AlbHDL criteria give P-E treatment benefits of6.2% and 8.9% compared to 4.2% without using these criteria. «A/’”^-

Table 3. Subgroup: Subjects with Gram-Negative Bacteremia, Nosocomial

Pneumonia or Pyelonephritis

Group	N	Mortality % (Deaths/Total)	Benefit
Placebo (P)	850 mg/kg of émulsion (E)	P-E	Relative
LIPOS	566	29.0% (80/276)	24.8% (72/290)	4.2%	14.3%
AlbTC	523	28.2% (72/255)	22.0% (59/268)	6.2%	22.0%
AlbHDL	336	28.0% (47/168)	19.0% (32/168)	8.9%	31.9%

[29] This subpopulation of subjects also surpassed the 5% P-E benefit criteria for both AlbTC and AlbHDL, with high Relative Benefits of 22.0% and 31.9% respectively.

[30] The foregoing disclosure sets forth the details of the invention which is a method for treating sepsis in a subject who (i) exhibits a sérum albumin Ievel of at least 1.5 g/dL, and (ii) exhibits at least one of a total cholestérol Ievel of at least 40 mg/dL, and high density lipoprotein of at least 20 mg/dL, by intravenously administering an émulsion, which comprises (i) a phospholipid, (ii) a neutral lipid, and (iii) a cholate sait, wherein relative to each other, the phospholipid is présent at about 80% to 90% by weight, the neutral lipid is présent at about 5% to 10% by weight, and the cholate sait is présent at about 5% to 10% by weight, in an amount sufficient to treat said sepsis. Preferably, the émulsion is administered over a three day period, in an amount ranging from about 500 mg/kg to about 1500 mg/kg of body weight, and more preferably from about 750 mg/kg of body weight to about 1000 mg/kg of body weight. Most preferably, the dosage is set at 850 mg/kg of body weight.

[31] The mode of administration can vary, i.e., it may be completely continuous over a given time frame, or can take the form of large, “up front” bolus doses followed by smaller, continuous dosing, as shown supra.

[32] The subjects to be treated by the invention may or may not hâve received a vasopressor, such as cortisol, and may be subjects who do not exhibit intra-abdominal infections, but exhibit one or more of nosocomial pneumonia, pyelonephritis, or bacteremia. The bacteremia may be caused by Gram-negative and/or Gram-positive bacteria, as may be sepsis in general.

[33] Other features of the invention will be clear to the skilled artisan and need not be reiterated here.

[34] The terms and expression which hâve been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expression of excluding any équivalents of the features shown and described or portions thereof, it being recognized that various modifications are possible within the scope of the invention, -vs''

Claims (16)

1. Use of an émulsion comprising (i) a phospholipid, (ii) a neutral lipid, and (iii) a cholate sait, in the manufacture of an agent for treating a subject suffering from sepsis who exhibits sérum albumin at a level of at least 1.5 g/dL, and one or both of a total cholestérol level of at least 40 mg/dL, and a high density lipoprotein level of at least 20 mg/dL

2. The use of claim 1, wherein said émulsion comprises:

(i) from about 80% to about 90% by weight phospholipid, (ii) from about 5% to about 10% by weight neutral lipid, and (iii) from about 5% to about 10% by weight cholate sait.

3. The use of claim 1, wherein said phospholipid is phosphatidylcholine.

4. The use of claim 1, wherein said neutral lipid is a triglycéride.

5. The use of claim 1, wherein said cholate sait is sodium cholate.

6. The use of claim 1, wherein said émulsion is in an amount ranging from about 500 mg/kg of body weight to about 1500 mg/kg of body weight of said subject.

7. The use of claim 6, wherein said émulsion is for administration over a 72 hour period.

8. The use of claim 6, wherein said émulsion is in an amount ranging from about 750 mg/kg of body weight to about 1000 mg/kg of body weight.

9. The use of claim 1, wherein said subject has received or is receiving a vasopressor.

10. The method of claim 1, wherein said subject has not received a vasopressor.

11. The use of claim 1, wherein said sepsis is caused by Gram-negative bacteria.

12. The use of claim 1, wherein said sepsis is caused by Gram-positive bacteria.

13. The use of claim 1, wherein said subject suffers from bacteremia.

14. The use of claim 1, wherein said subject suffers from nosocomial pneumonia.

15. The use of claim 1, wherein said subject suffers from pyelonephritis.

16.

The use of claim 1, wherein said subject does not suffer from an intra-abdominal infection.