WO2021126855A1

WO2021126855A1 - Methods for treating progressive hyperbilirubinemia

Info

Publication number: WO2021126855A1
Application number: PCT/US2020/065127
Authority: WO
Inventors: James POTENZIANO; Chitra SEKARAN; Douglas BOETTNER; Joseph GRIECO; Xiaofeng Wang
Original assignee: Mallinckrodt Hospital Products IP Unlimited Company
Priority date: 2019-12-16
Filing date: 2020-12-15
Publication date: 2021-06-24

Abstract

Methods of treating progressive hyperbilirubinemia are disclosed. The methods can include administering stannsoporfin to an infant exhibiting progressive hyperbilirubinemia.

Description

METHODS FOR TREATING PROGRESSIVE HYPERBILIRUBINEMIA

BACKGROUND OF THE INVENTION

Neonatal hyperbilirubinemia (elevated serum bilirubin concentration) results from the breakdown of hemoglobin and the limited ability to conjugate and excrete bilirubin. Neonatal jaundice resulting from hyperbilirubinemia occurs in up to 84% of term newborns. In most cases, jaundice is self-limiting and is not considered harmful. However, significant hyperbilirubinemia that reaches a threshold for intervention occurs in a portion of infants.

Phototherapy is generally a first line treatment for significant hyperbilirubinemia, e.g., Total Seram Bilirubin (TSB) levels above 2 mg/dL, and may be effective for lowering TSB levels in many infants. However, phototherapy may be less effective in certain populations of infants, e.g., infants with a hemolytic disorder or at risk of hemolysis. In certain cases, an additional treatment can be utilized in patients where phototherapy is ineffective at reducing TSB levels; however such treatments, e.g., exchange transfusion, may result in adverse consequences. Therefore, there is a need to improve treatment of hyperbilirubinemia in infants with a hemolytic disorder or at risk of hemolysis.

SUMMARY OF THE INVENTION

In some aspects, a method for treating progressive hyperbilirubinemia is provided, which can include initiating phototherapy on an infant in need thereof; determining one or more bilirubin levels of the infant subsequent to the initiating phototherapy; and in response to the determining one or more bilirubin levels of the infant, administering a therapeutic amount of stannsoporfin to the infant at least about 4 hours after the initiating phototherapy.

In some aspects, the determining one or more bilirubin levels of the infant can include determining one or more bilirubin levels of the infant between 4 and 6 hours after the initiating phototherapy.

In some aspects, the one or more bilirubin levels of the infant may be at or above 110 %, 120 %, or 125 % of the age-specific threshold for phototherapy specified in the 2004 AAP Guidelines. In some aspects, the one or more bilirubin levels can include at least two bilirubin levels, and wherein the at least two bilirubin levels indicate an increase in bilirubin in the infant of greater than or equal to 1.5 mg/dl/hr.

In some aspects, the infant exhibits a hemolytic disorder. In some aspects, the hemolytic disorder can include one or more of: ABO or Rh incompatibility and infant is DAT positive; GP6D deficiency; or hereditary spherocytosis.

In some aspects, the method for treating progressive hyperbilirubinemia can further include determining one or more post-stannsoporfin bilirubin levels in the infant between 30 minutes and 24 hours after the administering the therapeutic amount of stannsoporfin.

In some aspects, the method for treating progressive hyperbilirubinemia can further include administering one or more additional therapies in response to the one or more post-stannsoporfin bilirubin levels being within about 3 mg/dl of the threshold value for administration of exchange transfusion specified in the 2004 AAP Guidelines. In some aspects, the one or more additional therapies is intravenous immunoglobulin (IVIg), exchange transfusion, or a combination thereof.

In some aspects, the therapeutic amount of stannsoporfin is between about 0.5 mg/kg of the infant’s weight to about 4.0 mg/kg of the infant’s weight.

In some aspects, the therapeutic amount of stannsoporfin is selected from 1.5 mg/kg of the infant’s weight, and 3.0 mg/kg of the infant’s weight.

In some aspects, the administering the therapeutic amount of stannsoporfin to the infant is performed via a single intramuscular injection.

In some aspects, phototherapy is administered to the infant over a time period that extends from the initiating phototherapy to a time of at least about 2 hours after the administering the therapeutic amount of stannsoporfin.

In some aspects, a method for treating progressive hyperbilirubinemia is provided, which can include initiating phototherapy on an infant in need thereof, wherein the infant exhibits a hemolytic disorder; determining a plurality of serial bilirubin levels of the infant over a period of at least two hours subsequent to the initiating phototherapy; and administering a therapeutic amount of stannsoporfin to the infant at least about 4 hours after the imitating phototherapy, in response to: 1) at least one of the plurality of serial bilirubin levels being at least 110 % of the age- specific threshold for phototherapy specified in the 2004 AAP Guidelines; 2) at least a portion of the plurality of serial bilirubin levels indicating an of increase of bilirubin in the infant greater than or equal to 1.5 mg/dl/hr; or 3) a combination thereof.

In some aspects, the determining the plurality of serial bilirubin levels occurs at least partly during a time period of about 4 hours to about 6 hours after the initiating phototherapy.

In some aspects, the hemolytic disorder comprises one or more of: ABO or Rh incompatibility and the infant is DAT positive; GP6D deficiency; or hereditary spherocytosis.

In some aspects, the administering the therapeutic amount of stannsoporfin to the infant is performed via a single intramuscular injection. In some aspects, the method for treating progressive hyperbilirubinemia can further include determining one or more post-stannsoporfin bilirubin levels in the infant between 30 minutes and 24 hours after the administering the therapeutic amount of stannsoporfin.

In some aspects, the method for treating progressive hyperbilirubinemia can further include administering one or more additional therapies in response to the one or more post-stannsoporfin bilirubin levels being within about 3 mg/dl of the threshold value for administration of exchange transfusion specified in the 2004 AAP Guidelines, wherein the one or more additional therapies comprises intravenous immunoglobulin (IVIg), exchange transfusion, or a combination thereof. In some aspects, phototherapy is administered to the infant over a time period that extends from the initiating phototherapy to a time of at least about 2 hours after the administering the therapeutic amount of stannsoporfin.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the bilirubin level threshold values for instituting phototherapy in hospitalized infants of 35 or more weeks gestation as established by the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (Pediatrics 2004; 114:297-316), “2004 AAP Guidelines”.

FIG. 2 is a graph showing the bilirubin level threshold values for instituting exchange transfusion in hospitalized infants of 35 or more weeks gestation as established by the 2004 AAP Guidelines, i.e., American Academy of Pediatrics Subcommittee on Hyperbilirubinemia (Pediatrics 2004; 114:297-316). FIG. 3 is a graph schematically depicting the 2004 AAP Guidelines’ phototherapy threshold bilirubin levels, the 2004 AAP Guidelines’ exchange transfusion threshold bilirubin levels, and various additional example bilirubin level threshold levels for the administration of stannsoporfin or one or more additional therapies, in accordance with aspects described herein.

FIG. 4 is a graph schematically depicting the 2004 AAP Guidelines’ phototherapy threshold bilirubin levels, the 2004 AAP Guidelines’ exchange transfusion threshold bilirubin levels, and an example bilirubin level threshold levels for the administration of stannsoporfin or one or more additional therapies, in accordance with aspects described herein.

DET AILED DESCRIPTION OF THE INVENTION

Aspects described herein relate to methods of treating progressive hyperbilirubinemia. Neonatal jaundice is caused by elevated bilirubin levels with the potential to provoke severe neurological damage and is the most common cause of hospital readmission for term- and near-term infants. The management of neonatal jaundice poses a significant burden on the healthcare system.

Neonates with immune-mediated hemolytic disease, such as ABO or Rhesus (Rh) incompatibility, non-immune mediated-like enzyme deficiencies such as glucose-6- phosphate dehydrogenase (G6PD) deficiency, or red cell membrane disorders such as hereditary spherocytosis, have an increased rate of red cell destruction and, thus, an increase in bilirubin production. Newborn infants have immature liver function, with decreased bilirubin binding capacity and low serum albumin and do not conjugate bilirubin well. Thus, in these subjects, unbound bilirubin levels may rapidly rise to neurotoxic levels that require intervention. At present, phototherapy is the most frequently used treatment for hyperbilirubinemia. Phototherapy converts unconjugated bilirubin to less toxic water-soluble photo-isomers that are excreted without the need for conjugation. However, in a certain proportion of term and near-term infants with or without other neurotoxic risk factors, total serum bilirubin (TSB) may continue to rise, even after several hours of intensive phototherapy. This places the neonate at greater risk for neurotoxicity. Infants who do not respond to traditional intensive phototherapy are managed with higher levels of phototherapy or intravenous immunoglobulin (IVIg) and/or eventually exchange transfusion, which is considered a therapy of last resort because of its associated morbidity and mortality. Both phototherapy and exchange transfusion enhance the elimination of bilirubin, but have no impact on its production.

The methods disclosed herein can alleviate one or more of the issues discussed above with the current treatment practices for hyperbilirubinemia. In aspects, the methods disclosed herein relate to treating progressive hyperbilirubinemia in infants that can include the administration of stannsoporfin to the infant at least four hours after the initiation of phototherapy, which may reduce the bilirubin levels in the infant, reduce the need for rescue therapies, and/or reduce the duration of phototherapy. As used herein, “infants” is inclusive of the term neonates and can include children older than those considered neonates. As used herein, “neonates” refers to newborn children. In one aspect, a neonate is a child that is less than 30 days old.

As used herein, “progressive hyperbilirubinemia” refers to infants or neonates that are undergoing phototherapy but do not exhibit reduced bilirubin levels subsequent to the initiation of phototherapy. For instance in one aspect, progressive hyperbilirubinemia refers to neonates that are undergoing phototherapy but, at least four to six hours after the initiation of phototherapy, continue to exhibit an elevated bilirubin level above the bilirubin threshold values for instituting phototherapy as described in the 2004 AAP Guidelines.

Heme oxygenase is the enzyme involved in the rate-limiting step of the catabolism of heme to bilirubin, catalyzing the transformation of heme to biliverdin and subsequent conversion by biliverdin reductase to bilirubin. Stannsoporfin is a competitive inhibitor of heme oxygenase and, as such, temporarily blocks the production of bilirubin from heme.

At a high level, in aspects, the method disclosed herein can include monitoring the bilirubin levels of neonates or infants on phototherapy and administering stannsoporfin to neonates or infants experiencing progressive hyperbilirubinemia.

In aspects, the methods disclosed herein can be for treating infants that are > 35 weeks to < 43 weeks of gestational age. In the same or alternative aspects, the infant can exhibit a birth weight of > 2500 grams. In the same or alternative aspects, the infants can exhibit a hemolytic disorder or are at risk of hemolysis. In aspects, the infants that exhibit a hemolytic disorder may be considered at risk of hemolysis. In aspects, the hemolytic disorder can include, but is not limited to, ABO or Rhesus (Rh) incompatibility (anti C, c, D, E, or e), G6PD deficiency, or hereditary spherocytosis.

ABO incompatibility occurs in 20% to 25% of pregnancies, and a proportion of these develop problematic hyperbilirubinemia due to hemolysis. The direct antiglobulin test (DAT) or Coombs test may be used to help diagnose hemolytic disorder or disease of the newborn (HDN) due to an incompatibility between the blood types of a mother and baby. If the DAT is positive, then there are anti red cell antibodies present. If the DAT is negative, then antibodies are not detectable and the jaundice may be due to some other cause. In aspects, the infant can exhibit ABO incompatibility and is DAT positive. In alternative aspects, the infant can exhibit ABO incompatibility, is DAT negative (or unknown DAT), and exhibits an elevated reticulocyte count, such as a reticulocyte count greater than 6 %.

Rh incompatibility can occur, for example, when a mother with Rh-negative blood type is exposed to Rh-positive fetal blood cells, leading to the development of Rh antibodies. In aspects, the Rh incompatibility may be one or more of anti-C Rh incompatibility, anti-c Rh incompatibility, anti-D Rh incompatibility, anti-E Rh incompatibility, or anti-e Rh incompatibility. In aspects, the infant can exhibit Rh incompatibility and is DAT positive. In alternative aspects, the infant can exhibit Rh incompatibility, is DAT negative (or unknown DAT), and exhibits an elevated reticulocyte count, such as a reticulocyte count greater than 6 %. G6PD deficiency is the most common enzyme deficiency worldwide, and is associated with a spectrum of diseases including neonatal hyperbilirubinemia. G6PD deficiency is a genetic disorder resulting in a body not having enough of the glucose-6- phophate dehydrogenase (G6PD) enzyme, which can result in hemolysis. This X- linked inherited disorder most commonly affects persons of African, Asian, Mediterranean, or Middle-Eastern descent. However, G6PD deficiency is a global problem with approximately 400 million people affected worldwide.

Hereditary spherocytosis is a hemolytic disorder that is associated with various mutations that may lead to defects in red blood cell membrane proteins, and may be associated with a shortage of red blood cells. Severe cases of hereditary spherocytosis may present in neonates, while milder cases may not be uncovered until adulthood.

In certain aspects, the infant may exhibit indicators of hemolysis and a rapid rise in TSB levels after administration of phototherapy. In such aspects, the indicators for hemolysis can include but is not limited to an infant being DAT positive, having a reticulocyte count greater than about 6 %, or an elevated end-tidal carbon monoxide (ETCO) level. In aspects, the rapid rise in TSB levels after administration of phototherapy refers to a rise of > 1.5 mg/dL/hr, as discussed further below.

As used herein, the term “about” means plus or minus 10 % of the numerical value of the number with which it is being used unless otherwise indicated or custom in the art dictates otherwise. Therefore, for example, “about 50

means in the range of 45 % - 55 %.

In various aspects, the infant does not exhibit one or more exclusion factors. In such aspects, the exclusion factors can include an elevated direct bilirubin > 2 mg/dL or > 20% of the total serum bilirubin; alanine aminotransferase >2 times the upper limit of normal (ULN) and/or aspartate aminotransferase >3 times ULN; abnormal renal function defined as creatinine and/or blood urea nitrogen >2 times ULN; any clinically significant abnormalities on ECG or other screening laboratory evaluations that, in the opinion of the investigator, makes the subject unsuitable for treatment with stannsoporfin; Apgar score of <6 at age 5 minutes; potential or diagnosed sepsis; an unexplained existing rash or skin erythema; infants who are breast feeding have severe dehydration unless it is corrected; clinical suggestion of neonatal thyroid disease or current uncontrolled thyroid disease in the mother (maternal Hashimoto’s disease is not exclusionary); cardio-respiratory distress, defined as a respiratory rate >60 breaths per minute at time of potential treatment; clinically significant abnormal auditory or ophthalmologic findings on a screening physical exam; ECG finding of prolonged QTcB during three screening ECGs: average QTcB > 480 ms for neonates on day 1 (0-24 hours) or day 2 (>24-48 hours) of life or an average QTcB > 460 ms for neonates on day 3 (>48-72 hours) of life; treatment or need for treatment of the neonate with medications that may prolong the QT interval (see Table 1 below, which lists drugs used in newborns that are known to prolong the QT interval); known porphyrias or risk factors for porphyrias, including family history; a maternal history of systemic lupus erythematosus; maternal use of phenobarbital within 30 days before delivery, or after delivery if breast feeding; maternal current drug or alcohol abuse, or maternal history of drug or alcohol abuse; significant congenital anomalies and or infections; risk of requiring surgery or exposure to operating room (OR) lights in the first 2 weeks of life; persistent hypoglycemia unresponsive to medical intervention defined as three consecutive readings of blood glucose <40 mg/dL over a 3-hour period; current temperature instability defined as three consecutive readings <36 °C and/or >37.5 °C (axillary) over a 3-hour period; use of IVIg or albumin prior to stannsoporfin administration; use of photosensitizing drugs or agents (see Table 2 below, which lists known photosensitizing drugs used in newborns); post-delivery treatment with medications that are known or suspected to displace bilirubin from albumin; exposure to any investigational medications or devices after delivery; any other concurrent medical condition, which in the opinion of the clinician makes the subject unsuitable for treatment with stannsoporfin; postnatal age > 168 hours (7 days). Table 1: Drugs Used in Newborns Known to Prolong the QT Interval

a: Erythromycin ointment for eye prophylaxis is permitted. b: The infant should not be treated for stannsoporfin if: the mother received metronidazole within two days prior to delivery and the baby is less than 35 hours post last dose of maternal metronidazole administration or the mother began treatment with metronidazole while breast-feeding. Table 2: Photosensitizing Drugs Used in Newborns

a: Parenteral use of Gentamicin is allowed (only the topical use of Gentamicin is considered photosensitizing and should not be used while the patient is being treated.)

In certain aspects, the methods disclosed herein include initiating phototherapy on an infant in need thereof. In one aspect, initiating phototherapy on an infant or neonate can include beginning phototherapy for an infant or neonate according to the 2004 AAP Guidelines, i.e., the 2004 American Academy of Pediatrics Clinical Practice Guidelines from Subcommittee on Hyperbilirubinemia on the “Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation”, Pediatrics Vol. 114 No. 1, July 2004 listed above, the entirety of which is hereby incorporated by reference. The protocol for initiating phototherapy according to the 2004 AAP Guidelines is readily understood and utilized in practice, and thus, is not fully described in detail herein. At a high level, the 2004 AAP Guidelines, in part, provide threshold bilirubin levels for the initiation of phototherapy, based on the age and risk level of the infant. FIG. 1 provides a graphical representation of the age- specific threshold TSB levels for the initiation of phototherapy. It should be understood that according to the 2004 AAP Guidelines, intensive phototherapy should be administered when the infant has exceeded the threshold TSB levels indicated in the 2004 AAP Guidelines and reproduced in FIG. 1. Accordingly, in one aspect, initiating phototherapy on an infant in need thereof can include initiating intensive phototherapy as define in the 2004 AAP Guidelines. As used herein “intensive phototherapy” is referred to as that defined in the 2004 AAP Guidelines: irradiance in the blue-green spectrum (wavelengths of approximately 430-490 nanometers (nm)) of at least 30 DW/cm2 per nm (measured at the infant’s skin directly below the center of the phototherapy unit) and delivered to as much of the infant’s surface area as possible.

In aspects, the methods disclosed herein can include determining one or more bilirubin levels of an infant. In various aspects, determining one or more bilirubin levels of an infant can include determining a total serum bilirubin (TSB) level or a transcutaneous bilirubin level (TcB), or both. In various aspects, the methods disclosed herein can include determining one or more bilirubin levels of an infant subsequent to the initiation of phototherapy. In aspects, the one or more bilirubin levels of an infant can be determined at a time between about four hours to about six hours after the initiation of phototherapy. In various aspects, determining one or more bilirubin levels at a time from about four to about six hours after the initiation of phototherapy refers to obtaining one or more serum samples or other biological samples from the infant at a time of about four hours to about six hours after the initiation of phototherapy, and then quantifying or determining the bilirubin levels from such samples. In aspects, the one or more bilirubin levels can include serial bilirubin levels taken over a period of time that includes, but is not limited to, between four to six hours after the initiation of phototherapy. In one aspect, the one or more bilirubin levels can include a baseline bilirubin level (e.g., a bilirubin level taken at the time of initiation of phototherapy), and one or more bilirubin levels up to and including a period of time of four to six hours after the initiation of phototherapy. The methods disclosed herein, in various aspects, can include administering a therapeutic amount of stannsoporfin to the infant subsequent to the initiation of phototherapy. In aspects, administering a therapeutic amount of stannsoporfin to the infant subsequent to the initiation of phototherapy can occur in response to determining one or more bilirubin levels of the infant. For instance in one aspect, the one or more bilirubin levels may reveal that the infant exhibits progressive hyperbilirubinemia. In the same or alternative aspects, the one or more bilirubin levels may be at or above 110% of the age-specific threshold bilirubin level for phototherapy specified in the 2004 AAP Guidelines. In various aspects, the one or more bilirubin levels can include a baseline bilirubin level and at least one additional bilirubin level taken four to six hours after the initiation of phototherapy, where these one or more bilirubin levels mirror or remain at or above 110% of the age- specific threshold bilirubin level for phototherapy specified in the 2004 AAP Guidelines. In various aspects, the one or more bilirubin levels can include at least two bilirubin levels, where these bilirubin levels indicate an increase in bilirubin in the infant of greater than or equal to 1.5 mg/dl/hr. In aspects, “administering” when used in conjunction with a therapeutic, e.g., stannsoporfin, refers to applying, injecting, or otherwise providing a therapeutic directly into or onto a target tissue or to apply, inject, or otherwise provide a therapeutic to a patient systemically. Thus, as used herein, the term “administering”, when used in conjunction with stannsoporfin, can include, but is not limited to, providing the stannsoporfin into or onto the target tissue; providing the stannsoporfin systemically to a patient by, e.g., injection (e.g. intravenous, intramuscular, or sub-cutaneous) whereby the therapeutic reaches the target tissue. “Administering” a composition may be accomplished by injection (intravenous, intramuscular, or subcutaneous), topical administration, oral, or by other method, alone in combination with other known techniques. In certain aspects, the therapeutic amount of stannsoporfin is administered as a single intramuscular injection.

In aspects, a “therapeutic amount” of stannsoporfin refers to an amount of stannsoporfin that is calculated to treat, prevent or reduce jaundice or hyperbilirubinemia; to reduce bilirubin production; to increase bilirubin excretion; or combination thereof; or to reduce total serum bilirubin and/or total cutaneous bilirubin; or to otherwise delay, inhibit, or slow the progression of hyperbilirubinemia; to enhance the appearance of the skin; to reduce need for exchange transfusion; to reduce the duration of phototherapy; to decrease bilirubin levels; to decrease rebound (e.g. decrease in the likelihood of restarting phototherapy after being off of phototherapy for 6 hours of more); to decrease jaundice; to prevent or reduce zone 5 jaundice; to decrease the incidence of, or need for intravenous immunoglobulin administration; to reduce the length of hospital stay; to decrease the rate or likelihood of hospital readmission, etc. The specific dose of stannsoporfin administered according to the methods disclosed herein to obtain therapeutic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the route of administration, and the condition being treated. Stannsoporfin is effective in various dosages. However, it will be understood that the effective amount administered will be determined by the physician in light of the relevant circumstances including the condition to be treated, the chosen route of administration, and other factors, and therefore the dosage ranges disclosed herein are exemplary only. A therapeutic amount of stannsoporfin as disclosed herein is typically an amount such that when it is administered in a pharmaceutically acceptable composition it is sufficient to achieve an effective systemic concentration or local concentration in the tissue. In certain aspects, the therapeutic amount of stannsoporfin is of from about 0.5 mg/kg to about 4.0 mg/kg of the infant’s birth weight or current weight. In certain aspects, the therapeutic amount of stannsoporfin is selected from 1.5 mg/kg, or 3.0 mg/kg of the infant’s birth weight or current weight.

Stannsoporfin drug substance, tin-mesoporphyrin IX dichloride, is a magenta- colored powder with a chemical formula of C34H36C12N404Sn and a molecular weight of 754.30. In one aspect, the stannsoporfin is formulated as a solution for intramuscular injection at pH 7.4 to 7.9 and a concentration of 20 mg/mL of tin-mesoporphyrin IX dichloride in a final volume of 1.5 ±0.2 mL that is contained in a 2.0-mL amber vial.

In various aspects, the therapeutic amount of stannsoporfin is administered as a single intramuscular injection in an amount of from about 0.5 mg/kg to about 4.0 mg/kg of the infant’ s birth weight or current weight. In one aspect, the therapeutic amount of stannsoporfin is administered as a single intramuscular injection in an amount selected from 1.5 mg/kg, or 3.0 mg/kg, of the infant’s birth weight or current weight.

In certain aspects, the therapeutic amount of stannsoporfin is administered to the infant at least about 4 hours after the initiation of phototherapy. In aspects, the therapeutic amount of stannsoporfin is administered to the infant in a time period between about 4 hours to about 10 hours after the initiation of phototherapy. In aspects, the therapeutic amount of stannsoporfin is administered to the infant at about 7-9 hours after the initiation of phototherapy. In various aspects, the therapeutic amount of stannsoporfin is administered to the infant at about 4 hours, at about 5 hours, at about 6 hours, at about 7 hours, at about 8 hours, at about 9 hours, or at about 10 hours after the initiation of phototherapy. In one aspect, the therapeutic amount of stannsoporfin is administered to the infant at about 8 hours after the initiation of phototherapy.

In aspects, phototherapy is continued until the 2004 AAP Guidelines indicate that phototherapy should be a stopped. In aspects, where the infant is administered stannsoporfin, the infant’s bilirubin levels may be above the threshold in the 2004 AAP Guidelines for administering phototherapy, and thus, the infant may continue to receive phototherapy from the initiation of phototherapy to a time period after the administration of stannsoporfin. In one aspect, the infant may continue to receive phototherapy from the initiation of phototherapy until at least about 2 hours, at least about 4 hours, at least about 6 hours, at least about 8 hours, or at least about 12 hours after the administration of stannsoporfin.

In certain aspects, the methods disclosed herein can include determining one or more bilirubin levels after the administration of stannsoporfin, i.e., post-stannsoporfin bilirubin levels. In certain aspects, these one or more post-stannsoporfin bilirubin levels can be taken or determined between about 30 minutes and about 24 hours after the administration of stannsoporfin. In one aspect, the one or more post-stannsoporfin bilirubin levels can be taken or determined about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 18 hours, and about 24 hours after the administration of stannsoporfin.

In certain aspects as discussed above, the administration of stannsoporfin in accordance with the methods disclosed herein can decrease the level of bilirubin, e.g. to a level below the phototherapy threshold in the 2004 AAP Guidelines, where in such an aspect, phototherapy could be discontinued. In various aspects, the administration of stannsoporfin in accordance to the methods disclosed herein can reduce the duration of phototherapy, and/or can reduce the need for additional rescue therapies, such as IVIg or exchange transfusion. In certain alternative aspects, an infant may continue to exhibit a rise in bilirubin despite remaining on phototherapy and despite receiving stannsoporfin. For instance, the post- stannsoporfin bilirubin levels in an infant may continue to rise after the administration of stannsoporfin. In aspects, one or more additional therapies can be administered to the infant in response to one or more post-stannsoporfin bilirubin levels. For example in certain aspects, one or more additional therapies can be administered to the infant when the infant exhibits a post-stannsoporfin bilirubin level that is within about 3 mg/dl, within about 2 mg/dl, within about 1 mg/dl, or at about the age-specific threshold bilirubin level for the administration of exchange transfusion specified in the 2004 AAP Guidelines. FIG. 2 depicts the graphical representation of the age-specific threshold bilirubin levels for the administration of exchange transfusion specified in the 2004 AAP Guidelines. In certain aspects, the one or more additional therapies can include exchange transfusion and/or IVIg.

FIG. 3 schematically depicts a graph showing example age-specific threshold bilirubin levels for administering phototherapy (PT) and exchange transfusion (ET) specified by the 2004 AAP Guidelines. The graph in FIG. 3 also depicts three additional curves that schematically represent 110 %, 120 %, and 125 %, respectively, of the threshold bilirubin levels for administering phototherapy (PT) specified by the 2004 AAP Guidelines. Another curve, labeled “rescue” is depicted in FIG. 3 that depicts one example threshold bilirubin level to administer one or more additional therapies, such as the one or more additional therapies discussed above. In the aspect depicted in FIG. 3, this rescue curve is depicted as being 3 mg/dl below the ET threshold value, as an example. Table 3 below lists various total serum bilirubin values along the curves depicted in the graph of FIG 3 at various time points.

Table 3: Total Serum Bilirubin Levels (mg/dl) at Various Time Points for the Curves of FIG. 3

It should be understood that FIG. 3 is provided as merely one example schematic depiction of various bilirubin threshold values at various time points, and is not limiting or representative of the entire scope of the methods disclosed herein. In aspects, the three additional curves that schematically represent 110 %, 120 %, and 125 %, respectively, of the threshold bilirubin levels for administering phototherapy (PT) specified by the 2004 AAP Guidelines, may be threshold values at or over which an infant receiving phototherapy can be administered stannsoporfin. As can be seen in the graph of FIG, 3, the 110 %, 120 %, and 125 % of PT example threshold values for the administration of stannsoporfin are at their farthest distance from the exchange transfusion threshold curve at a time period of birth to about 48 hours. In certain aspects, this time period of birth to 48 hours may be the time period in which stannsoporfin is administered.

As noted above, FIG. 3 also depicts the rescue curve, which is a schematic representation of one example of bilirubin threshold values for the administration of one or more additional therapies, such as IVIg and/or exchange transfusion. As discussed in various aspects, one or more additional therapies may be administered when the infant’ s bilirubin levels continue to rise despite phototherapy and despite receiving stannsoporfin, e.g., when one or more bilirubin levels is within about 3 mg/dl, within about 2 mg/dl, or within about 1 mg/dl of the age-specific threshold bilirubin level for administration of exchange transfusion specified in the 2004 AAP Guidelines.

FIG. 4 is a graph depicting the TSB values vs. an infants postnatal age up to 60 hours, for a portion of the curves depicted in FIG. 3. For instance, a portion of the exchange transfusion threshold curve, the phototherapy threshold curve, and the 110 % of the phototherapy threshold curve are depicted in FIG. 4. FIG 4 also depicts an example time window of 0 - 6 hours, which is intended to schematically represent one example time period during which phototherapy may be administered and one or more bilirubin levels may be taken or determined, in accordance with various aspects of the methods disclosed herein. In this example time window, the time of 0-6 hours may represent the time period of 0-6 hours from the initiation of phototherapy according to the 2004 AAP Guidelines. Additionally, FIG. 4 depicts another example time window of 8-20 hours, which may schematically represent a time period where stannsoporfin is administered, one or more post-stannsoporfin bilirubin levels are determined, one or more additional therapies are administered, or a combination thereof, in accordance with various aspects of the methods disclosed herein. In this example time window, the time 8-20 hours may represent the time period of 8-20 hours from the initiation of phototherapy according to the 2004 AAP Guidelines.

The present disclosure can be described in accordance with the following numbered clauses. Clause 1. A method of treating progressive hyperbilirubinemia, comprising: initiating phototherapy on an infant in need thereof; determining one or more bilirubin levels of the infant subsequent to the initiating phototherapy; and in response to the determining one or more bilirubin levels of the infant, administering a therapeutic amount of stannsoporfin to the infant at least about 4 hours after the initiating phototherapy.

Clause 2. The method according to clause 1, wherein the determining one or more bilirubin levels of the infant comprises determining one or more bilirubin levels of the infant between 4 and 6 hours after the initiating phototherapy.

Clause 3. The method according to clause 1 or 2, wherein the one or more bilirubin levels of the infant is at or above 110 %, 120 %, or 125 % of the age-specific threshold for phototherapy specified in the 2004 AAP Guidelines.

Clause 4. The method according to any of clauses 1-3, wherein the one or more bilirubin levels comprises at least two bilirubin levels, and wherein the at least two bilirubin levels indicate an increase in bilirubin in the infant of greater than or equal to 1.5 mg/dl/hr.

Clause 5. The method according to any of clauses 1-4, wherein the infant exhibits a hemolytic disorder.

Clause 6. The method according to clause 5, wherein the hemolytic disorder comprises one or more of: ABO or Rh incompatibility and infant is DAT positive; GP6D deficiency; or hereditary spherocytosis.

Clause 7. The method according to any of clauses 1-6, further comprising determining one or more post-stannsoporfin bilirubin levels in the infant between 30 minutes and 24 hours after the administering the therapeutic amount of stannsoporfin.

Clause 8. The method according to clause 7, further comprising administering one or more additional therapies in response to the one or more post- stannsoporfin bilirubin levels being within about 3 mg/dl of the threshold value for administration of exchange transfusion specified in the 2004 AAP Guidelines.

Clause 9. The method according to clause 8, wherein the one or more additional therapies is intravenous immunoglobulin (IVIg), exchange transfusion, or a combination thereof.

Clause 10. The method according to any of clauses 1-9, wherein the therapeutic amount of stannsoporfin is between about 0.5 mg/kg of the infant’s weight to about 4.0 mg/kg of the infant’ s weight. Clause 11. The method according to any of clauses 1-10, wherein the therapeutic amount of stannsoporfin is selected from 1.5 mg/kg of the infant’s weight, and 3.0 mg/kg of the infant’s weight.

Clause 12. The method according to any of clauses 1-11, wherein the administering the therapeutic amount of stannsoporfin to the infant is performed via a single intramuscular injection.

Clause 13. The method according to any of clauses 1-12, wherein phototherapy is administered to the infant over a time period that extends from the initiating phototherapy to a time of at least about 2 hours after the administering the therapeutic amount of stannsoporfin.

Clause 14. A method of treating progressive hyperbilirubinemia, comprising: initiating phototherapy on an infant in need thereof, wherein the infant exhibits a hemolytic disorder; determining a plurality of serial bilirubin levels of the infant over a period of at least two hours, subsequent to the initiating phototherapy; and administering a therapeutic amount of stannsoporfin to the infant at least about 4 hours after the initiating phototherapy, in response to: 1) at least one of the plurality of serial bilirubin levels being at least 110 % of the age-specific threshold for phototherapy specified in the 2004 AAP Guidelines; 2) at least a portion of the plurality of serial bilirubin levels indicating an of increase of bilirubin in the infant greater than or equal to 1.5 mg/dl/hr; or 3) a combination thereof. Clause 15. The method according to clause 14, wherein the determining the plurality of serial bilirubin levels occurs at least partly during a time period of about 4 hours to about 6 hours after the initiating phototherapy, and wherein the administering a therapeutic amount of stannsoporfin to the infant occurs at least about 6 hours after the initiating phototherapy. Clause 16. The method according to clause 14 or 15, wherein the hemolytic disorder comprises one or more of: ABO or Rh incompatibility and the infant is DAT positive; GP6D deficiency; or hereditary spherocytosis.

Clause 17. The method according to any of clauses 14-16, wherein the administering the therapeutic amount of stannsoporfin to the infant is performed via a single intramuscular injection.

Clause 18. The method according to any of clauses 14-17, further comprising determining one or more post-stannsoporfin bilirubin levels in the infant between 30 minutes and 24 hours after the administering the therapeutic amount of stannsoporfin. Clause 19. The method according to clause 18, further comprising administering one or more additional therapies in response to the one or more post- stannsoporfin bilirubin levels being within about 3 mg/dl of the threshold value for administration of exchange transfusion specified in the 2004 AAP Guidelines, wherein the one or more additional therapies comprises intravenous immunoglobulin (IVIg), exchange transfusion, or a combination thereof.

Clause 20. The method according to any of clauses 14-19, wherein phototherapy is administered to the infant over a time period that extends from the initiating phototherapy to a time of at least about 2 hours after the administering the therapeutic amount of stannsoporfin.

Although the methods disclosed herein have been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification.

Claims

CLAIMS What is claimed is:

1. A method of treating progressive hyperbilirubinemia, comprising: initiating phototherapy on an infant in need thereof; determining one or more bilirubin levels of the infant subsequent to the initiating phototherapy; and in response to the determining one or more bilirubin levels of the infant, administering a therapeutic amount of stannsoporfin to the infant at least about 4 hours after the initiating phototherapy.

2. The method according to claim 1, wherein the determining one or more bilirubin levels of the infant comprises determining one or more bilirubin levels of the infant between 4 and 6 hours after the initiating phototherapy.

3. The method according to claim 1, wherein the one or more bilirubin levels of the infant is at or above 110 % of the age-specific threshold for phototherapy specified in the 2004 AAP Guidelines.

4. The method according to claim 1, wherein the one or more bilirubin levels comprises at least two bilirubin levels, and wherein the at least two bilirubin levels indicate an increase in bilirubin in the infant of greater than or equal to 1.5 mg/dl/hr.

5. The method according to claim 1, wherein the infant exhibits a hemolytic disorder.

6. The method according to claim 5, wherein the hemolytic disorder comprises one or more of: ABO or Rh incompatibility and infant is DAT positive; GP6D deficiency; or hereditary spherocytosis.

7. The method according to claim 1, further comprising determining one or more post-stannsoporfin bilirubin levels in the infant between 30 minutes and 24 hours after the administering the therapeutic amount of stannsoporfin.

8. The method according to claim 7, further comprising administering one or more additional therapies in response to the one or more post-stannsoporfin bilirubin levels being within about 3 mg/dl of the threshold value for administration of exchange transfusion specified in the 2004 AAP Guidelines.

9. The method according to claim 8, wherein the one or more additional therapies is intravenous immunoglobulin (IVIg), exchange transfusion, or a combination thereof.

10. The method according to claim 1, wherein the therapeutic amount of stannsoporfin is between about 0.5 mg/kg of the infant’s weight to about 4.0 mg/kg of the infant’ s weight.

11. The method according to claim 1, wherein the therapeutic amount of stannsoporfin is selected from 1.5 mg/kg of the infant’s weight, and 3.0 mg/kg of the infant’s weight.

12. The method according to claim 1, wherein the administering the therapeutic amount of stannsoporfin to the infant is performed via a single intramuscular injection.

13. The method according to claim 1, wherein phototherapy is administered to the infant over a time period that extends from the initiating phototherapy to a time of at least about 2 hours after the administering the therapeutic amount of stannsoporfin.

14. A method of treating progressive hyperbilirubinemia, comprising: initiating phototherapy on an infant in need thereof, wherein the infant exhibits a hemolytic disorder; determining a plurality of serial bilirubin levels of the infant over a period of at least two hours, subsequent to the initiating phototherapy; and administering a therapeutic amount of stannsoporfin to the infant at least about 4 hours after the initiating phototherapy, in response to: 1) at least one of the plurality of serial bilirubin levels being at least 110 % of the age- specific threshold for phototherapy specified in the 2004 AAP Guidelines; 2) at least a portion of the plurality of serial bilirubin levels indicating an of increase of bilirubin in the infant greater than or equal to 1.5 mg/dl/hr; or 3) a combination thereof.

15. The method according to claim 14, wherein the determining the plurality of serial bilirubin levels occurs at least partly during a time period of about 4 hours to about 6 hours after the initiating phototherapy, and wherein the administering a therapeutic amount of stannsoporfin to the infant occurs at least about 6 hours after the initiating phototherapy.

16. The method according to claim 14, wherein the hemolytic disorder comprises one or more of: ABO or Rh incompatibility and the infant is DAT positive; GP6D deficiency; or hereditary spherocytosis.

17. The method according to claim 14, wherein the administering the therapeutic amount of stannsoporfin to the infant is performed via a single intramuscular injection.

18. The method according to claim 14, further comprising determining one or more post-stannsoporfin bilirubin levels in the infant between 30 minutes and 24 hours after the administering the therapeutic amount of stannsoporfin.

19. The method according to claim 18 , further comprising administering one or more additional therapies in response to the one or more post-stannsoporfin bilirubin levels being within about 3 mg/dl of the threshold value for administration of exchange transfusion specified in the 2004 AAP Guidelines, wherein the one or more additional therapies comprises intravenous immunoglobulin (IVIg), exchange transfusion, or a combination thereof.

20. The method according to claim 14, wherein phototherapy is administered to the infant over a time period that extends from the initiating phototherapy to a time of at least about 2 hours after the administering the therapeutic amount of stannsoporfin.