Background Analysis: US FDA Advisory Committee to Review Stannsoporfin Injection for Severe Neonatal Jaundice – MAY 3, 2018 (GIDAC/PEDAC)

Announcement

The US FDA has scheduled a joint meeting of the Gastrointestinal Drugs Advisory Committee (GIDAC) and the Pediatric Advisory Committee (PEDAC) for Thursday, May 3, 2018. The Committees will discuss new drug application (NDA) 209904, for stannsoporfin injection for intramuscular use, submitted by InfaCare Pharmaceutical Corporation (InfaCare), a Mallinckrodt company, proposed for the treatment of neonates (newborns less than 1 month old) with greater than or equal to 35 weeks of gestational age and indicators of hemolysis (breakdown of red blood cells), who are at risk of developing severe hyperbilirubinemia.

Indication Background

Description of Indication

Severe hyperbilirubinemia occurs when there is an excess of bilirubin, a byproduct of the normal breakdown of red blood cells, in the blood and tissues. Newborns with isoimmune hemolytic disease, such as ABO blood type or Rhesus (Rh) incompatibility, or glucose-6-phosphate dehydrogenase (G6PD deficiency), have an increased rate of red cell destruction and therefore, an increase in bilirubin production that the liver may not be able to adequately clear.

According to the US Centers for Disease Control and Prevention (CDC) of the 3.97 million US births per year, approximately 750,000 newborns are treated for jaundice. Common symptoms include yellow staining of the skin and the whites of the eyes, darker than usual urine, and lighter than usual stool. The current standard of care is phototherapy, in which infants are placed under a blue light that breaks down bilirubin into a form that can be processed through the liver. Jaundice is a common cause of hospital readmission. Rare, but serious complications from going untreated include cerebral palsy, deafness, and kernicterus, which is a type of brain damage.

Product Background

Description of Product

Stannsoporfin is a heme oxygenase inhibitor that has been formulated for administration via intramuscular injection. Heme oxygenase is an enzyme involved in breaking down red blood cells.

Clinical Trials of Proposed Indication

According to Mallinckrodt, the FDA and InfaCare reached an agreement in July 2016 that an NDA could be filed for stannsoporfin using the totality of the drug's data package, including: a positive Phase 2(b) trial as its pivotal study, and data from a second positive Phase 2(b) trial, with no additional studies required, pre-approval. Tarius did not find detailed results of the two trials in a review of press releases issued by Mallinckrodt; however, ClinicalTrials.Gov provides information for two relevant phase 2 studies of stannsoporfin (ClinicalTrials.gov IDs: NCT00850993 and NCT01887327). Note that additional details will be presented in FDA and company briefing materials that will be posted ahead of the meeting. These materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary.

NCT00850993

On August 29, 2014, results from a Phase 2b dose-escalation and safety and efficacy trial that started in August 2008 were submitted to ClinicalTrials.gov. The study population was term and late preterm newborns with a minimum birth weight of 5.5 pounds who had risk factors for hyperbilirubinemia, including ABO blood type or Rh incompatibility (anti-C, c, D, E, or e, or G6PD deficiency). Randomization and treatment could not occur unless the subjects were within 1 mg/dl below the threshold for Phototherapy (PT) per the American Academy of Pediatrics (AAP) Guidelines at up to 12 hours of age or within 2 mg/dL below the threshold for PT at >12 to 48 hours of age. The study aimed to enroll 72 subjects; however, it was terminated early for the purpose of redefining the study population. This resulted in the randomization of 58 subjects (29 females and 29 males) across three study cohorts. The mean age ranged from 16.5 to 23.3 hours.

Subjects in the first cohort were randomized to receive placebo or 1.5 mg/kg stannsoporfin. Subjects in the second and third cohorts were randomized to receive placebo or 3.0 and 4.5 mg/kg stannsoporfin, respectively. Since the study termination occurred prior to enrollment of the full 4.5 mg/kg cohort, only 8 subjects completed the study on this dose level. For the other dose levels: 16 subjects completed the study on the 1.5 mg/kg dose (note that 1 subject on this dose did not complete the study); 18 subjects completed the study on the 3.0 mg/kg dose; and 15 subjects completed the study on placebo treatment.

On August 19, 2014, the company submitted a change of the primary endpoint to ClinicalTrials.gov. The company changed the endpoint from the safety of the 3 doses to an efficacy endpoint based on serum bilirubin levels. In particular, the endpoint was changed to be the proportion of subjects who reached an age-adjusted threshold of total serum bilirubin (TSB) for PT at 48 hours post-treatment. The results for the current primary endpoint are listed below.

·      placebo cohort (N=15)           0

·      1.5 mg/kg cohort (N=17)        -13.45 (95% Confidence Interval [CI]: -26.27, 0.62);

·      3.0 mg/kg cohort (N=18)        -10.02 (95% CI: -22.61, 2.58)

·      4.5 mg/kg cohort (N=8)          -14.93 (95% CI: -30.31, 0.44)

No statistical analyses of these results were provided.

The rates of serious adverse events, along with descriptions, are listed below.

·      placebo cohort (N=15)           13.33% (2 cases of hyperbilirubinemia.)

·      1.5 mg/kg cohort (N=17)        0.00% (0 cases)

·      3.0 mg/kg cohort (N=18)        5.56% (1 case of anemia.)

·      4.5 mg/kg cohort (N=8)          12.50% (1 case of meningitis)

The percentage of subjects who experienced one or more adverse event, along with descriptions, are shown below.

·      placebo cohort (N=15)           33.33% (1 case of umbilical hernia, 2 cases of hyperbilirubinemia, 1 case of jaundice, 2 cases of oral candidiasis, 1 case of diaper dermatitis and 1 case of papular rash)

·      1.5 mg/kg cohort(N=17)         47.06% (1 case of leukocytosis, 2 cases of hyperbilirubinemia, 5 cases of jaundice, 1 case of contusion, 1 case of C-reactive protein increased, 1 case of hemangioma, 1 case of infantile acne, 1 case of contact dermatitis, 2 cases of diaper dermatitis, 1 case of rash and 1 case of skin exfoliation)

·      3.0 mg/kg cohort(N=18)         55.56% (1 case of anemia, 2 cases of leukocytosis, 1 case of vomiting, 1 case of hyperbilirubinemia, 1 case of anal abscess, 1 case of contusion, 1 case of blood glucose decreased, 1 case of blood sodium decreased, 1 case of carbon dioxide decreased, 1 case of diaper dermatitis, 1 case of erythema, 3 cases of erythema toxicum neonatorum, 1 case of neonatal rash, 1 case of seborrheic dermatitis and 1 case of flushing)

·      4.5 mg/kg cohort (N=8)          12.50% (2 cases of anemia, 1 case of thrombocytopenia, 1 case of bradycardia, 1 case of meningitis, 1 case of hemoglobin increased, 1 case of depressed level of consciousness and 1 case of erythema)

Secondary outcomes were to determine the pharmacokinetics of the 3 doses and to assess the change in unadjusted TSB at 48 hours.

NCT01887327

The results for a second Phase 2 study of stannsoporfin have not yet posted to ClinicalTrials.gov. This study evaluated the safety and efficacy of stannsoporfin (3.0 mg/kg and the 4.5 mg/kg) in combination with phototherapy. ClinicalTrials.gov reports that this study started in September 2013 and completed in March 2016. A company press release refers to completion of this study in July 2017.

The study population was term and near-term newborns with a minimum birth weight of 5.5 pounds who have risk factors for hyperbilirubinemia, including ABO blood type or Rh incompatibility (anti-C, c, D, E, or e) who are Coombs positive, or age 0-72 hours with G6PD deficiency. Subjects had to be at or above the age-specific threshold for initiating PT per the AAP guidelines based on measurement of TSB, and parents had to agree to observe light precautions for 10 days post-treatment. 91 subjects were enrolled.

The primary outcome is the percent change in TSB at 48 hours post-dose.

Secondary outcomes are listed below.

·      Percent change from baseline in TSB (the baseline TSB is the TSB that qualifies for randomization) at 6, 12, 24, and 36 hours [Time Frame: 6, 12, 24, and 36 hours]

·      Total serum bilirubin area under the curve (AUC) above the baseline TSB (0 to 48 hours post-dose). [Time Frame: 48 hrs]

·      Peak serum bilirubin [Time Frame: 0 to 48 hrs]

·      Incidence of rebound hyperbilirubinemia defined as an increase in TSB above the age-specific threshold for initiating PT per the AAP Guidelines following the discontinuation of the initial PT [Time Frame: 30 days]

·      Incidence of readmission to hospital for hyperbilirubinemia due to a TSB at or above the age specific threshold for PT [Time Frame: 30 days]

·      Duration of clinical requirement for PT [Time Frame: 30 days]

·      Incidence of adverse events and serious adverse events [Time Frame: 30 days]

·      Changes in vital sign measurements [Time Frame: 30 days]

·      Results of physical exam (PE), including growth measurements [Time Frame: 30 days]

·      Results of neurologic exam, including eye and hearing assessment [Time Frame: 30 days]

·      Electrocardiographic (ECG) assessments [Time Frame: 14 days]

·      Clinical laboratory tests including hematology, serum chemistries, liver function and renal function tests [Time Frame: 30 days]

NCT02685137

In addition to the aforementioned Phase 2 studies, ClinicalTrials.gov lists a Phase 3 trial by InfaCare that was started in April 2002 and completed in February 2013. This study was a randomized, placebo-controlled safety and efficacy study of stannsoporfin (4.5 mg/kg) in a different population than in the aforementioned phase 2 studies. This study enrolled 185 subjects who met the following eligibility criteria:

·      A healthy infant who received, or whose mother had received, antibiotics and the infant is asymptomatic. For example, the baby has no signs of cardio respiratory distress and is feeding well. Symptomatic infants are excluded.

·      Born at the study hospital site and admitted to the well-baby nursery or admitted to the intensive-care nursery for less than 12 hours for post-delivery observation (delayed transition, temperature or dextrose instability, meconium staining and/or parental concern).

·      All babies on oral feeding with stable cardio respiratory status and deemed "healthy" upon clinical examination, with normal perfusion as defined by capillary filling of the fingernail.

·      Term neonate (≥38 weeks of completed gestation), OR

·      Near-term neonate (>36<38 weeks of completed gestation; > 4.4 pounds birth weight), OR

·      Near-term neonate (>35<38 weeks of completed gestation; > 5.5 pounds birth weight)

·      Care provided (primarily) in the well-baby nursery population;

·      Absence of concurrent cardio respiratory distress, sepsis, major congenital anomalies, or need for care in an intensive care nursery;

·      Not participating in another concurrent unrelated study.

The primary outcome measure was the proportion of subjects who needed PT. The secondary outcome measure was the change in serum bilirubin levels.

Regulatory Background

US Regulatory Background

August 22, 2018 – PDUFA date

January 4, 2018 – Completion of the NDA submission was announced. (NDA 209904).

Fast Track Designation

Ex-US Regulatory Background

Tarius was not able to locate press releases related to any ex-US development of this product.

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: InfaCare Pharmaceutical Corporation Drug Name: stannsoporfin Drug Class: heme oxygenase inhibitor Indication: hyperbilirubinemia

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.