Fosdenopterin (Nulibry)

Number: 0991

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

---

Policy

Scope of Policy

This Clinical Policy Bulletin addresses fosdenopterin (Nulibry) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification. 

Precertification of fosdenopterin (Nulibry) is required of all Aetna participating providers and members in applicable plan designs. For precertification of fosdenopterin (Nulibry), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a physician who specializes in the treatment of enzyme or metabolic disorders.

2. Criteria for Initial Approval

   Aetna considers fosdenopterin (Nulibry) medically necessary for molybdenum cofactor deficiency (MoCD) type A when criteria is met in either of the following settings:

   1. When the diagnosis of MoCD Type A was confirmed by genetic testing documenting a pathogenic variant(s) in the molybdenum cofactor synthesis 1 (MOCS1) gene; or
   2. When both of the following criteria are met:
      
      
      1. Member has a presumed diagnosis of MoCD Type A and genetic test results are pending; and
      2. Member has clinical signs and symptoms associated with MoCD Type A (e.g., encephalopathy, intractable seizures, developmental delay, decreased uric acid levels, elevated urinary S-sulfocysteine and/or xanthine levels).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of fosdenopterin (Nulibry) therapy medically necessary for members with an indication listed in Section II when one of the following is met:

   1. The member has received less than 12 months of therapy and has genetic testing results documenting a pathogenic variant(s) in the molybdenum cofactor synthesis 1 (MOCS1) gene; or
   2. Member has received 12 months of therapy or more and is experiencing benefit from therapy (e.g., improvement, stabilization, or slowing of disease progression for encephalopathy and/or seizure activity, improved or normalized uric acid, urinary S-sulfocysteine, and xanthine levels).

Dosage and Administration

Nulibry for injection is supplied as 9.5 mg of fosdenopterin lyophilized powder or cake in a single-dose vial for reconstitution and is administered as an intravenous infusion. 

Persons Less Than 1 Year of Age

The recommended dosage regimen in persons less than one year of age (by gestational age) is based on actual body weight as shown in Table below.

Table: Recommended Initial Dosage and Titration Schedule for Persons Less Than 1 Year of Age by Gestational Age

Titration Schedule	Preterm Neonates (Gestational Age Less than 37 Weeks)	Term Neonates (Gestational Age 37 Weeks and Above
Initial Dosage	0.4 mg/kg once daily	0.55 mg/kg once daily
Dosage at Month 1	0.7 mg/kg once daily	0.75 mg/kg once daily
Dosage at Month 3	0.9 mg/kg once daily	0.9 mg/kg once daily

Persons 1 Year of Age or Older

For persons one year of age or older, the recommended dosage of Nulibry is 0.9 mg/kg (based on actual body weight) administered as an intravenous infusion once daily.

Source: Sentynl Therapeutics, 2022

---

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
Fosdenopterin (Nulibry) - No specific code
Other HCPCS codes related to the CPB:
Q0084 - Q0085	Chemotherapy administration, infusion technique
ICD-10 codes covered if selection criteria are met:
E72.19	Other disorders of sulfur-bearing amino-acid metabolism [molybdenum cofactor deficiency (MoCD) type A]

---

Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Nulibry is cyclic pyranopterin monophosphate (cPMP) indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) Type A.

Fosdenopterin is branded as Nulibry (Alcami Carolinas Corporation/Sentynl Therapeutics, Inc.). Fosdenopterin provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulfites. In molybdenum cofactor deficiency type A, the lack of effective SOX leads to elevated levels of the neurotoxic sulfite, S-sulfocysteine (SSC). Fosdenopterin (Nulibry) reduces the level of urinary SSC normalized to creatinine.

Although there have been no reported contraindications for Nulibry therapy, the label includes warnings and precautions for potential photosensitivity. It is recommended to advise patients/caregivers to avoid patient exposure to sunlight, and to have the patient wear sunscreen, protective clothing, and sunglasses when exposed to the sun. If photosensitivity occurs, advise caregivers/patients to seek medical attention immediately and consider a dermatological evaluation. The most common adverse reactions (greater than 25%) include catheter-related complications, pyrexia, viral infection, pneumonia, otitis media, vomiting, cough/sneezing, viral upper respiratory infection, gastroenteritis, bacteremia, and diarrhea (Sentynl Therapeutics, 2022).

Molybdenum cofactor deficiency (MoCD) Type A

Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive metabolic disorder characterized by severe and rapidly progressive neurologic damage (i.e., intractable seizures, brain injury and death) which can present within the first few days of life. There are three forms of the disorder, types A, B, and C, that include the same signs and symptoms, but are distinguished by their genetic mutation (i.e., MOCS1 cause of type A; MOCS2 cause of type B, or GPHN cause of type C). The proteins produced from each of these genes are involved in the biosynthetic pathway of molybdenum cofactor. Molybdenum cofactor is essential to the function of several enzymes which assist in the metabolization of different substances in the body, some of which are toxic if not metabolized.  Approximately two-thirds of patients have MoCD type A, in which mutations in molybdenum cofactor synthesis gene 1 (MOSC1) result in the inability to synthesize the first intermediate in the pathway, cyclic pyranopterin monophosphate (cPMP), and can develop toxic accumulation of sulfites in the blood and urine. During the first few days of life, a neonate may present with exaggerated startle, lethargy, intractable seizures, autonomic dysfunction, and a complex of symptoms that may resemble hypoxic ischemic encephalopathy (NIH/NLM, 2020; Shellhaas, 2020).

Patients with MoCD type A have mutations in the MOCS1 gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with fosdenopterin provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulfite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulfites, S-sulfocysteine (SSC). Treatment with fosdenopterin contributes to the reduction in the level of urinary SSC normalized to creatinine and studies show that the reduction could be sustained with long-term treatment of fosdenopterin therapy (Origin Biosciences, 2021a).

In February 2021, the U.S. FDA approved Nulibry (fosdenopterin) for injection to reduce the risk of mortality due to MoCD type A. Nulibry, an intravenous medication that replaces deficient cPMP, is the first FDA approved treatment for MoCD type A. FDA approval was based on the efficacy data from three clinical studies that compared data from a natural history study. 

Study 1 (NCT02047461) was a prospective, open-label, single-arm, dose escalation study in patients with MoCD type A who were receiving treatment with recombinant cPMP (rcPMP, which has the same active moiety and biologic activity as fosdenopterin) prior to treatment with fosdenopterin. Study 1 included 8 patients, 6 of whom previously participated in Study 3, a retrospective, observational study that included patients who received rcPMP. The initial fosdenopterin dosage was matched to the patient’s rcPMP dosage upon entering the study, then the dosage was titrated over a period of 5 months to a maximum dosage of 0.9 mg/kg administered once daily as an intravenous infusion.  Study 2 (NCT02629393) was a prospective, open-label, single-arm, dose escalation study in one patient with MoCD type A who had not been previously treated with rcPMP. The initial dosage of fosdenopterin in Study 2 was based on the gestational age of the patient (i.e., 36 weeks). The initial dosage was then incrementally escalated up to a maximum dosage of 0.98 mg/kg administered once daily as an intravenous infusion (1.1 times the maximum approved recommended dosage). The efficacy of fosdenopterin and rcPMP were assessed in a combined analysis of the 13 patients with genetically confirmed MoCD type A from Study 1 (n=8), Study 2 (n=1), and Study 3 (n=4) who received substrate replacement therapy with fosenopterin or rcPMP.  The median gestational age was 39 weeks (range 35 to 41 weeks). Of these 13 treated patients, the age at first dose was 14 days or less for 10 patients (with 5 patients initiating treatment at 1 day of age) and 32 days or more and less than 69 days for the remaining 3 patients. For overall survival (OS), efficacy was assessed by comparing OS in pediatric patients treated with fosdenopterin or rcPMP (n=13) with an untreated natural history cohort of pediatric patients with genetically confirmed MoCD type A who were genotype- matched to the treated patients (n=18). Patients treated with fosdenopterin or rcPMP had an improvement in overall survival compared to the untreated, genotype-matched, historical control group. Results were similar when comparing treated patients with all patients in the untreated natural history cohort 10 with genetically confirmed MoCD type A (n=37, includes the 18 genotype-matched untreated patients as well as 19 additional untreated patients who were not genotype-matched) (Origin Biosciences, 2021a). 

---

References