Utah Medicaid Dur Report December 2017 Overview Of

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UTAH MEDICAID DUR REPORT DECEMBER 2017

OVERVIEW OF DRUGS WITH APPROVED ORPHAN INDICATIONS: WITH FOCUS ON CARBAGLU

Drug Regimen Review Center Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Research Assistant Professor Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Joanne LaFleur, Pharm.D., MSPH, Associate Professor

Data support David Servatius Jacob Crook, MStat

Contents

Introduction ...... 2 Methodology ...... 3 Search Results ...... 4 Table 1. Different viewpoints related to the marketing of orphan-drug products ...... 5 Descriptions of the Orphan Drug Subset ...... 6 Table 2. Examples of drugs with ≥ 3 orphan-designation approvals since 2011 ...... 6 Table 3. Selected drugs with an orphan-designated approval in the last 7 years and with common use indications ...... 7 Table 4. 2016 top 10 selling US drugs with orphan Indications ...... 8 Carbaglu (carglumic acid) for N-Acetylglutamate Synthase Deficiency (NAGSD) ...... 10 Table 5. Carbaglu indications, dosing, & use concerns ...... 11 Utah Medicaid Utilization Data ...... 13 Table 6. Orphan-only indicated products prescribed to > 100 unique patients between October 2016 through October 2017 ...... 13 Table 7. Utilization for products in Tables 2, 3 and 4 (October 2016 through October 2017) ...... 14 Table 8. Utilization for selected orphan-drugs (October 2016 through October 2017, in order by generic name) ...... 15 Table 9. Carbaglu utilization data ...... 17 Discussion Topics for Developing Prescribing Criteria ...... 17 Summary ...... 18 Appendix A: Websites with Additional Background Information ...... 19 Appendix B: Orphan-Drug Master Tables ...... 20 Table 1: Intramuscular orphan approved agents (1983- September 2017) ...... 20 Table 2: Subcutaneous orphan approved agents (1983- September 2017) ...... 20 Table 3: Oral orphan approved agents (1983- September 2017) ...... 22 Appendix C: Relevant ICD10 Diagnosis Codes ...... 26 References ...... 29

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Introduction

An estimated 25 million Americans suffer from a rare or “orphan” disease, defined as one that affects fewer than 200 thousand people across the United States (US).1,2 There are approximately 7,000 known rare diseases, of which fewer than 5% have developed treatments.1 Today, biotechnology and pharmaceutical companies, small and large, are filling this treatment vacancy at an accelerated pace.3,4 At the outset, the 1983 Orphan Drug Act (ODA) aimed to spur meaningful advancements for persons with rare diseases by providing tax and other marketing incentives to companies that brought “orphan drugs” (i.e., drugs that have indications for orphan diseases) to the market. It was perceived that a drug company would not otherwise be motivated to develop products in the rare-disease arena because research expenditures would not be recouped, much less a profit realized.5,6

Although a drug may be approved for a rare disease, its use may actually become widespread. Some factors that increase orphan-drug utilization include situations when (1) the orphan-approved drug also has non-orphan indications (e.g. Humira, Crestor), and/or (2) the orphan-approved drug has multiple approved orphan-designations or off-label supported uses (e.g. Gleevec).

The amplification of orphan-drug approvals has challenged health-plan designers. Orphan-related approvals are beginning to rival non-orphan-drug approval rates. From January through September 2017, 38% of the novel medications brought to market were approved for an orphan indication.7,8 EvaluatePharma, a company that analyzes financial markets, projects that the share of sales from orphan-drugs (among the total worldwide prescription-drug sales) is expected to continue growing.3,9 They estimated the 2016 US average cost per patient per year for orphan drug use was $140,443 compared to $27,756 for non-orphan drugs.3 Developing prescribing criteria to help ensure the appropriate patients receive these medications (according to labeled approved indications and guideline recommendations) may help minimize misuse.

This report provides an overview of the orphan drug landscape. Medicaid utilization data for selected orally, intramuscularly, and subcutaneously administered products with orphan- designation approvals is provided. In addition, a particular focus on one selected orphan drug, carglumic acid (Carbaglu; Recordati Rare Diseases, Inc. Lebanon, NJ) for the treatment of a rare urea-cycle enzyme deficiency, is also provided as a case study.

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Methodology

We searched PubMed, Google, and websites for the US Food and Drug Administration (FDA), the National Organization for Rare Disorders, Orpha.net, and the American Cancer Society for background information on orphan-drugs and for specific information related to carglumic acid and the treatment of N-acetylglutamate synthase deficiency (NAGSD). Additional drug information resources, such as Lexicomp and Micromedex, were also used.

Data Sources

Master orphan drug list: A list of orphan-drug approvals from 1983 through September 2017 was obtained from the website of the FDA’s ‘Search Orphan Drug Designations and Approvals’ database: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/. Since this list represents each orphan- approval for a drug, many of which have more than one approved indication, it was then duplicated to create a clean list of products to use for utilization queries. This list was then narrowed to focus only on products administered orally, subcutaneously, and intramuscularly for this review subset. Utilization for other subsets, such as intravenously administered products, will be provided in a future 2018 report. The route-of-administration detail for this selection process was derived one- by-one using drug information resources. Appendix B provides lists of the queried products.

Drug-utilization extraction: Medicaid references 412,310 distinct NDCs (national drug codes) in the database. An asymmetric spelling distance linkage algorithm was used to match product information maintained by Medicaid against the derived list of generic and trade names identified as orphan drugs (see Appendix B for lists). Using conservative matching algorithm parameters in order to maximize the number of relevant drugs captured, in addition to restricting drugs administered via oral, subcutaneous, and intramuscular routes, 8,463 possible orphan-drug matching NDCs were obtained. There are 136,766 Medicaid records from October 2016 to October 2017 that referenced NDCs from the finalized list. The current limitation to this process is that summary utilization data may reflect use for some generic drugs that are not considered “bioequivalent” (per the FDA Orange Book) to the orphan brand name product. In some instances there was also positive matching of other brand name products with the same generic name as the orphan product. To mitigate these issues, the list was narrowed to those products listed in Tables 6 through 8 for further examination to identify utilization for only the brand name orphan-designated approved product and its bioequivalent generic, if available on the market.

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Search Results

The 1983 Orphan Drug Act (ODA) ushered an incentivized drug-development opportunity for sponsors, granting a seven-year marketing exclusivity term and other financial incentives, for an orphan-designated approved drug brought to market.6 Amid enacting the ODA, the US Congress opined that it was in the best interest of the public to provide drug-development incentives to benefit persons with rare diseases for which there were inadequate or no drug therapies available. At that time, Huntington’s disease, myoclonus, Lou Gehrig’s, Tourette syndrome and muscular dystrophy were rare disorders of interest.6

From 1983 through November 2017, approximately 650 orphan-drug designations have been approved by the FDA. These approvals involve roughly 480 products, with some having multiple approved orphan indications. The Orphan Drug Designation Program (ODDP), overseen by the Food and Drug Administration’s Office of Orphan Products Development, requires either that the orphan- designated product treat a rare disease affecting less than 200,000 Americans or that the manufacturer convincingly show it will not recoup developmental costs from sales within the US.10 Incentives for orphan-drug development include a tax discount (50% tax credit on certain research/development costs11), an application fee waiver, grant availability, marketing exclusivity, and research design assistance. Additionally, there is flexibility in what the Food and Drug Administration (FDA) considers to be substantial evidence for demonstrating the drug’s safety and efficacy profile.6,12,13

Traditional randomized controlled trials are usually unfeasible in the study of rare diseases. The challenge of small patient populations has stemmed a case-by-case evidence consideration approach by the FDA, and the use of trial designs such as n-of-1, early escape, and adaptive randomization.13,14 Retrospective data from case reports may also be considered.15,16

Prior to performing a pivotal clinical trial, manufacturers must detail the natural history of the rare condition (e.g. disease manifestations, variability in the course and possible subtypes of the disease) and propose the trial design and endpoints to the FDA. Once an orphan-designated drug receives approval, the manufacturer is granted a seven-year marketing exclusivity period during which the FDA will not approve the same drug for the same indication, unless the subsequent drug moiety is shown to be clinically superior.10 Essentially, only the indication of a drug is protected; a drug can be marketed as a generic under older indications for which the approval exclusion period has expired. Although the exclusion period expires after seven years, the acquisition cost of an approved orphan-designated product may hardly change, especially if alternative manufacturers are not quick to produce generics.

From the beginning of 2012 to the end of 2016, an average of 39 orphan-designated drug approvals per year were granted by the FDA.7 This is a drastic advancement compared to pre-1983 when there were fewer than 10 orphan-related products that entered the market between 1973 and 1983.5 The number of orphan-drug designation requests submitted by companies continues to grow.17 In recent years this rate has overwhelmed the capacity of FDA review boards. The pace of orphan reviews will quicken with the goals of the new Orphan Drug Modernization Plan to overcome a significant backlog of applications. The FDA commissioner plans to address certain loopholes, especially those involving small affected pediatric subpopulations of a common adult

4 | Page disease state for which a drug company may seek a pediatric orphan designation to avoid the Pediatric Research Equity Act requirements.17

There are several concerns regarding a price premium for orphan-drug products. In some instances it is theorized that a manufacturer may set the drug price to reflect the “from-scratch” developmental value for an orphan-only indication despite the product being used for more common, high-demand indications. Even if not used for a common indication, orphan-drugs may still confer massive profits despite being used for small patient populations.3,18,19 Table 1 summarizes some concerns related to the orphan-drug marketing landscape.

Table 1. Different viewpoints related to the marketing of orphan-drug products3,18-23 Costs to Insurer and Beneficiaries • Orphan related drugs costs are perceived as • Drug costs and medical care costs in driving up overall healthcare costs versus general go up over time

• A small targeted population allows a price • This price premium is justified by premium for orphan drugs;3 however there is manufacturers as a means to recoup concern when profits become a windfall developmental costs and as a way to . Blockbuster sales: some propose that assign the rescue-of-life value for orphan status should be eliminated for a advanced personalized drugs. designated drug if sales meet a certain . Drug research and development profit threshold is a long process often leading to . The increasing average cost per many failures before a success beneficiary associated with the rapid molecule is obtained growth rate in orphan drug sales may be . Drug use for non-orphan related unsustainable. Worldwide orphan-drug indications may also contribute sales are expected to increase by 11% to profit from 2017 to 2022 and account for 21% of all brand-name drug sales by 20223

Concerns that a Drug Developer May Game the System • Salami slicing concept: breaking up a • Although a drug may be used widely versus widespread disease state into narrow disease for a common disease state, it still subtypes or age groups to accomplish low costs to perform research in a unique patient numbers to qualify for orphan status population or for a uniquely

characterized disease for which the • Going around the Pediatric Research Equity Act by proposing orphan designation for a drug has not been studied in full pediatric group when the drugs is approved for a non-orphan adult indication

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Descriptions of the Orphan Drug Subset

 Roughly 200 unique brand name products have an orphan indication currently protected by the 7-year exclusivity period, with some having more than one orphan-indication as referenced in the FDA’s orphan database.7 Table 2 provides examples of brand name medications with 3 or more orphan-designated indications that were approved for labeling since 2011.

Table 2. Examples of drugs with ≥ 3 orphan-designation approvals since 20117 Generic name (Brand name, route): # of orphan-designated approvals since 2011 Adalimumab (Humira, SQ): 4 Bevacizumab (Avastin, IV): 6 Brentuximab vedotin (Adcetris, IV): 3 Canakinumab (Ilaris, SQ): 4 Daratumumab (Darzalex, IV): 3 Deferasirox (Exjade, PO): 3 Everolimus (Afinitor, PO): 3 Ibrutinib (Imbruvica, PO): 10 Ipilimumab (Velcade, IV or SQ): 3 Lenalidomide (Revlimid, PO): 3 Ofatumumab (Arzerra, IV): 3 Pembrolizumab (Keytruda, IV): 4 Rituximab (Rituxan, IV): 3 Abbreviations: IM, intramuscularly; IV, intravenously; PO, orally; SQ, subcutaneously

o Medicaid Prior Authorization (PA) Criteria and Preferred Drug List (PDL): Note that the listed medications in Table 2 do not have developed PA-criteria, with the exception of Avastin.24 Only Humira is listed on the PDL (as a preferred product).25

 Since 2015, the majority of approved orphan-designated drugs are indicated for oncology- related uses. Other products are for indications related to the following conditions:

o Toxicity reversal involving transfusion-related iron overload, acetaminophen overdose, dabigatran reversal, and Crotaline snake poisoning; o Hormone deficiencies such as hypo- and hyperparathyroidism; o Enzyme disorders of the urea, tyrosine, cysteine, cholesterol, or bile acid synthesis/metabolism cycles; o Nervous system disorders such as Huntington’s disease; cerebral palsy, and late stage Parkinson’s; o Various genetic disorders: muscular dystrophy, cystic fibrosis, familial mediterranean fever, homozygous familial hypercholesterolemia, hereditary orotic aciduria, TNF-receptor associated periodic syndrome, congenital factor IX deficiency, hyperimmunoglobulinemia D o Infectious diseases: hepatitis C, parasitic worms, inhalation anthrax, invasive aspergillosis, and zygomycosis o Others: mastocytosis, biliary cirrhosis, and pulmonary arterial hypertension

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 Numerous drugs on the market are approved for common use indications in addition to orphan indications; a few examples of these are listed in Table 3.

Table 3. Selected drugs with an orphan-designated approval in the last 7 years and with common use indications7,26 Generic name Rare disease for which an orphan approval (Brand name), remains protected under the 7 year Additional labeled indications route marketing exclusivity period Rheumatoid arthritis • Moderate to severe hidradenitis o Ankylosing spondylitis suppurativa (Hurley stage 2 and Hurley o Crohn’s disease Adalimumab stage 3 disease) o Juvenile idiopathic arthritis (Humira), SQ • o Uveitis Plaque psoriasis • Pediatric Crohn's disease o o Psoriatic arthritis • Treatment of juvenile rheumatoid arthritis o Ulcerative colitis o Bipolar 1 disorder o Major depressive disorder Aripiprazole • Tourette’s syndrome o Schizophrenia (Abilify), PO o Irritability associated with Autistic disorder

Everolimus • Neuroendocrine tumors o Breast cancer (Afinitor), PO • Tuberous sclerosis complex o Renal cell carcinoma • Subependymal giant cell astrocytoma

o Prevention of cardiovascular disease o Hypertriglyceridemia o Primary hyperlipidemia and mixed hyperlipidemia Rosuvastatin • Pediatric homozygous familial Generalized atherosclerosis (Crestor), PO hypercholesterolemia o o Familial hypercholesterolemia homozygous o Familial type 3 hyperlipoproteinemia Abbreviations: IM, intramuscularly; IV, intravenously; PO, orally; SQ, subcutaneously

o Medicaid PA criteria and PDL: Humira and Crestor are listed as preferred products; Abilify is a non-preferred product; Afinitor is not on the PDL nor does it have developed PA criteria.24,25

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 The 2017 report by EvaluatePharma summarized the following trends and predictions for the orphan-drug marketplace.3 I. Top 10 selling orphan drugs in the US for 2016 (shown in Table 4)

Table 4. 2016 top 10 selling US drugs with orphan Indications3,7,26 Generic name Rare disease for which an orphan Other rare diseases for which the approval (Brand name), route approval remains protected by the 7 exclusion period has expired and other year marketing exclusivity term7 non-orphan indications Bortezomib • Mantle cell lymphoma first line • Multiple myeloma (OI) (Velcade), IV & SQ • Mantle cell lymphoma second line (OI) Cinacalcet • Severe hypercalcemia in primary • Hypercalcemia related to parathyroid (Sensipar), PO hyperparathyroidism carcinoma (OI) • Secondary hyperparathyroidism related to chronic kidney disease Glatiramer acetate • None • Multiple sclerosis (OI) (Copaxone), SQ Ibrutinib • Chronic graft vs. host disease in adults • None (Imbruvica), PO • Marginal zone lymphoma: nodal, splenic, and extranodal • Small lymphocytic lymphoma • Chronic lymphocytic leukemia • Waldenstrom’s macroglobulinemia • Mantle cell lymphoma Imatinib • Philadelphia+ acute lymphoblastic • Chronic myeloid leukemia (OI) (Gleevec), PO leukemia in pediatric patients • Aggressive systemic mastocytosis (OI) • Dermatofibrosarcoma protuberans (OI) • Gastrointestinal stromal tumors (OI) • Hypereosinophilic syndrome and/or chronic eosinophilic leukemia (OI) • Myelodysplastic/Myeloproliferative disease (OI) Interferon beta-1a • None • Multiple sclerosis (OI) (Avonex), IM Lenalidomide • Treatment of multiple myeloma (MM) as • Multiple myeloma (second line) (OI) (Revlimid), PO (1) maintenance following autologous • Myelodysplastic syndromes (OI) hematopoietic stem cell transplantation • Other off-label supported uses (auto-HSCT) and (2) in combination with dexamethasone for the treatment of patients with multiple myeloma who have not received at least one prior therapy (first line treatment) • Treatment of mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. Table 4 continues on the next page

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o Medicaid PA criteria and PDL: Avonex and Copaxone 20mg are listed as preferred agents on the current Utah Preferred Drug List. Xyrem has PA-criteria set in place (reviewed by DUR board in May 2016).24,25

II. Forecasted top selling orphan drugs for 2022 (worldwide): Revlimid, Opdivo, Keytruda, Darzalex, Soliris, Imbruvica, Orkambi, Yervoy, Rituxan.3 Orphan drugs are anticipated to account for 21% of worldwide brand-name prescription sales by 2022.3 o Orkambi is the only agent among this list with Utah Medicaid PA-criteria (reviewed by DUR board in September 2015).24

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Carbaglu (carglumic acid) for N-Acetylglutamate Synthase Deficiency (NAGSD)

Carbaglu has two FDA orphan designations for which one has received FDA approval: (a) designated for the treatment of organic acidemias, and (b) designated and approved for treatment of N- acetylglutamate synthesis deficiency. Off-label uses documented in case-reports include correction of hyperammonemia due to valproic acid induced encephalopathy,27,28 other urea acid cycle disorders (e.g. citrullinemia Type 1, partial carbamoyl-phosphate synthase I deficiency),29,30 organic acidemias,31,32 mixed ammonia clearing pathway deficiencies,33 and hyperammonemia secondary to malignancy and chemotherapy.34 Bench-work exploratory applications include repurposing the product for oncology related diseases.35

Carglumic acid is an N-acetylglutamate (NAG) analog, designed to replace the endogenous cofactor essential for activating carbamoyl phosphate synthetase-1 (CPS-1).16 Carbamoyl phosphate synthetase-1 is the initial enzyme in the urea cycle, which eliminates excess ammonia generated as waste product from protein metabolism. Persons who lack or partially lack N-acetylglutamate synthase (NAGS) are deficient in NAG and cannot sufficiently clear ammonia which becomes toxic to neurons upon accumulation.16 Table 5 provides a summary of the dosing and use concerns for carglumic acid.

N-acetylglutamate deficiency (NAGSD) is one of several rare urea cycle disorders, transferred as an autosomal recessive mutation.36 Persons with this rare disease are usually identified as neonates when symptoms are severe, due to complete lack of endogenous NAGS, or may be diagnosed later in life with milder symptoms from partial deficiency of NAGS.36,37 Symptomatic newborns presenting in acute hyperammonemia crisis (a normal anion gap is expected) within the first couple days of birth may develop respiratory distress and alkalosis, temperature instability, seizures, acute encephalopathy, and coma.36,38 Chronic symptoms generally include refusal to eat, lethargy, dizziness, tremor, vomiting, diarrhea, irritability, hepatomegaly, confusion, and psychiatric changes. Affected individuals may suffer from ongoing learning disabilities, developmental delays/disorders (ataxia, hypotonia), and recurrent hyperammonemia. 36,38

A treatment guideline for urea cycle disorders (all are rare diseases) was published in 2012 by a development group including pediatric metabolic specialists.38 During acute decompensation of NAGS deficiency, concomitant administration of carglumic acid with ammonia scavenger agents such as sodium benzoate and L-arginine is recommended.38 In retrospective case reports, carglumic acid reduced plasma ammonia levels within 24 hours in a non-dose-response relationship. 16 By day 3, all patients with follow-up data had normalized ammonia levels upon dose-titration. Carglumic acid has a terminal half-life between 4.3 and 9.5 hours and is primarily excreted, unchanged, through the feces. No drug interactions are expected, based on in-vitro studies.16

The drug application package submitted to the FDA consisted of a single open-label clinical trial including 3 patients, in addition to retrospective data for 23 patients, diagnosed with NAGSD who were prescribed Carbaglu for a median of 7.9 years.16,39 In the FDA’s report, the reviewer notes that only 25-50 patients with NAGSD are known of, worldwide.40 Although there is limited clinical data, the reviewer writes that the data presented by the sponsor supports “…the short and long-term

10 | Page effectiveness of Carbaglu in treatment of hyperammonemia based on the rapid and sustained normalization of plasma ammonia levels in all NAGS deficiency patients for whom data were available.”40

Table 5. Carbaglu indications, dosing, & use concerns16 Dosage Form & Carbaglu-carglumic acid, 200mg tablets; before opening, store refrigerated at 36-46◦F; after Storage opening store at temperature not to exceed 86◦F; discard 1 month after first opening 1) Acute hyperammonemia in patients with NAGS deficiency: indicated as an adjunctive therapy with other ammonia lowering therapies (e.g. alternate pathway medications, hemodialysis, and dietary protein restriction) in pediatric and adult patients for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase FDA Approved (NAGS) Indications 2) Maintenance therapy for chronic hyperammonemia in patients with NAGS deficiency: for pediatric and adult patients with chronic hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS). Concomitant use of other ammonia lowering therapies and protein restriction may be reduced or discontinued during maintenance therapy based on plasma ammonia levels Adult Dosing o Initial dose for acute hyperammonemia: 100 mg/kg/day to 250 mg/kg/day, then titrated based on individual patient plasma ammonia o Maintenance dose: titrate dose to age-specific target normal plasma ammonia level and administer in 2 to 4 divided daily doses, rounded to the nearest 100mg. In retrospective case- series data from 22 patients, maintenance doses were usually less than 100 mg/kg/day Pediatric Dosing Dosage & o Initial dose for acute hyperammonemia: 100 mg/kg/day to 250 mg/kg/day, then titrated based Administration on individual patient plasma ammonia o Maintenance dose: titrate dose to age-specific target normal plasma ammonia level and administer in 2 to 4 divided daily doses. In retrospective case-series data from 22 patients, maintenance doses were usually less than 100 mg/kg/day Administration  Should be initiated by a physician experienced in metabolic disorders  Tables must be dispersed in water immediately before use (see package insert for dose preparation details); tablets should not be swallowed whole or crushed . Contraindications: None . Hyperammonemia: Acute symptomatic hyperammonemia is a life-threatening emergency which may require dialysis. Uncontrolled hyperammonemia can result in rapid brain injury/damage or death. Coordination with medical personnel experienced in metabolic disorders should take place for the management of this disorder . Monitoring: Ongoing monitoring of plasma ammonia levels, neurological status, laboratory tests and clinical responses in patients receiving Carbaglu is crucial to assess patient response to Warnings, treatment Precautions & . Nutritional management: Upon hyperammonemia, complete protein restriction is Adverse recommended to be maintained for the initial 24 to 48 hours and caloric supplementation Reactions should be maximized to reverse catabolism and nitrogen turnover . Common adverse reactions (occurring in ≥ 13% of patients of retrospective case-series data): infections, vomiting, abdominal pain, pyrexia, tonsillitis, anemia, ear infection, diarrhea, nasopharyngitis and headache . Over-dosage: May present as a monosodium glutamate intoxication-like syndrome with tachycardia, profuse sweating, increased bronchial secretion, increased body temperature and restlessness. Symptoms resolved upon dose reduction in the one overdose case report discussed in the product labeling prescribing information

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 Information pertaining to NAGS-deficiency diagnosis

38 o A diagnostic algorithm based on blood chemistries by Haberle et al is available. NAGS- deficiency typically presents with elevated ammonia, elevated glutamine, decreased citrulline, and normal urine orotic acid levels; 30 however, this is also the case for CPS-1 deficiency. DNA testing is the primary method to differentiate between NAGS and CPS-1 deficiencies, however, enzymatic activity assays on liver biopsies may be needed when genetic diagnosis is inconclusive.38 Molecular testing has some limitations: sensitivity varies by laboratory or over time,41 and Mew et al, explain that enzyme activity test may be helpful when DNA-testing produces an uninformative result.41 Inconclusive results may occur especially in those with phenotypic heterogeneity and/or late onset disease.42

o The package insert for Carbaglu includes DNA information for the 23 patients among the retrospective assessment where available. Eighteen of the 23 (78%) had a known DNA testing result showing either homozygous or heterozygous NAGS gene mutations; 5 patients of the 23 had an unavailable DNA test result.

o For the clinical trial (IND# 68-185) involving 3 patients diagnosed with NAGSD, the inclusion criteria required the patients to be diagnosed per molecular confirmation: 2 patients had compound heterozygote mutations and 1 patient had a single heterozygote mutation

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Utah Medicaid Utilization Data

 Orphan-only indicated brand name products prescribed to > 100 unique patients between October 2016 through October 2017

Table 6. Orphan-only indicated products prescribed to > 100 unique patients between October 2016 through October 2017 Rx claims Related rare disease ICD10 Query Route Generic Brand(s) (patient) for approved (between 10/16 to 10/17) counts indication7,26 OR Clobazam Onfi* 1,377 (194) • Lennox-Gastaut • Of the 194 patients, 185 did not Syndrome have any of the ICD10 codes (listed in Table 1 of Appendix C) with “Lennox-Gastaut” term submitted

OR Levocarnitine Carnitor 526 (111) • Primary & • Of the 111 patients, 110 did not secondary carnitine have any of the ICD10 codes deficiency (MEE) (listed in Table 2 of Appendix C) with “carnitine” term; 14 of these patients received a brand name product and the others filled generic equivalents OR Albendazole Albenza* 189 (181) • Echinococcosis • None of the 111 patients had (MEE) any of the ICD10 codes (listed in • Neurocysticercosis Table 3 of Appendix C) with (MEE) “echinococcus granulosus” OR “taenia” terms submitted *Notates a drug that only comes as a brand name product; where there is not an asterisk, the utilization data reflects that for the brand and approved generics Abbreviations: MEE, marketing exclusion period has ended; OR, orally; Rx, prescription

o Specific PA criteria has not been developed by Utah Medicaid for the listed brand name products in Table 6; Onfi is listed as a non-preferred drug on the Utah Medicaid PDL. o Information per US National Library of Medicine: “Lennox-Gastaut syndrome affects an estimated 1 in 50,000 to 1 in 100,000 children. This condition accounts for about 4 percent of all cases of childhood epilepsy.”43

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 Utilization for products listed in Tables 2, 3, and 4

Table 7. Utilization for products in Tables 2, 3 and 4 (October 2016 through October 2017) Route Generic Brand (s) Rx claims (patient) counts SQ Adalimumab Humira* 874 (177) OR Aripiprazole Abilify 16,844 (2,870) SQ Canakinumab Ilaris* 11 (2) OR Cinacalcet HCl Sensipar* 114 (21) OR Deferasirox Exjade* 7 (2) OR Everolimus Afinitor* 44 (8) SQ Glatiramer Acetate Copaxone (MEEA); Galtopa 189 (41) OR Imatinib Mesylate Gleevec (MEES) 92 (14) IM Interferon Beta-1a Avonex* 89 (17) OR Lenalidomide Revlimid* 43 (10) OR Rosuvastatin Calcium Crestor 918 (211) *Notates a drug that only comes as a brand name product; where there is not an asterisk, the utilization data reflects that for the brand and generics Abbreviations: IM, intramuscularly; MEEA, marketing exclusion has expired for all of the product’s orphan-approved designations; MEES; marketing exclusion has expired for some of the product’s orphan- approved designations; OR, orally; Rx, prescription; SQ, subcutaneously

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 Top 30 Oral, Intramuscular, and Subcutaneous Subset of Orphan-drugs per Patient Reimbursement

Table 8. Utilization for selected orphan-drugs (October 2016 through October 2017, in order by generic name) • Rare disease or condition for orphan approval Rx Route Generic Brands o Related disease for non-orphan approvals (patient) counts OR Alectinib HCl Alecensa* • Anaplastic lymphomas kinase+ non-small cell lung 3 (1) cancer OR Ambrisentan Letairis* • Pulmonary arterial hypertension 129 (18) OR Bexarotene Generic • Primary cutaneous T-cell lymphoma 7 (1) OR Bosentan Tracleer* • Pulmonary arterial hypertension 53 (7) OR Bosutinib Bosulif* • Philadelphia chromosome+ chronic myelogenous 5 (1) leukemia OR Brigatinib Alunbrig* • Anaplastic lymphoma kinase positive non-small 4 (1) lung cancer SQ Canakinumab Ilaris* • Cryopyrin associated periodic syndromes: familial cold autoinflammatory syndrome and Muckel- Wells Syndrome • Familial mediterranean fever 11 (2) • Hyper-IgD syndrome/Mevalonate Kinase Deficiency • Systemic juvenile idiopathic arthritis • TNF receptor-associated periodic fever syndrome OR Carglumic Acid Carbaglu* • Acute hyperammonemia in patients with N- acetylglutamate synthase deficiency • Maintenance therapy for chronic 5 (1) hyperammonemia in patients with N- acetylglutamate synthase deficiency OR Dabrafenib Tafinlar* • Melanoma (metastatic or unresectable 8 (2) Mesylate • Non-small cell lung metastatic cancer OR Dasatinib Sprycel* • Chronic myelogenous leukemia 40 (7) • Philadelphia+ acute lymphoblastic leukemia OR Deferiprone Ferriprox* • Transfusional iron overload 12 (2) SQ Ecallantide Kalbitor* • Hereditary angioedema 3 (2) OR Everolimus Afinitor* • Renal angiomyolipoma and tuberous sclerosis complex • Tuberous sclerosis syndrome with subependymal giant cell astrocytoma 44 (8) • Neuroendocrine tumors of pancreatic, gastrointestinal and lung origin o Advanced renal cell carcinoma o Breast cancer OR Glycerol Ravicti* • For use as a nitrogen-binding agent in urea cycle 14 (3) Phenylbutyrate disorders OR Imatinib Mesylate Gleevec • Chronic myeloid leukemia • Aggressive systemic mastocytosis • Dermatofibrosarcoma protuberans • Gastrointestinal stromal tumors 92 (14) • Hypereosinophilic syndrome and/or chronic eosinophilic leukemia • Myelodysplastic/Myeloproliferative disease

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Table 8. Utilization for selected orphan-drugs (October 2016 through October 2017, in order by generic name) • Rare disease or condition for orphan approval Rx Route Generic Brands o Related disease for non-orphan approvals (patient) counts • Philadelphia+ acute lymphoblastic leukemia in pediatric patients Ivacaftor Kalydeco* • Cystic fibrosis, In patients with an ivacaftor- 45 (7) OR responsive mutation in the CFTR gene SQ Lanreotide Somatuline* • Acromegaly Acetate • Carcinoid syndrome 17 (3) • Neuroendocrine tumors Ledipasvir- Harvoni* • Hepatitis C (genotypes 1,4,5, or 6) in pediatric Sofosbuvir patients 86 (35) OR o Hepatitis C (genotypes 1,4,5, or 6) in adult patients Lenalidomide Revlimid* • Multiple myeloma • Mantle cell lymphoma 43 (10) OR • Myelodysplastic syndromes Lumacaftor- Orkambi* • Cystic fibrosis 82 (14) OR Ivacaftor OR Macitentan Opsumit* • Pulmonary arterial hypertension 81 (10) OR Nilotinib HCl Tasigna* • Chronic myelogenous leukemia 48 (6) OR Olaparib Lynparza* • Ovarian cancer 16 (2) PO Ponatinib Iclusig* • Acute lymphoblastic leukemia 3 (2) • Chronic myeloid leukemia Regorafenib Stivarga* • Hepatocellular carcinoma 4 (1) OR • Metastatic gastrointestinal stromal cancer OR Selexipag Uptravi* • Pulmonary arterial hypertension 14 (2) Sofosbuvir Sovaldi* • Hepatitis C (genotypes 2, or 3) in pediatric patients 19 (7) OR o Hepatitis C (genotypes 1,2,3,or 4) in adult patients SQ Somatropin (Non- Serostim* • AIDS wasting cachexia Refrigerated) 8 (1) OR Tasimelteon Hetlioz* • Non-24 hour sleep-wake disorder 10 (2) Vigabatrin Sabril • Infantile spasms 118 (17) OR o Refractory complex partial epileptic seizures Please refer to the prescribing information (product labeling) for the full details of the FDA-approval *Notates a drug that only comes as a brand name product; where there is not an asterisk, the utilization data reflects that for the brand and generics

o Products in Table 8 with specific PA criteria developed: Kalydeco (reviewed by DUR board in September 2015).24 o Medicaid PDL: Of the products listed in Table 8, Letairis, Tracleer, Sovaldi, and Harvoni are listed as preferred; and Opsumit, Hetlioz, Uptravi, Sabril, and Serostim are listed as non-preferred.25

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 Carbaglu Utilization (All: ACO + FFS)

Table 9. Carbaglu utilization data

Query for ICD10 diagnosis codes: Claims (patient) Patient E7220; E7229; P746; 2706; 2763 Prescriber counts from 2014 age at (see Table 4, Appendix C for to November 2017 first fill definitions)

13 (1) 4 years None found in the patient’s record Specializes in pediatric genetics

Discussion Topics for Developing Prescribing Criteria

 PA Criteria for Carbaglu • Indication: PA criteria for outpatient prescribing may require documentation of maintenance treatment for chronic hyperammonemia in patients with diagnosed NAGS deficiency.

o Consider that initial fills will likely be requested during hospital admission for treatment of an acute hyperammonemia crisis when the patient has not previously been diagnosed and/or confirmed by genetic analysis. This is an emergent situation and a guideline recommends use of carglumic acid in patients with unspecified urea cycle disorders in acute decompensation.38 • The diagnosis rationale (including symptoms, ammonia levels, and DNA-testing, etc.) should be documented.

o Some flexibility may be needed since there may be scenarios in which genetic testing is inconclusive, yet blood chemistries, enzyme activity, or other hallmark laboratory findings, may correspond with the diagnosis. • Therapy should be initiated by a health care provider experienced in the treatment of metabolic disorders.

o Flexibility may be considered for those in rural areas where metabolic specialists may be limited, especially since presentation may be an emergent situation. Consultation with a metabolic disorder specialist may be considered as therapy continues. • For continuation of therapy, condition improvement may be demonstrated by providing documentation of normalization trends in ammonia levels, symptomatic improvements (e.g. neurologic/psychiatric), and reduced need for adjunctive ammonia lowering therapies.

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Summary

Rapid advancements in disease specific treatments, genetic characterization, and personalized medicine are expected to continue amplifying the development of orphan drugs. Financial trend studies suggest that market-share costs associated with orphan-drugs will continue to increase.3,18 Medications with orphan indications span a vast set of drug-classes. Some orphan-approved drugs may have multiple orphan-designation approvals and some are additionally approved for common disorders. Considerations for prior authorization criteria pertaining to carglumic acid are outlined in addition to utilization data for selected orphan drugs. The board may wish to consider further reviews specific for agents listed in Table 6 especially.

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Appendix A: Websites with Additional Background Information

Urea Cycle Graphics30,44 • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056327/figure/f1-ijgm-4-021/ • http://www.sciencedirect.com/science/article/pii/S0169409X15000654?via%3Dihub#f0020 • https://www.carbaglu.net/dtc/about-carbaglu/#what-is-carbaglu

Orphanet.com ICD10 coding recommendations for rare diseases • http://www.orpha.net/consor/cgi-bin/Education.php?lng=EN Prevalence and incidence of rare diseases • http://www.orpha.net/consor/cgi-bin/Education.php?lng=EN

National Organization for Rare Disorders Physician Guides for Rare Disorders • https://rarediseases.org/for-patients-and-families/information-resources/physician-guides/

Shire Rare-Disease Presentation Accessible Online: Greissing J. Coverage of Rare Disease Therapies in Medicaid and Medicare and the Impact on Patient Care. • http://www.cbinet.com/sites/default/files/files/Greissing_Jay_pres.pdf

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Appendix B: Orphan-Drug Master Tables

Table 1: Intramuscular orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Adagen (IM) Pegademase bovine Avonex (IM) Interferon beta-1a Cibacalcin (IM, SQ, Inhalation) Calcitonin-human for injection Dysport (IM) Botulinum toxin type A Erwinase (IM, IV, SQ) Erwinia L-asparaginase Gammagard Liquid (IM) Immune globulin infusion Ixiaro (IM) Japanese encephalitis vaccine Makena (IM) Hydroxyprogesterone caproate Methotrexate (IM, IV, PO, SQ) Methotrexate sodium Metrodin (IM, SQ) Urofollitropin Oncaspar (IM, IV) Pegaspargase Pentam 300 (IM, IV) Pentamidine isethionate Sandostatin Lar (IM) Octreotide Thyrogen (IM) Thyrotropin alfa Triptodur (IM) Triptorelin pamoate Varizig (IM) Varicella Zoster Immune Globulin Winrho Sd (IM, IV) Rho (D) immune globulin intravenous (human)

Table 2: Subcutaneous orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Actemra (SQ, IV) Tocilizumab Actimmune (SQ) Interferon gamma-1b Apokyn (SQ) Apomorphine HCl Arcalyst (SQ) Rilonacept Betaseron (SQ) Interferon beta-1b Cibacalcin (IM, SQ, Inhalation) Calcitonin human for injection Copaxone (SQ) Glatiramer acetate Enbrel (SQ) Etanercept Epogen (IV, SQ) Epoetin alfa Erwinase (IV, IM, SQ) Erwinia L-asparaginase Firazyr (SQ) Icatibant Gamimune N (IM, SQ, IV) Immune globulin intravenous, human Gattex (SQ) Teduglutide

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Table 2: Subcutaneous orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Genotropin (SQ) Somatropin Gonal-F (SQ) Follitropin alfa, recombinant Haegarda (SQ and IV) C1-esterase-inhibitor, human, pasteurized Humatrope (SQ) Somatropin Humira (SQ) Adalimumab Ilaris (SQ) Canakinumab Increlex (SQ) Mecasermin Kalbitor (SQ) Ecallantide Kineret (SQ) Anakinra Kynamro (SQ) Mipomersen Lutrepulse (IV, SQ) Gonadorelin acetate Luveris (SQ) Recombinant human luteinizing hormone Methotrexate (IV, IM,PO, SQ) Methotrexate sodium Metrodin (IM, SQ) Urofollitropin Mozobil (SQ) Plerixafor Myalept (SQ) Metreleptin Natpara (SQ) Parathyroid hormone Neulasta (SQ) Pegfilgrastim Neumega (SQ) Oprelvekin Neupogen (SQ, IV) Filgrastim Norditropin (SQ) Somatropin Nplate (SQ) Romiplostim Nutropin AQ Somatropin Remodulin (SQ, IV) Treprostinil Repatha (SQ) Evolocumab Rituxan Hycela (SQ) Rituximab and recombinant human hyaluronidase Saizen (SQ) Somatropin Serostim (SQ) Somatropin Signifor (SQ) Pasireotide Somatuline Depot (SQ) Lanreotide acetate Somavert (SQ) Pegvisomant Strensiq (SQ) Asfotase alfa Supprelin La (SQ) Histrelin Sylatron (SQ) Peginterferon alfa-2b Synribo (SQ) Omacetaxine mepesuccinate Velcade (SQ, IV) Bortezomib Xgeva (SQ) Denosumab Zorbtive (SQ) Somatropin (r-DNA)

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Table 3: Oral orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Abilify (PO) Aripiprazole Adcirca (PO) Tadalafil Adempas (PO) Riociguat Afinitor (PO) Rverolimus Agrylin (PO) Anagrelide Albenza (PO) Albendazole Alecensa (PO) Alectinib Alinia (PO) Nitazoxanide Alunbrig (PO) Brigatinib Amatine (PO) Midodrine HCl Ampyra (PO) Dalfampridine Aromasin (PO) Exemestane Austedo (PO) Deutetrabenazine Banzel (PO) Rufinamide Betapace (PO) Sotalol HCl Bosulif (PO) Bosutinib Buphenyl (PO) Sodium phenylbutyrate Caprelsa (PO) Vandetanib Carbaglu (PO) Carglumic acid Carnitor (PO) Levocarnitine Cayston (PO Inhalation) Aztreonam Cerdelga (PO) Eliglustat Cetylev (PO) Acetylcysteine Chemet (PO) Succimer Cholbam (PO) Cholic acid Coartem (PO) Artemether/lumefantrine Colazal (PO) Balsalazide disodium Colcrys (PO) Colchicine Cometriq (PO) Cabozantinib Crestor (PO) Rosuvastatin Cuvposa (PO) Glycopyrrolate Cystadane (PO) Betaine Cystagon (PO) Cysteamine Didronel (PO) Etidronate disodium Droxia (PO) Hydroxyurea Duodopa (Enteral) Levodopa and carbidopa Eldepryl (PO) Selegiline HCl Elmiron (PO) Pentosan polysulfate sodium Emflaza (PO) Deflazacort

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Table 3: Oral orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Endari (PO) L-glutamine Envarsus XR (PO) Tacrolimus Esbriet (PO) Pirfenidone Evista (PO) Raloxifene Exjade (PO) Deferasirox Fareston (PO) Toremifene Farydak (PO) Panobinostat Felbatol (PO) Felbamate Ferriprox (PO) Deferiprone Galzin (PO) Zinc acetate Gastrocrom (PO) Cromolyn sodium Gilotrif (PO) Afatinib Gleevec (PO) Imatinib Gocovri (PO) Amantadine hydrochloride Gralise (PO) Gabapentin Halfan (PO) Halofantrine Harvoni (PO) Ledipasvir/sofosbuvir Hemangeol (PO) Propranolol Hetlioz (PO) Tasimelteon Hexalen (PO) Altretamine Horizant ER (PO) Gabapentin enacarbil Iclusig (PO) Ponatinib Idhifa (PO) Enasidenib Imbruvica (PO) Ibrutinib Impavido (PO) Miltefosine Iressa (PO) Gefitinib Jakafi (PO) Ruxolitinib Juxtapid (PO) Lomitapide Kalydeco (PO) Ivacaftor Korlym (PO) Mifepristone Kuvan (PO) Sapropterin Lamictal (PO) Lamotrigine Lamprene (PO) Clofazimine Lariam (PO) Mefloquine HCL Lenvima (PO) Lenvatinib Letairis (PO) Ambrisentan Leucovorin Calcium (PO) Leucovorin Lynparza (PO) Olaparib Marinol (PO) Dronabinol

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Table 3: Oral orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Megace (PO) Megestrol acetate Mekinist* (PO) And Tafinlar* (PO) Trametinib and Dabrafenib Mepron (PO) Atovaquone Mobic (PO) Meloxicam Mycobutin (PO) Rifabutin Nexavar (PO) Sorafenib Ninlaro (PO) Ixazomib citrate Normix (PO) Rifaximin Northera (PO) Droxidopa Nutrestore (PO) Glutamine Nymalize (PO) Nimodipine Ocaliva (PO) Obeticholic acid Ofev (PO) Nintedanib Onfi (PO) Clobazam Opsumit (PO) Macitentan Orfadin (PO) Nitisinone Orkambi (PO) Lumacaftor/Ivacaftor Paser Granules (PO) Aminosalicylic acid Pomalyst (PO) Pomalidomide Priftin (PO) Rifapentine Procysbi (PO) Cysteamine Prograf (PO) Tacrolimus Promacta (PO) Eltrombopag Provigil (PO) Modafinil Purixan (PO) Mercaptopurine Radiogardase (PO) Ferric Hexacyanoferrate Rapamune (PO) Sirolimus Ravicti (PO) Glycerol phenylbutyrate Rebetol (PO) Ribavirin Revlimid ((PO) Lenalidomide Rifater (PO) Rifampin, isoniazid, pyrazinamide Rilutek (PO) Riluzole Rubraca (PO) Rucaparib Rydapt (PO) Midostaurin Sabril (PO) Vigabatrin Salagen (PO) Pilocarpine Sensipar (PO) Cinacalcet Sirturo (PO) Bedaquiline fumarate Sovaldi (PO) Sofosbuvir

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Table 3: Oral orphan approved agents (1983- September 2017) Trade Name (Route) Generic Name Sprycel (PO) Dasatinib Stivarga (PO) Regorafenib Suboxone (PO) Buprenorphine/naloxone Subutex (PO) Buprenorphine hydrochloride Sucraid (PO) Sacrosidase Syprine (PO) Trientine HCl Tafinlar (PO) Dabrafenib Tagrisso (PO) Osimertinib Targretin (PO) Bexarotene Tasigna (PO) Nilotinib Temodar (PO, IV) Temozolomide Thalomid (PO) Thalidomide Thiola (PO) Tiopronin Tindamax (PO) Tinidazole Topamax (PO) Topiramate Tracleer (PO) Bosentan Trexan (PO) Naltrexone HCl Tyvaso (PO) Treprostinil Uptravi (PO) Selexipag Urocit-K (PO) Potassium citrate Urso 250 (PO) Ursodiol Venclexta (PO) Venetoclax Vermox (PO) Mebendazole Vesanoid (PO) Tretinoin Viread (PO) Tenofovir Votrient (PO) Pazopanib Xalkori (PO) Crizotinib Xatmep (PO) Methotrexate Xenazine (PO) Tetrabenazine Xermelo (PO) Telotristat etiprate Xyrem (PO) Oxybate Zavesca (PO) Miglustat Zejula (PO) Niraparib Zelboraf (PO) Vemurafenib Zemplar (PO) Paricalcitol Zolinza (PO) Vorinostat Zydelig (PO) Idelalisib Zykadia (PO) Ceritinib

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Appendix C: Relevant ICD10 Diagnosis Codes

ICD10 codes with “Lennox-Gastaut” term:

Table 1. ICD10 codes with “Lennox-Gastaut” term ICD Diagnosis G40811 LENNOX-GASTAUT SYNDROME, NOT INTRACTABLE, W STAT E G40812 LENNOX-GASTAUT SYNDROME, NOT INTRACTABLE, W/O STAT G40813 LENNOX-GASTAUT SYNDROME, INTRACTABLE, W STATUS EPI G40814 LENNOX-GASTAUT SYNDROME, INTRACTABLE, W/O STATUS E

ICD 10 codes with “Carnitine” term:

Table 2. ICD10 codes with “Carnitine” term ICD Diagnosis 27781 PRIMARY CARNITINE DEFICIENCY 27782 CARNITINE DEFICIENCY INBORN ERRORS OF METABOLISM 27783 IATROGENIC CARNITINE DEFICIENCY 27784 OTHER SECONDARY CARNITINE DEFICIENCY E71314 MUSCLE CARNITINE PALMITOYLTRANSFERASE DEFICIENCY E7140 DISORDER OF CARNITINE METABOLISM, UNSPECIFIED E7141 PRIMARY CARNITINE DEFICIENCY E7142 CARNITINE DEFICIENCY DUE TO INBORN ERRORS OF METAB E7143 IATROGENIC CARNITINE DEFICIENCY E71448 OTHER SECONDARY CARNITINE DEFICIENCY

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ICD10 codes with “Echinococcus granulosus” OR “Taenia”

Table 3. ICD10 codes with “Echinococcus granulosus” OR “Taenia” terms ICD Diagnosis

B670 ECHINOCOCCUS GRANULOSUS INFECTION OF LIVER B671 ECHINOCOCCUS GRANULOSUS INFECTION OF LUNG B672 ECHINOCOCCUS GRANULOSUS INFECTION OF BONE B6731 ECHINOCOCCUS GRANULOSUS INFECTION, THYROID GLAND B6732 ECHINOCOCCUS GRANULOSUS INFECTION, MULTIPLE SITES B6739 ECHINOCOCCUS GRANULOSUS INFECTION, OTHER SITES B674 ECHINOCOCCUS GRANULOSUS INFECTION, UNSPECIFIED 1230 TAENIA SOLIUM INTESTINE 1232 TAENIA SAGINATA INFECT 1233 TAENIASIS NOS B680 TAENIA SOLIUM TAENIASIS B681 TAENIA SAGINATA TAENIASIS B689 TAENIASIS, UNSPECIFIED

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Examples of ICD10 codes that may relate to N-acetylglutamate synthase deficiency, however are not entirely specific to this disease state:

Table 4. Selected ICD10 codes related to NAGS deficiency ICD Diagnosis

P746 TRANSITORY HYPERAMMONEMIA OF NEWBORN 2763 ALKALOSIS 2706 DIS UREA CYCLE METABOL E7220 DISORDER OF UREA CYCLE METABOLISM, UNSPECIFIED E7229 OTHER DISORDERS OF UREA CYCLE METABOLISM

Examples of other ICD10 codes that may be applicable in N-acetylglutamate deficiency:

ICD Diagnosis 2708 DIS AMINO-ACID METAB NEC 2709 DIS AMINO-ACID METAB NOS E728 OTHER SPECIFIED DISORDERS OF AMINO-ACID METABOLISM E729 DISORDER OF AMINO-ACID METABOLISM, UNSPECIFIED 2763 ALKALOSIS E889 METABOLIC DISORDER, UNSPECIFIED G9341 METABOLIC ENCEPHALOPATHY

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References

1. Rare Disease Day at NIH, 2017: NCATS and Rare Disease Research. NIH, National Center for Advancing Translational Sciences. https://ncats.nih.gov/rdd. Accessed October 30, 2017. 2. Orphan Products: Hope for People with Rare Diseases. U.S. Food & Drug Administration. Silver Spring, MD. https://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143563.htm. 3. EvaluatePharma Orphan Drug Report 2017. 4th Edition-February 2017. 2017 Evaluate Ltd. Boston, MA. http://www.evaluategroup.com/public/Reports/EvaluatePharma-Orphan-Drug- Report-2017.aspx. 4. Wellman-Labadie O, Zhou Y. The US Orphan Drug Act: rare disease research stimulator or commercial opportunity? Health policy (Amsterdam, Netherlands). 2010;95(2-3):216-228. 5. Developing Products for Rare Diseases & Conditions. U.S. Food & Drug Administration. Silver Spring, MD. https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default.htm. Accessed June 6, 2017. 6. Orphan Drug Act- Relevant Excerpts. U.S. Food & Drug Administration. Silver Springs, MD. https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/Howtoapplyfo rOrphanProductDesignation/ucm364750.htm. Accessed June 6, 2017. 7. Search Orphan Drug Designations and Approvals: Orphan Drug Designation Database. U.S. Food and Drug Administration. Silver Spring, MD. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. 8. Novel Drug Approvals for 2017. Updated 10/20/2017. U.S. Food & Drug Administration. Silver Spring, MD. https://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm537040.htm. Accessed October 20, 2017. 9. Evaluate: About Us, Our Clients. http://www.evaluategroup.com/public/OurClients.aspx. Accessed November 15, 2017. 10. Title 21: Food and Drugs--Orphan Drugs: Electronic Code of Federal Regulations: U.S. Government Publishig Office. https://www.ecfr.gov/cgi- bin/retrieveECFR?gp=&SID=0e737d105ef9a1632b19a1e713b93cc4&mc=true&n=pt21.5.316&r= PART&ty=HTML. Accessed June 6, 2017. 11. National Organization for Rare Disorders. Policy Issues. https://rarediseases.org/advocate/policy-priorities/issues/. Accessed November 22, 2017. 12. Guidance for Industry: User Fee Waivers, Reductions, and Refunds for Drug and Biological Products. OMB Control No. 0910-0693. U.S. Department of Health and Human Services Food and Drug Administration. Silver Springs, MD. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances /ucm079298.pdf. Accessed June 7, 2017. 13. Gobburu J, Pastoor D. Drugs Against Rare Diseases: Are The Regulatory Standards Higher? Clinical pharmacology and therapeutics. 2016;100(4):322-323. 14. Cornu C, Kassai B, Fisch R, et al. Experimental designs for small randomised clinical trials: an algorithm for choice. Orphanet journal of rare diseases. 2013;8:48. 15. Drug@FDA: FDA Approved Drug Products Summary Review. Application Number 208169Orig1s000. U.S. Food and Drug Administration. Silver Spring, MD. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/208169Orig1s000SumR.pdf. Accessed November 13, 2017.

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16. Carbaglu (carglumic acid) tablets [packate insert]. Lebanon, NJ. Recordati Rare Disease, Inc. Revised November 2012. 17. Gottlieb S. FDA is Advancing the Goals of the Orphan Drug Act. 2017; https://blogs.fda.gov/fdavoice/index.php/2017/09/fda-is-advancing-the-goals-of-the-orphan- drug-act/. Accessed October 5, 2017. 18. Meekings KN, Williams CS, Arrowsmith JE. Orphan drug development: an economically viable strategy for biopharma R&D. Drug discovery today. 2012;17(13-14):660-664. 19. Elgin B, Bloomfield D, Chen C. When the Patient Is a Gold Mine: The Trouble With Rare-Disease Drugs. Bloomberg Businessweek, May 24, 2017 https://www.bloomberg.com/news/features/2017-05-24/when-the-patient-is-a-gold-mine-the- trouble-with-rare-disease-drugs. Accessed October 30, 2017. 20. Patel KR. Orphan Drug Debate: A Cheat Sheet. June 2017. Managed Care https://www.managedcaremag.com/archives/2017/6/orphan-drug-debate-cheat-sheet. Accessed November 6, 2017. 21. Jack A. Financial Times. Combating Rare Disease: Orphan drugs attract rich returns for pharmaceuticals. February 27, 2017. 2017; https://www.ft.com/content/2016a758-d674-11e6- 944b-e7eb37a6aa8e. Accessed November 7, 2017. 22. Health News from NPR. Drugs For Rare Diseases Have Become Uncommonly Rich Monopolies. January 17, 2017. https://www.npr.org/sections/health-shots/2017/01/17/509506836/drugs- for-rare-diseases-have-become-uncommonly-rich-monopolies. Accessed November 7, 2017. 23. Hyde R, Dobrovolny D. Orphan drug pricing and payer management in the United States: are we approaching the tipping point? American health & drug benefits. 2010;3(1):15-23. 24. Utah Department of Health, Medicaid Prior Authorization. https://medicaid.utah.gov/pharmacy/prior-authorization. Accessed November, 2017. 25. Utah Departement of Health, Medicaid Preferred Drug List November 2017. https://medicaid.utah.gov/pharmacy/preferred-drug-list. Accessed November, 2017. 26. Lexi-Drugs (drug monographs). Lexicomp Online. Wolters Kluwer Clinical Drug Information, Inc. Indianapolis, IN. . http://online.lexi.com/lco/action/home. 27. Nava-Mateos JJ, Roiz-Rey P, Diaz Alvarez-Mediavilla J, Cebrian-Novella D, Gomez-Del Olmo V, Ceberio-Hualde L. [Treatment of encephalopathy by means of valproic acid with carglumic acid: two case reports and a review of the literature]. Revista de neurologia. 2017;65(9):409-414. 28. Kasapkara CS, Kangin M, Tas FF, Topcu Y, Demir R, Ozbek MN. Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid. Journal of pediatric neurosciences. 2013;8(3):250-252. 29. Kose E, Kuyum P, Aksoy B, Haberle J, Arslan N, Ozturk Y. First report of carglumic acid in a patient with citrullinemia type 1 (argininosuccinate synthetase deficiency). Journal of clinical pharmacy and therapeutics. 2017. 30. Daniotti M, la Marca G, Fiorini P, Filippi L. New developments in the treatment of hyperammonemia: emerging use of carglumic acid. International journal of general medicine. 2011;4:21-28. 31. Levrat V, Forest I, Fouilhoux A, Acquaviva C, Vianey-Saban C, Guffon N. Carglumic acid: an additional therapy in the treatment of organic acidurias with hyperammonemia? Orphanet journal of rare diseases. 2008;3:2. 32. Kasapkara CS, Ezgu FS, Okur I, Tumer L, Biberoglu G, Hasanoglu A. N-carbamylglutamate treatment for acute neonatal hyperammonemia in isovaleric acidemia. European journal of pediatrics. 2011;170(6):799-801.

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33. van Karnebeek CD, Sly WS, Ross CJ, et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. American journal of human genetics. 2014;94(3):453-461. 34. Lazier J, Lupichuk SM, Sosova I, Khan AA. Hyperammonemic encephalopathy in an adenocarcinoma patient managed with carglumic acid. Current oncology (Toronto, Ont). 2014;21(5):e736-739. 35. Chen CT, Chen YC, Yamaguchi H, Hung MC. Carglumic acid promotes apoptosis and suppresses cancer cell proliferation in vitro and in vivo. American journal of cancer research. 2015;5(12):3560-3569. 36. NORD Online Physician Guides: N-Acetylglutamate Synthetase Deficiency. https://rarediseases.org/rare-diseases/n-acetylglutamate-synthetase-deficiency/. Accessed November 13, 2017. 37. Cartagena A, Prasad AN, Rupar CA, et al. Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 2013;40(1):3-9. 38. Haberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet journal of rare diseases. 2012;7:32. 39. Drug Approval Package: Carbaglu Tablets, Application No.:022562. U.S. Food and Drug Administration. Silver Springs. MD. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000TOC.cfm. Accessed November 13, 2017. 40. Center For Drug Evaluation And Research, Application Number 22-562: Cross Discipline Team Leader Review. U.S. Food and Drug Administration, Silver Springs, MD https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022562s000TOC.cfm. Accessed November 14, 2017. 41. Ah Mew N, Simpson KL, Gropman AL, Lanpher BC, Chapman KA, Summar ML. Urea Cycle Disorders Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(R). Seattle (WA): University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993. 42. Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N- acetylglutamate synthase (NAGS) gene. Human mutation. 2007;28(8):754-759. 43. Genetics Home Reference, Lennox-Gastaut syndrome. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/condition/lennox-gastaut-syndrome#statistics. Accessed November 20, 2017. 44. Matoori S, Leroux JC. Recent advances in the treatment of hyperammonemia. Advanced drug delivery reviews. 2015;90:55-68.

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