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
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
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.
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
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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
driving up overall healthcare costs versus
• Drug costs and medical care costs in general go up over time
• A small targeted population allows a price
premium for orphan drugs;3 however there is concern when profits become a windfall Blockbuster sales: some propose that
orphan status should be eliminated for a designated drug if sales meet a certain profit threshold
The increasing average cost per beneficiary associated with the rapid growth rate in orphan drug sales may be unsustainable. Worldwide orphan-drug sales are expected to increase by 11% from 2017 to 2022 and account for 21% of all brand-name drug sales by 20223
• This price premium is justified by manufacturers as a means to recoup developmental costs and as a way to assign the rescue-of-life value for advanced personalized drugs. Drug research and development
is a long process often leading to many failures before a success molecule is obtained
Drug use for non-orphan related indications may also contribute to profit
Concerns that a Drug Developer May Game the System • Salami slicing concept: breaking up a
widespread disease state into narrow disease subtypes or age groups to accomplish low patient numbers to qualify for orphan status
• Going around the Pediatric Research Equity Act
by proposing orphan designation for a pediatric group when the drugs is approved for a non-orphan adult indication
versus
• Although a drug may be used widely for a common disease state, it still costs to perform research in a unique population or for a uniquely characterized disease for which the drug has not been studied in full
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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
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
o Rheumatoid arthritis o Ankylosing spondylitis o Crohn’s disease o Juvenile idiopathic arthritis o Plaque psoriasis o Psoriatic arthritis o Ulcerative colitis
Aripiprazole (Abilify), PO
• Tourette’s syndrome
o Bipolar 1 disorder o Major depressive disorder o Schizophrenia o Irritability associated with Autistic
o Prevention of cardiovascular disease o Hypertriglyceridemia o Primary hyperlipidemia and mixed
hyperlipidemia o Generalized atherosclerosis 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
(Brand name), route Rare disease for which an orphan
approval remains protected by the 7 year marketing exclusivity term7
Other rare diseases for which the approval exclusion period has expired and other
non-orphan indications Bortezomib
(Velcade), IV & SQ • Mantle cell lymphoma first line
• Multiple myeloma (OI) • Mantle cell lymphoma second line (OI)
Cinacalcet (Sensipar), PO
• Severe hypercalcemia in primary hyperparathyroidism
• Hypercalcemia related to parathyroid carcinoma (OI)
• Secondary hyperparathyroidism related to chronic kidney disease
Glatiramer acetate (Copaxone), SQ
• None • Multiple sclerosis (OI)
Ibrutinib (Imbruvica), PO
• Chronic graft vs. host disease in adults • Marginal zone lymphoma: nodal, splenic,
and extranodal • Small lymphocytic lymphoma • Chronic lymphocytic leukemia • Waldenstrom’s macroglobulinemia • Mantle cell lymphoma
• None
Imatinib (Gleevec), PO
• Philadelphia+ acute lymphoblastic leukemia in pediatric patients
• Treatment of multiple myeloma (MM) as (1) maintenance following autologous hematopoietic stem cell transplantation (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.
(Rituxan), IV • Wegener's Granulomatosis, Microscopic
Polyangiitis, and Churg-Strauss Syndrome • Chronic lymphocytic leukemia • Diffuse large B-cell lymphoma • Follicular lymphoma
• Non-Hodgkin B lymphoma (OI) • Rheumatoid arthritis • Other off-label supported uses
Sodium oxybenzatate (Xyrem), PO
• None • Cataplexy in narcolepsy (OI) • Excessive day time sleepiness in narcolepsy
Abbreviations: IM, intramuscularly; IV, intravenously; OI, orphan indication approved for this disease state; PO, orally; SQ, subcutaneously
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
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
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 & Storage
Carbaglu-carglumic acid, 200mg tablets; before opening, store refrigerated at 36-46◦F; after opening store at temperature not to exceed 86◦F; discard 1 month after first opening
FDA Approved Indications
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 (NAGS)
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
Dosage & Administration
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 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. 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
Warnings, Precautions & Adverse Reactions
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 treatment
Nutritional management: Upon hyperammonemia, complete protein restriction is recommended to be maintained for the initial 24 to 48 hours and caloric supplementation 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
o A diagnostic algorithm based on blood chemistries by Haberle et al is available.38 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
Route Generic Brand(s) Rx claims (patient) counts
Related rare disease for approved indication7,26
ICD10 Query (between 10/16 to 10/17)
OR Clobazam Onfi* 1,377 (194) • Lennox-Gastaut
Syndrome • Of the 194 patients, 185 did not
have any of the ICD10 codes (listed in Table 1 of Appendix C) with “Lennox-Gastaut” term submitted
• Of the 111 patients, 110 did not have any of the ICD10 codes (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 (MEE)
• Neurocysticercosis (MEE)
• None of the 111 patients had any of the ICD10 codes (listed in Table 3 of Appendix C) with “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)
Route Generic Brands • Rare disease or condition for orphan approval o Related disease for non-orphan approvals
Rx (patient) counts
OR Alectinib HCl Alecensa* • Anaplastic lymphomas kinase+ non-small cell lung cancer
3 (1)
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
leukemia 5 (1)
OR Brigatinib Alunbrig* • Anaplastic lymphoma kinase positive non-small lung cancer
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
• Chronic myeloid leukemia 3 (2)
OR Regorafenib Stivarga* • Hepatocellular carcinoma
• Metastatic gastrointestinal stromal cancer 4 (1)
OR Selexipag Uptravi* • Pulmonary arterial hypertension 14 (2)
OR Sofosbuvir Sovaldi* • Hepatitis C (genotypes 2, or 3) in pediatric patients
o Hepatitis C (genotypes 1,2,3,or 4) in adult patients 19 (7)
SQ Somatropin (Non-Refrigerated)
Serostim* • AIDS wasting cachexia 8 (1)
OR Tasimelteon Hetlioz* • Non-24 hour sleep-wake disorder 10 (2)
OR Vigabatrin Sabril • Infantile spasms
o Refractory complex partial epileptic seizures 118 (17)
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
Claims (patient) counts from 2014 to November 2017
Patient age at first fill
Query for ICD10 diagnosis codes: E7220; E7229; P746; 2706; 2763
(see Table 4, Appendix C for definitions)
Prescriber
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
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
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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