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A Physician Primer: Drugs with Orphan Designations for the Treatment of Pain Conditions

A review of three rare pain disorders: sarcoidosis, complex regional pain syndrome, and GI issues associated with regressive autism

A rare disease is a condition that affects less than 200,000 people in the United States or greater than 200,000 people when the cost of drug development is not expected to be repaid.1 The IQVIA report funded by the National Organization of Rare Disorders (NORD) estimates that 25 to 30 million Americans are living with a rare disease and approximately 7,000 rare diseases exist.

The years 2017 and 2018 had the highest quantity of orphan drug and orphan indication approvals since the creation of the Orphan Drug Act in 1983.2 As of August 2018, 503 orphan drugs have been approved in the United States; the majority (78%) of which have been approved for an orphan indication alone and 22% which have been approved for both orphan and non-orphan indications (see Figure 1).3,4 In 2017, orphan drugs constituted 0.4% of the total amount of medications in the United States, and there are currently 27 orphan drugs designated or approved for rare pain disorders (see Table I).

Orphan Drug Designation Review

FDA’s list of orphan drug designations and approvals for pain conditions (available here) contains several familiar drugs such as bupivacaine and ketamine that have additional roles in other non-orphan indications, and less known drugs that are only approved for orphan indications.5 This review highlights some of the drugs that currently have orphan designations from the FDA for the treatment of various rare pain conditions, with a focus on drug and disease-state descriptions and literature supporting each drug’s use. The drugs chosen for review are less known for the treatment of pain conditions and have either published or unpublished clinical trials available.

ARA 290 (Cibinetide) for the Treatment of Neuropathic Pain with Sarcoidosis

Sarcoidosis is a multi-system inflammatory disease that affects many organs, with a key feature of causing granulomas to accumulate in the tissues.6-8 The clinical presentation varies depending on the organ system(s) involved with more than 90% of patients presenting with pulmonary, ocular, and/or skin complications.6,7 Common symptoms include fatigue, night sweats, and weight loss.6 Pulmonary symptoms may include dyspnea, wheezing, cough, and chest discomfort; skin involvement may present with lesions; and the most common ocular complication is anterior uveitis.6,7

A potential clinical feature of sarcoidosis is neuropathic pain, which most commonly develops in relation to small fiber neuropathy.9 Small fiber neuropathy involves the impairment of peripheral afferent small myelinated Aδ fibers and unmyelinated C fibers.8,10 The etiology is not well-defined, but may be due to inflammation.8 Small fiber neuropathy presents as burning, itching, or electric-shock-like pain with allodynia, dysesthesia, and autonomic dysfunction.

In the United States, the estimated incidence of sarcoidosis is 10.9 cases per 100,000 Caucasians and 35.5 cases per 100,000 African Americans.7 The prevalence is unknown for small fiber neuropathy in the US; however, a report from The Netherlands found a minimum incidence of 11.73 cases per 100,000 people per year and a minimum prevalence of 52.95 cases per 100,000 patients per year.11,12 Another report found that over 30% of sarcoidosis patients have small fiber neuropathy.13 Additional reporting has shown that 44% to 88% of patients with sarcoidosis report neuropathic pain, paresthesia, and/or symptoms of autonomic dysfunction, with small fiber neuropathy potentially presenting in up to 29% of patients.9

In September 2011, ARA 290, a synthetic 11-amino acid erythropoietin (EPO) derivative peptide, was designated by the FDA as an orphan drug for the treatment of neuropathic pain in patients with sarcoidosis.5,14 This drug acts as an innate repair receptor (IRR) agonist by activating IRR, a receptor composed of the β-common receptor and EPO receptor.14 The innate repair receptor is upregulated in areas of tissue injury, and activation of the IRR leads to an anti-inflammatory response and prevents further tissue damage while promoting tissue repair.

There are three small, short-duration published studies assessing the efficacy and safety of ARA 290 for the treatment of neuropathic pain in patients with sarcoidosis (see Table II for details).8,15,16 All three studies evaluated the efficacy and safety of either intravenous (IV) or subcutaneous (SC) ARA 290 at varying doses after 28 days of treatment as compared to placebo. The endpoints varied among the trials, but each assessed change in the outcomes from baseline to day 28 for indices such as the Brief Pain Inventory (BPI) for pain and Small Fiber Neuropathy Screening List (SFNSL) for neuropathic symptoms. The authors did not define what they considered a clinically significant score for these tools. None of the 3 studies found a statistical significance between-group difference in the change of mean overall BPI scores or BPI pain intensity/severity scores from baseline to the end of treatment in patients treated with any dose of ARA 290 compared to placebo.

BPI is Brief Pain Inventory; CNFA is corneal nerve fiber abundance; IENFD is intra-epidermal nerve fiber density; IV is intravenously; NS is non-significant; QST is quantitative sensory testing; RCT is randomized controlled trial; SC is subcutaneous; SD is standard deviation; SEM is standard error of the mean; SF-36 is Short Form Health Survey; SFNSL is Small Fiber Neuropathy Screening List

Although Culver and colleagues did not find a statistically significant difference in SFNSL scores at day 28 compared to baseline for any ARA 290 doses or placebo, both Dahan and colleagues,15 and Heij and colleagues,8 found statistically significant decreases in the SNFSL score from baseline with ARA 290 compared to placebo when measured at day 35 and day 28, respectively. When evaluating the individual components of the SNFSL score, Dahan and colleagues found that treatment with ARA 290 led to significant improvements in autonomic and pain symptoms compared to placebo. Heij and colleagues also found that ARA 290 significantly improved autonomic symptoms compared to placebo, but differences in pain symptoms did not reach significance.8 In addition, Heij and colleagues found significant improvements in both the pain and physical functioning dimensions of the Short Form Health Survey (SF-36) in the ARA 290 group at 4 weeks compared to baseline. Based on these studies, ARA 290 may have a role in reducing symptoms of neuropathy and possibly pain in patients with neuropathic pain from sarcoidosis.

More than 500 orphan drugs have been approved in the United States; the majority (78%) of which have been approved for an orphan indication alone and 22% which have been approved for both an orphan and non-orphan indication.

Zoledronic Acid (AXS-02) and Neridronate for the Treatment of CRPS

Complex regional pain syndrome (CRPS) is a chronic pain condition with progressively worsening pain in a region of the body.17 The clinical presentation may include disproportionate burning pain that does not distribute by dermatome, hyperalgesia, allodynia, changes in skin temperature, and muscle weakness.18 CRPS can be further classified by different subtypes depending on the type of pain involved and presence of major nerve damage. CRPS-I is described as nociceptive pain in the absence of major nerve damage.17,18 CRPS-II is characterized by neuropathic pain with presence of major nerve damage. A third subtype, CRPS not otherwise specified (NOS), is diagnosed when a patient’s symptoms do not fully meet criteria for CRPS, but other conditions are ruled out.17 A 2016-nationwide population-based study in the United States found an estimated overall incidence of CRPS-I of 0.07% from 2007 to 2011 and a higher incidence in females.19

Neridronate received orphan drug designation on March 25, 2013 for treatment of CRPS-I, CRPS-II, and CRPS-NOS.5 This was followed by zoledronic acid’s orphan drug designation on May 6th, 2013 for the treatment of CRPS. Both neridronate and zoledronic acid are bisphosphonates that act as osteoclast inhibitors.20,21 The speculative mechanism behind bisphosphonates and the treatment of pain in CRPS involves a number of factors, some of which include osteoclast activity inhibition and effects on the production of pro-inflammatory cytokines.22

Currently, there are no published studies in humans for zoledronic acid in the treatment of pain with CRPS; however an unpublished randomized, double-blind, placebo-controlled, 24-week study called CREATE-1 is underway to compare zoledronate taken orally once weekly for 6 weeks versus matched placebo in patients with CRPS-I.23 The primary outcome is change in patient reported pain intensity at week 12 versus baseline and secondary outcomes include several measures such as change in bone turnover markers from baseline to week 52 and change in BPI pain score. The study started in July 2015 with an estimated completion date of January 2019 (at this time, there are no posted results).

Neridronate currently has one published study and two unpublished studies to assess its use for the treatment of CRPS.24-26 The published multi-center, double-blind, placebo-controlled randomized controlled trial (RCT) by Varenna and colleagues included 82 patients with CRPS-I of either the hand or foot and evaluated the efficacy of IV neridronate 100 mg given every third day over a total of 10 days versus placebo.24 The primary endpoint was comparative changes in the visual analogue scale (VAS) score 40 days after the first infusion. The VAS assesses pain with a range of scores from 0 (no pain) to 100 mm (maximal pain). Treatment with neridronate resulted in a significant decrease in pain score compared to placebo, based on VAS scores from baseline to 40 days following the first neridronate infusion (-47 mm; 95% CI, -53.7 to -40.3 for neridronate vs -22.6 mm; 95% CI, -29.5 to -15.6 for placebo; P < 0.0001). The authors also found significant improvements in the pain domain (9.8; 95% CI, 2.1 to 17.4; P = 0.013) and physical functioning domain (13.2; 95% CI, 4.7 to 21.8; P = 0.003) of the SF-36 from baseline to day 40 for neridronate compared to placebo. Drug-related adverse events included mild to moderate musculoskeletal disorders (eg, polyarthralgia) in 29.3% of patients in the neridronate group versus 12.2% in the placebo group, and fever, reported in 21.9% of patients in the neridronate group vs. 2.4% in the placebo group. There were no reported serious drug-related adverse events.

One of the unpublished clinical trials was an open-label safety trial of neridronate 100 mg IV administered on day 1, day 4, day 7, and day 10 in patients with CRPS.25 The second unpublished study is a double-blind RCT assessing efficacy and safety of neridronate 62.5 mg IV administered on day 1 and day 4 (with placebo given on days 7 and 10) or neridronate 62.5 mg IV administered on days 1, 4, 7, and 10 versus placebo in patients with CRPS-I, with the primary endpoint as change in the pain intensity score from baseline to week 12.26 Both of these studies have completed, with the last update posted in January 2019 for the open-label safety trial and May 2018 for the double-blind RCT; however, results have not been posted yet.25,26

Human Gammaglobulin (Oralgam) for the Treatment of Gastrointestinal Disturbances Associated with Regression-Onset Autism in Pediatric Patients

Regressive autism is a pattern of onset for autism spectrum disorders (ASDs) when the child seems to develop for the first and second years of life, but then loses previously developed skills and exhibits the onset of autistic symptoms, typically between the first and second birthday.27 Regressive forms of autism are estimated to occur in approximately 21% of children with ASD.28 Children with late-onset regressive ASDs may have chronic symptoms associated with gastrointestinal (GI) conditions, including moderate to severe abdominal pain.29 The proposed mechanisms involve inflammation in the GI tract with lymphocyte infiltration and immune system dysfunction due to immune-related gene expression modification, altered cytokine production, changes in T-cell function, and a heightened innate immune reaction.29,30 When this dysfunction occurs in mucosal immune cells, it may lead to GI disturbances in patients with ASD.29 The clinical presentation of GI symptoms in ASD is similar to irritable bowel syndrome (IBS), and includes symptoms such as diarrhea, constipation, vomiting, heartburn, abdominal pain, and malodorous stools.31 The prevalence of GI disorders in children with ASD in general is variable with a reported range of 9 to 91% with abdominal pain and discomfort symptoms reported with a prevalence of 2 to 41%.29

Human gammaglobulin is an oral drug expected to have similar effects as intravenous human immunoglobulin (IVIG).30 Intravenous human immunoglobulin affects T and B cell functioning, stimulates complement, and affects Fc receptor expression and function, leading to anti-inflammatory and immunological effects overall. Human gammaglobulin was designated as an orphan drug on September 16, 2002 for treatment of GI disturbances including constipation, diarrhea, and abdominal pain in pediatric patients with regression-onset autism.5

There are two published studies (see Table III) assessing oral human gammaglobulin in the treatment of GI disturbances associated with regression-onset autism in pediatric patients.30,32 Out of the published studies, the populations are small with limited results. As the primary endpoint, Schneider and colleagues assessed the change in severity of GI signs and symptoms with the use of the Gastrointestinal Severity Index (GSI) score.30 This is a composite score of 9 variables that assesses signs and symptoms of GI disturbances, including 1 variable pertaining to abdominal pain. The GSI score ranges from 0 to 15 with a higher score indicating greater severity. Schneider and colleagues found an improvement in GI and behavioral symptoms among pediatric males with regressive ASD and chronic GI signs and symptoms; however, GI symptom improvement was not maintained after discontinuation of human gammaglobulin.

As the primary endpoint, Handen and colleagues assessed the clinical response to human gammaglobulin vs placebo after 12 weeks of therapy by a 7-point Likert scale called the Modified Global Improvement Scale (MGIS), which is often utilized in IBS studies.32 The MGIS includes abdominal pain and discomfort as a variable. Parents of the study subjects also assessed abdominal pain and discomfort by a 7-point Likert scale on a weekly and daily basis. The daily GI symptom assessment required the parents to report on the consistency and severity of abdominal pain/discomfort. Based on the MGIS score and other indices, the Handen and colleagues’ trial did not find a beneficial effect of human gammaglobulin on GI dysfunction or autistic behavior. There was no difference in global assessment of abdominal pain/discomfort between human gammaglobulin and placebo.


The quantity of orphan drug designations have significantly increased since the passage of the Orphan Drug Act in 1983 and drug manufacturers continue to concentrate on orphan drug development. This article highlighted four drugs with varying mechanisms of action that have been studied for orphan designations in the treatment of pain for various disease states and conditions including CRPS, neuropathy associated with sarcoidosis, and GI pain in pediatric patients with ASD. The published studies described are small and based on mostly subjective data, which limit their results. Currently, there are several potential orphan drug candidates that are in development for pain-specific medical conditions, including sickle cell pain crisis and acute attacks of porphyria. The number of ongoing, unpublished clinical trials and the increasing focus on orphan drug development provide hope that research in orphan designations related to the treatment of pain will continue to grow.

Last updated on: November 20, 2019
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