Practitioner Forum The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question

Rola Khedraki, MD; Zorawar Noor, MD; and James Rick, MD, PhD

Tailoring treatment based on genetics and medical history may be preferable for patients with atypical hemolytic uremic syndrome who face lifelong therapy on an expensive medication and increased risk of infection.

59-year-old man with a During his hospitalization, he 1.55 mg/dL. His hemogram showed 20-year history (1994) of developed pronounced expressive normochromic normocytic ane- HIV well controlled on aphasia and lethargy but was able to mia (hemoglobin [Hb] level A highly active antiretroviral follow simple commands. A com- 10.2 g/dL) with schistocytes. Serum therapy (HAART) therapy (base- puted tomography (CT) scan of the samples were initially unreportable line viral load undetectable, CD4+ head revealed a left lacunar infarc- by the laboratory due to severe he- cell count 781), presented to a com- tion, and he was transferred to the molysis, but his haptoglobin level was munity hospital (May 7, 2014) with VA Long Beach Healthcare System in found to be low and, conversely, LDH abdominal pain. The patient’s girl- California for further care of a pos- remarkably high. Fifteen days after friend reported unusual behavior for sible stroke. admission, his CD4+ cell count was 1 week before admission, including Shortly after arrival, he devel- 141. An abdominal CT scan showed decreased appetite, binge drinking, oped a fever of 100.9º F. His pulse right lower quadrant abdominal free and nonadherence to HAART therapy. was 100 bpm and regular, blood fluid and thickening of the termi- There was no history of fever, il- pressure was 164/92 mm Hg, and nal ileum with surrounding strand- legal medication use, or diarrhea. respiratory rate was 14 breaths per ing, suggestive of terminal ileitis, and In addition to HIV, his past history minute. A physical examination he was started on piperacillin- was remarkable for hepatitis B, hy- was remarkable for somnolence, tazobactam. A lumbar puncture was pertension, and left lower extremity disorientation, and aphasia. He was unremarkable, and HAART medica- amputation secondary to a motor ve- grimacing to light palpation in all tions were resumed. The patient re- hicle accident. He had a remote his- 4 quadrants of the abdomen and had quired intubation and a ventilator for tory of cocaine, PCP (phencyclidine), diffuse purpura on skin examination. acute respiratory failure. LSD (lysergic acid diethylamide), Laboratory results showed worsen- Empiric treatment for presumed marijuana, and alcohol misuse and a ing thrombocytopenia, acute kidney thrombotic thrombocytopenic pur- 50 pack-year smoking history. His injury with proteinuria and hemoglo- pura (TTP) with plasmapheresis and family history was remarkable for a binuria, and hemolysis (schistocytes, methylprednisolone was ineffective, mother who died of pancreatic cancer. low haptoglobin level, and elevated and the patient required mechanical lactate dehydrogenase [LDH]). ventilation and hemodialysis. Dr. Khedraki is a resident physician and Dr. Noor The patient’s changes in base- In refractory cases of TTP- is chief resident physician, both in internal medi- line laboratory results were platelet hemolytic uremic syndrome, ritux- cine at the University of California, Irvine. Dr. Rick 3 3 is a staff physician at the Long Beach Healthcare count 206,000 mm to 64,000 mm , imab, a monoclonal antibody di- System in California. serum creatinine level 0.98 mg/dL to rected at CD20 present on B

22 • FEDERAL PRACTITIONER • JULY 2016 www.fedprac.com lymphocytes, is added empirically Thrombotic Thrombocytopenic is usually seen in young children as effective salvage therapy and was Purpura secondary to Shiga toxin-producing therefore tried in this case.1 Thrombocytopenic purpura oc- Escherichia coli (STEC).6 Hemolytic However, the addition of ritux- curs in about 3 cases per 1,000,000 uremic syndrome, also referred to as imab failed to improve the patient’s adults per year.3 It occurs when STEC-HUS or typical HUS, is a rare condition, and he developed fur- the metalloproteinase enzyme disease affecting 10 to 20 people per ther seizure activity and evidence ADAMTS13 activity is impaired, million annually. About 10% of these of new lacunar infarctions as seen interrupting its function to cleave patients are classified as having aHUS on magnetic resonance imaging of large sticky von Willebrand fac- because STEC is not implicated in the brain. His hospital course was tor (vWF) multimers, resulting in their disease. It is of interest that, un- complicated by recurrent hemopty- coagulation in microvasculature by like aHUS, STEC-HUS is usually a sis and respiratory failure, requiring increased platelet aggregation, hemo- self-limited disease of children, the assisted ventilation and eventually lysis from shearing of red blood cells, majority of whom recover without tracheostomy. and compromised circulation to the relapse, and evidence that eculi- A normal ADAMTS13 level (72%) highly vascularized kidney and other zumab improves prognosis in STEC- and negative Shiga toxin test changed vital organs.4 The hallmark of TTP HUS is not compelling.5 the diagnosis to atypical hemolytic is a severely decreased ADAMTS13 uremic syndrome (aHUS). Mean activity (< 5% of normal) second- Atypical Hemolytic Uremic complement C3 (74 mg/dL) and ary to coexisting conditions, such as Syndrome C4 (9 mg/dL) levels were low. Plas- cancer, pregnancy, HIV infection, ad- Atypical HUS is a complement- mapheresis was discontinued, and verse effects (AEs), or antibodies to mediated disease. The usual func- treatment with eculizumab (Soliris, ADAMTS13.5 tion of complement proteins is to Alexion Pharmaceuticals) was initi- The TTP pentad of thrombocy- destroy foreign cells and activate im- ated. Meningococcal vaccine was ad- topenia, hemolytic anemia, neuro- mune cells. However, in aHUS this ministered post-eculizumab, aimed at logic symptoms, renal failure, and protective defense system goes awry reducing but not eliminating the risk fever were present in our patient. resulting in a pathologic thrombotic of meningococcemia.2 Two weeks The patient had a known HIV in- milieu. Specifically, aHUS is a contin- later, the patient’s platelet count nor- fection but no exposure to medica- uous complement mediated attack malized, renal function improved, tions associated with TTP (such as on vascular endothelial beds due to hemolysis resolved, and the patient acyclovir, quinine, oxymorphone, the failure of protein regulators to regained full mental status. Eight platelet aggregation inhibitors, or terminate the complement cascade. weeks after initiating eculizumab, he immunosuppressants). Prior to ob- Unlike typical HUS, which is usu- no longer required dialysis. taining ADAMTS13 level, the patient ally associated with a Shiga-toxin was treated empirically for TTP with producing gastrointestinal infection, DISCUSSION early and daily plasma exchange to the trigger in aHUS is unknown and Generalized thrombosis of smaller remove the inhibitor of ADAMTS13 thought to be associated with a ge- blood vessels (thrombotic micro- and replace it with fresh frozen netic predisposition. angiopathy [TMA]) occurs in 3 un- plasma. Rituximab also was used to Atypical HUS distinguishes itself common syndromes—TTP, HUS, inhibit production of antibodies to from TTP and HUS in that it does not and aHUS—all with similar clinical ADAMTS13 from CD20 B lympho- respond to plasma exchange, corti- presentations but distinct pathologic cytes. These empiric clinical mea- costeroids, rituximab, or other im- etiologies and treatment. These syn- sures were not effective in stopping munosupressants. This is due to the dromes share a clinical picture of his decline in renal and neurologic distinct underlying pathophysiology thrombocytopenia, hemolytic ane- functions. of aHUS in which the problem is the mia, and renal failure. Hemolysis in unbridled activation of the alternate these conditions is manifested by Hemolytic Uremic Syndrome arm of the complement system. schistocytes, elevated lactate dehy- Like TTP, HUS is also a consequence The complement system is part drogenase from damaged cells, de- of thrombotic microangiopathy. of the innate immune system, which creased haptoglobin, anemia, and However, in contrast to TTP, which is acts with or without the adaptive im- hemoglobinuria. more commonly seen in adults,3 HUS mune system it “complements” by

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amplifying a cascade of responses to The patient achieved full recovery of erning generic drugs, and informed eliminate the trigger pathogen. There neurologic, renal, and hematologic consent from patients participating in are 3 complement pathways—clas- impairments after treatment with ec- clinical trials. sical, lectin, and alternate. The al- ulizumab, the recombinant human- An unintended consequence was ternate complement pathway, whose ized monoclonal antibody that binds that the development of medications activation generates C5a complement to the complement protein C5 brake for uncommon diseases became fis- (anaphylotoxin), was most pertinent and inhibits its enzymatic cleavage, cally unattractive to the pharma- to this case. This precipitates a num- thereby interfering with the produc- ceutical industry, ie, “orphaned.” ber of downstream protein cleaving tion of the MAC and cell lysis. The Orphan Drug Act was enacted events that lead to the cell lysing Although the patient did not have by Congress in 1983 to encour- membrane attack complex (MAC), an identifiable mutation in the panel age development of drugs to treat which creates a pore in the cell mem- of complement regulatory genes less common diseases (diseases/dis- brane of pathogens seen as foreign. In tested, the rather dramatic efficacy orders affecting fewer than 200,000 aHUS, the patient’s own cells come of the orphan drug eculizumab was people in the U.S.) through incen- under attack by their own comple- in a sense confirmation of his com- tives such as exclusive use approval ment, which is no longer inhibited plement related hemolytic uremia. for 7 years, reduced taxes, grants, due to mutations in regulatory pro- Left undecided are the questions of and favorable laws. Ironically, tha- teins of the alternate pathway. how long to continue eculizumab, lidomide was designated an orphan With the foot off the comple- the potential risk of relapse with drug on October 14, 1998 for treat- ment brake (the hallmark feature discontinuation, and the ethical di- ment of multiple myeloma. Since its underlying aHUS), endothelial cells, lemma of proper length of treatment enactment in 1983, more than 400 leukocytes, and platelets become with the most expensive medication orphan drugs and biologic products hyperactive and thrombogenic, in the world given its total cost and have been marketed. There may be as thereby resulting in microangiop- no clear discontinuation criteria.12-15 many as 7,000 orphan diseases to tar- athy and ischemia of involved or- The cost of medications for rare and get for drug therapy, and the 17 of the gans.7 These mutations may be ultra-rare orphan drugs have ap- 20 most expensive drugs in the sporadic or familial and occur in proached unsustainable levels, posing world in 2013 were for rare orphan a genetically susceptible host.8 It ethical challenges to many developed diseases.16 should be emphasized that genetic countries.16 Paroxysmal nocturnal hemoglo- testing in complement mediated binuria (PNH) is one of those rare HUS is a specialized and slow pro- ECULIZUMAB AND ORPHAN diseases. Mutations of hematopoi- cess (weeks); the initial clinical di- DRUGS etic stem cells produce red blood cell agnosis is one of exclusion and does Several months before his assassina- membranes deficient in the glycopro- not rest on genetic testing. Further- tion, President Kennedy awarded tein to which signaling proteins at- more, serum complement levels Frances Kathleen Oldham Kelsey, tach (glycosyl phosphatidylinositol) may be normal in cases of comple- MD, PhD, the President’s Award for and serve to inhibit complement- ment mediated aHUS.9-11 Distinguished Federal Civilian Ser- induced lysis. This results in intra- This patient had a life-threatening vice (August 7, 1962) for her insis- vascular hemolysis (increased LDH condition that required distinguish- tence that more safety evidence for and decreased haptoglobin) and in- ing it from 2 rare diseases with very thalidomide be presented before she creased thrombosis. The FDA ap- similar presentations; failure to do would approve its use in the U.S. As proved the orphan drug eculizumab so in a timely fashion could easily a result of the thalidomide tragedy, for the treatment of the orphan dis- have resulted in his demise. TTP or the Kefauver Harris amendment was ease PNH on March 16, 2007. HUS was the important question, and passed unanimously by Congress and Eculizumab is a humanized ADAMTS13 level was one of the de- signed into law by President Kennedy mouse monoclonal antibody that termining diagnostic tests. The usual on October 10, 1962. It required gained FDA orphan drug ap- interventions for TTP and HUS (plas- stringent evidence of safety and effi- proval (and exclusivity rights until mapheresis/plasma exchange and, cacy for FDA approval of a new med- 2019) for the treatment of aHUS in some cases, rituximab) were in- ication, reporting of AEs to the FDA, on September 23, 2011, based on effective in this patient with aHUS. truth in drug advertising, rules gov- 2 industry-sponsored small trials of

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17 and 20 patients, and it remains the 62-year-old treatment for proto- pharmaceutical extinction. Telapra- the primary and only known effec- zoan infection toxoplasmosis from vir succumbed to competition tive treatment for this disease.17-19 $13.50 to $750 per pill. The debacle and ceased to be manufactured on Eculizumab has raised many in- may also serve to highlight the com- August 12, 2014. Shortly after ap- teresting questions. Its mechanism plexities and ethical issues involved proval of sofosbuvir, Gilead also of action wets the appetite of phar- when profit intersects with health gained approval of its combination macologists and unveils more basic care. Some drug costs have dramati- product for hepatitis C ledipasvir science questions regarding other cally increased in the U.S. because of 90 mg/sofosbuvir 400 mg (Har- related mechanisms of disease, rec- greed, a belief that a marketplace can voni) on October 10, 2014. ognition of foreign vs self, genetic control costs, and the lack of regula- influences, virulence of organisms, tion. The usual suspects, such as cost The Most Expensive Drug and more. National and international of research, length of development, in the World dilemmas have arisen because of the stimulus to innovation, and return Although there are no shortages of extreme cost of eculizumab, its posi- on investment, are difficult to apply contenders for the coveted most ex- tion as the only effective treatment to old medications whose marketing pensive title, eculizumab is the cur- for this rare and often fatal disease, rights were acquired by purchase of rent champion. Drugs that offer a and the manufacturer’s recommenda- another company. Can marketplace cure, such as antibiotics, usually tion and promotion that it be con- economics be applied in health situ- involve a relatively short, onetime tinued indefinitely. How should the ations where there is no competition, course. Lack of return on the cost price of a drug, developed in large legal protections afforded manufac- of development of curative agents part by government-supported re- turers, consumers unable to make an may have reduced industrial incen- search and tax incentives, and with- informed decision? tives to develop antibiotics. On the out competition, be determined and While pharmacy and therapeutics other hand, the extent of infectious justified? committees were debating treatment diseases, such as malaria, Ebola, tu- of hepatitis C with either of 2 drugs berculosis, HIV, hepatitis, and the Pharmaceutical Inflation approved in 2011, boceprevir (Vic- proliferation of drug-resistant organ- A marketplace for pharmaceuticals trelis, Merck) or telapravir (Incivek, isms, continues to fuel industrial is simply not analogous to other in- Vertex and Johnson & Johnson), Gil- interest for this lifesaving class of dustries. Advances in pharmacother- ead Pharmaceuticals acquired Phar- medications. apy, some miraculous, have come at masset Inc. and its hepatitis C drug Cancer medications touting a brief a substantial cost. The high cost of sofosbuvir (Sovaldi) for a whopping interruption of the race to death have drugs became newsworthy with the $11.2 billion in 2012. It received raised questions of affordability, equi- AIDS pandemic and the approval of FDA approval April 8, 2013, under table access, and quality vs quantity the lifesaving azidothymidine (AZT) Breakthrough Therapy Designation. of life. The $11,000 per month endo- in 1989 (Burroughs Wellcome–also While economists argued over the thelial growth factor inhibitor afliber- the developer of pyrimethamine [Da- wisdom of such a high-cost acquisi- cept (Zaltrap, Regeneron, and Sanofi) raprim]) and its then record price. tion, Gilead generated $9 billion in was approved by the FDA in Novem- Cancer treatment that used to cost sales during the first 3 quarters of ber 2012 for colorectal cancer and $10,000 per year now costs $10,000 2014, surpassing adalimumab (Hu- was followed by a historic rejection per month while the oncology com- mira), which had been the highest by Memorial Sloan-Kettering Can- munity extolls a 2- or 3-month pro- earning drug in 2014. Hepatitis C cer Center, since its cost was nearly gression free survival benefit. Patients could now be quickly treated with double that of a similar medication must now deal with the shock of truly unprecedented efficacy and bevacizumab (Avastin) with similar a cancer diagnosis followed by the without the AEs of interferon. The meager benefit of a median progres- shock of an exorbitant copayment. oft-quoted cost $1,000 per pill or sion free survival of 1.4 months.20 Recent media attention focused about $84,000 per treatment in the Moreover Medicare is mandated derision on Martin Shkreli, chief U.S. drew international attention. to cover the price the manufactur- executive officer of Turing Pharma- Prior options for hepatitis C treat- ers charge plus a 6% cushion for any ceuticals, for purchasing pyrimeth- ment, which preceded sofosbuvir cancer drug that the FDA approves.21 amine and then raising the price of by a mere couple of years, fell into Patients with private insurance, often

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elderly and on a fixed income, are lifelong therapy of its product that lapse following discontinuation of burdened with a copayment require- has no competitors. Our patient was eculizumab. Three of 10 patients ex- ment of 20% of the cost of the drug. treated with 47 fixed-dose infusions perienced a relapse when monitored The nonnegotiation clause of Medi- of eculizumab at 2-week intervals for a cumulative 95 months, but all care has not reduced cost of medica- from May 31, 2014, to February 3 had immediate and complete re- tions, particularly for cancer, which 18, 2016, at a cost of $737,957.80. covery after resuming therapy. All many of the elderly will likely face. The commercial cost outside the 3 patients who experienced relapse The VA, a single-payer system VA would be about 1.8 times this carried a complement factor H muta- distinguished by bipartisan congres- amount ($1.3 million). This extraor- tion. Their relapses occurred within sional support, can directly negoti- dinary cost is the basic ethical issue. 6 weeks from the last dose and ate with pharmaceutical companies, Without competition there is little to were detected simply by performing resulting in lower drug prices than negotiate. home urine dipstick monitoring for discounts guaranteed by federal law; Need the treatment be lifelong? haptoglobin 3 times per week. The but what if there is no competitor? The AEs of eculizumab are not triv- 3 patients who relapsed promptly re- Biosimilar drugs are currently being ial, and some clinicians felt evidence sponded to eculizumab reinstitution debated by those seeking to prolong for indefinite use in this patient was with return of their labs to baseline. their patent protection. Stem cell not compelling. Our patient’s initial Monitoring of complement func- therapies that offer a cure for some critical and unstable condition had tion in patients with aHUS can rare diseases or hope for common completely resolved after 2 months guide clinically appropriate dosing diseases are certain to command as- of eculizumab. The initial unknown intervals without changing disease tronomical prices. Gene therapy of- precipitating event triggering the pa- activity markers.24 The half-life of ec- fers hope for cure of both rare and tient’s aHUS probably had resolved. ulizumab is about 11 days, and dos- common afflictions but at astound- His genetic testing did not disclose ing intervals may be safely extended ing prices. any HUS-related mutation. The pa- beyond 2 weeks in select patients.25 The medication alipogene tipar- tient’s serum was sent to Cincinnati The target minimum inhibitory vovec (Glybera, UniQure) delivered Children’s Hospital (CCH) Clinical serum eculizumab level necessary by adenovirus, for example, has been Laboratory Service to determine his to inhibit complement-mediated he- approved for use in the rare disorder eculizumab level and complement in- molysis is 50 µg/mL and 35 mg/mL lipoprotein lipase deficiency and is hibition. His complement inhibition, for aHUS and PNH, respectively. In anticipated to cost $1.6 million for as measured by CH50 activity, was a small pharmacokinetic pilot study, a onetime curative treatment. The adequately suppressed at 6% on ecu- Gatault and colleagues noted that pharmaceutical industry has joined lizumab (target of < 10%) in spite of a trough levels during eculizumab the gene therapy race. While this is free serum eculizumab level (81 mg/ maintenance by enzyme-linked im- indeed a record acquisition sum for mL) that was somewhat below the munoabsorbent assay (ELISA) of alipogene tiparvovec, at least it offers therapeutic range of > 100 mg/mL. 44 mg/mL to 59 mg/mL inhibited a cure. Eculizumab, although unique Arguments for lifelong eculi- the complement cascade.26 We sug- and effective, offers indefinite admin- zumab therapy are based in part on gested that weight-based dosing istration at a cost exceeding $600,000 the theoretical development of anti- aiming at a trough > 50 mg/mL per year, every year, for life. In 2014, eculizumab antibodies that could (rather than fixed dosing at a fixed sales of eculizumab climbed 44% to render reinstitution of eculizumab interval) would be a better mainte- $2.234 billion. ineffective.22 Monitoring patients nance strategy. for relapse of their aHUS involves In select patients, a trial of grad- To Continue or Discontinue Treatment following markers of disease activ- ual discontinuation by lengthening The duration of treatment with ity (levels of creatinine, LDH, hap- the dosing interval of eculizumab eculizumab poses a challenging di- toglobin, platelet counts, and Hb seems a reasonable and safe alter- lemma for patients, clinicians, and in urine). A report of 10 adult pa- native to indefinite continuation of health care providers. Eculizumab tients with aHUS who were treated the drug. After a patient’s successful is the only effective treatment for a effectively with eculizumab sup- recovery, the initial and unknown life-threatening condition, and the ports a trial of discontinuation.23 trigger of aHUS may no longer play manufacturer, Alexion, recommends Seven of the 10 patients did not re- a role. Improvement in the patient’s

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medical condition may permit the may be effectively restarted in case necessarily reflect those of Fed- restoration of the patient’s defenses to of relapse. eral Practitioner, Frontline Medi- once again function normally. Eculi- We propose that in these cases it cal Communications Inc., the U.S. zumab seemed to retain its efficacy in would be reasonable to perform a Government, or any of its agencies. the small number of patients who re- trial of discontinuation after 1 year This article may discuss unlabeled or lapsed. Those who relapsed had posi- of therapy with urine dipstick moni- investigational use of certain drugs. tive genetic markers. toring for relapse, as lifelong therapy Please review the complete prescrib- Further arguments favoring trial may pose unnecessary expense and ing information for specific drugs discontinuation in patients without risk for infection. In fact, given the fi- or drug combinations—including known genetic predisposition are nancial burden of prolonged therapy indications, contraindications, warn- that continuation is not without on society, we believe it is unethical ings, and adverse effects—before risk, particularly of meningococ- to continue treatment in a patient administering pharmacologic ther- cal infection, necessity for infu- with unknown risk for relapse with- apy to patients. sion every 2 weeks for life, little out a trial of discontinuation, as evi- is known regarding long-term risk dence has shown good response to REFERENCES of the drug, and a lot is known of re-initiation of therapy in the event 1. Caramazza D, Quintini G, Abbene I, et al. Re- 28 lapsing or refractory idiopathic thrombotic its extreme cost. Suppression of of relapse. Agencies that have ne- thrombocytopenic purpura-hemolytic uremic C5 inhibitory effect can lead to in- gotiated or attempted to regulate the syndrome: the role of rituximab. Transfusion. 2010;50(12):2753-2760. creased susceptibility to infections, cost of eculizumab have been met 2. Köse O, Zimmerhackl LB, Jungraithmayr T, Mache whereas increased C5 activity may with public media campaigns featur- C, Nürnberger J. New treatment options for atypi- cal hemolytic uremic syndrome with the comple- lead to a continued autoimmune ing afflicted children at risk of death ment inhibitor eculizumab. Semin Thromb Hemost. attack on native cells. without eculizumab. The public rela- 2010;36(6):669-672. 3. Reese JA, Muthurajah DS, Kremer Hovinga JA, As proposed by others, we sug- tions company behind these efforts Vesely SK, Terrell DR, George JN. Children and gest that this decision be made received support from Alexion.29-31 adults with thrombotic thrombocytopenic pur- pura associated with severe, acquired Adamts13 on a case by case basis, tailoring deficiency: comparison of incidence, demo- treatment based on an individual’s CONCLUSION graphic and clinical features. Pediatr Blood Cancer. 27 2013;60(10):1676-1682. genetics and medical history. Al- Given the formidable cost and the 4. Sadler JE. Von Willebrand factor, ADAMTS13, and though the European Medicines international monopoly status of thrombotic thrombocytopenic purpura. Blood. 2008;112(1):11-18. Agency has approved lifelong ther- eculizumab for a life-threatening 5. Tsai H-M. Pathophysiology of thrombotic thrombo- apy for aHUS, this may be appro- condition, prospective discontinua- cytopenic purpura. Int J Hematol. 2010;91(1):1-19. 6. Noris M, Remuzzi G. Hemolytic uremic syndrome. priate only for patients who have tion trials supported by the manufac- J Am Soc Nephrol. 2005;16(4):1035-1050. aHUS complement mutations asso- turer would seem warranted in select 7. Liszewski MK, Atkinson JP. Exploring the com- 27 plement system in human disease. The Rheuma- ciated with poor outcomes. This cases. Delineating which patients will tologist website. http://www.the-rheumatologist approach may not be warranted, have a chronic relapsing course and .org/article/exploring-the-complement-system -in-human-disease. Published February 1, 2010. however, in a patient, such as the those who will not should be one of Accessed May 9, 2016. one presented with no genetic mu- these clinical trials. For now, one can 8. Mayer CL, Leibowitz CS, Kurosawa S, Stearns-Ku- rosawa DJ. Shiga toxins and the pathophysiology tations, or in those with mutations only wonder: What’s worse than hav- of hemolytic uremic syndrome in humans and ani- of uncertain clinical consequence. ing a rare disease like aHUS? Perhaps mals. Toxins (Basel). 2012;4(11):1261-1287. 9. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical In such cases, given that 90% of the cost of treatment for a potentially HUS and TTP are all diseases of complement activa- adults who have a relapse experi- indefinite period of time—now that’s tion. Nat Rev Nephrol. 2012;8(11):622-633. 32 10. Geerdink LM, Westra D, van Wijk JA, et al. Atypical ence within the first year after an a “bitter pill.” ● hemolytic uremic syndrome in children: comple- aHUS episode, a reasonable alter- ment mutations and clinical characteristics. Pediatr Nephrol. 2012;27(8):1283-1291. native may be a trial discontinua- Author disclosures 11. Sellier-Leclerc AL, Frémeaux-Bacchi V, Dragon- tion.27,28 After 1 year of eculizumab The authors report no actual or poten- Durey MA, et al; French Society of Pediatric Nephrology. Differential impact of complement therapy, a trial of discontinuation tial conflicts of interest with regard to mutations on clinical characteristics in atypical with urine dipstick monitoring for this article. hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18(8):2392-2400. Hb (Hemastix) 3 times a week for 12. Herper M. The worlds most expensive drugs. relapse may avoid the unnecessary Disclaimer Forbes. February 22, 2010. 13. Nordrum A. Drug prices: world’s most expensive expense and risk for infection posed The opinions expressed herein are medicine costs $440,000 a year, but is it worth the by lifelong therapy, and eculizumab those of the authors and do not expense? International Business Times website.

www.fedprac.com JULY 2016 • FEDERAL PRACTITIONER • 27 Atypical Hemolytic Uremic Syndrome

http://www.ibtimes.com/drug-prices-worlds-most cal hemolytic-uremic syndrome. N Eng J Med. 2015;7(6):1205-1211. -expensive-medicine-costs-440000-year-it-worth 2013;368(23):2169-2181. 27. Zuber J, Fakhouri F, Roumenina LT, Loirat C, -expense-2302609. Updated February 13, 2016. 20. Bach PB, Saltz LB, Wittes RE. In cancer care, Frémeaux-Bacchi V; French Study Group for aHUS/ Published June 24, 2015. Accessed June 15, 2016. cost matters. New York Times. October 14, C3G. Use of eculizumab for atypical haemolytic 14. CBC News. The real cost of the world’s most ex- 2012:Opinion Pages. uraemic syndrome and C3 glomerulopathies. Nat pensive drug [video]. CBC/Radio Canada website. 21. Medicare Prescription Drug, Improvement, and Rev Nephrol. 2012;8(11):643-657. http://www.cbc.ca/player/play/2670383596. Ac- Modernization Act of 2003, Public Law 108-173;117 28. Fakhouri F, Frémeaux-Bacchi V, Loirat C. Atypical cessed June 15, 2016. Stat 2066. U.S. Government Printing Office website. hemolytic uremic syndrome: from the rediscovery 15. EvaluatePharma. Orphan Drug Report 2014. https://www.gpo.gov/fdsys/pkg/PLAW-108publ173 of complement to targeted therapy. Eur J Intern Med. EvaluatePharma website. http://www.evaluate /pdf/PLAW-108publ173.pdf. Approved December 8, 2013;24(6):492-495. group.com/orphandrug2014. Published 2014. 2003. Accessed June 6, 2016. 29. Crowe K. Analysis: how pharmaceutical company Accessed June 15, 2016. 22. Jodele S, Fukuda T, Vinks A, et al. Eculizumab Alexion set the price of the world’s most expensive 16. Isaacs D. Ethical dilemmas about orphan drugs therapy in children with severe hematopoietic drug. CBC/Radio Canada website. http://www.cbc for orphan diseases. J Paediatr Child Health. stem cell transplantation-associated thrombotic .ca/news/health/how-pharmaceutical-company 2014;50(4):249-250. microangiopathy. Biol Blood Marrow Transplant. -alexion-set-the-price-of-the-world-s-most 17. Licht C, Muus P, Legendre CM, et al. Eculizumab 2014;20(4):518-525. -expensive-drug-1.3125251 Updated June 25, 2015. (ECU) safety and efficacy in atypical hemolytic ure- 23. Ardissino G, Testa S, Possenti I, et al. Discontinu- Accessed June 21, 2016. mic syndrome (aHUS) patients with long disease ation of eculizumab maintenance treatment for 30. Drug campaign for sick child was a PR stunt. duration and chronic kidney disease (CKD): 2-year atypical hemolytic uremic syndrome: a report of 10 FlandersToday website. http://www.flanderstoday results. Poster presented at: 54th Annual Meeting cases. Am J Kidney Dis. 2014;64(4):633-637. .eu/business/drug-campaign-sick-child-was-pr-stunt. of the American Society of Hematology; December 24. Cugno M, Gualtierotti R, Possenti I, et al. Published May 8, 2013. Accessed June 21, 2016. 8-12, 2012; Atlanta, GA. Complement functional tests for monitoring 31. Herald on Sunday editorial: miracle cure, mor- 18. Greenbaum L, Legendre CM, Babu S, et al. Ecu- eculizumab treatment in patients with atypical ally derelect. New Zealand Herald website. http:// lizumab (ECU) in atypical hemolytic uremic hemolytic uremic syndrome. J Thromb Haemost. www.nzherald.co.nz/opinion/news/article.cfm?c syndrome (aHUS) patients with progressing throm- 2014;12(9):1440-1448. _id=466&objectid=10861630. Published January botic microangiopathy (TMA): 2-year data. Poster 25. Waters AM, Licht C. aHUS caused by complement 27, 2013. Accessed June 21, 2016. presented at: 54th Annual Meeting of the American dysregulation: new therapies on the horizon. Pediatr 32. Brill S. Bitter pill: why medical bills are killing us. Society of Hematology; December 8-12, 2012; At- Nephrol. 2011;26(1):41-57. http://healthland.time.com/2013/02/20/bitter-pill lanta, GA. 26. Gatault P, Brachet G, Ternant D, et al. Thera- -why-medical-bills-are-killing-us/print/[2/26/2013. 19. Legendre CM, Licht C, Muus P, et al. Termi- peutic drug monitoring of eculizumab: rational Time website. Published February 20, 2013. Ac- nal complement inhibitor eculizumab in atypi- for an individualized dosing schedule. MAbs. cessed June 6, 2016.