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

Hemolytic Uremic Syndrome

Like TTP, HUS is also a consequence of thrombotic microangiopathy. However, in contrast to TTP, which is more commonly seen in adults,³ HUS is usually seen in young children secondary to Shiga toxin-producing Escherichia coli (STEC).⁶ Hemolytic uremic syndrome, also referred to as STEC-HUS or typical HUS, is a rare disease affecting 10 to 20 people per million annually. About 10% of these patients are classified as having aHUS because STEC is not implicated in their disease. It is of interest that, unlike aHUS, STEC-HUS is usually a self-limited disease of children, the majority of whom recover without relapse, and evidence that eculizumab improves prognosis in STEC-HUS is not compelling.⁵

Atypical Hemolytic Uremic Syndrome

Atypical HUS is a complement-mediated disease. The usual function of complement proteins is to destroy foreign cells and activate immune cells. However, in aHUS this protective defense system goes awry resulting in a pathologic thrombotic milieu. Specifically, aHUS is a continuous complement mediated attack on vascular endothelial beds due to the failure of protein regulators to terminate the complement cascade. Unlike typical HUS, which is usually associated with a Shiga-toxin producing gastrointestinal infection, the trigger in aHUS is unknown and thought to be associated with a genetic predisposition.

Atypical HUS distinguishes itself from TTP and HUS in that it does not respond to plasma exchange, corticosteroids, rituximab, or other immunosupressants. This is due to the distinct underlying pathophysiology of aHUS in which the problem is the unbridled activation of the alternate arm of the complement system.

The complement system is part of the innate immune system, which acts with or without the adaptive immune system it “complements” by amplifying a cascade of responses to eliminate the trigger pathogen. There are 3 complement pathways—classical, lectin, and alternate. The alternate complement pathway, whose activation generates C5a complement (anaphylotoxin), was most pertinent to this case. This precipitates a number of downstream protein cleaving events that lead to the cell lysing membrane attack complex (MAC), which creates a pore in the cell membrane of pathogens seen as foreign. In aHUS, the patient’s own cells come under attack by their own complement, which is no longer inhibited due to mutations in regulatory proteins of the alternate pathway.

With the foot off the complement brake (the hallmark feature underlying aHUS), endothelial cells, leukocytes, and platelets become hyperactive and thrombogenic, thereby resulting in microangiopathy and ischemia of involved organs.⁷ These mutations may be sporadic or familial and occur in a genetically susceptible host.⁸ It should be emphasized that genetic testing in complement mediated HUS is a specialized and slow process (weeks); the initial clinical diagnosis is one of exclusion and does not rest on genetic testing. Furthermore, serum complement levels may be normal in cases of complement mediated aHUS.^9-11

This patient had a life-threatening condition that required distinguishing it from 2 rare diseases with very similar presentations; failure to do so in a timely fashion could easily have resulted in his demise. TTP or HUS was the important question, and ADAMTS13 level was one of the determining diagnostic tests. The usual interventions for TTP and HUS (plasmapheresis/plasma exchange and, in some cases, rituximab) were ineffective in this patient with aHUS. The patient achieved full recovery of neurologic, renal, and hematologic impairments after treatment with eculizumab, the recombinant humanized monoclonal antibody that binds to the complement protein C5 brake and inhibits its enzymatic cleavage, thereby interfering with the production of the MAC and cell lysis.

Although the patient did not have an identifiable mutation in the panel of complement regulatory genes tested, the rather dramatic efficacy of the orphan drug eculizumab was in a sense confirmation of his complement related hemolytic uremia. Left undecided are the questions of how long to continue eculizumab, the potential risk of relapse with discontinuation, and the ethical dilemma of proper length of treatment with the most expensive medication in the world given its total cost and no clear discontinuation criteria.^12-15 The cost of medications for rare and ultra-rare orphan drugs have approached unsustainable levels, posing ethical challenges to many developed countries.¹⁶

Eculizumab and Orphan Drugs

Several months before his assassination, President Kennedy awarded Frances Kathleen Oldham Kelsey, MD, PhD, the President’s Award for Distinguished Federal Civilian Service (August 7, 1962) for her insistence that more safety evidence for thalidomide be presented before she would approve its use in the U.S. As a result of the thalidomide tragedy, the Kefauver Harris amendment was passed unanimously by Congress and signed into law by President Kennedy on October 10, 1962. It required stringent evidence of safety and efficacy for FDA approval of a new medication, reporting of AEs to the FDA, truth in drug advertising, rules governing generic drugs, and informed consent from patients participating in clinical trials.