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

The Most Expensive Drug in the World

Although there are no shortages of contenders for the coveted most expensive title, eculizumab is the current champion. Drugs that offer a cure, such as antibiotics, usually involve a relatively short, onetime course. Lack of return on the cost of development of curative agents may have reduced industrial incentives to develop antibiotics. On the other hand, the extent of infectious diseases, such as malaria, Ebola, tuberculosis, HIV, hepatitis, and the proliferation of drug-resistant organisms, continues to fuel industrial interest for this lifesaving class of medications.

Cancer medications touting a brief interruption of the race to death have raised questions of affordability, equitable access, and quality vs quantity of life. The $11,000 per month endothelial growth factor inhibitor aflibercept (Zaltrap, Regeneron, and Sanofi) was approved by the FDA in November 2012 for colorectal cancer and was followed by a historic rejection by Memorial Sloan-Kettering Cancer Center, since its cost was nearly double that of a similar medication bevacizumab (Avastin) with similar meager benefit of a median progression free survival of 1.4 months.²⁰ Moreover Medicare is mandated to cover the price the manufacturers charge plus a 6% cushion for any cancer drug that the FDA approves.²¹ Patients with private insurance, often elderly and on a fixed income, are burdened with a copayment requirement of 20% of the cost of the drug. The nonnegotiation clause of Medicare has not reduced cost of medications, particularly for cancer, which many of the elderly will likely face.

The VA, a single-payer system distinguished by bipartisan congressional support, can directly negotiate with pharmaceutical companies, resulting in lower drug prices than discounts guaranteed by federal law; but what if there is no competitor? Biosimilar drugs are currently being debated by those seeking to prolong their patent protection. Stem cell therapies that offer a cure for some rare diseases or hope for common diseases are certain to command astronomical prices. Gene therapy offers hope for cure of both rare and common afflictions but at astounding prices.

The medication alipogene tiparvovec (Glybera, UniQure) delivered by adenovirus, for example, has been approved for use in the rare disorder lipoprotein lipase deficiency and is anticipated to cost $1.6 million for a onetime curative treatment. The pharmaceutical industry has joined the gene therapy race. While this is indeed a record acquisition sum for alipogene tiparvovec, at least it offers a cure. Eculizumab, although unique and effective, offers indefinite administration at a cost exceeding $600,000 per year, every year, for life. In 2014, sales of eculizumab climbed 44% to $2.234 billion.

To Continue or Discontinue Treatment

The duration of treatment with eculizumab poses a challenging dilemma for patients, clinicians, and health care providers. Eculizumab is the only effective treatment for a life-threatening condition, and the manufacturer, Alexion, recommends lifelong therapy of its product that has no competitors. Our patient was treated with 47 fixed-dose infusions of eculizumab at 2-week intervals from May 31, 2014, to February 18, 2016, at a cost of $737,957.80. The commercial cost outside the VA would be about 1.8 times this amount ($1.3 million). This extraordinary cost is the basic ethical issue. Without competition there is little to negotiate.

Need the treatment be lifelong? The AEs of eculizumab are not trivial, and some clinicians felt evidence for indefinite use in this patient was not compelling. Our patient’s initial critical and unstable condition had completely resolved after 2 months of eculizumab. The initial unknown precipitating event triggering the patient’s aHUS probably had resolved. His genetic testing did not disclose any HUS-related mutation. The patient’s serum was sent to Cincinnati Children’s Hospital (CCH) Clinical Laboratory Service to determine his eculizumab level and complement inhibition. His complement inhibition, as measured by CH50 activity, was adequately suppressed at 6% on eculizumab (target of < 10%) in spite of a free serum eculizumab level (81 mg/mL) that was somewhat below the therapeutic range of > 100 mg/mL.

Arguments for lifelong eculizumab therapy are based in part on the theoretical development of anti-eculizumab antibodies that could render reinstitution of eculizumab ineffective.²² Monitoring patients for relapse of their aHUS involves following markers of disease activity (levels of creatinine, LDH, haptoglobin, platelet counts, and Hb in urine). A report of 10 adult patients with aHUS who were treated effectively with eculizumab supports a trial of discontinuation.²³ Seven of the 10 patients did not relapse following discontinuation of eculizumab. Three of 10 patients experienced a relapse when monitored for a cumulative 95 months, but all 3 had immediate and complete recovery after resuming therapy. All 3 patients who experienced relapse carried a complement factor H mutation. Their relapses occurred within 6 weeks from the last dose and were detected simply by performing home urine dipstick monitoring for haptoglobin 3 times per week. The 3 patients who relapsed promptly responded to eculizumab reinstitution with return of their labs to baseline.