Study: Opportunities to Improve Management of PNH Exist

An earlier version of this story incorrectly said that the FDA approved Alexion Pharmaceuticals, Inc.’s Ultomiris (ravulizumab-cwvz), on Dec. 21, 2019. The drug was approved Dec. 21, 2018. This version has been corrected.

Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare, potentially fatal disease. The FDA approved the first therapy, Alexion Pharmaceuticals, Inc.’s Soliris (eculizumab), a complement C5 inhibitor (C5I), to treat adults with the condition on March 16, 2007. Then the agency approved another C5I to treat adults with PNH from the same company, Ultomiris (ravulizumab-cwvz), on Dec. 21, 2018. A recent study of those two therapies from Prime Therapeutics LLC shows that there may be opportunities for payers in PNH management that will result in better health care outcomes for their members.

Prime presented findings from the study at the Academy of Managed Care Pharmacy (AMCP) Nexus meeting, which was held Oct. 18 through 21 in Denver. Funding for the study was provided by Apellis Pharmaceuticals, Inc., manufacturer of Empaveli (pegcetacoplan), a C3 inhibitor approved May 14, 2021, for the treatment of PNH in treatment-naïve people, as well as ones switching from any C5I. Researchers were from Prime, Apellis and the University of Minnesota College of Pharmacy.

Prime is collectively owned by 19 Blue Cross and Blue Shield plans, subsidiaries or affiliates of those plans and serves almost 33 million people.

PNH is an acquired, life-threatening blood disorder that causes the destruction of red blood cells (hemolysis), formation of blood clots and impairment of bone marrow function. It is an ultra-rare disease, impacting about 1 to 1.5 people per million, according to Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center. The median age of diagnosis is between 35 and 40 years old, with a 10-year median survival after diagnosis, although some people may live for decades with minor symptoms. Blood tests that can confirm the diagnosis are available. PNH may be cured only by bone marrow transplant, but many risks exist with this action.

Treatment goals for people on the therapies include a reduction in the number of blood transfusions, an improvement in the levels of hemoglobin and a decrease in debilitating symptoms such as severe fatigue and difficulty breathing. When patients on C5Is experience ongoing hemolysis, providers may treat them with transfusions or increase the C5I dose beyond its FDA-approved label.

Researchers analyzed integrated medical and pharmacy claims from about 15 million commercially insured members from Jan. 1, 2018, through Dec. 31, 2019. Members were placed into one of three mutually exclusive groups:

(1) At least two medical claims for eculizumab from Jan. 1, 2018, through Dec. 31, 2019;

(2) At least one medical claim for ravulizumab from Jan. 1, 2018, through Dec. 31, 2019; or

(3) An ICD-10-CM code for PNH on at least two medical claims at least 30 days apart from Jan. 1, 2018, through Dec. 31, 2019.

For the first two groups, the index date was the date of the first infusion. For the third, the index date was the date of the first PNH claim. Members in the analysis must have been at least 18 years old and continuously enrolled at least six months before the index date and 12 months after the index date. Members were excluded if a claim indicated atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis or neuromyelitis optica spectrum disorder. Both C5Is are approved for aHUS, and eculizumab is approved for the latter two conditions.

Multiple outcomes measurements were assessed. First was standard of care treatment, based on the drugs’ FDA-approved labels. Recommended dosing for eculizumab is 600 mg weekly for the first four weeks, then 900 mg one week later and then a 900 mg maintenance dose every two weeks. Dosing for ravulizumab is weight-based; the expected loading dose is between 600 mg and 3,000 mg, followed two weeks later with a weight-based maintenance dose that is then administered every four or eight weeks. People taking 25% more or less maintenance doses of eculizumab were considered not having standard of care treatment. Time between doses also was tracked.

Researchers also tracked the number of transfusions a member received in the post-index period, cases of breakthrough hemolysis and discontinuation rates. Members were considered to have discontinued eculizumab if there was a gap of more than 28 days between doses. Members on ravulizumab with a gap of more than 112 days were deemed discontinued. Members who switched from eculizumab to ravulizumab within 28 days or those who switched from ravulizumab to eculizumab within 112 days were not considered discontinued.

Health care utilization was assessed based on hospitalization and emergency room and office visits. Site of care was determined, as were health care costs in the post-index period, including all pharmacy and medical claims.

Eculizumab Dosing Was Higher Than Label

Researchers identified 505 members with a claim for eculizumab or ravulizumab or an ICD-10-CM PNH code. Of those, 162 members met all the additional criteria. Of those, 57 fell in the eculizumab group, six were in the ravulizumab set, and 99 were in the ICD-10-CM PNH group. Members’ mean age was 43 years, 61.9% were female, and 39.7% were new to C5I therapy.

Within the eculizumab group, the mean index dose was 1,068 mg, which is higher than the FDA-approved 900 mg maintenance dose. Almost 40% of members in this group — 38.5% — had dosing that was higher than recommended. The median C5I cost per day for members on above-standard dosing was $3,767, compared with $1,669 for those with standard dosing.

In the post-index period, the mean per member claim count was 21.7 in the eculizumab set compared with 6.0 in the ravulizumab group. Of the 57 members on eculizumab, 22 — or 38.6% — discontinued treatment. Half of the six members in the ravulizumab group halted the therapy. Both groups had similar mean durations on therapy. Across both treatment groups, a total of 39.6% of members had at least one infusion in the post-index period; 20.6% had at least four infusions.

The mean time between infusions was 15.0 days for members taking eculizumab and 52.3 days for ravulizumab. A provider’s office was the most common site of care for eculizumab. Site of care was split evenly between a provider’s office and hospital outpatient department for people on ravulizumab. The mean cost/mg for eculizumab was “substantially higher” when the agent was administered in a hospital outpatient department compared with a provider’s office or in the home.

Of the 57 people in the eculizumab group, 14 — or 24.6% — had at least one episode of breakthrough hemolysis, compared with one — or 16.7% — of the six taking ravulizumab and 16 — or 16.2% — of the people in the PNH ICD-10-CM set. The mean cost per episode was “substantially higher” if a member was hospitalized: $12,299 vs. $394.

Researchers also found that for the post-index period, total health care costs were highest in the eculizumab group: $729,683. That compared with $371,648 in the ravulizumab set and $79,295 in the ICD-10-CM PNH group. Costs for the drugs represented 87.1% of the total health care costs for the eculizumab group; they were 74.4% of the total costs within the ravulizumab group.

Almost one-quarter — 24.6% — of members in the eculizumab group had a hospitalization, compared with 33.3% within the ravulizumab set and 26.3% in the ICD-10-CM PNH group. The eculizumab group had the highest proportion of members with an ER visit at 29.8%, followed by 16.7% in the ravulizumab group and 12.1% in the ICD-10-CM PNH group. Provider office visits were common; the proportion of members with these was 98.2% among people taking eculizumab, 83.3% for those on ravulizumab and 98.0% within the PNH ICD-10-CM group.

PNH Is ‘Challenging’ Condition to Treat

Patrick Gleason, Pharm.D., assistant vice president of health outcomes at Prime, notes that PNH is known to be a “challenging” condition to treat. He tells AIS Health, a division of MMIT, that some interesting findings of the study are that “four in 10 [members] appear to have a substantial gap in C5I therapy, indicating they discontinued their initial C5I drug; one in five individuals had four or more transfusions during the 12 months after initiating their C5I, suggesting that their disease many not be completely controlled, along with the finding that drug costs were 75% or more of an individual’s total cost of care, resulting in drug expense in the $100,000s per year. The biggest takeaway is the C5I drug therapy requires constant surveillance by the provider and insurer due to the extreme expense, at between $300,000 to $600,000 a year or more, with potentially inadequate disease control as [seen in] the discontinuation rate and transfusion rate.”

Asked why a person would receive a PNH diagnosis and not have a claim for either therapy, he replies, “a person can have a PNH diagnosis and be asymptomatic, and/or they could be responding to standard-of-care treatments that may include intermittent blood transfusions, erythropoietin therapy and iron supplementation.”

Providers may decide to administer a higher-than-recommended maintenance dose “as necessary to control signs and systems of breakthrough hemolysis, and/or the provider may have laboratory evidence of inadequate complement 5 blockade indicating a higher eculizumab dose may better control the disease,” explains Gleason, a co-author of the study. “Optimizing PNH drug therapy is essential. This can be accomplished through ensuring the PNH drug therapy is appropriate for the individual at the time therapy is initiated through a payer’s prior authorization (PA) review.”

PBMs such as Prime that have integrated medical and pharmacy claims analytic knowledge and pharmacists who are PNH specialists can provide “ongoing PNH drug therapy surveillance via clinical services” and can “automate PNH outlier drug regimen identification,” he says. “The integrated medical and pharmacy data and knowledge are required to have successful PNH drug therapy optimization conversations with the PNH drug therapy prescribers.”

Researchers did not collect reasons for why members discontinued therapy, he notes. That said, “some of the known reasons for drug discontinuation are side effects, lack of effectiveness and affordability,” explains Gleason. Standard-of-care therapies are options for people with PNH. “However, if a patient is receiving C5I therapy, they have generally exhausted standard-of-care therapies.”

Of the 22 members taking eculizumab who discontinued the therapy, two of them switched to ravulizumab, while none of the three members who halted ravulizumab switched to eculizumab.

For people receiving eculizumab in the hospital outpatient setting, the “total paid amount to providers averaged 56% higher per mg of eculizumab,” states Gleason. “Providing drug therapy in the hospital outpatient setting is known to be generally the most expensive site of care. In this analysis, eculizumab therapy provided in the hospital outpatient setting was the most expensive site of care, due to hospital outpatient clinic favorable network rates.”

PNH varies in severity among patients, so “it is not surprising” that the ICD-10-CM PNH group had the lowest percentage of people with a breakthrough hemolysis episode, as these members would have less severe PNH and not require treatment with a C5I.

The third FDA-approved therapy for PNH, pegcetacoplan, “works at a different point, complement protein C3 and its activation fragment C3b, in the complement cascade to control PNH than the C5I agents eculizumab and ravulizumab,” explains Gleason. “Therefore, there is the potential for individuals to switch from current C5I therapy if their PNH is inadequately controlled or they have previously failed C5I therapy. We currently don’t have real-world claims data experience analytics to tell how pegcetacoplan may be impacting PNH therapy.”

Given that ravulizumab was approved 12 months before the end date of the claims used, Prime is working on an updated study, says Gleason.

“Further exploration of ravulizumab (Ultomiris) and exploration of pegcetacoplan (Empaveli) real-world utilization, costs and outcomes are essential for managed care pharmacy formulary and utilization management program decision making,” he contends.

Contact Gleason through Denise Lecher at

This story was reprinted from AIS Health’s monthly publication RADAR on Specialty Pharmacy.

© 2024 MMIT
Angela Maas

Angela Maas

Angela has an extensive background of editing, reporting and writing for trade and consumer publications. She has written Radar on Specialty Pharmacy (formerly called Specialty Pharmacy News) since she joined AIS Health in 2005 and has broad knowledge of the various issues at play within the space. Before joining AIS Health, she was managing editor at Employee Benefit News and Employee Benefit News Canada and managing editor at HemAware (a hemophilia publication), Lupus Living and Momentum (a multiple sclerosis publication). She has a B.A. in English and an M.A. in British literature from Arizona State University.

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