FDA Approval Gives Third Option to Treat Rare, Deadly Disease

The FDA recently approved a third agent to treat paroxysmal nocturnal hemoglobinuria (PNH). With some conditions, that number of treatments may prompt payer preferencing, but that is unlikely to happen with this ultra-rare, potentially fatal disease, observe industry experts.

On May 14, the FDA approved Apellis Pharmaceuticals, Inc.’s Empaveli (pegcetacoplan) as the first and only targeted C3 therapy for the treatment of adults with PNH. It is approved for both treatment-naïve people, as well as ones switching from any C5 inhibitor. The FDA has approved two of those drugs: Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz), both from Alexion Pharmaceuticals, Inc., which was just acquired by AstraZeneca in July.

PNH is an acquired, life-threatening blood disorder that causes the destruction of red blood cells, 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.

Empaveli’s approval was based on the Phase III PEGASUS trial, a head-to-head study against Soliris. Over 16 weeks of treatment of people with severe anemia, people in the Empaveli group had an average hemoglobin increase of 2.4 g/dL, while people in the Soliris arm had an average decrease of 1.5 g/dL. In addition, 85% of people treated with Empaveli were transfusion free over those 16 weeks compared with 15% of those treated with Soliris. In a head-to-head study between Ultomiris and Soliris, Ultomiris had a 73.6% transfusion avoidance rate compared with Soliris’ 66.1%.

The FDA initially approved Soliris as a treatment for PNH on March 16, 2007, making it the first therapy for the condition. More than a decade later, on Dec. 21, 2019, the agency approved Ultomiris to treat adults with PNH, with Alexion looking to transition Soliris patients to the newer agent. More recently, on June 7, the FDA gave an additional indication to Ultomiris as a PNH treatment in children at least 1 month old and adolescents, making it the only PNH therapy approved for use in these age groups. Both drugs also are approved to treat people with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Soliris also is approved for the treatment of myasthenia gravis and neuromyelitis optica spectrum disorder.

Apellis estimates that there are 1,500 people with PNH in the U.S. who are on a C5 inhibitor. About one-third have normal or near-normal levels of hemoglobin, another third have below-normal hemoglobin and symptoms such as fatigue, and another third need to undergo transfusions to treat falling hemoglobin levels, it says.

Empaveli’s recommended dose is 1,080 mg twice weekly via subcutaneous infusion using an infusion pump. While people need to initiate dosing of the drug under the guidance of a health care professional, after patients and/or their caregivers are trained in subcutaneous infusion, they can administer the drug themselves.

Soliris is dosed through intravenous infusion, starting at 600 mg weekly for the first four weeks, then 900 mg for the fifth dose one week later and then 900 mg every two weeks. Also given via intravenous infusion, Ultomiris requires loading and maintenance doses, which are based on a patient’s weight. For patients weighing less than 20 kg, maintenance dosing is every four weeks; for those weighing more, it’s every eight weeks.

Empaveli’s annual wholesale acquisition cost is $458,000, which Apellis has said is at parity with Ultomiris’ WAC and less than that of Soliris.

Drugs Have REMS Requirements

All three drugs are available through a Risk Evaluation and Mitigation Strategy (REMS) program due to the potential for life-threatening meningococcal infections.

So will the third entrant in the class lead to payers selecting a preferred product for PNH? If so, what might be some considerations?

“This third option for PNH is another example that shows even in the world of rare diseases, choices for treatment options (and market competition that it brings) require payers to stay on top of evolving market dynamics,” observes Lynn Nishida, R.Ph., head of clinical operations at Evio. “Although Empaveli was approved based on studies that involved switching patients from their existing PNH therapy, it also won labeling [from the] FDA for treatment-naïve patients without studies in this patient population. From this perspective, payers may be able to consider Empaveli on equal footing as a treatment option with Soliris and Ultomiris, despite the lack of studies in treatment-naïve patients with PNH.”

Dea Belazi, president and CEO of AscellaHealth, agrees that having multiple agents will help with management and treatment of PNH. “The newest therapeutic option, pegcetacoplan, provides a different mechanism of action compared to the prior therapies. Each payer will carefully review the different therapeutic options through their respective review process. In this case, pegcetacoplan is the first PNH therapy to be approved by the FDA that targets the C3 rather than C5 cell surface complement regulatory proteins.”

He tells AIS Health, a division of MMIT, that “having a different mechanism of action may provide for differentiation. Pegcetacoplan comes to market with a Phase III study comparing it to eculizumab in PNH. The trial showed that pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. Pegcetacoplan also provided data on a crossover study design, which may assist with potential switches from eculizumab therapy. Also, a large number of patients receiving pegcetacoplan, as compared to eculizumab, no longer required transfusions, which may provide an additional quantifiable benefit.”

According to Nishida and Belazi, most payers have prior authorization on these drugs due to not only their high costs but also the need to make sure that the appropriate patients are receiving the right therapy and oversight of that treatment.

“Criteria used in the review process are developed as part of the pharmacy and therapeutics (P&T) committee process and utilize available published clinical studies, comparative information, guidelines, information from the National Association of Rare Diseases (NORD) and input from practicing medical providers,” says Belazi.

Such criteria could be “as basic as confirming diagnosis of PNH, age, prescribing by an appropriate specialist (hematologist, oncologist, immunologist or genetic specialist), age and dosing within recommended limits,” Nishida explains. Some payers, though, “may lean toward additional criteria that looks at diagnosis that’s confirmed based on additional hematology blood work and their transfusion dependency. Payers will often do follow-up with patients every three to six months to look for documentation of improved hematology labs and reductions in the need for transfusions. However, because these are not cures, once on therapy, they are likely to be considered on this for life, and it would be very rare that a patient will come off therapy over time.”

Dosing Differences Offer Patients Choice

Asked how much of a factor the different dosing regimens may have, Nishida tells AIS Health that it “will come down to a choice and type of patient being dealt with. Considerations are adherence vs. convenience to the patient in maintaining a twice-weekly dosing schedule but allows the patient independence on administering on their own vs. going to the office/clinic to have it administered less often and having someone do it for you. There will certainly be some patients that have difficulty getting to the clinic or doctor’s office, such that Empaveli may be a more favorable option for this patient population.” In addition, she states, “it will also come down to patient choice if payers determine they do not want to select a preferred product that is considered first, despite these differences in administration schedule.”

“Having alternative routes of administration is beneficial for various products,” declares Belazi, offering “added dosing flexibility for the physician to find the optimal therapy and site for the patient and their specific situation. Care must be taken to ensure that patients who are self-administering the subcutaneous infusions with pegcetacoplan have received the proper instruction and appropriate support to ensure proper administration and monitoring.”

As far as the additional cost for administration by a health care professional, “generally, self-administration by a patient provides cost savings for the patient and the payer when compared to health care professional administration,” he says. “For PNH therapies, the cost of the drug therapies is extremely expensive, typically exceeding $450,000 annually. Due to this prohibitive cost, the additional cost of health care professional administration is minimal compared to the drug acquisition cost. In these situations, the emphasis is on ensuring an optimal treatment regimen for the patient and, where clinically appropriate, utilize administration routes that support the chosen therapy regimen.”

With Empaveli having only the PNH indication on its label, the additional indications for the other two drugs could impact payer management. “Payers will review the available clinical data for these other indications and available therapies with the physician to ensure that patients receive the appropriate therapy for their specific condition,” Belazi says. “While having additional indications is beneficial for a product, this is included in the drug review process considered by each payer’s P&T committee.”

“Payers have become very savvy in being able to manage medication options that overlap across their various indications,” declares Nishida. “When selecting medications for formulary and building their utilization management criteria, they will generally review medications by therapeutic options by conditions. Therefore, we see that a medication could be nonpreferred for one indication among three or four options available but preferred for other indications for which it may have stronger evidence against those therapeutic alternatives and the only treatment option available. Payers currently do this with therapeutic options to treat cancer, rheumatology/inflammatory conditions, etc. where options may have several other indications and may vary for their preferred status as a treatment option by disease condition.”

Pediatric Indication Will Not Be Big Factor

She says that the novel pediatric indication for Ultomiris “will not likely play too much emphasis in the payers’ management of the class. For most payers, most coverage criteria are silent on age as a requirement for coverage.”

“PNH is a rare disease, and those that have it need treatment,” asserts Belazi. “Currently, PNH requires what I call a mild management model, and I don’t see that changing with the approval of this product. People with PNH are part of a very vulnerable population in the rare disease category. I think the approval of a treatment like Ultomiris for children and adolescents with PNH will become somewhat status quo as that is what the other PNH therapies are after as well.”

Nishida maintains that if a biosimilar enters the market, “this will be challenging for payers to be able to embrace quickly.” That situation might become a reality soon: On May 29, 2020, Alexion filed a Form 8-K with the U.S. Securities and Exchange Commission saying it had entered into an agreement with Amgen Inc. to settle three inter partes review proceedings over Amgen’s Soliris biosimilar. Through their settlement agreement, Amgen’s agent could enter the U.S. market as of March 1, 2025, “or an earlier date in certain circumstances.” ABP 959 is in Phase III clinical trials. Another biosimilar — SB12 from Samsung Bioepis Co., Ltd. — is in Phase I trials.

Belazi says the Amgen drug may launch as soon as 2023, and it “may provide a potential alternative therapy to consider as that date approaches.”

According to DelveInsight, in addition to second-generation C5 and C3 inhibitors, the PNH pipeline also consists of Factor B and D inhibitors, monoclonal antibody-derived compounds and ones based on small interfering RNA (siRNA), also known as short interfering RNA or silencing RNA.

Contact Belazi via Caroline Chambers at cchambers@cpronline.com and Nishida at lynn@evio.com.

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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