Denise Myshko is your editorial contact for the Formulary Watch. She joined Formulary Watch as editor is June 2021 from Oncology Live. Prior to that, she was managing editor of PharmaVOICE, a trade publication in the pharmaceutical industry. Email: dmyshko@mjhlifesciences.com

Denise Myshko

The utilization of higher cost medications for rare diseases is driving higher spend on prescription drugs. In fact, nonspecialty drug utilization has remained relatively flat but specialty drug utilization is forecasted to increase, according to a 

“Almost every new chemical entity to the market is a specialty drug; they are coming to market faster through various programs, such as orphan drug and other pathways through the FDA,” Nick Taylor, R.Ph., VP, national pharmacy practice leader consulting services at Segal, said in an interview.

Specialty drug prices are rising as these therapeutics replace lower-cost therapies, and the majority of the pipeline is specialty or orphan drugs, the Segal study found. Specialty drugs now account for 53% of spending, according to IQVIA Institute for Human Data Science. Segal analysts project a cost trend for specialty drugs in 2022 of 14.4%, up from the projected 11.5% for 2021.

That pressure could ease a bit in 2023, when Boehringer Ingelheim’s interchangeable biosimilar of AbbVie’s Humira is expected to launch. The FDA approved Cyltezoz) adalimumab-adbm) on Oct. 15, 2021, but it won’t launch until July 1, 2023. This date was the result of a patent ligation with AbbVie. Boehringer Ingelheim will pay royalties to AbbVie for licensing its Humira patents once Cyltezo is available.

Related: FDA Approves First Interchangeable Biosimilar of Humira

“It'll be interesting to see what happens with negotiation of price and rebates,” Taylor said. “We will continue to see the uptick in the use of biosimilars, particularly on the medical side with infused products in the cancer category.”

Biosimilar utilization has increased 60% over the last two years, according to IQVIA. Taylor said that biosimilars are expected to provide some savings, especially in the oncology categories. “But it's not going to be like the traditional brand-generic type situation where you have 60%, 70% or 80% savings. Biosimilars are still quite expensive to produce and market. I think it’s going to become a price game with rebates and price concessions if pharma companies want to status of these drugs.”

The Segal report found that the average impact of rebates was a 2.4 percentage point reduction in prescription drug spend. Additionally, other plan strategies, such as prior authorization and step therapy, Taylor said, are effective in managing specialty drug spend, and he predicts health plans will continue to adopt these strategies.

Taylor said health plans are also starting leverage manufacturer coupon programs to maximize the value of these coupons. “Unless there's regulatory change where coupons are not available, or manufacturers decide to go a different route and not offer coupons, we can see them continuing going forward.”

Beyond plan design, member cost-sharing also can have an impact on drug spend, often influencing patient behavior. “Members with plans that have lower cost sharing choose differently from members who have plans that have higher cost share. The idea of a high deductible health plan is that people shop for price.”

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Specialty drug prices are rising as these therapeutics replace lower-cost therapies.

Segal: Specialty Drugs Driving Cost Trend 

 the safety labeling of Cyltezo (adalimumab-adbm) with data from the trial that was used to support its application for interchangeability with Humira (adalimumab). The FDA 

 Cyltezo as the first interchangeable biosimilar of AbbVie’s Humira on Oct. 15, 2021.

“All FDA-approved biosimilars to Humira have the same label as the reference product. However, an interchangeable biosimilar is a separate, additional regulatory designation on top of the high FDA standards for a biosimilar,” a company spokesperson said in an email.

Specifically, in addition to first meeting the requirements of biosimilarity, an interchangeable biosimilar must additionally demonstrate that the risk in terms of safety or diminished efficacy of switching with the reference product is not greater than staying on the reference product in any given patient. This requirement is satisfied through an additional study of multiple switches in patients.”

 in April 2021 from the VOLTAIRE-X phase 3 trial. Results showed that in patients with moderate-to-service chronic plaque psoriasis switching several times between Cyltezo and Humira resulted in no meaningful clinical differences for pharmacokinetics, efficacy, immunogenicity, and safety. The 32-week data were presented at the American Academy of Dermatology 2021 conference. 

Related: FDA Approves First Interchangeable Biosimilar for Humira

Cyltezo’s label now includes additional information about immunogenicity, as well as pediatric use. Within the section on immunogenicity, the label now says:

“There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples.

Rheumatoid Arthritis and Psoriatic Arthritis: 

Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12-month period.

For pediatric use, the label adds information about use in children with juvenile idiopathic arthritis and Crohn’s disease:

“A pediatric assessment for Cyltezo demonstrates that Cyltezo is safe and effective for pediatric patients in an indication for which Humira (adalimumab) is approved. However, Cyltezo is 

 approved for such indication due to marketing exclusivity for Humira (adalimumab). The safety and effectiveness of adalimumab products have not been established in pediatric patients with JIA less than 2 years of age.

The safety and effectiveness of adalimumab products for the treatment of moderately to severely active Crohn’s disease have been established in pediatric patients 6 years of age and older. Use of adalimumab products for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients. The adverse reaction profile in patients 6 years to 17 years of age was similar to adults.

The safety and effectiveness of adalimumab products have not been established in pediatric patients with Crohn’s disease less than 6 years of age."

Boehringer Ingelheim will make Cyltezo available when its commercial license begins on July 1, 2023. This date was the 

 with AbbVie. Boehringer Ingelheim will pay royalties to AbbVie for licensing its Humira patents once Cyltezo is available.

Cyltezo was approved by the FDA in August 2017 for the treatment of multiple chronic inflammatory diseases including rheumatoid arthritis, psoriasis and Crohn's disease.

The label now includes new data from the trial that supported Cyltezo’s application for interchangeability with Humira.

Boehringer Ingelheim Updates Safety Labeling of Cyltezo

Cigna will be removing 45 drugs covered under the pharmacy benefit from its 

 beginning in January 2022. Most of these drugs have generic alternatives. (See table below.)

For medications that don’t have an available generic available, Cigna recommends a different branded therapeutic. For example, among diabetes medications removed from the standard formulary are Janssen’s Invokana and Invokamet, as well as Merck’s/Pfizer’s Segluromet and Steglatro. For Invokana (canagliflozin) and Steglatro (ertugliflozin), the recommended alternative is Farxiga (dapaglifozin), which has a list price of $532 for a 30-day supply. For the combination products Invokamet (canagliflozin/metformin) and Segluromet (ertugliflozin/metformin), the recommended alternative is Synjardy (empagliflozin/metformin), which has a list price of $582 for a 60-day supply.

Among cholesterol medications removed from the standard formulary are Crestor (rosuvastatin), where there is a generic available, and Juxtapid (lomitapide). Because there is no generic for Juxtapid, Cigna recommends Amgen’s Repatha (evolocumab), where the list price is less than $500 a month. Juxtapid has a list price of almost $50,000 for 28 capsules.

Additionally, Cigna will move four therapeutics to a higher, non-preferred drug tier in 2022, and another four drugs have moved to a lower, preferred tier. Moving to the non-preferred tier are Apokyn, Remodulin, Sandostatin LAR, and Tasigna.

Apokyn (apomorphine) is indicated for the acute, intermittent treatment of hypomobility during “off” episodes in patients with advanced Parkinson’s disease. It is marketed by Supernus Pharmaceuticals. Levodopa is used to manage patients with Parkinson’s disease, but it can become less effective over time, and patients can experience a diminished clinical response marked by motor fluctuations. Cigna recommends Sunovion’s Kynmobi (apomorphine) as an alternative. The FDA approved Kynmobi in October 2020. It is a novel formulation of apomorphine that is delivered through a thin film that dissolves under the tongue.

Remodulin (treprostinil), developed by United Therapeutics, treats patients with pulmonary arterial hypertension. Cigna recommends using a generic treprostinil. Sandoz launched the first generic of trepostinil injection in 2019, and in May 2021, Sandoz launched a subcutaneous version.

Both Sandostatin and Tasigna are used by patients with cancer. Novartis’ Sandostatin LAR Depot (octreotide) treats severe diarrhea associated with metastatic tumors. Cigna recommends another Novartis therapeutic instead: Somatuline Depot (lanreotide). Tasigna (nilotinib), also developed by Novartis, treats patients with chronic myeloid leukemia. Cigna recommends Sprycel (dasatinib) from Bristol Myers Squibb as an alternative.

Moving to a lower tier are the COPD therapies Spiriva/Spiriva Respimat and Stiolto Respimat, as well as the biosimilars Udencya (pegfilgrastim-cbqv) and Ziextenzo (pegfilgrastim-bmez), which are used to prevent infection after chemotherapy.

Fourteen therapies now have coverage restrictions, including needing approval from Cigna. For several medications for age-related macular degeneration, physicians will have to show that patients have already tried Avastin (bevacizumab). These include Beovu (brolucizumab-dbll), Eylea (aflibercept), and Lucentis (ranibizumab).

Some diabetes medicines will require current patients to have approval from Cigna to continue on these therapeutics. These include Bydureon/Byetta (exenatide), Ozempic/Rybelsus (semaglutide), and Victoza (liraglutide).

Cigna plans to remove 45 drugs from its Standard Prescription Drug List and add restrictions for other therapeutics.

Cigna Releases Formulary Changes for 2022

Spending on oral therapies that treat patients with cancer without a documented overall survival benefit has increased and even surpassed spending on therapies with such clinical data, according to a 

Investigators assessed 44 new oral targeted drugs dispensed between 2011 and 2018. Most patients (97%) received drugs for which evidence of overall survival from randomized clinical trials existed. But investigators found that a growing share of patients received drugs without such data: from 12.7% in 2011 to 58.8% in 2018. Cumulative spending on drugs without overall survival data was $1.8 billion and surpassed that of drugs with documented overall survival benefit of $1.7 billion by the end of 2018.

“The results we describe in our study — increasing use of and spending on cancer drugs without documented overall survival benefit — reflect characteristics of the U.S. cancer drug ecosystem, which includes drug development, regulation, pricing, advertising, and reimbursement,” lead author Anita Wagner, Pharm.D., Dr.PH., associate professor of population medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, said in an email to Formulary Watch. She is also director of the ethics program at Point32Health, the parent company of Harvard Pilgrim Health Care and Tufts Health Plan.

Of the 44 drugs investigators analyzed, 34 (77.3%) were supported by at least one randomized clinical trial for at least one indication; 10 drugs (22.7%) were approved on the basis of single-arm studies or noncomparative trials alone. Only 11 drugs (25%) had documented, statistically significant overall survival benefit for at least one indication in FDA-approved labels by the end of 2018, and four those had overall survival as primary end point.

The investigators suggested that the increased spending on cancer drugs without overall survival data is a result of several factors, including: increasingly lenient FDA approvals, drugs advertised directly to consumers, no price regulation, fragmented purchasing and reimbursement systems, coverage mandates, and limited ability by payers to negotiate prices.

Given the U.S cancer drug ecosystem, payers have limited options to address the challenges posed by expensive drugs with uncertain benefits, Wagner said. “Nevertheless, as key actors in a complex system, payers can play a role in member and clinician education about evidence of benefits and risks. They can target drug coverage according to evidence, seek risk sharing contracts with pharmaceutical companies, and they can publicly advocate for better evidence.”

The authors suggested in the paper that value-based pricing might reduce the cost of some drugs with high spending amounts. They point to Nerlynx (neratinib), which was ranked 11th in this study in terms of spending. Developed by Puma Biotech, this therapy was approved in 2017 as adjuvant treatment of adult patients with early stage HER2-positive breast cancer. One 

 suggested Nerlynx’s price would need to be reduced by 85% for it to be cost-effective at a willingness-to-pay threshold of $150,000 per quality-adjusted life-year gained.

Wagner said policy changes in this complex ecosystem likely need to be multi-pronged. “They are likely challenging and controversial as most require cooperation of stakeholders with different priorities,” she said. “They include, for example, validated surrogate end points with pre-defined thresholds predictive of clinically meaningful benefit.”

But she indicated that some changes may be more readily feasible than others. Among those may be FDA efforts to make explicit and easily accessible for patients, their clinicians, and others what is known and what is not known about the clinical benefits of newly approved highly priced cancer drugs.

“Such efforts could start with consistent documentation of overall survival information in FDA-approved labeling as we have suggested based on another recent study and clear visual alerts in labels of limited evidence underlying accelerated approvals akin to black box warnings as colleagues at Institute for Clinical and Economic Review have suggested.”

Cumulative spending on drugs without overall survival data was $1.8 billion in 2018 and surpassed that of drugs with such data.

Study: Spending Increasing for Cancer Therapies Without Evidence of Overall Survival

The specialty drug industry is poised for continued and accelerated growth. More than 40 drugs in the specialty pipeline are expected to be FDA-approved within the next 10 months to 12 months, according to AllianceRx Walgreens Prime.

All indicators suggest a continued rise in specialty product as evidenced by the rich pipeline, Tracey James, R.Ph., senior vice president, pharmacy services, said by email. “When you factor biosimilars and gene and cell therapies into the mix, the industry is poised for continued and accelerated growth.”

Like all medications – including oncology therapies and biosimilars – gene and cell products require a lot of money to develop and test. “With such a significant expenditure in research for each disease, combined with a limited number of patients per disease, a large price tag is often necessary for manufacturers to receive return on investment,” James said.

For example, already approved gene and cell therapies average between $400,000 and $850,000, with one product priced just over $2 million dollars. “Despite the high costs, manufacturers argue the upfront cost is worth the long-term savings in many cases,” she said.

Specialty medicines are now 53% of spending, up from 27% in 2010 and driven by growth in autoimmune and oncology therapies, according to 

. Immunology, oncology and neurology will be the main sources of growth through 2025, IQVIA predicts. Oncology spending will exceed $110 billion by 2025, up from $72 billion in 2020 and continuing at a slower growth rate due to the impact of biosimilars and new drug launches increasingly focused on rare cancers. Immunology will exceed $130 billion in the United States by 2025, with growth slowing after 2023.

IQVIA’s report find that the largest proportion of new medicines launched in the past five years has been specialty drugs, and specialty spending per person has doubled from $285 in 2010 to $572 in 2020. Specialty medicines treat relatively few patients and have costs far higher per patient than traditional medicines.

Growth in specialty drug spend can be attributed to an increase in product offering, more advanced research and development, and smaller, more targeted populations in need of such drugs, James said. “Additionally, these medications often require special handling or physician administration, complicating distribution channels and increasing costs.”

Overall, the average amount that patients pay for out-of-pocket costs for prescriptions has dropped, according to IQVIA. But 8% of patients have annual out-of-pocket costs more than $500 in commercial plans and 1.8% pay more than $1,500 out-of-pocket for prescriptions. In Medicare, 17% of patients pay more than $500 out of pocket, and 4% pay more than $1,500 out of pocket.

James said both formulary status and plan benefit design influence a patient's out-of-pocket costs. AllianceRx Walgreens Prime helps patients connect with copayment assistance programs. The company has invested in tools and technology to help connect qualified patients with resources that help patients start and stay on therapy. 

"We recently launched a new financial navigation technology platform that identifies patients with financial risk and automatically connects them with personalized financial assistance resources, when necessary," James said. "This includes manufacturer assistance programs and national foundations, and also provides access to local charitable foundations and government programs.”

Specialty medicines are now 53% of spending, up from 27% in 2010 and driven by growth in autoimmune and oncology therapies.

AllianceRx: Number of Specialty Drugs Expected to Increase

Patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with C5 inhibitors often discontinued therapy, had breakthrough hemolysis events and blood transfusion needs, and there was an underutilization of optimal sites of care, according to a 

“It is known paroxysmal nocturnal hemoglobinuria (PNH) can be a challenging disease to treat,” Patrick Gleason, Pharm.D., assistant vice president, health outcomes at Prime Therapeutics, said in an email. “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 seeing the discontinuation rate and transfusion rate.”

PNH is a serious ultra-rare blood disorder that is characterized by the destruction of red blood cells. PNH occurs when the complement system — a part of the body’s immune system — over-responds, leading the body to attack its own red blood cells. PNH often goes unrecognized, with delays in diagnosis from one to more than five years. Patients with PNH may experience a range of symptoms, such as fatigue, difficulty swallowing, shortness of breath, abdominal pain, erectile dysfunction, dark-colored urine and anemia.

Two C5 inhibitors are available to treat PNH, both developed by Alexion Pharmaceuticals. Soliris (eculizumab) was approved in 2007 for PNH. The FDA also 

 Soliris in June 2019 for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults.

 in 2021 for children with paroxysmal nocturnal hemoglobinuria (PNH). It was originally approved in 2018 to treat adults with PNH and adult and pediatric patients with atypical hemolytic uremic syndrome.

During 2018 through 2019, Prime analyzed commercially insured members over a two-year period to identify individuals with PNH claims. In this analysis, 162 members were identified and divided into three categories based on treatment approach: 57 patients who received Soliris; six patients who received Ultomiris; and 99 patients with a PNH diagnosis but without a C5 inhibitor prescription claim at time of identification.

Prime assessed total treatment cost, which included medical and pharmacy benefits calculation of the actual paid amounts for all health care claims, including all medical care and drugs, after network discounts.

Prime found PNH drug therapy can exceed $1 million for an individual annually. Patients receiving Soliris had the highest total costs of care (averaging nearly $730,000 each), followed by patients receiving Ultomiris (averaging more than $370,000 each) and those with only a PNH diagnosis (averaging nearly $80,000 each).

“Optimizing PNH drug therapy is essential,” Gleason said. “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 review. Important also is ongoing PNH drug therapy surveillance via clinical services provided by a PBM that has integrated medical and pharmacy claims analytic knowledge to automate PNH outlier drug regimen identification and specialized pharmacists who are skilled in PNH drug therapy.”

Gleason said integrated medical and pharmacy data and knowledge are required to have successful PNH drug therapy optimization conversations with the PNH drug therapy prescribers.

 The mean dose for Soliris users was higher than the dose recommended by the FDA with four in 10 members.

 Nearly 40% of members on therapy had at least one transfusion while about 21% had four or more transfusions. A common treatment goal for PNH is to eliminate the need for transfusions.

 Another treatment goal for PNH is to eliminate breakthrough hemolysis events. One in four individuals had medical claims indicating a likely event.

 Nearly 40% of Soliris users and 50% of Ultomiris users discontinued therapy within 12 months.

Treating and managing patients with paroxysmal nocturnal hemoglobinuria is expensive and requires constant surveillance by the provider and health plan.