Erin Johanek, PharmD

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Cholesterol is one of the primary causal risk factors for developing atherosclerotic cardiovascular disease (ASCVD) and one of seven critical metrics the American Heart Association (AHA) has used to define cardiovascular health in adults and children, according to AHA’s Heart Disease and Stroke Statistics - 2020 Update.  

“High cholesterol is of significance because it can increase one’s risk of ... heart attack or stroke, especially in patients with other risk factors, such as smoking, diabetes, hypertension and/or a family history of heart disease,” says David Calabrese, RPh, M.H.P., senior vice president and chief pharmacy officer at OptumRx and a member of the 

Despite a variety of available treatment options, some patients fail to respond to common treatments, notes Calabrese, so alternatives must be considered. 

Hyperlipidemia’s consequences for American health and healthcare are comparable to those from hypertension, says Elliot Marino, Pharm.D., BCPS, a CompleteRx pharmacist in Olean, New York. “Patients need to be tested regularly, and the impact on their health may not be noticed for decades, making it very difficult to realize benefits to treatment,” says Marino.

Statins are, of course, the front-line therapy for hyperlipidemia. Repatha (evolocumab, Amgen) and Praluent (alirocumab, Sanofi and Regeneron) are currently the only FDA-approved medications in a relatively new drug class know as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. PCSK9 is a protein that binds to and prevents LDL receptors in the liver from clearing circulating LDL cholesterol. PCSK9 inhibitors prevent this binding, thereby increasing the number of LDL receptors available to clear LDL from the bloodstream. 

But PCSK9 inhibitors have had a difficult time catching on. The 2018 cholesterol guidelines from the AHA, the American College of Cardiology and other groups position them as third-line therapies after statins and Zetia (ezetimibe). What’s more, the guidelines say the cost of PCSK9 inhibitors would need reduced by 70% to 85% to meet conventional cost-effectiveness standards. Amgen and Sanofi dropped the price of their products by about 60% in late 2018 to just under $6,000 per year, but use is still far below the companies’ expectations when they launched their PCSK9 inhibitors in 2015. Sanofi CEO Paul Hudson announced late last year that the company was leaving the U.S. cardiovascular market, so Regeneron is now marketing Praluent on its own. 

Journal of the American Heart Association

 looked a lipid-lowering prescribing data from Jan. 1, 2015, to March 31, 2017, for 2.2 million people with dyslipidemia (which includes high triglycerides and high LDL) and about 940,000 with coronary artery or coronary heart disease. Just 362 (.02%) people with dyslipidemia had been prescribed a PCSK9 inhibitor, and 1,952 (.21%) people with coronary artery disease or coronary heart disease had been prescribed a PCSK9 inhibitor. 

The bumpy ride of the PCSK9 inhibitors has, understandably, made drugmakers wary of jumping into the market for medications for hyperlipidemia, despite the many people affected. Still, there are a handful of newcomers. Nexletol (bempedoic acid, Esperion) was approved by the FDA in February 2020 as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional lowering of LDL. Nexletol is a first-in-class ATP citrate lyase (ACL) inhibitor that lowers LDL levels by inhibiting cholesterol synthesis in the liver. Studies show that compared to placebo, Nexletol reduced LDL levels by an average of 18% when used with moderate or high intensity statins. 

Evinacumab (Regeneron) is an angiopoietin-like 3 protein (ANGPTL3) antagonist currently being investigated to treat homozygous familial hypercholesterolemia. ANGPTL3 acts as an inhibitor of lipoprotein lipase and endothelial lipase and appears to play a central role in lipoprotein metabolism. In a phase 3 trial, evinacumab resulted in a 49% reduction in cholesterol compared to placebo. 

Inclisiran (Novartis) may be the most intriguing candidate because like Repatha and Praluent, it is a PCSK9 inhibitor - although it works by another mechanism, RNA interference, that keeps PCSK9 from being made in the liver. Results published in the April 16, 2020, issue of the 

 show that the new drug lowered LDL levels by about 50% in patients who still have high cholesterol despite taking statin therapy at the highest tolerated dose. Novartis has submitted inclisiran for FDA approval. If approved and launched, which seems likely, it will have one major advantage over Repatha and Praluent: Inclisiran only needs to be injected twice a year to be effective, whereas Repatha and Praluent need to be injected at least once a month. On the plus side for Repatha and Praluent, patients can inject themselves; a clinician needs to inject inclisiran.

“Given that there are several existing treatments for high cholesterol on the market today, including several oral generic statins with extensive outcomes data, these new products are likely to be used as second- or third-line agents in patients who have failed to achieve optimal benefit or have contraindications or intolerances to first-line therapy,” says Calabrese. 

One thing to watch for is research showing that these new agents  influence cardiovascular disease - that they treat the disease and not just a number. 

“Cardiovascular outcomes trials typically take years to complete but will significantly impact how these drugs are used in clinical practice down the road,” says Calabrese.   

Erin Johanek, Pharm.D., is a pharmacist at Southwest General Health Center in Middleburg Heights, Ohio.  

Articles

The two PCSK9 inhibitors have fallen far short of expectations. Inclisiran, which works by RNA inference, only needs to be injected twice a year. 

High Hopes for Inclisiran. Will the Third Time be the Charm for PCSK9 Inhibition? 

Although there is no cure for rheumatoid arthritis, therapies have greatly improved in the past 30 years. 

“The goals of RA treatment are to stop inflammation, relieve symptoms, prevent joint and organ damage, improve physical function and overall well-being, and reduce long-term complications,” explains Julie Rubin, director of clinical services for 

, a pharmacy management company in Houston.

According to the American College of Rheumatology, RA patients should begin their treatment with disease-modifying antirheumatic drugs (DMARDs) which slow the worsening of joint damage as well as relieve symptoms. Commonly prescribed DMARDs include methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.

“DMARDs have greatly improved symptoms, function and quality of life for nearly all patients with RA; however, RA treatment is complicated and often progressive in nature,” observes David Calabrese, RPh, MHP, senior vice president and chief pharmacy officer, OptumRx. It is common for patients to switch therapies multiple times in their lives, he notes. People with RA also take medications such as ibuprofen and corticosteroids to manage the pain and inflammation on an as-needed basis.

“While the last few years have seen a string of new drug approvals for RA, there are very few products in the drug pipeline now that are in late stage development,” observes Calabrese.
	
	The most notable, he says, is filgotinib (Gilead Sciences and Galapagos NV), a highly selective, oral Janus kinase (JAK) inhibitor. Janus kinases are tyrosine kinases that play a critical role in the signaling pathways that are increasingly seen as critical to the pathogenesis of rheumatoid arthritis and a number of autoimmune diseases. The new drug application for filgotinib was submitted in December 2019, along with a priority review voucher, which should shorten the anticipated time for review. 

If gets approved and makes it on to the market, filgotinib would compete with previously approved JAK inhibitors, Xeljanz (tofacitinib), Olumiant (baricitinib), and Rinvoq (upadacitinib), explains Calabrese. Rinvoq was just approved last year.

ATI-450 (Aclaris Therapeutics) is an oral MK2 (mitogen-activated protein kinase-activated protein kinase 2) inhibitor currently in Phase 1 trials for the treatment of RA. The FDA approved the investigational new drug application in May 2019, and Phase 1 clinical trials started in August 2019. 

Rubin expects more DMARDs and new additions to the JAK inhibitor drug class.
	
	“The RA drug pipeline is focused on minimizing disease progression and immune system malfunction,” she says. “These new drug classes could reduce and, in some cases, reverse clinical symptoms.”

Biosimilars may not be novel therapies, but they are one of the key areas to monitor in RA therapy in Calabrese’s opinion. 

Acceptance of biosimilars-by providers and patients-will be key to determining uptake and realizing their savings potential, he says. Payers are attempting to transition patients from existing branded biologics to less costly biosimilar alternatives with the goal, he adds, “of improving patient care and lowering total cost of care.”   

Erin Johanek, PharmD, RPh is a staff pharmacist at Southwest General Health Center, Middleburg Heights, Ohio.

DMARDs and the JAK Inhibitors have improved RA treatment. But not many new drugs are in the offing at the moment.

Rheumatoid Arthritis Drug Pipeline at a Trickle

, nonalcoholic steatohepatitis (NASH) is a form of nonalcoholic fatty liver disease (NAFLD). The NIH defines NAFLD as a condition in which a buildup of fat-not caused by heavy alcohol consumption-occurs in the liver. Patients with NASH also have inflammation of the liver, known has hepatitis, and resultant liver cell damage.  

, NASH currently affects between 6.5 million to 16.3 million Americans, and up to 25% of adults with NASH may also have liver cirrhosis. By 2030, ALF reports NASH is expected to be the most frequent reason for liver transplants in the United States.

Current management and NASH pipeline drugs

According to the American Association for the Study of Liver Diseases the management of patients with NASH consists of treating liver disease as well as the associated metabolic comorbidities such as obesity, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus.

There are currently no FDA-approved medications for the treatment of NASH, but the guidelines recommend lifestyle modifications like weight loss, pioglitazone (biopsy-proven NASH), and vitamin E as treatment options.

 for patients with type 2 diabetes and NAFLD based on positive results from the 

 study demonstrating the medication reduces liver fat. Intercept has submitted the new drug application for 

 (Ocaliva) for the treatment of liver fibrosis due to NASH and was granted priority review by the FDA, with a target approval date of March 26, 2020.

Obeticholic acid has a unique mechanism of action as an oral farnesoid X receptor (FXR) agonist. It’s the only therapy the FDA has designated as a Breakthrough Therapy for NASH with fibrosis, according to results from the phase 3 

"If approved, obeticholic acid would be the first FDA-approved product for NASH, and it would likely have a year or more marketing head start over the rest of the pipeline," says David Calabrese, RPh, MHP, senior vice president and chief pharmacy officer, OptumRx.

 is studying elafibranor, an oral medication currently in a phase 3 trial 

 for the treatment of NASH. After a favorable 

, the study is continuing and expected to be completed in 2021. Elafibranor is a dual agonist of PPAR-alpha and PPAR-delta receptors, which both play an important role in numerous processes involved in the development of NASH and its comorbidities. The FDA has granted elafibranor fast-track designation for the treatment of NASH.

"Allergan's cenicriviroc and Madrigal Pharmaceutical's resmetirom are in phase 3 trials and are anticipated to be approved in 2021-2022,” says Nicole Kjesbo, PharmD, BCPS, principal clinical program pharmacist, Prime Therapeutics. 

 is currently recruiting an estimated 2,000 participants to evaluate cenicriviroc for the treatment of NASH, with topline results expected in the fourth quarter of 2020. Resmetirom would be a first-in-class oral thyroid hormone receptor-beta selective agonist, and the phase 3 study 

 began March 2019.  The endpoint is resolution of NASH after one year of treatment.  In addition to the drugs mentioned, Kjesbo revealed there are at least 10 other drugs for the treatment of NASH that are in Phase II/III trials and are anticipated to be approved in 2021 and beyond.

"Many of the pipeline drugs are being developed by different manufacturers and some manufacturers are developing multiple drugs for NASH," says Calabrese. "Therefore, there may be potential for combination therapy down the road which would further increase the future cost of treatment."

"This is going to be an emerging category in the coming years," says Kjesbo. "Currently, pharmacotherapy is reserved for NASH patients with fibrosis; it will be interesting to see if lifestyle changes will continue to be the first-line treatment over medications." According to Kjesbo, analysts have forecasted the market for NASH drugs could reach $20 billion by 2025.

Erin Johanek, PharmD, RPh is a staff pharmacist at Southwest General Health Center, Middleburg Heights, Ohio

The first FDA-approved product for NASH on the horizon.

NASH Drug Pipeline Shows Promise

	The average monthly cost of drugs to treat inflammatory conditions was more than $3,000 in 2015, according to 

Express Scripts’ 2015 Drug Trend Report

, released in March 2016. Additionally, per member per year spend on drugs to treat autoimmune diseases was $89.10 in 2015, making inflammatory conditions the leading specialty therapy class as well as the leading class overall in the report.

	“Spending on autoimmune drugs continues to increase and utilization is rising,” says April Kunze, PharmD, senior director, clinical formulary development and trend management strategy, Prime Therapeutics. “Autoimmune is the number one specialty drug spend category at Prime Therapeutics within our commercially insured business, comprising approximately one in 10 dollars spent on all drug expenditures through the medical and pharmacy benefits.”

	According to Kunze, there are 15 autoimmune specialty drugs and more to be approved soon, making this class one of the fastest and most challenging to manage.

	Specialty drugs available to treat inflammatory conditions include tumor necrosis factor (TNF) inhibitors, injectable biologics, and oral targeted synthetic DMARDs (disease-modifying antirheumatic drugs), says Aimee Tharaldson, PharmD, senior clinical consultant in the emerging therapeutics department at Express Scripts.

	“The majority of the spend for autoimmune drugs is related to the biological products and especially the TNF inhibitors, says Kunze. “Humira and Enbrel are two of the top drugs by percent expenditure within Prime’s book of business (pharmacy benefit) and Remicade is the top drug on the medical benefit.”

	The oral DMARDs include Xeljanz (tofacitinib, Pfizer) and Otezla (apremilast, Celgene).

	Injectable biologics used to treat autoimmune conditions include Actemra (tocilizumab, Genentech), Stelara (ustekinumab, Janssen), Cosentyx (secukinumab, Novartis) and Taltz (ixekizumab, Eli Lilly and Company).

	Several new options are in the pipeline for autoimmune conditions. Saracta (sarilumab, Sanofi) is a subcutaneous injection being studied for the treatment of rheumatoid arthritis (RA). Similarly, sirukumab, a human interleukin monoclonal antibody that targets interleukin-6, is being studied by GlaxoSmithKline in adults with moderately to severely active RA. Baricitinib, developed by Eli Lilly, is a once-daily oral option for RA with anticipated approval in early 2017.

	There are also potential new options coming for the treatment of plaque psoriasis including Siliq (brodalumab, Valeant Pharmaceuticals), a monoclonal antibody that targets the IL-17 receptor.  Additionally, Tharaldson explains that IL-23 inhibitors are another important therapy class to watch for in the psoriasis pipeline. These drugs include Janssen’s guselkumab and AbbVie’s risankizumab.

Next: How biosimilars will affect the autoimmune drug class

	For the first time in the autoimmune drug class, biosimilars will be coming to market, says Kunze. A few examples include:

			Amjevita (adalimumab-atto, Amgen), Humira’s biosimilar;

			Erelzi (etanercept-szzs, Sandoz), Enbrel’s biosimilar; and

			Inflectra (infliximab-dyyb, Celltrion), Remicade’s biosimilar.

	“Biosimilars for inflammatory conditions can help to mitigate spend in this therapy class.” says Tharaldson.

	Kunze says competition from biosimilars will most likely not bring down the cost as much as traditional generic drugs. Current market examples indicate biosimilars may sell for 10% to 30% less than the original brand products.

	Comprehensive management requires integrating medical and pharmacy benefits and data because, according to Kunze, more than 25% of the autoimmune drug class is processed and paid via the medical benefit and consequently, if the medical and pharmacy drug expenditures are not integrated, the autoimmune drug class cannot be optimally managed.

	Kunze also says that savings within the autoimmune drug class are likely possible through an indication-based formulary followed by alignment of medical benefit policy approval criteria and pharmacy benefit utilization management criteria. An indication-based formulary will need to have integrated medical and pharmacy benefits and data to obtain optimal savings.

	Erin Bastick, PharmD, is a graduate intern at University Hospitals Elyria Medical Center in Elyria, Ohio.

Find out what’s in the drug pipeline for autoimmune disease.

Author | Erin Johanek, PharmD

Articles

High Hopes for Inclisiran. Will the Third Time be the Charm for PCSK9 Inhibition?

Rheumatoid Arthritis Drug Pipeline at a Trickle

NASH Drug Pipeline Shows Promise

Will new autoimmune drugs address cost concerns?