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Medical World News: Regulatory Updates

Evidence-Based Diabetes ManagementDecember 2017
Volume 23
Issue SP14

Novo Nordisk's Fiasp for Mealtime Use Gains FDA Approval

Christina Mattina

THE FDA HAS APPROVED Novo Nordisk’s Fiasp, an insulin aspart injection that can rapidly improve glycemic control at mealtimes for patients with type 1 and type 2 diabetes (T1D and T2D).

According to a statement from the company, the new injection is similar to the fast-acting insulin aspart NovoLog but also contains niacinamide, known as vitamin B3, which helps the body absorb insulin faster. “According to an analysis in our FDA submission, Fiasp appeared in the bloodstream in 2.5 minutes. In that same analysis, NovoLog appeared in the bloodstream in 5.2 minutes. Due to its fast onset and appearance in the bloodstream, Fiasp can be dosed at the beginning of a mealtime or within 20 minutes after the start of a meal,” said Todd Hobbs, MD, chief medical officer of Novo Nordisk in North America, in an email.

Similar to NovoLog, Fiasp will be sold in both 10-mL vials and pre filled delivery pens marketed as FlexTouch by Novo. It will also have an identical list price to NovoLog, and the statement indicates that it will be eligible for the manufacturer’s savings card and Patient Assistance Program.

While the original insulin aspart is meant to be fast acting, Fiasp and its niacinamide will help the drug act even more quickly. Speed is especially important during meals, which can lead to blood sugar fluctuations that make it difficult for people with either type of diabetes to achieve optimal blood glucose levels. Fiasp may be used at the start of a meal or within 20 minutes of when the patient begins eating.

The FDA approved Fiasp based on positive results from the Onset clinical trial program, which enrolled more than 2000 adults with T1D or T2D. In phase 2a, patients of both types had a reduction in glycated hemoglobin (A1C) levels after taking Fiasp, whether it was administered at mealtime or after they had started eating. Participants reported some adverse effects, including nasopharyngitis, upper respiratory tract infection, nausea, diarrhea, and back pain. Fiasp is not approved for children.

“With Fiasp, we’ve built on the insulin aspart molecule to create a new treatment option to help patients meet their postmeal blood sugar target,” Bruce Bode, MD, FACE, president of Atlanta Diabetes Associates and an associate professor at Emory University School of Medicine, said in the statement. “The intention of rapid-acting insulin therapy is to mimic, as much as possible, the natural physiological insulin response that occurs after meals, a process that is important for optimal A1C management.”


Novo Nordisk receives FDA approval for Fiasp, a new fast-acting mealtime insulin [press release]. Plainsboro, NJ: Novo Nordisk; September 29, 2017. press.novonordisk-us.com/2017-09-29-Novo-Nordisk-Receives-FDA-Approval-for- Fiasp-R-a-New-Fast-Acting-Mealtime-Insulin. Accessed October 28, 2017.

CV Indication Sought for Canagliflozin, Combinations

Mary Caffrey

JANSSEN RESEARCH & DEVELOPMENT has led a supplemental new drug application with the FDA to add a cardiovascular (CV) indication to canagliflozin, its popular therapy for type 2 diabetes (T2D) sold as Invokana. Company officials announced the application on October 2, 2017.1

In the application, Janssen also seeks CV indications for canagliflozin fixed dose combinations Invokamet and Invokamet XR, the statement said.

The filing was anticipated after a presentation in June at the 77th Scientific Sessions of the American Diabetes Association in San Diego, California, where results of the CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (CANVAS-Renal) studies showed a 14% reduction in the combined primary end point of nonfatal heart attacks, nonfatal strokes, and CV death.2 Results simultaneously published in the New England Journal of Medicine also found that patients taking canagliflozin had a lower risk of hospitalization for heart failure, less loss of kidney function, and a lower risk of progression to albuminuria.3

“People with type 2 diabetes have a substantially increased risk of developing cardiovascular disease, and it’s encouraging that we now have data to show Invokana may help address this challenge,” James F. List, MD, PhD, global therapeutic area head, Cardiovascular and Metabolism, Janssen, said in the company’s statement. “Invokana has shown a clear benefit in reducing cardiovascular risk in adults with type 2 diabetes, and we look forward to working with [the] FDA as it reviews our filing.”1

In March 2013, canagliflozin became the rst sodium glucose cotransporter-2 (SGLT2) inhibitor approved to treat T2D.4 The FDA previously approved a CV indication for empagliflozin, an SGLT2 inhibitor sold as Jardiance by Eli Lilly and Boehringer-Ingelheim.5 SGLT2 inhibitors have a mechanism of action that involves blocking a protein that normally allows the body to reabsorb glucose; instead, the body discharges excess glucose through the urine, offering people with T2D glycemic control, reduced blood pressure, and modest weight loss.

Another agent approved to treat T2D, the glucagonlike peptide-1 receptor agonist liraglutide, sold by Novo Nordisk as Victoza, received a CV Indication in August 2017 based on results that found it reduced the risk of major CV events by 13%.6


1. Janssen submits supplemental new drug application to US FDA seeking new indication for INVOKANA (cana- gliflozin) to reduce the risk of major adverse cardiovascular events (MACE) based on landmark CANVAS program [press release]. Raritan, NJ: Johnson & Johnson; October 2, 2017. www.jnj.com/media-center/press-releases/janssen- submits-supplemental-new-drug-application-snda-to-us-fda-seeking-new-indication-for-invokana-canagliflozin- to-reduce-the-risk-of-major-adverse-cardiovascular-events-mace-based-on-landmark-canvas-program. Accessed October 2, 2017.

2. INVOKANA (canagliflozin) significantly reduces the combined risk of cardiovascular death, myocardial infarction, and stroke in the CANVAS program [press release]. Raritan, NJ, and San Diego, CA: Johnson & Johnson; June 12, 2017. www.jnj.com/media-center/press-releases/invokana-canagliflozin-significantly-reduces-the-combined-risk-of-car- diovascular-death-myocardial-infarction-and-stroke-in-the-canvas-program. Accessed October 2, 2017.

3. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

4. US FDA approves INVOKANA (canagliflozin) for the treatment of adults with type 2 diabetes [press release]. Raritan, NJ: Johnson & Johnson; March 29, 2013. www.jnj.com/media-center/press-releases/us-fda-approves-invokana-cana- gliflozin-for-the-treatment-of-adults-with-type-2-diabetes. Accessed August 21, 2017.

5. US FDA approves Jardiance (empagliflozin) tablets to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease [press release]. Ingelheim, Germany, and Indianapolis, IN: Boehring- er-Ingelheim; December 6, 2016. www.boehringer-ingelheim.com/press-release/fda-approval-jardiance-cv-label. Accessed October 17, 2017.

FDA Updates Afrezza Label; MannKind to Launch New Talks With Payers

6. Victoza (liraglutide) is approved in the US as the only type 2 diabetes treatment to reduce the risk of three major adverse cardiovascular events [press release]. Plainsboro, NJ: Novo Nordisk; August 25, 2017. press.novonordisk-us. com/2017-08-25-Victoza-R-liraglutide-is-approved-in-the-US-as-the-only-type-2-diabetes-treatment-indicated-to- reduce-the-risk-of-three-major-adverse-cardiovascular-events. Accessed October 17, 2017.EBDMTM Staff

ON SEPTEMBER 29, 2017, the FDA granted MannKind Corp a label update for the inhaled mealtime insulin, Afrezza, which CEO Michael Castagna, PharmD, said will let the company set itself apart from rivals for the first time. Castagna said the change will allow a fresh round of conversations with payers about the drug’s advantages, including lower rates of hypoglycemia.1

The new label, unveiled in an investor call October 2, 2017, states that Afrezza shows up in the bloodstream in approximately 1 minute and reaches its first measurable effects at 12 minutes. More importantly, Castagna pointed to a new table that shows how different doses of Afrezza enter and leave the body quickly, which he said will be crucial in explaining Afrezza’s value to doctors and patients.

“This will allow stronger wording with the sales force,” Castagna said in an interview with Evidence-Based Diabetes ManagementTM (EBDMTM), as he dis- cussed plans for MannKind to revamp discussions with doctors about dosing, especially the problem of underdosing. Castagna has said patients sometimes need more units of Afrezza than the number of insulin units they used in an injected form. The FDA, he said, “wants us to be very specific,” which he described as “a positive surprise.”

The new label also features updated instructions and a new table for titrating the drug, which includes the familiar color-coded insulin cartridges—blue for 4 units of insulin, green for 8 units, and yellow for 12 units—that will help patients new to Afrezza learn what works for them.

Patients who use Afrezza and market watchers who follow MannKind had been waiting to see the language that the FDA would include in the new label to see if it will make a meaningful difference in the way MannKind can position the inhaled insulin with payers and physicians. Afrezza enjoys a loyal core of users who tout its benefits online, and some were urging the FDA to approve an “ultra-fast-acting” designation, which Castagna himself said was a long shot. While the FDA did not add this to the label, Castagna said several key issues were resolved.

Meanwhile, Afrezza will have to compete with Novo Nordisk’s faster-acting mealtime insulin, Fiasp, which received FDA approval for patients with type 1 and type 2 diabetes on the same day as the Afrezza label change.2 Novo Nordisk’s chief medical o cer for diabetes in North America, Todd Hobbs, MD, said in an e-mail that the FDA’s analysis found that Fiasp appeared in the bloodstream in 2.5 minutes.

Castagna said Afrezza acts even more quickly, but the more clinically relevant issue is how quickly it leaves the body—90 minutes for 4 units, and 3 hours for 12 units.

Afrezza’s old label said the drug’s onset was comparable with insulin lispro, which made payers skeptical of its value and created barriers to reimbursement. “We have removed the language that restricted our promotional activity,” Castagna said during a conference call with analysts.

The Afrezza label update is based on data that MannKind presented at the American Diabetes Association Scientific Sessions in June 2016.3 “These data articulate the rapid-acting nature of Afrezza to address post-prandial hyperglycemia, setting it apart from other mealtime options available to help patients maintain greater control over their blood glucose levels,” said Satish Garg, MD, MBBS, DM, of the Barbara Davis Center for Diabetes at the University of Colorado, in a statement.1

The FDA retained the safety warning on Afrezza, which advises that bronchospasms have been observed in certain patients who have asthma or chronic obstructive pulmonary disease. Afrezza is contraindicated in those patients, and the FDA also kept a requirement that patients clear a spirometry test before they gain access to the drug.4 (The product is delivered through a special inhaler that resembles a whistle.)

It would have been surprising if the FDA altered these requirements, although Castagna said he does hope to address the lung testing requirement in the future. It remains to be seen if this issue is still a barrier for some doctors, now that both Afrezza and Fiasp are approved.

Because Afrezza takes effect within minutes and passes out of the body quickly, advocates for the product say it gives people with diabetes far more flexibility over when they can eat and what foods they can consume, while maintaining glycemic control.5 But Castagna said endocrinologists have not always appreciated the benefits of rapid-acting insulin and Afrezza’s less conspicuous inhaler, which some patients prefer to use in public instead of an injector. Patients have shared stories of difficulty overcoming both physician and payer resistance, in interviews for EBDMTM.6

Afrezza has traveled a bumpy road both before its 2014 approval and beyond. MannKind had a marketing agreement with Sanofi for Afrezza’s launch, but that relationship was severed after sales fell far short of expectations. The spirometry requirement was viewed as a barrier because few endocrinologists had this equipment, and many were reluctant to try an inhaled product.

The biggest problem in the beginning was formulary access. MannKind leaders pressed forward, and sales have improved in 2017. Castagna’s arrival was key. Before coming to MannKind he spent time talking to patients who were enthusiastic Afrezza users, and he became convinced that the product was a hit—the problem involved market barriers, and a need to better train doctors and pharmacists to properly titrate Afrezza.

In a September presentation at the Cantor Fitzgerald Global Healthcare Conference, Castagna said that MannKind would look to produce new data on Afrezza to show that the product was underdosed in early pivotal trials. “I believe if you really dose the product, if you look at some of our modeling data, we believe we can have potentially a superior insulin,” Castagna said September 25, according to a Seeking Alpha transcript.7

Castagna told EBDMTM he anticipates a new agreement with a major pharmacy benefit manager by January 2018, as well as improved access with other payers, although these changes are typically not announced. Castagna has argued for some time that Afrezza is a “completely differentiated” product from competing mealtime insulins and deserves better consideration.

“Payers don’t turn overnight on anything,” he said. “But if you take the label change, and the fact that we can now use a lot of the data we have, there is clearly a difference between us and other drugs.”


1. FDA updates Afrezza prescribing information [press release]. Westlake Village, CA: Globe Newswire; October 2, 2017. globenewswire.com/news-release/2017/10/02/1138593/0/en/FDA-Updates-Afrezza-Prescribing-Information.html. Accessed October 2, 2017.

2. Novo Nordisk receives FDA approval for Fiasp, a new fast-acting mealtime insulin [press release]. Plainsboro, NJ: Novo Nordisk; September 29, 2017. press.novonordisk-us.com/2017-09-29-Novo-Nordisk-Receives-FDA-Approval- for-Fiasp-R-a-New-Fast-Acting-Mealtime-Insulin. Accessed October 28, 2017.

3. MannKind announces late-breaking data demonstrating faster onset and shorter duration of action compared to mealtime insulins [press release]. New Orleans, LA: Globe Newswire; June 12, 2016. investors.mannkindcorp.com/ releasedetail.cfm?ReleaseID=975358. Accessed October 28, 2017.

4. Afrezza website. afrezza.com. Accessed October 28, 2017.

5. Campbell RK. Afrezza: treating diabetes in a physiologic manner. Am J Manag Care. 2016;22(SP13):SP473-SP474.

6. Caffrey M. Patients report barriers to getting Afrezza, but A1C results are worth it. Am J Manag Care. 2016;22(SP13):SP475-SP476.

7. MannKind’s CEO Michael Castagna on Cantor Fitzgerald Global Healthcare Conference (Transcript). Seeking Alpha. seekingalpha.com/article/4109298-mannkinds-mnkd-ceo-michael-castagna-cantor-fitzgerald-global-health- care-conference-transcript?page=3. Published September 25, 2017. Accessed September 29, 2017.

Intarcia Receives Complete Response Letter From FDA

Mary Caffrey

INTARCIA THERAPEUTICS, INC, maker of a matchstick-size pump that delivers exenatide to treat type 2 diabetes (T2D), announced September 27, 2017, it had received a complete response letter (CRL) from the FDA, asking the company to address manufacturing issues.

A statement said, “The company received clear and constructive guidance from the agency regarding manufacturing aspects of the CRL and is on a clear path to move forward.” The company said no additional pivotal trials are anticipated to meet FDA approval requirements but offered no further comment.1

Intarcia’s ITCA 650, an osmotic mini-pump that delivers continuous microscopic doses of exenatide, outperformed sitagliptin in a 52-week trial,2 and evidence presented at the most recent meeting of the American Diabetes Association showed patients with T2D were less likely to progress to additional therapy.3 The treatment method has been seen as a game-changer for populations that struggle with adherence because the mini-pump only has to be replaced once or twice a year.

The company also recently unveiled topline results about the ability of patients to switch from liraglutide, another drug in the class of glucagon-like peptide-1 (GLP-1) receptor agonists. Liraglutide, sold as Victoza by Novo Nordisk, recently received an FDA indication for its cardioprotective benefits based on results of the LEADER trial.4 (Intarcia has announced that ITCA 650 met the endpoints of its FREEDOM-CVO cardiovascular outcomes trial, but has not presented full results.5)

According to a statement from Intarcia, the trial showed that patients switching from 1.2 mg or 1.8 mg doses of injectable liraglutide can go directly to a full 6-month dose of the ITCA 650 60 mcg per day osmotic mini-pump. Patients who made the switch showed no statistical differences in safety or tolerability, according to the statement, and glycemic control was stable over 26 weeks after the switch.6

Patients making the switch showed a statistically significant reduction in weight, the statement said. The GLP-1 receptor agonist class is known to help patients lose weight, although some experience nausea when they start taking the drug. Intarcia’s statement said discontinuation for nausea post-switch was in the 0% to1.5% range.

“These findings support the safety and efficacy profile of ITCA 650 from the FREEDOM clinical development program, and provide important dosing information to assist healthcare providers in clinical decision making,” said Michelle Baron, MD, vice president of clinical research and chief medical officer of Intarcia Therapeutics. “We look forward to presenting further details of the study data at a future date.”6


1. Intarcia provides corporate update [press release]. Boston, MA: Intarcia Therapeutics; September 27, 2017. intarcia. com/media/press-releases/2017-sep-27-intarcia-provides-corporate-update.html. Accessed October 27, 2017.

2. Rosenstock J, Denham D, Prabhakar R, Azeem R, Kjehms L, Baron M. Superior efficacy of ITCA 650 vs sitagliptin in uncontrolled type 2 diabetes on metformin: the FREEDOM 2 randomized, double-blind, 1-year study. Diabe-tes. 2016;65(suppl 1):183-OR. app.core apps.com/tristar_ada16/abstract/92b0eac0f984437a5bebc08c57accd16.

3. Caffrey M. Latest results on Intarcia’s mini-pump show “clear value to payers,” says study author. Am J Manag Care. 2017;23(SP11):SP439.

4. Victoza (liraglutide) is approved in the US as the only type 2 diabetes treatment indicated to reduce the risk of three major adverse cardiovascular events [press release]. Plainsboro, NJ: Novo Nordisk; August 25, 2017. press.novonor- disk-us.com/2017-08-25-Victoza-R-liraglutide-is-approved-in-the-US-as-the-only-type-2-diabetes-treatment-indicat- ed-to-reduce-the-risk-of-three-major-adverse-cardiovascular-events. Accessed October 28, 2017.

5. Intarcia announces successful cardiovascular safety results in phase 3 FREEDOM-CVO trial for ITCA 650, an investigational therapy for type 2 diabetes [press release]. Boston, MA: Intarcia Therapeutics; May 6, 2016. intarcia. com/media/press-releases/2016-may-6-cardiovascular-safety.html. Accessed October 28, 2017.

FDA Approves Semaglutide, Novo Nordisk's Once-Weekly GLP-1 Receptor Agonist for Type 2 Diabetes

6. New Intarcia study evaluates optimal way to switch from daily liraglutide injections to ITCA 650 in patients with type 2 diabetes [press release]. Boston, MA: Intarcia Therapeutics; September 15, 2017. intarcia.com/media/press-releas- es/2017-sep-15-intarcia-announces-topline-results-from-freedom-3s.html. Accessed October 28, 2017.Mary Caffrey

SEMAGLUTIDE, NOVO NORDISK’S once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist for type 2 diabetes (T2D), received FDA approval on December 5, 2017, after beating its rival dulaglutide in a head-to-head trial and coming to the approval process with proof of cardiovascular (CV) benefits in hand. Novo Nordisk announced the approval of the therapy, to be sold as Ozempic, in a statement.1

The FDA approved 2 doses of semaglutide, 0.5 mg and 1.0 mg, which will be administered in a prefilled pen. As part of its post-approval requirements, Novo Nordisk will conduct a pediatric trial in adolescents under age 18 and add semaglutide to the 15-year medullary thyroid carcinoma registry being kept for all long-acting GLP-1 therapies.

“We are very excited about the first approval of Ozempic and look forward to making this important innovation available to people in the US with type 2 diabetes in the beginning of 2018,” said Mads Krogsgaard Thomsen, executive vice president and chief science officer. “Type 2 diabetes is a complex disease, but with the unique clinical profile of Ozempic, we believe it has the potential to set a new standard for the treatment of the disease.”1

The approval is based on results from the SUSTAIN clinical research program, which included 8000 patients. The FDA received results from SUSTAIN 6, a 2-year preapproval CV outcomes trial whose results showed a 26% risk reduction in the primary outcome, a composite of nonfatal heart attacks, nonfatal strokes, and CV death.2 In SUSTAIN 7, semaglutide outperformed the GLP-1, dulaglutide, sold by Eli Lilly as Trulicity, both in lowering glycated hemoglobin (A1C) and resulting in more weight loss.3

That 40-week trial compared the 0.5-mg dose of semaglutide with the 0.75- mg dose of dulaglutide and the 1.0-mg dose of semaglutide with the 1.5-mg dose of dulaglutide when added to metformin. From a mean baseline of 8.2% A1C, the lower dose of semaglutide achieved a 1.5% reduction compared with 1.1% for low-dose dulaglutide, and the higher dose of semaglutide achieved a 1.8% reduction compared with 1.4% for the higher dose of dulaglutide.3

An FDA panel voted 16-0 to recommend semaglutide for approval on October 18, 2017,4 after discussing concerns raised in the SUSTAIN 6 trial about increased retinopathy. However, those results did not repeat in SUSTAIN 7, and further analyses suggest those earlier results were due to rapid A1C reduction, not the drug itself.5

Novo Nordisk has big plans for semaglutide, as it is designing a new round of clinical trials to gain indications for obesity. In addition, results all 10 trials from the PIONEER program, which are examining an oral form of the drug, are expected to be reported in 2018.6

Although Novo Nordisk already has a daily GLP-1 on the market with liraglutide ( Victoza), the company does not see the 2 as competitors, Todd Hobbs, MD, vice president and chief medical officer, told Evidence-Based Diabetes ManagementTM in an interview. Rather, Hobbs said, the company’s research shows that patients with T2D who would benefit from a GLP-1 but have declined to start an injectable drug would be less wary of a once-weekly therapy.

“In our strategy, we agree with others in the industry and with patient groups that GLP-1 agents are underutilized in the treatment of type 2 diabetes. Less than 10% of all diabetes prescriptions are GLP-1 agents,” Hobbs said.

“So, the goal would be that primary care physicians initiating the first injectable early on in therapy could choose an agent like semaglutide and see the results that we’ve seen—the robust results we’ve seen—in the SUSTAIN program,” Hobbs continued. “We’re not looking to capture other agent market share as much as we’re looking to grow the GLP-1 space that, again, is much underutilized, as GLP-1 agents are underappreciated as excellent agents for type 2 diabetes.”

In August, the formulation of liraglutide for T2D, Victoza, received an FDA indication for reducing the risk of CV events, based on results of the LEADER trial.7 Novo Nordisk also markets a different formulation of liraglutide, called Saxeda, for obesity.

Hobbs said that semaglutide’s weight loss benefits are important in the population that needs GLP-1 therapy, along with the A1C lowering. Depending on the dose, he said, the difference with dulaglutide was between 10 and 15 pounds.

In the interview, Hobbs said early discussions about the clinical results for semaglutide have been positive, “both from thought leaders in the community, but more importantly, payers now are looking at this data and agreeing that this is a very robust agent, with A1C lowering, weight reduction, as well as the lower risk of hypos. They are excited to have this.”

Discussions about pricing will not occur until the FDA finalizes the semaglutide label, Hobbs said. “We hope to quickly turn that around...and then slowly and gradually have formulary access in 2018 to support the semaglutide launch.”


1. Ozempic (semaglutide) approved in the US [press release]. Bagsvaerd, Denmark: Globe Newswire; December 5, 2017. https://www.novonordisk.com/media/news-details.2154210.html.

2. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844. doi: 10.1056/NEJMoa1607141.

3. Semaglutide superior to dulaglutide on glucose control and weight loss in people with type 2 diabetes in SUSTAIN 7 [press release]. Bagsværd, Denmark: Globe Newswire; August 16, 2017. globenewswire.com/news-re- lease/2017/08/16/1086742/0/en/Semaglutide-superior-to-dulaglutide-on-glucose-control-and-weight-loss-in-peo- ple-with-type-2-diabetes-in-SUSTAIN-7.html. Accessed December 4, 2017.

4. Semaglutide receives positive 16-0 vote in favour of approval from FDA Advisory Committee [press release]. Bagsværd, Denmark: Globe Newswire; October 18, 2017. novonordisk.com/content/Denmark/HQ/www-novonor- disk-com/en_gb/home/media/news-details.2142854.html. Accessed December 4, 2017.

5. Tucker ME. New SUSTAIN 6 data could explain retinopathy worsening. Medscape website. medscape.com/viewarti- cle/881413. Published June 10, 2017. Accessed December 4, 2017.

6. Highlights to be presented at Novo Nordisk’s Capital Markets Day 2017 [press release]. Bagsværd, Denmark: Globe Newswire; November 21, 2017. globenewswire.com/news-release/2017/11/21/1197832/0/en/Highlights-to-be-pre- sented-at-Novo-Nordisk-s-Capital-Markets-Day-2017.html. Accessed December 4, 2017.

FDA Approves CV Indication for PCSK9 Inhibitor Evolocumab

7. Mattina C. Liraglutide gains new indication for reducing CV event risk. The American Journal of Managed Care. http://www.ajmc.com/newsroom/liraglutide-gains-new-indication-for-reducing-cv-event-risk. Published August 25, 2017. Accessed December 4, 2017.EBDMTM Staff

THE FDA HAS APPROVED evolocumab (Repatha, Amgen) as the first PCSK9 inhibitor to prevent heart attacks, strokes, and coronary revascularizations in adults with established cardiovascular disease. Amgen announced the approval December 1, 2017, a day ahead of the agency’s deadline to act.1

The approval is based on results of the FOURIER trial presented in March.2 The update gives evolocumab an edge over rival alirocumab (Praluent, Sanofi /Regeneron), as sponsors of both proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors work to convince payers their cholesterol- fighting powers are worth a list price of $14,500 a year.3

“We are pleased that the FDA made the inclusion of our outcomes data a priority so that patients can benefit from Repatha’s ability to reduce life-changing events of heart attacks and strokes,” said Sean E. Harper, MD, executive vice president of Research and Development at Amgen. “Despite treatment with current best therapy, many patients are still at high risk for cardiovascular events. Physicians now have a new FDA-approved treatment option to prevent cardiovascular events by dramatically lowering LDL [low-density lipoprotein] cholesterol with Repatha, especially for patients already on maximally-tolerated statin therapy who need further LDL cholesterol lowering.”

Evolocumab achieved the new indication through the FDA’s priority review process, granted to drugs that treat serious conditions and would offer

major improvements in safety or effectiveness over existing options. The agency granted that status in July. FDA also approved evolocumab to be used alongside drugs like statins to treat patients with primary hyperlipidemia.1

When PSCK9 inhibitors were approved in 2015, payers set up strict protocols for allowing access to the drug. It remains to be seen whether the label change will improve access to evolocumab for patients.

Results in FOURIER, presented at the American College of Cardiology (ACC) Scientific Sessions, showed evolocumab produced a 15% reduction in the combined primary endpoint of heart attack, stroke, unstable angina, coronary revascularization, or cardiovascular death. As noted in Amgen’s statement, these results included the drug’s ability to reduce the risk of heart attack by 27%, the risk of stroke by 21%, and the risk of coronary revascularization by 22%.1,2

Cardiovascular benefits from evolocumab increased after the first year. However, there was no improvement in cardiovascular death, and payers did not share cardiologists’ enthusiasm for the results.2

Studies presented at the ACC meeting—and reports from specialists since that time—show that clinicians continue to hit roadblocks when they prescribe PCSK9 inhibitors for patients.4 “In my experience, it has changed very little. Maybe we have changed a little in terms of our approach to this, possibly some of the payers are little more relaxed,” Eliot A. Brinton, MD, FAHA, FNLA, president of the Utah Lipid Center, told Evidence-Based Diabetes ManagementTM in an interview (See SP564). With the FOURIER results, he said, “I’m hopeful that this will become less of an issue.”

As FOURIER was released, Amgen offered payers a money-back guarantee if patients had a heart attack while taking the drug. The announcement did trigger some contracting agreements with payers, including an early one with Harvard Pilgrim.5 But others asked whether the arrangement would yield any real savings.6 A cost-effectiveness analysis published in JAMA Cardiology earlier this year found that the current list price of $14,523 “exceeds generally accepted cost-effectiveness thresholds,” and that the price would need to fall to $9669 in the United States to achieve the accepted standard of $150,000 per quality-of-life year (QALY). Or, the authors wrote, the drug would need to be targeted to higher-risk populations. (Signers of the analysis included the first 3 authors of listed on the FOURIER trial.)3

Last month at the American Heart Association Scientific Sessions, additional analyses from FOURIER showed the drug’s effectiveness among 2 groups of very high-risk patients: those with peripheral artery disease, and those with recent or multiple heart attacks and with residual coronary artery disease. Authors of the second study concluded, “These data may permit clinicians to target PCSK9 inhibition to patients who benefit the most.”7

Big drops in “bad” cholesterol

A monoclonal antibody, evolocumab works to dramatically reduce low-density lipoprotein or “bad” cholesterol by blocking a protein that prevents the liver from carrying cholesterol out of the body. The injectable drug has been shown in clinical trials to reduce LDL cholesterol as much as 60% when patients take it with metformin.8

Evolocumab was approved in August 2015, a month after alirocumab. Both were seen as potential blockbusters, but FDA limited labels for both drugs to patients with 2 forms of familial hypercholesterolemia and to high-risk patients with clinical atherosclerotic cardiovascular disease. FDA said that these high-risk cardiovascular patients must use evolocumab alongside maximally tolerated statins.9

Prior to approval, an FDA panel declined to recommend evolocumab for broader groups of patients—including the large number who don’t tolerate statins well—before seeing cardiovascular outcomes results.


1. FDA approves Amgen’s Repatha (evolocumab) to prevent heart attack and stroke [press release]. Thousand Oaks, CA: Amgen; December 1, 2017. amgen.com/media/news-releases/2017/12/fda-approves-amgens-repatha-evolocumab- to-prevent-heart-attack-and-stroke/. Accessed December 1, 2017.

2.SabatineMS.GiuglianoRP,KeechACetal,fortheFOURIERSteeringCommitteeandInvestigators.Evolocumabandclin- ical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376(18):1713-1722. doi: 10.1056/NEJMoa1615664.

3. Fonarow GC, Keech AC, Pedersen TR et al. Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2(10):1069-1078. doi:10.1001/jamacar- dio.2017.2762.

4. Caffrey M. Data show it’s hard to fill PCSK9 prescriptions, confirming cardiologists’ complaints. The American Journal of Managed Care®. ajmc.com/conferences/acc-2017/data-show-its-hard-to-fill-pcsk9-prescriptions-confirming-cardiolo- gists-complaints. Published March 19, 2017. Accessed December 1, 2017.

5. Amgen and Harvard Pilgrim agree to first cardiovascular outcomes-based refund contract for Repatha (evolocumab) [press release]. Thousand Oaks, CA: Amgen; May 2, 2017. amgen.com/media/news-releases/2017/05/amgen-and-har- vard-pilgrim-agree-to-first-cardiovascular-outcomesbased-refund-contract-for-repatha-evolocumab/. Accessed December 1, 2017.

6. Hernandez I. Revisiting outcomes-based pricing propositions for the PCSK9 inhibitor evolocumab. JAMA Intern Med. 2017;177(9):1388-1390. doi:10.1001/jamainternmed.2017.3143.

​​​​​​​7. Caffrey M. More FOURIER results highlight evolocumab outcomes among high-risk patients. The American Journal of Managed Care®. http://www.ajmc.com/conferences/aha-2017/more-fourier-results-highlight-evolocumab-out- comes-among-higherrisk-patients. Published November 13, 2017. Accessed December 1, 2017.

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