Eptinezumab-jjmr (Vyepti)

Number: 0970

Policy

Note: Requires Precertification:

Precertification of Vyepti is required of all Aetna participating providers and members in applicable plan designs. For precertification, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies for eptinezumab-jjmr (Vyepti). For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Criteria for Initial Approval

   Aetna considers eptinezumab-jjmr (Vyepti) medically necessary for the preventive treatment of migraine in an adult member when either of the following criteria are met:

   1. The member experienced an inadequate treatment response with an 8-week trial of any of the following: Antiepileptic drugs (AEDs) (e.g., divalproex sodium, topiramate, valproate sodium), Beta-adrenergic blocking agents (e.g., metoprolol, propranolol, timolol, atenolol, nadolol), Antidepressants (e.g., amitriptyline, venlafaxine); or
   2. The member experienced an intolerance or has a contraindication that would prohibit an 8-week trial of any of the following: Antiepileptic drugs (AEDs) (e.g., divalproex sodium, topiramate, valproate sodium), Beta-adrenergic blocking agents (e.g., metoprolol, propranolol, timolol, atenolol, nadolol), Antidepressants (e.g., amitriptyline, venlafaxine);

   And when the following criterion is met:

   1. The requested drug will not be used concurrently with another calcitonin gene-related peptide (CGRP) receptor antagonist (e.g., Aimovig, Ajovy, Emgality).

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of eptinezumab-jjmr (Vyepti) therapy medically necessary in adult members requesting reauthorization for preventive treatment of migraine if the member received at least 3 months of treatment with the requested drug and had a reduction in migraine days per month from baseline, and the requested drug will not be used concurrently with another calcitonin gene-related peptide (CGRP) receptor antagonist (e.g., Aimovig, Ajovy, Emgality).

Dosage and Administration

Vyepti is supplied as 100 mg/mL solution in a single-dose vial for intravenous use.

The recommended dosage of Vyepti is 100 mg administered as an intravenous infusion over approximately 30 minutes every 3 months. Some member may benefit from a dosage of 300 mg administered by intravenous infusion every 3 months.

Source: Lundbeck Seattle BioPharmaceuticals, 2020

Background

U.S. Food and Drug Administration (FDA)-Approved Indication

• Vyepti is a calcitonin gene-related peptide antagonist indicated for the preventive treatment of migraine in adults.

Eptinezumab-jjmr is available as Vyepti (Lundbeck Seattle BioPharmaceuticals, Inc.), which is a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocks its binding to the receptor. 

Vyepti is contraindicated in patients with serious hypersensitivity to eptinezumab-jjmr or to any of the excipients. Vyepti carries warnings and precautions for hypersensitivity reactions. Reactions have included angioedema, urticaria, facial flushing, and rash. The most common adverse reactions (≥2% and 2% or greater than placebo) include nasopharyngitis and hypersensitivity (Lundbeck Seattle BioPharmaceuticals, 2020).

Calcitonin Gene-Related Peptide Antagonists for Migraine Prevention

Migraine is a chronic neurologic disease that affects approximately 12 percent of the general population and is more frequently seen in women. Migraine-related symptoms are addressed with acute treatments, preventive treatments, or both. According to the 2019 American Headache Society AHS Consensus Statement, the goals of migraine prevention are to:

• Reduce attack frequency, severity, duration, and disability
• Improve responsiveness to and avoid escalation in use of acute treatment
• Improve function and reduce disability
• Reduce reliance on poorly tolerated, ineffective, or unwanted acute treatments
• Reduce overall cost associated with migraine treatment
• Enable patients to manage their own disease to enhance a sense of personal control
• Improve health-related quality of life (HRQoL)
• Reduce headache-related distress and psychological symptoms.

Although none of the currently available oral preventive treatments were designed specifically for migraine, and many oral preventive treatments have limited to moderate efficacy, moderate to high rates of adverse events (AEs), contraindications, or interactions, the 2012 report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN) and the American Headache Society (AHS) state that the following oral treatments have either established efficacy or probable efficacy and should be offered for migraine prevention: antiepileptic drugs (divalproex sodium, valproate sodium, topiramate); beta-blockers (metoprolol, propranolol, timolol, atenolol, nadolol); and onabotulinum toxin A (Botox) (Silberstein 2012).

More recently, a new class of injectable therapies have been approved for migraine prophylaxis in adults in the United States. These calcitonin gene-related peptides (CGRP) monoclonal antibodies include: erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab- (Vyepti). Emgality is also indicated for the treatment of episodic cluster headaches in adults. The first three are subcutaneous injectable therapies, whereas Vyepti is administered via intravenous administration. The benefits associated with the injectable route of administration compared with traditional oral prophylactic therapy options include the lack of need for slow dose escalation, the rapid onset of therapeutic benefits, and the favorable tolerability profiles (AHS 2019).

On May 17, 2018, the U.S. Food and Drug Administration approved Aimovig (erenumab-aooe) for the preventive treatment of migraine in adults. The treatment is given by once-monthly self-injections. Aimovig is the first FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide, a molecule that is involved in migraine attacks. The effectiveness of Aimovig for the preventive treatment of migraine was evaluated in three clinical trials. The first study included 955 participants with a history of episodic migraine and compared Aimovig to placebo. Over the course of six months, Aimovig-treated patients experienced, on average, one to two fewer monthly migraine days than those on placebo. The second study included 577 patients with a history of episodic migraine and compared Aimovig to placebo. Over the course of three months, Aimovig-treated patients experienced, on average, one fewer migraine day per month than those on placebo. The third study evaluated 667 patients with a history of chronic migraine and compared Aimovig to placebo. In that study, over the course of three months, patients treated with Aimovig experienced, on average, 2 ½ fewer monthly migraine days than those receiving placebo. The most common side effects that patients in the clinical trials reported were injection site reactions and constipation (FDA 2018).

On September 14, 2018, the FDA approved fremanezumab (Ajovy) for the prevention of migraine in adults based on results from two clinical trials, Trial 1/NCT02629861 and Trial 2/NCT02621931, in a total of 1986 patients with chronic or episodic migraine headaches. Investigators observed that fremanezumab reduced monthly migraines by >50% in roughly 45% of patients with episodic migraine and in about 40% of patients with chronic migraine. Injection site reactions were among the most common adverse events (>5% and greater than placebo) recorded in the clinical trials. Other hypersensitivity reactions observed include pruritus, rash, and urticaria. Most hypersensitivity reactions were mild to moderate, but some led to discontinuation (FDA 2018).

On September 27, 2018 the U.S. Food and Drug Administration approved galcanezumab-gnlm (Emgality) based its approval of galcanezumab on the results of three phase 3 double-blind, randomized, placebo-controlled clinical trials that evaluated its safety and efficacy in a cohort of episodic migraine patients and chronic migraine patients. The first two six-month trials, EVOLVE-1 and EVOLVE-2, included more than 1,700 patients with episodic migraine, defined as four to 14 migraine headache days per month. In EVOLVE-1, the drug significantly reduced monthly migraine days: 4.7 days for 120 mg and 4.6 days for 240 mg versus 2.8 days for placebo (p<0.001.). Similarly, in EVOLVE-2, participants had a mean reduction of 4.3 days for 120 mg and 4.2 days for 240 mg versus 2.3 days for placebo (p<0.001). Th third trial, REGAIN, tested both doses of galcanezumab over three months in patients with chronic migraine, defined as at least 15 headache days per month, with eight migraine days per month. Participants experienced greater reductions in migraine days than with placebo: 4.8 days for 120 mg and 4.6 days for 240 mg versus 2.7 days for placebo (p<0.001). Adverse events reported in all three trials, included injection site pain, reactions, and erythema. Subsequently, on June 04, 2019, the U.S. Food and Drug Administration also approved Emgality (galcanezumab-gnlm) solution for injection for the treatment of episodic cluster headache in adults (NeurologyToday 2018; Stauffer 2018).

On February 21, 2020, the FDA approved the intravenous eptinezumab-jjmr (Vyepti) for migraine prophylaxis in adults. Approval was based on results from two clinical studies: PROMISE-1 (NCT02559895) in episodic migraine and PROMISE-2 ( NCT02974153) in chronic migraine. The PROMISE-1 (PRevention Of Migraine via Intravenous ALD403 Safety and Efficacy-1) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with episodic migraine were randomized to eptinezumab 30 mg, 100 mg, 300 mg, or placebo for up to four intravenous (IV) doses administered every 12 weeks. The primary endpoint was change from baseline in monthly migraine days (MMDs) over weeks 1–12. A total of 888 patients received treatment across 84 study sites. Mean MMDs at baseline was ∼8.6 across treatment groups. Eptinezumab 100 mg and 300 mg met the primary endpoint, significantly reducing MMDs across weeks 1-12 compared with placebo (30 mg, -4.0; 100 mg, -3.9, p= 0.0182; 300 mg, -4.3; placebo, -3.2, p= 0.0001). Treatment-emergent adverse events were reported by 58.4% (30 mg), 63.2% (100 mg), 57.6% (300 mg), and 59.5% (placebo) of patients. Treatment-emergent adverse events reported by ≥2% of eptinezumab-treated patients at an incidence greater than placebo included: upper respiratory tract infection (30 mg, 11.4%; 100 mg, 9.9%; 300 mg, 10.3%; placebo, 7.2%), and fatigue (30 mg, 2.3%; 100 mg, 3.6%; 300 mg, 3.6%; placebo, <1%). The authors concluded that eptinezumab (100 mg or 300 mg) significantly reduced migraine frequency, was well tolerated, and had an acceptable safety profile when used for the preventive treatment of migraine in adults with episodic migraine (Ashina 2020). 

The PROMISE-2 study included adults with a history of chronic migraine (15 to 26 headache days per month, of which at least 8 were migraine days). A total of 1072 patients were randomized and received placebo (N=366), 100 mg eptinezumab (N=356), or 300 mg eptinezumab  (N=350) every 3 months for 6 months. Patients were allowed to use and to continue an established stable regimen of acute migraine or headache preventive medication (except onabotulinumtoxinA). Patients with a dual diagnosis of chronic migraine and medication overuse headache attributable to acute medication overuse (triptans, ergotamine, or combination analgesics greater than 10 days per month) were included in the study population. Patients using opioids or butalbital-containing products greater than 4 days per month were not allowed. The study excluded patients with a history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, or cerebrovascular disease. The primary efficacy endpoint was the change from baseline in mean monthly migraine days (MMD) over Months 1–3. Secondary endpoints included the percentages of patients with 50% or greater and 75% or greater reductions from baseline in monthly migraine days over Months 1–3. Patients had a median age of 41 years (range: 18 to 65 years), 88% were female, and 91% were white. Forty-one percent of patients were taking concomitant preventive medication for migraine. The mean migraine frequency at baseline was approximately 16.1 migraine days per month and was similar across treatment groups. Eptinezumab  treatment demonstrated statistically significant improvements compared to placebo for the primary efficacy endpoint. In 100mg-treated patients, changes from baseline in MMDs were −7.7 (p<0.0001) and −8.1 (p<0.0001) over Months 1–3 and Months 4–6, respectively. The ≥75% migraine RRs were: 30.9% (Month 1; p<0.0001), 26.7% (Months 1–3; p=0.0001), and 38.5% (Months 4–6). The ≥50% migraine RRs were: 57.6% (Months 1–3; p<0.0001) and 60.7% (Months 4–6). In 300mg-treated patients, changes from baseline in MMDs were −8.2 (p<0.0001) and −8.8 (p<0.0001) over Months1–3 and Months 4–6, respectively. The ≥75% migraine RRs were: 36.9% (Month1; p<0.0001), 33.1% (Months 1–3; p<0.0001), and 42.3% (Months 4–6). The ≥50% migraine RRs were: 61.4% (Months 1–3; p<0.0001) and 63.4% (Months 4–6). In placebo-treated patients, changes from baseline in MMDs were −5.6 and −6.1 over Months 1–3 and Months 4–6, respectively. The ≥75% migraine RRs were: 15.6% (Month 1), 15.0% (Months 1–3), and 22.7% (Months 4–6). The ≥50% migraine RRs were: 39.3% (Months 1–3) and 44.5% (Months 4–6). Rates of treatment-emergent adverse event were similar between groups. The authors concluded that eptinezumab significantly reduced MMDs over 3 months, which was further improved through Month 6 following a second quarterly infusion. Migraine RRs were greater with eptinezumab vs placebo over 3 months and were sustained or increased through Month 6. The eptinezumab safety profile was consistent with previous trials (Kudrow 2019).

Calcitonin Gene-Related Peptide Antagonists for Acute Migraine

An UpToDate review on “Acute treatment of migraine in adults” (Smith, 2020) states that “Several oral calcitonin gene-related peptide (CGRP) antagonist medications are emerging as treatment options for acute migraine attacks. In randomized controlled trials evaluating a single migraine attack, the CGRP antagonists rimegepant and ubrogepant were beneficial compared with placebo; both led to greater rates of freedom from pain and/or absence of the most bothersome migraine symptom at two hours. Ubrogepant (Ubrelvy) received FDA approval for the treatment of acute migraine in adults in December 2019, and rimegepant (Nurtec) received similar FDA approval in February 2020. However, given the short-term, single-attack design of these trials, long-term data are needed to determine safety and tolerability. In addition, their efficacy compared with existing acute migraine therapies (eg, triptans) is not yet known.”

Cui and associates (2015) stated that calcitonin gene-related peptide (CGRP) receptor antagonists, such as telcagepant, have been under investigation as a treatment for acute migraine. In a meta-analysis, these researchers evaluated the effectiveness of telcagepant versus placebo and triptans (zolmitriptan or rizatriptan).  Randomized controlled trials were identified from databases using the following search terms: migraine; calcitonin gene-related peptide; calcitonin gene-related peptide receptor antagonists; efficacy; safety, and telcagepant.  The primary outcome measure was pain freedom 2 hours after first treatment.  The secondary outcome measure was pain relief 2 hours after first treatment.  A total of 8 trials were included in the meta-analysis (telcagepant = 4,011 participants).  The difference in pain freedom at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.70, 95 % confidence interval = 2.27-3.21, P < 0.001) and triptans over telcagepant (odds ratio = 0.68, 95% confidence interval = 0.56-0.83, P < 0.001). The difference in pain relief at 2 hours significantly favored telcagepant over placebo (odds ratio = 2.48, 95% confidence interval = 2.18-2.81, P < 0.001). The difference in pain relief at 2 hours did not significantly favor telcagepant over triptans or vice versa (OR = 0.76, 95 % CI: 0.57 to 1.01, p = 0.061).  The authors concluded that these findings indicated that telcagepant can be effective for treating acute migraine; and CGRP receptor antagonists represent a potentially important alternative means of treating acute migraine.

In a meta-analysis, Hong and Liu (2017) evaluated the effectiveness of CGRP antagonisms in treating acute migraine attack. PubMed, Cochrane Library, Web of Science and OvidSP were systematically searched up to April 9, 2015 for RCTs that dealt with the effectiveness of CGRP antagonisms in treating acute migraine attack.  The bias and quality of RCTs were assessed with Cochrane collaboration's tool for assessing risk of bias.  Reviewer manager 5.2 was utilized for data analysis.  A total of 13 publications matched the inclusion criteria, including 10 independent RCTs and 6,803 patients.  Pooled analysis indicated that CGRP antagonisms had better outcomes in number of patients with pain free at 2 hours, 2 to 24 hours sustained pain free, phonophobia free at 2 hours, patients with photophobia free at 2 hours and nausea free at 2 hours post-dose, as compared with placebo.  However, CGRP antagonisms were no superior than 5-HT agonists in the afore-mentioned indices.  The authors concluded that CGRP antagonisms may be an effective and promising treatment for acute migraine attack.

Huang et al (2019) evaluated the response rate of migraines by using anti-calcitonin gene-related peptide (anti-CGRP) for patients with migraines by searching three main medical databases up to 29 March 2019. No restriction on language and publication time were applied. Eligible trials included randomized clinical trials investigating a 50%, 75%, and 100% response rate of migraine patients after anti-CGRP intervention. The collected data were dichotomous, and risk ratios (RRs) with a 95% confidence interval (CI) were used to present the quantitative synthesis results. The systematic review identified 16 eligible randomized clinical trials (RCTs) with 9439 patients. Eight of the 16 trials with 2516 patients reported a 50% response rate, and the pooled results showed a significant benefit from anti-CGRP. However, the effects seem to gradually reduce from the first month (RR 1.99, 95% CI 1.59 to 2.49) to the third month (RR 1.48, 95% CI 1.26 to 1.75) of treatment. The magnitude of effect was influenced by the type of anti-CGRP, according to the test for differences between subgroups (I-square = 53%). The funnel plots and Egger's tests did not show serious small study effects in the results. In conclusion, the current evidences confirmed that anti-CGRP treatment can reduce migraine pain in the short term (within three months), but the long-term effect should be investigated in the future. Moreover, its effects may be influenced by the type and dose of anti-CGRP. Therefore, future studies should make direct comparisons among anti-CGRP medications.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
+96366	each additional hour (List separately in addition to code for primary procedure)
HCPCS codes covered if selection criteria are met:
J3032	Injection, eptinezumab-jjmr, 1 mg
Other HCPCS codes related to the CPB:
Aimovig, Emgality - no specific code
J3031	Injection, fremanezumab-vfrm, 1 mg
ICD-10 codes covered if selection criteria are met:
G43.001 - G43.919	Migraine

The above policy is based on the following references: