Ubrogepant (Ubrelvy™) New Drug Update

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Ubrogepant (Ubrelvy™) New Drug Update January 2020 Nonproprietary Name ubrogepant Brand Name Ubrelvy Manufacturer Allergan Form Oral tablet Strength 50 mg, 100 mg FDA Approval December 23, 2019 Market Availability Anticipated 1Q2020 FDA Approval Classification Standard Review FDB Classification- Specific TBD Therapeutic Class (HIC3) INDICATION1 Ubrogepant (Ubrelvy) is a calcitonin gene-related peptide (CGRP) receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. It is not indicated for the preventive treatment of migraine. PHARMACOKINETICS Within the recommended dosing range, ubrogepant exhibits dose-proportional pharmacokinetics with a time to maximum plasma concentration (Tmax) of ~1.5 hours. Following administration with a high-fat meal, Tmax was delayed by 2 hours, and the maximum concentration was decreased by 22%; overall, there was no change in ubrogepant exposure. In vitro, ubrogepant is 87% bound to plasma proteins with a mean central volume of distribution of 350 L following oral administration. The predominant route of metabolism and elimination is by CYP3A4. The primary compounds in plasma are the parent drug and 2 inactive glucuronide conjugates. Ubrogepant’s half-life is about 5 to 7 hours, and the mean clearance is approximately 87 L/hr. It is primarily excreted via the feces (42%, as unchanged parent drug) with minor renal elimination (6%, as unchanged parent drug). CONTRAINDICATIONS/WARNINGS Use of ubrogepant is contraindicated with strong CYP3A4 inhibitors. There are no warnings/precautions for ubrogepant.

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DRUG INTERACTIONS Ubrogepant has the potential for interactions with CYP3A4 inhibitors and inducers. Concurrent use with a strong, moderate, or weak CYP3A4 inhibitors increases plasma levels of ubrogepant; do not co- administer ubrogepant with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin). Dose adjustments are recommended if ubrogepant is used concurrently with moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) or weak CYP3A4 inhibitors. Concurrent use with a strong, moderate, or weak CYP3A4 inducer decreases plasma levels of ubrogepant which can result in loss of efficacy; avoid concurrent use with strong CYP3A4 inducers (e.g., phenytoin, barbiturates, rifampin, St. John’s wort). Dose adjustments are recommended if ubrogepant is used concurrently with moderate or weak CYP3A4 inducers. Ubrogepant also has the potential for interactions with Breast Cancer Resistance Protein (BCRP) and/or P-glycoprotein (P-gp) inhibitors as it is a substrate for BCRP and P-gp efflux transporters. Concurrent use with these inhibitors (e.g., quinidine, carvedilol, eltrombopag, curcumin) is expected to increase ubrogepant levels; dose adjustments are recommended if ubrogepant is coadministered with BCRP and/or P-gp inhibitors. COMMON ADVERSE EFFECTS The most common adverse effects (≥ 2%) reported with ubrogepant relative to placebo, respectively, in clinical trials, were nausea (4% for 100 mg dose versus 2% for 50 mg dose versus 2% placebo) and somnolence (3% for 100 mg dose versus 2% for 50 mg dose versus 1% placebo). Dry mouth was also reported in 2% of ubrogepant patients receiving the 100 mg dose and < 1% of ubrogepant 50 mg patients as compared to 1% of placebo patients. In a long-term safety study, 2.5% of patients withdrew from treatment due to an adverse effect with the most common reason being nausea. SPECIAL POPULATIONS Pregnancy Data for ubrogepant in pregnancy are inadequate to advise of maternal or fetal risk; however, data from animal studies demonstrated use of ubrogepant during pregnancy, at doses higher than the recommended human dose, resulted in adverse outcomes (e.g., embryofetal mortality, decreased body weight of offspring). Pediatrics Safety and efficacy of ubrogepant has not been established in pediatric patients (≤ 18 years of age). Geriatrics In pharmacokinetic studies, no difference in pharmacokinetic profiles of ubrogepant were reported between patients ≥ 65 years of age and younger populations. However, clinical trials did not include an adequate number of patients ≥ 65 years of age to inform of differences of ubrogepant compared to younger patients. In general, elderly patients should receive cautious dose selection.

Hepatic Impairment Higher degrees of hepatic impairment are associated with higher ubrogepant levels; mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic insufficiency, respectively, resulted in 7% and 50% increases in ubrogepant exposure. Dose adjustments are not required for mild to moderate hepatic impairment, but are recommended for patients with severe hepatic impairment (Child-Pugh Class C) who are anticipated to have a 115% increase in ubrogepant levels. Renal Impairment As renal elimination is not the primary route of ubrogepant clearance, no dose adjustments are required in mild to moderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min). However, dose adjustments are recommended in severe renal impairment (CrCl 15 to 29 mL/min), and use should be avoided in patients with end-stage renal disease (CrCl < 15 mL/min). DOSAGES The recommended dose is 50 mg or 100 mg orally with or without food. If a second dose is required, it should be taken ≥ 2 hours after the first dose. The maximum dose is 200 mg per 24-hour period. The safety of using ubrogepant for > 8 migraines in a month has not been established. Dose modifications are required if used concurrently with certain medications and in patients with hepatic/renal impairment. • Severe hepatic impairment (Child-Pugh Class C): 50 mg initial dose, 50 mg second dose • Severe renal impairment (CrCl 15 to 29 mL/min): 50 mg initial dose, 50 mg second dose • Moderate CYP3A4 inhibitors: 50 mg initial dose, avoid administering the second dose within 24 hours of the first dose. • Weak CYP3A4 inhibitors: 50 mg initial dose, 50 mg second dose • Weak and moderate CYP3A4 inducers: 100 mg initial dose, 100 mg second dose • BCRP and/or P-gp inhibitors: 50 mg initial dose, 50 mg second dose CLINICAL TRIALS2,3 A literature search was performed using “ubrogepant” and “migraine.” The approval of ubrogepant for the acute treatment of migraine in adults was primarily based on findings from 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trials (ACHIEVE I and ACHIEVE II). In the ACHIEVE I study, patients were stratified based on prior response to triptans (response, inadequate response, or no prior use) and use of preventive migraine therapy. Patients were then randomized 1:1:1 to placebo (n=559), ubrogepant 50 mg (n=556), or ubrogepant 100 mg (n= 557). Two to 48 hours after the first dose of study medication, patients who experienced persistent or recurrent moderate or severe headache were allowed to take an optional second dose of study drug or their own rescue therapy. Patients in the placebo group were given 2 tablets of placebo for the optional second dose, whereas patients in the ubrogepant arms were rerandomized to either receive the second dose as 2 placebo tablets or the same dose of ubrogepant they had previously

received. If a patient utilized the optional second dose, rescue medication was not allowed until ≥ 2 hour following the second dose of study drug. Patients enrolled were 18 to 75 years old with ≥ 1 year history of migraine with or without aura as defined by the International Classification of Headache Disorders, 3rd edition. Patients were required to have migraine onset prior to 50 years of age and have a history of migraines lasting 4 to 72 hours with migraine attacks separated by ≥ 48 hours free from headache pain. Patients were also required to have a history of 2 to 8 migraines per month and moderate to severe headache pain in each of the 3 months prior to enrollment. Individuals with a history of ≥ 15 headache days/month during the prior 6 months were excluded. Patients determined to have chronic migraine with < 15 headache days/month due to concurrent preventive therapy were able to enroll. Patients who received an acute migraine treatment on ≥ 10 days during the prior 3 months or who had been enrolled in a study assessing an injectable CGRP antagonist were excluded. Although patients with clinically significant cardiovascular (CV) or cerebrovascular disease were excluded, subjects with moderate to severe CV risk factors were enrolled. The coprimary efficacy endpoints were evaluated at 2 hours following the first dose of ubrogepant or placebo and included freedom from pain (change in the severity of headache pain from moderate or severe pain prior to the initial dose to no pain) and absence of the most bothersome migraine symptom (photophobia, phonophobia, or nausea). Secondary efficacy endpoints included pain relief at 2 hours following the first dose; sustained pain relief from 2 to 24 hours after the first dose without using the optional second dose or rescue therapy; sustained freedom from pain from 2 to 24 hours following the first dose without using the optional second dose or rescue therapy; and absence of photophobia, phonophobia, and nausea at 2 hours following the first dose. Patients enrolled were an average age of 40.5 years, predominantly female (88%), and Caucasian (83%). At baseline, more than 98% of patients were taking an acute migraine treatment and 23% used a preventive medication for migraine. The majority of patients (63%) had moderate severity headache pain while 37% had severe pain. More than half of subjects stated the most bothersome non-headache migraine symptoms was photophobia. Baseline characteristics were similar between the treatment arms. At 2 hours post-dose, a significantly greater number of patients in the 50 mg (19.2%; p=0.002 versus placebo) and 100 mg (21.2%; p<0.001 versus placebo) ubrogepant groups exhibited freedom from migraine pain compared to placebo (11.8%). Absence of the most bothersome migraine symptoms was also significantly improved with ubrogepant 50 mg (38.6%; p=0.002 versus placebo) and 100 mg (37.7%; p=0.002 versus placebo) compared to placebo (27.8%). In addition, significantly more patients in the ubrogepant groups than in the placebo group exhibited improvements in the secondary endpoints of pain relief at 2 hours and had sustained pain relief from 2 to 24 hours (p=0.002 versus placebo for both endpoints for the 50 mg and 100 mg ubrogepant groups). As there was not a statistically significant difference between the 50 mg ubrogepant and placebo for the sustained freedom from pain from 2 to 24 hours or for the 100 mg group and placebo for the absence of phonophobia at 2 hours, no further assessment of secondary endpoints was performed due to the hierarchical testing design. Overall, the types of adverse events as well as proportion of patients who experienced side effects were comparable across study groups. The most common adverse events determined to be related to the trial drug and occurring in ≥ 2% of patients in any group were nausea, somnolence, and dry mouth. There were no serious adverse events, deaths, or adverse events leading to discontinuation of the study in any of the study arms within 48 hours after the first dose or optional second dose. Limitations of the study included lack of an active comparator study arm and assessment of only a single migraine attack. At 2 hours post- dose, significantly more ubrogepant-treated patients than placebo patients experienced freedom from

pain and absence of the most bothersome migraine symptoms, however additional studies are needed to assess the durability of the response with repeated use as well as long-term safety. In the ACHIEVE II study, adults with moderate to severe migraine headache with or without aura experiencing 2 to 8 migraine attacks per month were stratified by prior response to triptans and current use of preventive therapy for migraine and randomized 1:1:1 to placebo (n=563), ubrogepant 25 mg (n=561), or 50 mg of ubrogepant (n=562). Other inclusion criteria were identical to ACHIEVE I. The coprimary efficacy endpoints were the same as in the ACHIEVE I study and were evaluated at 2 hours after taking the medication for a migraine attack of moderate or severe pain intensity. Patients were required to have ≥ 1 migraine symptom, take study medication within 4 hours of headache onset, had not taken triptans, ergot derivatives, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), an analgesic, an antiemetic, or a proton pump inhibitor, and had a new migraine headache. Beginning 2 to 48 hours after the first dose of medication, an optional second dose or rescue therapy was permitted with placebo patients receiving placebo for the second dose and ubrogepant-treated patients being randomized to receive the same dose of study drug as previously taken or placebo. Patients who decided not to take a second dose of study drug were eligible to receive rescue medication (e.g., acetaminophen, NSAIDs, opioids, antiemetics, triptans). Patients enrolled were predominantly female, Caucasian, and had previously used acute treatments for migraine with 24% of patients currently using a preventive migraine therapy. At baseline, demographic characteristics were similar between treatment groups. At 2 hours post-dose, significantly more 50 mg (21.8%; treatment difference 7.5%; 95% CI, 2.6% to 12.5%; adjusted p=0.01) and 25 mg ubrogepant patients (20.7%; treatment difference 6.4%; 95% CI, 1.5% to 11.5%; adjusted p=0.03) exhibited freedom from pain as compared to placebo (14.3%). For the coprimary endpoint assessing absence of the most bothersome migraine-associated symptom at 2 hours post-dose, significantly more patients in the 50 mg group (38.9%; treatment difference 11.5%; 95% CI, 5.4% to 17.5%; adjusted p=0.01) achieved this endpoint compared to placebo, but the 25 mg ubrogepant group (34.1%; treatment difference 6.7%; 95% CI, 0.6% to 12.7%; adjusted p=0.07) did not achieve a statistically significant improvement compared to placebo (27.4%). The secondary efficacy endpoints were also the same as in ACHIEVE I and demonstrated statistically significant improvements with the 50 mg ubrogepant dose compared to placebo for all endpoints evaluated with the exception of absence of nausea at 2 hours. For the 25 mg ubrogepant group, statistical analysis was not conducted for the secondary endpoints. The proportion of treatment-emergent adverse effects were comparable between ubrogepant-treated patients and placebo patients with nausea being the most frequent event within the first 48 hours and within 30 days. Limitations of the study include assessment of the 25 mg dose, which is not an approved treatment dose, as well as evaluation of only a single migraine attack. OTHER DRUGS USED FOR CONDITION4,5 There are a number of potential therapies for the acute treatment of migraine. Agents included in clinical practice guidelines include NSAIDs, acetaminophen (Tylenol®), caffeinated analgesic combinations (e.g., acetaminophen/aspirin/caffeine [Excedrin® Extra Strength]), as well as migraine-specific agents such as the triptans and dihydroergotamine (D.H.E. 45®, Migranal®). Other agents FDA-approved for the acute treatment of migraine include the oral serotonin receptor 5-HT1F agonist lasmiditan (Reyvow™), an ergot alkaloid ergotamine (Ergomar®), the combination caffeine/ergotamine products (Cafergot®, Migergot®), the opioid agonist-antagonist butorphanol, and the combination agent acetaminophen/ dichloralphenazone/isometheptene, which includes a pain reliever, sedative, and sympathomimetic. There are also 3 injectable CGRP antagonists (erenumab-aooe [Aimovig®], fremanezumab-vfrm [Ajovy®],

galcanezumab-gnlm [Emgality®], however these products are only indicated for the preventive treatment of migraine, with the exception of galcanezumab-gnlm which is also indicated for the treatment of episodic cluster headache. PLACE IN THERAPY6,7,8,9,10,11 Migraine headache is a prevalent condition and is characterized by a headache, nausea, and sensitivity to light and/or sound. The 2015 American Headache Society (AHS) Evidence Assessment of Migraine Pharmacotherapies addressed the acute treatment of migraine in adults and lists the following agents as having Level A evidence establishing their efficacy for acute migraine treatment: triptans, NSAIDs, opioids (butorphanol nasal spray), ergots (D.H.E.), acetaminophen, and combination products containing acetaminophen/aspirin/caffeine or sumatriptan/naproxen. In 2019, the AHS published a consensus statement describing the integration of new migraine treatments into clinical practice and updating prior recommendations. For mild to moderate attacks, NSAIDs (e.g., aspirin, diclofenac, ibuprofen, naproxen) acetaminophen, and caffeinated analgesic combinations are recommended. For moderate to severe migraine attacks, migraine-specific agents such as the triptans and dihydroergotamine are recommended; these agents are also used for mild to moderate attacks that are unresponsive to NSAIDs or caffeinated combination products. Butorphanol is also considered to have established efficacy, although regular use is not recommended, similar to other opioid combination products (e.g., codeine/acetaminophen, tramadol/acetaminophen). Ubrogepant as well as the recently approved selective serotonin (5-HT1F) receptor agonist lasmiditan are described as emerging acute treatments in the consensus statement; these agents are proposed to be utilized in patients with contraindications to triptans or who have not responded or tolerated ≥ 2 oral triptans based on either a validated patient- reported outcome questionnaire or prescriber attestation. Ubrogepant (Ubrelvy) is an oral small molecule CGRP receptor antagonist, also known as a gepant, and is a first-in-class agent for the acute treatment of migraine. It provides a 1 to 2 dose, novel treatment option for mitigating an acute migraine attack in adults and has demonstrated efficacy in clinical trials of patients with migraine with or without aura and moderate to severe headache pain. Notably, it does not carry any warnings/precautions for use but is not appropriate for use in patients concurrently using strong CYP3A4 inhibitors. Dose adjustments are required in patients with severe hepatic impairment or severe renal impairment as well as in patients who are concurrently receiving certain medications (e.g., moderate or weak CYP3A4 inhibitors or inducers, BCRP and/or P-gp inhibitors). Ubrogepant is generally well tolerated with the most common side effects being nausea, somnolence, and dry mouth. It is expected to be used in adult patients with acute migraine with or without aura and moderate to severe headache pain who have a contraindication, intolerance, or non-response to first-line acute migraine treatments (e.g., analgesics, triptans). Although patients with clinically significant CV or cerebrovascular disease were excluded in ACHIEVE I and ACHIEVE II, subjects with moderate to severe CV risk factors were allowed to be enrolled in ACHIEVE I; nonetheless, further evaluation of the use of ubrogepant in these patient populations is warranted to more fully elicit its place in therapy.

SUGGESTED UTILIZATION MANAGEMENT Anticipated Therapeutic Class Review TBD (TCR) Placement Clinical Edit Initial Approval Criteria ▪ Patient must be ≥ 18 years of age; AND ▪ Patient must have a diagnosis of migraine, with or without aura; AND ▪ Patient must NOT have headache frequency ≥ 15 headache days per month during the prior 6 months; AND ▪ Patient must NOT be concurrently using a strong CYP3A4 inhibitor; AND ▪ Patient must NOT have end-stage renal disease (creatinine clearance [CrCl] < 15 mL/min); AND ▪ Patient must have tried and failed ≥ 1 of the following: NSAID, non- opioid analgesic, acetaminophen, OR caffeinated analgesic combination; AND ▪ Patient must have tried and failed, or have contraindication to, ≥ 2 preferred triptans.

Renewal Criteria ▪ Patient must continue to meet the above criteria; AND ▪ Patient must demonstrate resolution in headache pain or reduction in headache severity, as assessed by prescriber; AND ▪ Patient has not have experienced any treatment-restricting adverse effects (e.g., nausea, somnolence, dry mouth). Quantity Limit 16 doses per 30 days Duration of Approval Initial: 1 year Renewal: 1 year Drug to Disease Hard Edit End-stage renal disease

REFERENCES

1 Ubrelvy [package insert]. Madison, NJ; Allergan; December 2019. 2 Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019; 381(23): 2230-2241. DOI: 10.1056/NEJMoa1813049. 3 Lipton RB, Dodick DW, Ailani J, et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA. 2019; 322(19): 1887-1898. DOI: 10.1001/jama.2019.16711. 4 The American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019; 59(1): 1-18. DOI: 10.1111/head.13456. Available at: https://americanheadachesociety.org/resources/guidelines/guidelines-position- statements-evidence-assessments-and-consensus-opinions/. Accessed January 6, 2020. 5 Clinical Pharmacology. Available at: www.clinicalpharmacology.com. Accessed January 6, 2020. 6 Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015; 55(1): 3-20. DOI: 10.1111/head.12499. Available at: https://americanheadachesociety.org/resources/guidelines/guidelines-position-statements-evidence-assessments-and-consensus-opinions/. Accessed January 6, 2020. 7 The American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019; 59(1): 1-18. DOI: 10.1111/head.13456. Available at: https://americanheadachesociety.org/resources/guidelines/guidelines-position- statements-evidence-assessments-and-consensus-opinions/. Accessed January 6, 2020. 8 Lipton RB, Dodick DW, Ailani J, et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA. 2019; 322(19): 1887-1898. DOI: 10.1001/jama.2019.16711. 9 FDA approves new treatment for adults with migraine. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new- treatment-adults-migraine. Accessed January 6, 2020. 10 Dodick DW, Lipton RB, Ailani J, et al. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019; 381(23): 2230-2241. DOI: 10.1056/NEJMoa1813049. 11 Lipton RB, Dodick DW, Ailani J, et al. Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA. 2019; 322(19): 1887-1898. DOI: 10.1001/jama.2019.16711.