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. 2024 Jan 10;17(1):e13675. doi: 10.1111/cts.13675

Ubrogepant: Mechanism of action, clinical and translational science

Ramesh Boinpally 1,✉, Mohamad Shebley 1, Joel Trugman 2
PMCID: PMC10777434  PMID: 38266060

Abstract

In recent years, the treatment of migraine has experienced a breakthrough in the development of drugs that target the calcitonin gene‐related peptide (CGRP) signaling pathway. Monoclonal antibodies against the receptor or ligand have been developed for the preventive treatment of migraine; whereas, orally administered small molecule CGRP receptor antagonists, called gepants, have been developed for both acute and/or preventive treatment. Both modalities have demonstrated safe and effective treatment of migraine, reducing the number of migraine days for patients as well as reducing symptoms and improving patient function and overall quality of life. Here, we provide an abridged review of ubrogepant, an oral CGRP receptor antagonist, approved for the acute treatment of migraine. We briefly summarize the role of CGRP in migraine pathophysiology, describing the mechanism of action of ubrogepant in the context of this pathway, the clinical pharmacology properties and the clinical development and outcomes, including safety, efficacy, pharmacokinetics, and pharmacodynamics, that supported ubrogepant's approval.

Clinical and Translational Card for Ubrogepant.

Mechanism of action: Calcitonin gene‐related peptide receptor antagonist

Indication (s): Acute treatment of migraine

Dosage and administration: 50 mg or 100 mg taken orally, as needed; a second dose may be administered at least 2 h after the initial dose, if needed

Major Metabolic Pathway: CYP3A4‐mediated oxidation

Key PK characteristics for 100 mg dose: AUC: 1249 ng h/mL, C max: 274 ng/mL, T max: 1.7 h, t 1/2: 5–7 h

INTRODUCTION

Migraine is a neurological disorder of sensory processing, 1 affecting individuals with a broad range of episodic symptoms before, during, and following the primary symptom of a moderate to severe, unilateral, throbbing, or pulsating headache, lasting from 4 to 72 h. Nausea, photophobia, phonophobia, and sometimes aura accompany migraine attacks, all of which vary from one migraine attack to the next as well as from person to person. Despite the high variability in the clinical features of migraine, the convergence of migraine symptomatology and advancements in neurobiology and neuroimaging over the last 4 decades have led to improved diagnosis and management of migraine with migraine‐specific therapeutics. 2

The trigeminovascular system is an expansive network of trigeminal nerve endings, intra‐and extracranial blood vessels, and neurotransmitters that respond to sensory stimuli and participate in nociception. In 1979, Moskowitz and colleagues 3 first postulated that “the release of substance P or other vasoactive compounds from the trigeminal nerve terminals may mediate the head pain and the vasodilation of migraine headaches.” This model became the seed for the discoveries in migraine pathophysiology and therapeutic developments that have occurred to date. Calcitonin gene‐related peptide (CGRP) was discovered in 1982. 4 CGRP is expressed in both the central and peripheral nervous systems, especially in the trigeminovascular system, where it is the central neuropeptide released by trigeminal nerves to cause dilation and maintain cerebral blood flow in response to local cerebral vasoconstriction. 1 CGRP is also involved in nociceptive transmission and modulation as well as neurogenic inflammation, leading to increased sensitization of meningeal nociceptors. 5 In individuals with migraine, recurrent activation and sensitization of the trigeminovascular pathways results in altered brain excitability, hypersensitivity to sensory stimulation, and impairment of descending inhibitory pain pathways. 6 , 7 , 8 , 9 Studies in the 1990's demonstrating selective release of CGRP from the trigeminal ganglion during migraine headache, induction of migraine‐like headaches during CGRP infusion in patients with migraine, and prevention of CGRP release with triptans, provided the key evidence for the fundamental role of CGRP and the trigeminovascular system in migraine pathophysiology. 10 A decade later, olcegepant, 10 a small molecule CGRP receptor antagonist which are also known as gepants, was evaluated in the clinic, demonstrating migraine relief and validation of CGRP as a therapeutic target for migraine. However, hepatic safety issues with first generation gepants redirected anti‐migraine therapeutic developments to CGRP‐targeting monoclonal antibodies (mAbs) for the prevention of migraine with the first approval of erenumab in May 2018. Approval of the first oral small molecule CGRP receptor antagonist, ubrogepant, in December 2019 for the acute treatment of migraine quickly followed.

DRUG REGULATORY APPROVAL

Ubrogepant is a highly potent, orally administered small molecule CGRP receptor antagonist approved for acute treatment of migraine, with or without aura, in adults. Ubrogepant was approved by the US Food and Drug Administration (FDA) in December 2019, Health Canada in November 2022, and six additional countries as of May 2023. Ubrogepant is formulated into 50 and 100 mg tablets with a recommended 50 or 100 mg dose taken orally as needed. If needed, an additional dose may be administered at least 2 h after the initial dose with a maximum dose of 200 mg in 24 h.

MECHANISM OF ACTION

CGRP is a 37‐amino acid neuropeptide of the calcitonin (CT) family of peptides, which also includes CT, adrenomedullin (AM1), and adrenomedullin 2 (intermedin; AM2). Seven receptors (CGRP, AM1, AM2, CT, Amylin 1 [AMY1], AMY2, and AMY3), their molecular components (calcitonin receptor‐like receptor [CLR], calcitonin receptor [CTR], and receptor activity‐modifying protein [RAMP1, RAMP2, and RAMP3]), and the binding affinities/selectivity of each receptor‐ligand pair have been established within this pathway. 11 CGRP has the highest affinity for the heterodimeric CGRP receptor composed of CLR, a family B G‐protein‐coupled receptor, and RAMP1, which determines ligand specificity. 11 Receptor component protein, a peripheral intracellular membrane protein, is required for Gα coupling. CGRP also activates the AMY1 (CTR/RAMP1) receptor, attributed to RAMP1. The vasodilatory effects of CGRP occur upon binding to the CGRP receptor, located on vascular smooth muscles, resulting in activation of adenylyl cyclase and increased intracellular cyclic adenosine monophosphate (cAMP; see Figure 1). Although CGRP is an inflammatory mediator and CGRP receptors are expressed on dural mast cells, a migraine is unlikely to occur through dural inflammatory mechanisms. 1

FIGURE 1.

FIGURE 1

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Antagonism of the Calcitonin Gene‐Related Peptide (CGRP) receptor. CGRP binding occurs at the CGRP receptor extracellular domains of calcitonin‐like receptor (CLR) and receptor activity‐modifying protein (RAMP1) with the N‐terminus nestled into the alpha helix bundle of CLR. Receptor component protein (RCP) is required for Gα coupling. Binding of CGRP activates adenylate cyclase (AC) to increase intracellular cyclic adenosine monophosphate (cAMP). Competitive binding of ubrogepant, a CGRP receptor antagonist, prevents CGRP from binding and blocks generation of cAMP. Created with BioRender.com.

Ubrogepant competitively and selectively binds to the CGRP receptor with high affinity (K i  = 0.07 nM) in human and nonhuman primates relative to other species (see Figure 1). 12 Within the CT receptor family, ubrogepant demonstrated 100‐ and greater than 29,000‐fold higher affinity to the human CGRP receptor compared to the human AMY1 (K i  = 8.2 nM) and AM2 (K i  = 2059 nM) receptors, respectively. 12 In a functional assay, ubrogepant blocked CGRP‐mediated cAMP signaling with subnanomolar potency (cAMP IC50 = 0.08 nM), which was reduced 2.4‐fold in the presence of 50% human serum. 12 Low nanomolar activity (cAMP IC50 = 8.4 nM) was observed for cloned human AMY1 receptor. 13 Ubrogepant binding affinities and antagonist activities across the CT family of receptors were consistent across in vitro assays demonstrating a 100‐fold difference with AMY1 followed by greater than 2000‐fold difference with the other CT family receptors. 12 No significant off‐targets were identified following a 116 therapeutically relevant off‐target screen. 12 Blockade of CGRP binding to its receptor by ubrogepant may relieve migraine by blocking CGRP‐induced neurogenic vasodilation, halting the cascade of CGRP‐induced neurogenic inflammation, and/or inhibiting the central relay of pain signals from the trigeminal nerve to the caudal trigeminal nucleus. Ubrogepant is highly distributed (apparent volume of distribution = 350 L) with limited brain penetration (cerebrospinal fluid: plasma = 0.03) 12 , 14 ; thus, it is believed that ubrogepant, as well as other gepants, works peripherally where there is systemic exposure of CGRP receptors in the trigeminovascular system (e.g., peripheral cranial blood vessels, trigeminal neurons, glial cells in the trigeminal ganglion, terminals of trigeminal afferents, the dura matter, and the brain stem, cerebellum, and cerebral hemispheres). 15

PHARMACOKINETICS/PHARMACODYNAMIC CHARACTERISTICS

Ubrogepant pharmacokinetics are dose‐proportional from 1 to 400 mg. 13 , 16 Following oral administration of a 100 mg dose, ubrogepant is rapidly absorbed with pharmacologically active plasma concentrations reached within 11 min, maximum plasma concentrations (C max) attained in ~1.5 h (time of maximum concentration, T max), and an elimination half‐life of 5 to 7 h (see Table 1). 13 , 16 Consumption of food delays peak plasma concentrations by 2 h resulting in a 22% reduction in C max with no change in area under the curve (AUC). Pharmacokinetics in patients with migraine and healthy participants are similar. No accumulation is observed with repeated once‐daily dosing, and steady state is achieved within 2 days. 13

TABLE 1.

Mean (± SD) plasma pharmacokinetic parameters following administration of a single dose of ubrogepant 100 mg to healthy fasted participants.

Pharmacokinetic parameter Ubrogepant 100 mg (N = 78)
C max (ng/mL) 274.2 (99.3)
AUC 0−t (ng h/mL) 1220.6 (430.3)
AUC 0−∞ (ng h/mL) 1249.4 (434)
T max (h) a 1.7 (1.1, 6.1)
t 1/2 (h) 4.4 (1.1)
V z/F (L) 561.4 (238.9)
CL/F (L/h) 89 (29.3)
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Note: Data obtained from Ref. 13

Abbreviations: AUC 0−t , area under the plasma concentration‐time curve from time 0 to time t; AUC 0‐∞, area under the plasma concentration‐time curve from time 0 to infinity; CL/F, apparent total body clearance; C max, maximum plasma concentration; t 1/2, terminal elimination half‐life; T max, time to reach C max; V z/F, apparent volume of distribution.

a

Median (min, max).

Metabolism and elimination of ubrogepant occurs primarily via cytochrome P 450 (CYP) 3A4. Ubrogepant is eliminated mainly via the biliary/fecal route (42% of unchanged ubrogepant recovered in feces) with minor elimination through the renal route (6% unchanged ubrogepant recovered in urine). 16 The parent compound (ubrogepant) and two glucuronide conjugate metabolites, with ~6000‐fold less potency to CGRP and no expected pharmacological activity, were the most prevalent circulating components in human plasma. 16 Drug–drug interaction studies have resulted in recommendations for dose reductions of ubrogepant when concomitantly used with moderate or weak CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inhibitors is contraindicated, whereas strong CYP3A4 inducers should be avoided (see Table 2). 16 In vitro, ubrogepant is a substrate for breast cancer resistance protein (BCRP) and P‐glycoprotein (P‐gp); thus, increases in ubrogepant exposure may occur and the lower 50 mg dose of ubrogepant with BCRP or P‐gp inhibitors is recommended. In patients with severe hepatic or renal impairment, a dose reduction to 50 mg for the first and the optional second dose are recommended; patients with end‐stage renal disease should avoid use. 16 Additionally, no clinically significant changes in ubrogepant pharmacokinetics have been identified when co‐administered with oral contraceptives, acetaminophen, naproxen, esomeprazole, or other anti‐migraine therapies (sumatriptan, erenumab, galcanezumab, or atogepant 17 ). 14

TABLE 2.

Drug–drug interaction and dose modification summary for ubrogepant.

Mechanism/class of concomitant drug Co‐administered drug evaluated in phase I Clinical or theoretical findings Initial dose/second dose
Strong CYP3A4 inhibitors Ketoconazole 10‐Fold increase in ubrogepant exposure Contraindicated
Moderate CYP3A4 inhibitors Verapamil 3.5‐Fold increase in ubrogepant exposure 50 mg/avoid within 24 h
Weak CYP3A4 inhibitors Not evaluated Potentially mild increase in ubrogepant exposure 50 mg/50 mg
Strong CYP3A4 inducers Rifampin 80% Reduction in ubrogepant exposure Avoid use
Weak or moderate CYP3A4 inducers Not evaluated Potential reduction in ubrogepant exposure 100 mg/100 mg
Inhibitors of BCRP and/or P‐gp efflux transporters Not evaluated Potential increase of ubrogepant exposure 50 mg/50 mg
Proton pump inhibitors Esomeprazole 23% Reduction in ubrogepant C max; ubrogepant T max increased by 1.5 h No dose modifications
Serotonin receptor agonists (triptans) Sumatriptan 24% Reduction in ubrogepant C max, ubrogepant T max increased by 1.5 h, and sumatriptan T max increased by 2 h No dose modifications
CGRP receptor antagonists (gepants) Atogepant 19% and 26% Increase in ubrogepant AUC and C max, respectively; potential for additive pharmacodynamic effects No dose modifications
CGRP‐targeted monoclonal antibodies Erenumab and galcanezumab No significant change on ubrogepant PK No dose modifications
Oral contraceptives Ethinyl estradiol and norgestimate 26% Reduction in peak plasma concentrations of ethinyl estradiol; no effect on AUC; and no effect on norelgestromin PK No dose modifications
Non‐steroidal anti‐inflammatory drugs (NSAIDs) Naproxen No significant change on ubrogepant and naproxen PK No dose modifications
Analgesic Acetaminophen ~40% Increase in ubrogepant AUC and C max and 24% reduction in acetaminophen C max No dose modifications
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Note: Data obtained from Ref. 14 , 16

Abbreviations: AUC, area under the plasma concentration‐time curve; CGRP, calcitonin gene‐related peptide; C max, maximum plasma concentration; PK, pharmacokinetics; T max, time to maximum plasma concentration.

The capsaicin‐induced dermal vasodilation (CIDV) model used for pharmacodynamic assessments (i.e., target engagement) of CGRP antagonist activity was first validated in the rhesus monkey then translated to humans. 18 Capsaicin applied to the skin induces neurogenic inflammation and dose‐dependent release of CGRP from the skin by binding to the transient receptor potential vanilloid type 1 receptor on dermal sensory nerve endings. 18 , 19 Laser Doppler perfusion imaging assesses changes in dermal blood flow at baseline, following capsaicin application, and at appropriate timepoints following administration of CGRP‐targeting therapeutics. Although this is not an efficacy model, the CIDV model has proven to be a valuable tool in guiding dose selection for gepants and mAbs alike, despite its limitation in CGRP response in the forearm, which has historically underestimated the clinical efficacious dose. 20 Binding of ubrogepant to CGRP receptors is highly species‐specific for human and nonhuman primates relative to CGRP receptors of other species. Thus, the K i values were 11.6 ± 1.1, 9.6 ± 1.1, 11 ± 0.5, 47 ± 4, 0.079 ± 0.005, and 0.07 ± 0.006 nM in mouse, rat, rabbit, dog, rhesus monkey, and human, respectively. Evaluation of ubrogepant inhibition of CIDV in the rhesus monkey and humans demonstrated a mean effective concentration required to inhibit 50% capsaicin effect (EC50) of 3.19 and 2.56 nM, respectively. 12 The estimated EC90 in rhesus monkeys and humans was 29 and 23 nM, respectively, suggesting similar ubrogepant affinity toward CGRP receptors in monkeys and humans. 12 Effective coverage of the CGRP receptor in humans occurs within 11 min after oral administration of ubrogepant 50 mg and is sustained for nearly 12 h. 21 However, prolonged efficacy compared to pharmacokinetics was observed in phase III studies likely due to:

  1. Episodic nature of migraine. When a migraine attack is aborted through pharmacological intervention, there is an interictal period before a new attack occurs.

  2. Exposure‐response modeling using sustained pain relief and pain freedom models provided a predicted effective AUC50 of 74.5 ng⋅h/mL. This effective AUC50 is the AUC24h of a typical phase III patient if they were administered 6 mg ubrogepant, suggesting that the approved 50 and 100 mg doses, with much higher AUC24h, could result in prolonged efficacy.

In support of phase III dose selection for ubrogepant, population pharmacokinetic modeling and exposure‐response analyses were performed utilizing data from two phase IIb studies. 22 The phase IIb trials consisted of a parallel dose‐finding/efficacy study (N = 834 enrolled) and a smaller pharmacokinetics/efficacy (N = 195 enrolled) study. Ubrogepant doses of 1, 10, 25, 50, and 100 mg were evaluated for a single migraine attack and compared to placebo; additional doses were taken by participants on day 3 and day 4 following the migraine attack (day 1) in the pharmacokinetics study. Both studies were conducted in participants with a history of migraine for greater than or equal to 1 year and maintained the same eligibility criteria and end points. Primary efficacy end points included pain freedom (the reduction in headache pain severity from moderate or severe at baseline to no pain) and pain relief (a change in the severity of headache pain from moderate or severe pain to mild pain or no pain at 2 h after the initial dose) following ubrogepant administration at the onset of a moderate to severe migraine headache. Clinical doses greater than or equal to 25 mg were predicted to achieve targeted efficacy for 2‐h pain relief. In comparison, the higher doses of 50 and 100 mg were predicted to achieve targeted efficacy for 2‐h pain freedom in the exposure‐response analysis. 22

KEY CLINICAL TRIALS

Two pivotal phase III clinical trials (ACHIEVE I [NCT02828020] 15 and ACHIEVE II [NCT02867709] 23 ) with a 56‐week, long‐term safety extension study (NCT02873221) conducted between 2016 and 2018 led to ubrogepant's FDA approval for acute treatment of migraine (see Table 3). Phase III study designs were informed from phase IIb dose‐finding studies (1–100 mg) that demonstrated superior efficacy at the 100 mg dose, no significant cardiovascular events, and a dose‐dependent response. In these studies, participants included adults with at least a 1‐year history of migraine, with or without aura, and two to eight migraine attacks per month with moderate to severe headache. In the ACHIEVE trials, participants were advised to take ubrogepant as soon as possible, no later than 4 h of headache onset, to treat a qualifying migraine attack with moderate or severe headache. The co‐primary efficacy end points included the percentage of participants with pain freedom and absence of the most bothersome symptoms (MBS; among nausea, photophobia, and phonophobia) from migraine at 2 h following the first dose. A second dose was permitted 2 h after the first dose. Secondary end points evaluated pain relief, photophobia, phonophobia, and nausea at 2 h and sustained pain relief and pain freedom from 2 to 24 h following the first dose. Safety was monitored throughout all trials. A phase III (NCT04492020) study evaluating ubrogepant treatment during the prodrome phase of a migraine attack concluded in April 2022. Evaluation of the long‐term safety of CGRP blockade with simultaneous acute and preventive migraine treatments is being investigated in phase IV studies (NCT05264129 and NCT05503082).

TABLE 3.

Primary efficacy results for ubrogepant in key clinical trials.

Ubrogepant dose (n) Phase IIb (NCT01613248) 29 Achieve 1 (NCT02828020) 15 Achieve II (NCT02867709) 23
1 mg (n = 107) 10 mg (n = 108) 25 mg (n = 104) 50 mg (n = 106) 100 mg (n = 102) Placebo (n = 113) 50 mg (n = 423) 100 mg (n = 448) Placebo (n = 456) 25 mg (n = 435) 50 mg (n = 464) Placebo (n = 456)
Pain freedom at 2 h a , b
No./total no. (%) c 6/107 (5.6%) 16/108 (14.8%) 22/103 (21.4%) 22/105 (21.0%) 26/102 (25.5%) 10/112 (8.9%) 81/422 (19.2%) 95/448 (21.2%) 54/456 (11.8%) 90/435 (20.7%) 101/464 (21.8%) 65/456 (14.3%)
Odds ratio (95% CI) 0.60 (0.21–1.72) 1.71 (0.74–3.97) 2.78 (1.24–6.21) 2.61 (1.17–5.83) 3.32 (1.5–7.31) 1.83 (1.25–2.66) 2.04 (1.41–2.95) 1.56 (1.09–2.22) 1.62 (1.14–2.29)
Adjusted p value 0.344 0.211 0.013 0.020 0.003 0.002 <0.001 0.03 0.01
Absence of most bothersome migraine‐associated symptoms at 2 h d , e
No./total no. (%) f 162/420 (38.6%) 169/448 (37.7%) 126/454 (27.8%) 148/434 (34.1%) 180/463 (38.9%) 125/456 (27.4%)
Odds ratio (95% CI) 1.70 (1.27–2.28) 1.63 (1.22–2.17) 1.37 (1.02–1.83) 1.65 (1.25–2.20)
Adjusted p value 0.002 0.002 0.07 0.01
Pain relief at 2 h b , g
No./total no. (%) c 40/107 (37.4%) 57/108 (52.8%) 55/103 (53.4%) 60/105 (57.1%) 60/102 (58.8%) 50/112 (44.6%) 256/422 (60.7%) 275/448 (61.4%) 224/456 (49.1%) 263/435 (60.5%) 291/464 (62.7%) 220/456 (48.2%)
Odds ratio (95% CI) 0.74 (0.43–1.27) 1.35 (0.79–2.32) 1.44 (0.83–2.47) 1.60 (0.93–2.75) 1.69 (0.98–2.93) 1.69 (1.28–2.23) 1.69 (1.28–2.21) 1.65 (1.25–2.17) 1.77 (1.35–2.32)
Adjusted p value 0.275 0.268 0.191 0.089 0.061 0.002 0.002 0.01
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Note: Randomized participant completion rate for phase 2, ACHIEVE 1, and ACHIEVE II studies was 98%, 98.5%, and 86%, respectively.

Abbreviations: CI, confidence interval; n, number of participants.

a

Pain freedom was defined by the reduction in headache pain severity from moderate or severe at baseline to no pain.

b

Odds ratio (OR), 95% CI, and p value are based on logistic regression, with treatment group, historical triptan response, use of medication for migraine prevention, and baseline headache severity as explanatory variables.

c

The total number is the number of participants who did not have missing data for the assessment of pain severity up to 2 h after the initial dose.

d

Symptoms reported individually as secondary end points in phase II studies and not reported here.

e

Odds ratio (95% CI) and p value are based on logistic regression, with treatment group, historical triptan response, use of medication for migraine prevention, baseline headache severity, and the underlying symptom as explanatory variables.

f

The total number is the number of participants who did not have missing data for the presence or absence of the most bothersome symptom (photophobia, phonophobia, or nausea) up to 2 h after the initial dose.

g

Pain relief was defined as a change in the severity of headache pain from moderate or severe pain to mild pain or no pain at 2 h after the initial dose. Reported as “Headache response at 2 h” as primary efficacy end point in phase II study and secondary efficacy end point in phase III studies.

SUMMARY OF CLINICAL EFFICACY AND SAFETY

In ACHIEVE I, ubrogepant demonstrated superior efficacy to placebo in 2‐h pain freedom and 2‐h MBS freedom at the 50 and 100 mg doses. In ACHIEVE II, doses of 25 and 50 mg were evaluated, in which 50 mg demonstrated efficacy for the co‐primary end points. Outcomes for individual ubrogepant efficacy studies are summarized in Table 3. In a pooled analysis of the ACHIEVE I and II trials for the 50 mg dose, co‐primary end points of 2‐h pain freedom and 2‐h MBS freedom were significantly greater in participants receiving ubrogepant compared with those randomized to placebo with (p < 0.001) or without (p = 0.004) use of preventive medication. 24 In a time course analysis, the magnitude and duration of effect of ubrogepant 50 mg compared to placebo for pain relief and absence of MBS demonstrated significant improvements from 1 (6.3% for both) to 2 h (13.0% and 11.1%, respectively), reaching their maximum effect at 4 h (15.9% and 14.2%, respectively). Pain freedom followed with nearly double the treatment response at 2 (7.5%) to 3 h (14.2%), reaching maximum effect at 8 h (17.7%). 21 These analyses demonstrated ubrogepant's long duration of action with efficacy observed out to 48 h. 21 Ubrogepant treatment during the prodrome phase, which can occur 1 to 2 days before an attack, resulted in statistically significant reductions in the absence of any headache at 24 h with ubrogepant‐treated migraine attacks compared to placebo (23.7% vs. 13.9%, p < 0.0001) and increased likelihood of normal functioning at 24 h (odds ratio = 1.66, p < 0.0001) were observed, demonstrating that early blockade of the CGRP pathway reduces or prevents progression of a migraine attack thereby maximizing the benefit of ubrogepant treatment. 25 In a real‐world study on ubrogepant, headache relief was achieved by 47.6% (50/105) of patients, followed by headache freedom for 19.0% (20/105) of patients. 26 No difference in responder rate in patients with and without preventive treatment continues to be observed for ubrogepant efficacy. 26

Throughout the ACHIEVE trials of ubrogepant, the types and frequencies of adverse events were similar across treatment groups and placebo, demonstrating its safety and tolerability in nearly 2000 participants who received ubrogepant. The most commonly reported treatment‐related adverse events within 48 h of any dose in the ACHIEVE trials were nausea, dizziness, somnolence, and dry mouth. 15 , 23 Clinical events related to hepatic safety concerns have been limited within a study and not found conclusively related to ubrogepant by blinded review boards. Hypersensitivity reactions including anaphylaxis, dyspnea, facial or throat edema, rash, urticaria, and pruritus have been reported. If a serious or severe hypersensitivity reaction occurs, ubrogepant should be discontinued. 16 In the only reported real‐world study for ubrogepant, the most common adverse events were fatigue (27.4%), dry mouth (7.5%), nausea/vomiting (6.6%), constipation (4.7%), dizziness (2.8%), and other adverse events (6.6%). 26 Frequent use of non‐CGRP migraine medications can lead to medication overuse headache (MOH), and poor treatment of episodic migraine can lead to chronic migraine. However, CGRP receptor antagonists have shown no evidence that MOH occurs. 17 Progression of episodic migraine to a chronic state continues to be evaluated in the new era of CGRP‐targeted therapies; management of episodic migraine (i.e., reducing headache frequency) may prevent disease progression.

CURRENT AND FUTURE CLINICAL DEVELOPMENTS IN MIGRAINE‐SEPCIFIC THERAPEUTICS

Migraine pathophysiology is potentially the act of multiple pain signaling cascades that result in the heterogeneity of a patients’ migraine symptomatology and response to therapeutics. Whereas CGRP‐targeted therapies (e.g., gepants and mAbs) have had a substantial breakthrough in pain relief and the absence of MBS as well as overall improved function in the lives of patients, there is currently no cure for migraine. Pharmacokinetics aimed at rapid absorption and exposure has played a key role in the development of ubrogepant as well as rimegepant, an orally administered FDA‐approved gepant for acute and preventive treatment of migraine; and, recently, the FDA approved the first intranasally administered gepant, zavegepant, for the acute treatment of migraine. Intranasal administration provides an alternative for patients who cannot take oral medication due to migraine‐induced nausea or vomiting. An additional gepant, atogepant, was also recently approved for preventive treatment of both episodic and chronic migraine in adults. A continued study of “good responders” identified in the real‐world ubrogepant study will aid in directing research efforts and physicians in determining the proper medication for their patients. Migraine occurs as early as age 3 years; pediatric studies (NCT05125302 and NCT05127954) for ubrogepant in patients aged 6 to 17 are currently enrolling. Women have a higher rate of migraine; thus, a study (NCT05158894) in women during pregnancy has been initiated to evaluate the safety of ubrogepant. Migraine is not alone in the need for polypharmacy, and recent research demonstrates that intravenous infusion of pituitary adenylate cyclase‐activating peptide (PACAP) can also initiate migraine‐like pain 27 ; however, initial attempts to drug this pathway failed, 28 and further understanding of PACAP‐related biology is needed. Individuals with migraine may need both acute and preventive treatment; thus, current clinical studies to evaluate dual and long‐term blockade of the CGRP pathway with these therapeutics remain a crucial area of investigation.

AUTHOR CONTRIBUTIONS

RB and JT: wrote the manuscript and designed the research. MS: wrote the manuscript.

FUNDING INFORMATION

AbbVie provided financial support for the writing, review, and approval of the manuscript.

CONFLICT OF INTEREST STATEMENT

All authors are employees of AbbVie and may hold AbbVie stock or stock options.

ACKNOWLEDGMENTS

Medical writing support was provided by Stormy Koeniger, PhD, an employee of AbbVie.

Boinpally R, Shebley M, Trugman J. Ubrogepant: Mechanism of action, clinical and translational science. Clin Transl Sci. 2024;17:e13675. doi: 10.1111/cts.13675

DATA AVAILABILITY STATEMENT

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial‐level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvieclinicaltrials.com/hcp/data‐sharing/.html.

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Data Availability Statement

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