Atogepant: Mechanism of action, clinical and translational science

Abstract

Since the discovery of calcitonin gene‐related peptide (CGRP) in 1982, its integral role in migraine pathophysiology, specifically migraine pain, has been demonstrated through cumulative scientific discoveries that have led to the development and approval of migraine‐specific therapeutics. Today, eight drugs, including monoclonal antibodies and small molecule CGRP receptor antagonists, known as gepants, have received approval for acute or preventive treatment of migraine. The primary mechanism of these drugs is to block CGRP signaling, thus preventing CGRP‐mediated nociception and neurogenic inflammation. Here, we focus on atogepant, a highly potent and selective gepant and the first and only oral medication approved for the preventive treatment of both episodic and chronic migraine in adults. In this article, we summarize the role of CGRP in migraine pathophysiology and the mechanism of action of atogepant. In addition, we provide an overview of atogepant's pharmacology and the key clinical trials and outcomes that have demonstrated the safety and efficacy of atogepant.

Clinical & Translational Card for Atogepant.

Mechanism of action: Calcitonin gene‐related peptide receptor antagonist.

Indication (s): preventive treatment of episodic and chronic migraine.

Dosage and administration: 10, 30, or 60 mg taken orally once daily depending on migraine severity/frequency, comorbidities, and concomitant medications.

Major Metabolic Pathway: CYP3A4 mediated oxidation.

Key PK characteristics for a 60 mg dose: AUC = 3470 ng⋅h/mL, C _max = 740 ng/mL, T _max = 2 h, t _1/2 = 11 h.

INTRODUCTION

Migraine treatment has experienced a significant shift since the discovery of the role of calcitonin gene‐related peptide (CGRP) in migraine pathophysiology and the development of migraine‐specific therapeutics targeting CGRP or its receptor. There is no cure for migraine; thus, migraine treatment aims at reducing migraine attack frequency, intensity, and accompanying symptoms (such as nausea, vomiting, photophobia, and phonophobia) to improve patient function and quality of life. Migraine is characterized and diagnosed based on the duration of the headache (4 to 72 h), the characteristics of the headache (at least 2 of the following: unilateral, pulsating, moderate or severe pain intensity, or causing avoidance of routine physical activity), and the associated symptoms (at least one of the following: nausea, vomiting, photophobia, or phonophobia). ¹ Migraine is classified as episodic migraine (EM; <15 headache days per month) or chronic migraine (CM; ≥15 headache days per month for more than 3 months, with features of migraine ≥8 days per month) based on attack frequency. Proper management of migraine with acute and/or preventive treatment may impede migraine chronification, where the most significant measure of progression to CM is the increase in headache frequency. ² Medication overuse headache (MOH) has also been identified as a strong risk factor for the progression of migraine. ³ MOH has not been observed with CGRP‐targeting therapeutics. Recent longitudinal studies on cessation of CGRP monoclonal antibodies (mAbs) demonstrate that migraine frequency and disability gradually increase after treatment interruption. ⁴ , ⁵ These data demonstrate that long‐term use of CGRP‐targeted therapeutics is needed; and thus, the improvements in the safety profiles of CGRP‐targeting therapeutics compared to non‐migraine‐specific medications expand treatment options to patients with cardiovascular risk factors and have the potential to improve patient adherence and migraine management.

Migraine is a disorder of physiologic dysregulation of sensory processing in both the peripheral and central nervous systems. In each of the phases of migraine (premonitory, aura, headache, and postdrome), specific physiological mechanisms in specific brain regions occur. Symptoms in the premonitory phase of migraine suggest hypothalamic and brainstem dysfunction, and symptoms in the aura phase represent focal cortical dysfunction. ² In the headache phase, activation of the trigeminovascular system and release of predominately CGRP has been identified as the primary mechanism where increased sensitivity of trigeminal nociceptors that innervate the dura mater is responsible for intracranial headache pain. Central sensitization occurs due to prolonged activity in the trigeminal afferents, which increases the sensitivity of the central trigeminal neurons and is accompanied by increases in regional cerebral blood flow in the pons and mesencephalon during a migraine attack. ² Brainstem modulation influences the trigeminal nociceptive system through axons of brainstem nuclei which can modulate the sensitivity of central trigeminal nociceptive pathways. ² These physiological changes can persist after the headache phase into the postdrome phase. Migraine progression is thought to proceed through neuronal hyperexcitability in the brain areas responsible for migraine pathogenesis and/or diminished brainstem inhibitory control. ²

CGRP is a 37‐amino acid neurotransmitter released from nociceptive terminals during a migraine attack. CGRP and its receptor are widely expressed in the central and peripheral nervous system, including the cardiovascular and enteric systems. CGRP plays a crucial role in the development of peripheral sensitization by facilitating nociceptive transmission and neurogenic inflammation leading to the associated pain of migraine headaches. CGRP release contributes to the development and maintenance of a sensitized, hyper‐responsive state of the primary afferent sensory neurons and central sensitization through second‐order pain transmission neurons within the central nervous system. ² The cumulative experimental and clinical work following the discovery of CGRP in 1982 to the first gepant, olcegepant, evaluated in the clinic in 2004 led to the validation of CGRP as a target for migraine treatment. ⁶ , ⁷ Key studies demonstrated that CGRP was the primary neuropeptide released during a migraine attack, infusion of CGRP in patients with migraine (and not healthy individuals) initiated migraine‐like symptoms, and administration of triptans normalized CGRP levels and relief to migraine symptoms. ⁶ In the last 5 years, eight CGRP‐targeting therapeutics, which include four mAbs (erenumab, fremanezumab, galcanezumab, and eptinezumab) and four CGRP receptor antagonists called gepants (ubrogepant, atogepant, rimegepant, and zavegepant), have been approved for acute and/or preventive treatment of migraine (see Table 1). Here, we present an overview of atogepant, approved for the preventive treatment of migraine in adults.

TABLE 1.

Summary of migraine therapeutics targeting CGRP.

Generic drug name	Indication	Dosage and administration	T max	t 1/2
Small molecule CGRP receptor antagonists
Atogepant	Preventive treatment of migraine in adults	10, 30, or 60 mg taken orally daily	~1–2 h	~11 h
Rimegepant	Acute treatment of migraine with or without aura in adults, and Preventive treatment of episodic migraine in adults	Acute: 75 mg taken orally, as needed; maximum 24‐h dose is 75 mg preventive: 75 mg taken every other day	1.5 h	~11 h
Ubrogepant	Acute treatment of migraine with or without aura in adults	50 or 100 mg taken orally, as needed; maximum 24‐h dose is 200 mg	1.7 h	5–7 h
Zavegepant	Acute treatment of migraine with or without aura in adults	10 mg single intranasal spray taken as needed; maximum 24‐h dose is 10 mg	~30 min	6.55 h
mAb targeting the CGRP receptor
Erenumab	Preventive treatment of migraine in adults	70 or 140 mg monthly single dose s.c. injection	4–6 days a	28 days
mAbs targeting the CGRP ligand
Eptinezumab	Preventive treatment of migraine in adults	100 or 300 mg i.v. infusion over 30 min every 3 months	End of infusion	~27 days
Fremanezumab	Preventive treatment of migraine in adults	225 mg monthly, or 675 mg every 3 months s.c. injection	5–7 days a	~31 days
Galcanezumab	Preventive treatment of migraine, and Treatment of episodic cluster headache	240 mg s.c. injection loading dose, followed by monthly doses of 120 mg	5 days a	27 days

Note: All data obtained from drug prescribing information as of November 2023. Please consult respective drug prescribing information for more details.

Abbreviations: CGRP, calcitonin gene‐related peptide; mAbs, monoclonal antibodies; s.c., subcutaneous; T _max, time to reach maximum plasma concentration; t _1/2, elimination half‐life.

^a Obtained from ref. 27.

DRUG REGULATORY APPROVAL

Atogepant (Qulipta/Aquipta) is a highly potent, orally administered small molecule CGRP receptor antagonist approved for preventive treatment of migraine, with or without aura, in adults. Atogepant was approved by the US Food and Drug Administration in September 2021 and April 2023 for EM and CM, respectively. As of August 11, 2023, atogepant has also been approved for the preventive treatment of migraine (EM, or both EM and CM) in adults in the European Union, Puerto Rico, Israel, Canada, Argentina, and Mexico and is currently under review in 15 other countries. Atogepant is formulated into 10, 30, and 60 mg tablets. Patients may be prescribed doses of 10, 30, or 60 mg taken once daily (q.d.) depending on their migraine severity/frequency, comorbidities, and concomitant medications.

MECHANISM OF ACTION

The calcitonin (CT) family of peptides includes CGRP, CT, amylin (AMY), adrenomedullin (AM1), and adrenomedullin 2 (intermedin; AM2). CGRP is expressed in two isoforms in humans. These include α‐CGRP, prominently found in the primary spinal afferent C and Aδ fibers of sensory ganglia in the central and peripheral nervous system, and β‐CGRP, primarily found in the enteric nervous system. ⁸ The calcitonin family of receptors consists of the calcitonin receptor (CTR) and six heterodimers, transmembrane‐bound, class B G‐protein‐coupled receptors composed of different subunit configurations of three orthologues of receptor activity‐modifying protein (RAMP1, RAMP2, and RAMP3), and either CTR or calcitonin receptor‐like receptor (CLR). ⁹ , ¹⁰ Each of these receptors is accompanied by an intracellular membrane protein, receptor component protein (RCP), that is required for Gα coupling. The CGRP receptor consists of CLR, RAMP1, and RCP (see Figure 1). The NH₂ terminus of the CLR extracellular domain is responsible for initial peptide ligand binding, whereas RAMP1 contributes to the orthosteric binding site; each RAMP orthologue with CTR or CLR contributes to ligand specificity to the CT peptide family. ⁹ The shared RAMP1 subunit in the CGRP and Amylin 1 (AMY₁ [CTR/RAMP1]) receptors results in CGRP binding to AMY₁ and activation at both receptors. The role of AMY₁ receptor in migraine continues to be investigated. ¹¹ CGRP binding to CGRP receptor on vascular smooth muscle cells results in vasodilatory effects through activation of adenylyl cyclase that catalyzes the synthesis of cyclic adenosine monophosphate (cAMP; Figure 1), which activates protein kinase A (PKA). ¹⁰ Activation of PKA results in the outflow of potassium resulting in the hyperpolarization of vascular smooth muscle and vasodilation that ultimately results in sensitization of perivascular nociceptors. ¹⁰

FIGURE 1.

Calcitonin gene‐related peptide (CGRP) receptor antagonism within the trigeminovascular pathway. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CLR, calcitonin receptor‐like receptor; RAMP1, receptor activity‐modifying protein; RCP, receptor component protein. Created with BioRender.com.

Atogepant is a competitive, highly selective, and potent antagonist of the human CGRP receptor. In vitro, atogepant exhibited low picomolar affinity for both cloned and native human CGRP receptors (K _i  = 0.015 ± 0.002 nM and K _i  = 0.026 ± 0.005 nM, respectively) with high affinity also for the rhesus CGRP receptor (K _i  = 0.009 ± 0.001 nM) and lower affinities for other species (K _i  = 0.13–2.1 nM). ¹² In a human α‐CGRP‐stimulated intracellular cAMP functional assay in HEK293 cells, atogepant exhibited low picomolar antagonist potency with a half‐maximal inhibitory concentration (IC₅₀) of 0.026 nM. The IC₅₀ of atogepant for cloned human CGRP is greater than 10,000‐fold lower than that of AM₁, AM₂, CTR, and AMY₃ and 92‐fold lower than the IC₅₀ for the AMY₁ receptor (IC₅₀ = 2.4 nM). ¹² In a therapeutically relevant screen against 116 targets, atogepant showed no activity less than 10 μM against any of the targets tested. Further assessment of atogepant binding properties and association kinetics in SK‐N‐MC membranes demonstrated that the specific binding of atogepant was saturable with an apparent equilibrium dissociation constant value of 0.03 nM with rapid equilibrium (K _on = 6.7 × 10⁸ M⁻¹ min⁻¹) and reversible binding (K _off = 0.03 min⁻¹; elimination half‐life [t _1/2] = 40 min). ¹² By blocking CGRP binding to its receptor, atogepant may relieve or prevent migraine not only by preventing vasodilation but also by preventing CGRP‐induced neurogenic inflammation, nociceptive transmission, and the various functions of CGRP that contribute to the development and maintenance of a sensitized hyper‐responsive state. ¹¹ With limited brain penetration and a high apparent volume of distribution (V _z /F = 292 L), ¹³ atogepant is believed to mainly act peripherally by inhibiting CGRP receptors outside of the blood–brain barrier (BBB). Although peripheral or central therapeutic intervention for migraine continues to be debated, CGRP‐targeting therapeutics, all of which lack significant BBB penetration, have demonstrated that peripheral interventions facilitate control of central sensitization to relieve or prevent migraine headache and central migraine symptoms (e.g., photophobia and phonophobia). ¹⁴

PHARMACOKINETICS/PHARMACODYNAMIC CHARACTERISTICS

Atogepant is rapidly absorbed following oral administration with pharmacologically effective plasma concentrations reached within 30 min and median time to reach peak plasma concentration (T _max) of ~2 h, t _1/2 of ~11 h, and maximum plasma concentration (C _max) of 740 ng/mL, and an area under the plasma drug concentration‐time curve (AUC) of 3470 ng⋅h/mL at the 60 mg dose (see Table 2). Atogepant pharmacokinetics (PKs) are dose proportional up to 170 mg/day with no accumulation and no clinically significant food effect on PKs (i.e., no effect on T _max, 18% reduction in AUC, and 22% reduction in C _max). ¹³ Atogepant PKs in patients with migraine and healthy participants are similar, and atogepant was administered without any food restriction in the pivotal phase III studies.

TABLE 2.

Single‐dose mean (±SD) pharmacokinetics of atogepant.

Pharmacokinetic parameter	Atogepant 60 mg (N = 40)
C max (ng/mL)	740 (231)
AUC 0−t (ng⋅h/mL)	3440 (1030)
AUC 0−∞ (ng⋅h/mL)	3470 (1040)
T max (h) a	2.0 (1.0–3.0)
t 1/2 (h)	11.2 (7.78)
CL/F (L/h)	19.2 (7.49)
V z /F (L)	292 (175)

Sources: See refs. 13, 28.

Abbreviations: AUC _0−t  = area under the plasma concentration versus time curve from time 0 to time t; AUC _0−∞ = area under the plasma concentration versus time curve from time 0 to infinity; CL/F = apparent total body clearance of drug from plasma after extravascular administration; C _max = maximum plasma drug concentration; t _1/2 = terminal elimination half‐life; SD, standard deviation; T _max = time to reach maximum plasma drug concentration; V _z /F = apparent volume of distribution during the terminal phase after extravascular administration.

^a Median (min–max).

Atogepant is primarily eliminated through cytochrome P450 (CYP) 3A4 metabolism, with the parent compound (atogepant) and a glucuronide conjugate metabolite as the most prevalent circulating components in human plasma. ¹³ Unchanged atogepant was primarily found in feces (42% of the dose) and urine (5% of the dose) following a 50 mg dose of ¹⁴C‐atogepant in healthy male participants. ¹³ Considering that atogepant is primarily metabolized through CYP3A4, atogepant exposure may be increased by CYP3A4 inhibitors and reduced by CYP3A4 inducers (see Table 3). Atogepant is also a substrate of drug transporters, including organic anion transporting polypeptide (OATP) 1B1, OATP1B3, BCRP, and P‐gp. Drug–drug interaction studies have resulted in recommendations for dose adjustments of atogepant for preventive treatment of migraine with concomitant use of strong CYP3A4 inhibitors; strong, moderate, or weak CYP3A4 inducers; and OATP inhibitors (Table 3). Renal route being a minor route of elimination for atogepant, a dedicated PK study in renally impaired patients was not conducted. No dose adjustment is recommended in patients with mild or moderate hepatic/renal impairment, and the lowest 10 mg dose is recommended in EM patients with severe renal impairment or end‐stage renal disease (ESRD) in the United States, and in both EM and CM patients with severe renal impairment or ESRD in the European Union. Patients with severe hepatic impairment should avoid the use of atogepant.

TABLE 3.

Drug–drug interactions and dose modification summary for atogepant.

Mechanism/class of concomitant drug	Co‐administered drug evaluated in phase I or PBPK	Clinical or theoretical findings	US PI: recommended daily dose for episodic migraine	US PI: Recommended daily dose for chronic migraine	EU SmPC: Recommended daily dose for episodic and chronic migraine
Strong CYP3A4 inhibitors	Itraconazole	5.5‐ and 2.15‐fold increase in atogepant AUC and C max, respectively	10 mg	Avoid use	10 mg
Moderate or weak CYP3A4 inhibitors	PBPK a	1.68‐ and 1.21‐fold increase in atogepant exposure with moderate inhibitors; no change in PKs with weak CYP3A4 inhibitors	No dose modifications
Strong, moderate, or weak CYP3A4 inducers	Rifampin	60% and 30% reduction in atogepant AUC and C max, respectively	30 mg or 60 mg	Avoid use	No dose modifications
	Topiramate	25% and 24% reduction in atogepant AUC and C max, respectively; no change in topiramate PKs
OATP inhibitor	Rifampin	2.85‐ and 2.23‐fold increase in atogepant AUC and C max, respectively	10 mg or 30 mg	30 mg	10 mg
BCRP inhibitors	PBPK a	1.18‐fold and 1.29‐fold increase in atogepant AUC and C max, respectively	No dose modifications
P‐gp efflux transporter inhibitors	Quinidine	26% and 4% increase in atogepant AUC and C max, respectively	No dose modifications
Proton pump inhibitors and/or H2 blockers	Esomeprazole	~8% and 23% reduction in atogepant AUC and C max, respectively, and delayed atogepant T max by ~1.5 h	No dose modifications
	Famotidine	21% and 49% reduction in atogepant AUC and C max, respectively.
Serotonin receptor agonists (triptans)	Sumatriptan	5% and 22% reduction in atogepant AUC and C max, respectively; delayed atogepant T max by 1.5 h; no change in sumatriptan PKs	No dose modifications
CGRP receptor antagonists (gepants)	Ubrogepant	19% and 26% increase in ubprogepant AUC and C max, respectively; 4% increase in atogepant AUC and C max	No dose modifications
Oral contraceptives	EE and LNG	19% increase in LNG AUC; no statistically significant effect on EE and atogepant	No dose modifications
NSAIDs	Naproxen	1% decrease in atogepant AUC; 2% and 6% reduction in naproxen AUC and C max, respectively	No dose modifications
Analgesic	Acetaminophen	13% increase in atogepant AUC; 6% and 11% reduction in acetaminophen AUC and C max, respectively	No dose modifications

Sources: See references. ¹³ , ²⁹ , ³⁰

Abbreviations: AUC, area under the plasma‐concentration time curve; BCRP, breast cancer resistance protein; CGPR, calcitonin gene‐related peptide; C _max, maximum plasma concentration; CYP3A4, cytochrome P 450 3A4; EE, ethinyl estradiol; EU, European Union; LNG, levonorgestrel; NSAIDs, non‐steroidal anti‐iflammatory drugs; OATP, organic anion transporting polypeptides; PBPK, physiologically‐based pharmacokinetic modeling; P‐gp, p‐glycoprotein; PI, prescribing information; PK, pharmacokinetics; SmPC, Summary of Product Characteristics; US, United States.

^a Data are based on population pharmacokinetic analysis and PBPK modeling.

In vivo pharmacodynamic assessment of CGRP antagonist activity has been established in a validated capsaicin‐induced dermal vasodilation (CIDV) model and used extensively in the clinical development of CGRP therapuetics. ¹⁵ Evaluation of atogepant inhibition of CIDV in the rhesus monkey and humans demonstrated a mean effective concentration required to inhibit 50% capsaicin effect (EC₅₀) of 1.04 and 1.51 nM, respectively, with an estimated EC₉₀ of 13.6 nM in humans. ¹² Following a therapeutic oral dose, atogepant EC₉₀ concentrations are reached within 0.5 h and maintained for 24 h at or above doses of 60 mg total daily dose.

KEY CLINICAL TRIALS

The efficacy and safety of atogepant for the preventive treatment of migraine was demonstrated in two multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group phase III studies in adults with EM (ADVANCE; NCT03777059) ¹⁶ conducted between 2018 and 2020 and with CM (PROGRESS; NCT03855137) ¹⁷ conducted between 2019 and 2022. Phase III study designs were supported by a phase IIb/III (NCT02848326) dose‐finding study conducted between 2016 and 2018 in participants with EM. All three studies evaluated the efficacy, safety, and tolerability of atogepant for 12 weeks with atogepant administered orally q.d. The primary efficacy end point was change from baseline in mean monthly migraine days (MMDs). Additional secondary end points measured monthly headache days, acute medication use days, 50% reduction in 3‐month average MMDs, and changes in disability and function. The phase IIb/III and ADVANCE studies were conducted in the United States, and the PROGRESS study was conducted globally, with 28.7% of patients recruited in North America, 35.4% in Europe, and 35.9% in East Asia. ¹⁷ In these studies, migraine definition and diagnosis were based on the International Classification of Headache Disorders‐3 criteria for EM and CM participants who had a history (≥1 year) of migraine.

In the phase IIb/III study, participants (aged 18–75 years) with EM were randomly assigned 2:1:2:2:1:1 to receive placebo or atogepant 10 mg q.d., 30 mg q.d., 60 mg q.d., 30 mg twice daily (b.i.d.), or 60 mg b.i.d. In the ADVANCE study, participants (aged 18–80 years) with EM were randomly assigned 1:1:1:1 to receive placebo or atogepant 10, 30 mg, or 60 mg q.d. In the PROGRESS study, participants (aged 18–80 years) with CM were randomly assigned 1:1:1 to receive placebo or atogepant 60 mg q.d. or 30 mg b.i.d. Atogepant has also been evaluated in a 12‐week study (ELEVATE; NCT04740827) in patients who have not responded to two to four classes of migraine preventive treatments and in a 52‐week long‐term safety study (NCT03700320) comparing atogepant to standard‐of‐care (SOC). For EM, long‐term safety and tolerability of atogepant 60 mg q.d. were evaluated in a 40‐week extension study (NCT03939312) of the ADVANCE trial. ¹⁸ For CM, extension studies at the 60 mg q.d. dose have also been conducted in China (NCT04829747) and are ongoing in Japan (NCT05861427) and for participants who completed the PROGRESS and ELEVATE trials (NCT04686136). For patients that require both acute and preventive treatment, a 30‐day phase I study (NCT04818515) to evaluate the safety and PK of atogepant in combination with ubrogepant was conducted, and a 28‐week, long‐term safety study (NCT05264129) of the concomitant use of atogepant taken daily and ubrogepant taken as needed is clinically completed.

SUMMARY OF CLINICAL EFFICACY AND SAFETY

In phase IIb/III and ADVANCE trials for EM, atogepant in dosages of 10, 30, and 60 mg q.d. was superior to placebo in the preventive treatment of migraine (see Table 4). In the PROGRESS trial for CM, atogepant dosages of 60 mg q.d. or 30 mg b.i.d. demonstrated superiority over placebo (see Table 4). In time course efficacy analyses of the ADVANCE trial (12 weeks) and 52‐week comparison to SOC (NCT03700320) studies, treatment benefits were observed after 24 h, and statistically significant responder rates were observed within the first 4 weeks of treatment and continued to increase over the 12‐ or 52‐week duration of the studies, demonstrating rapid onset of action of atogepant and continued improvement with extended treatment. ¹⁹ , ²⁰ In the 52‐week study, the proportion of participants with a greater than or equal to 50%, greater than or equal to 75%, and 100% reduction in MMDs was 60.4%, 37.2%, and 20.7%, in weeks 1–4 and increased to 84.2%, 69.9%, and 48.4%, respectively, by weeks 49–52. ¹⁹ Furthermore, atogepant has demonstrated statistically and clinically significant improvements in patient‐reported outcomes for EM and CM regarding patient quality of life and daily functioning in 12‐week pivotal trials and long‐term studies. ¹⁷ , ²¹

TABLE 4.

Primary efficacy results for atogepant key clinical trials assessed across 12 weeks of treatment.

Indication	Study	Atogepant dose	Primary end point: monthly migraine days
			Baseline, mean (SD)	Change from baseline, LSM (SE) a	Atogepant versus placebo, LSMD (95% CI) a	Adjusted p value b
Episodic migraine	Phase IIb/III (NCT02848326) 31	Placebo (n = 178)	7.8 (2.5)	−2.9 (0.2)	–	–
		10 mg q.d. (n = 92)	7.6 (2.5)	−4.0 (0.3)	−1.2 (−1.9 to −0.4)	0.024
		30 mg q.d. (n = 182)	7.6 (2·4)	−3.8 (0.2)	−0.9 (−1.6 to −0.3)	0.039
		60 mg q.d. (n = 177)	7.7 (2.6)	−3.6 (0.2)	−0.7 (−1.4 to −0.1)	0.039
		30 mg b.i.d. (n = 79)	7.4 (2·4)	−4.2 (0.4)	−1.4 (−2.2 to −0.6)	0.0034
		60 mg b.i.d. (n = 87)	7.6 (2.6)	−4.1 (0.3)	−1.3 (−2.1 to −0.5)	0.0031
	ADVANCE (NCT03777059) 16	Placebo (n = 214)	7.5 (2.4)	−2.5 (0.2)
		10 mg q.d. (n = 214)	7.5 (2.5)	−3.7 (0.2)	−1.2 (−1.8 to −0.6)	<0.001
		30 mg q.d. (n = 223)	7.9 (2.3)	−3.9 (0.2)	−1.4 (−1.9 to −0.8)	<0.001
		60 mg q.d. (n = 222)	7.8 (2.3)	−4.2 (0.2)	−1.7 (−2.3 to −1.2)	<0.001
Chronic migraine	PROGRESS (NCT03855137) 17	Placebo (n = 246)	18.9 (4.8)	−5.1 (0.4)
		30 mg b.i.d. (n = 253)	18.6 (5.1)	−7.5 (0.4)	−2.4 (−3.5 to −1.3)	<0.0001
		60 mg q.d. (n = 256)	19.2 (5.3)	−6.9 (0.4)	−1.8 (−2.9 to −0.8)	0.0009

Abbreviations: b.i.d., twice daily; CI, confidence interval; LSM, least‐squares mean; LSMD, least‐squares mean difference; q.d., once daily; SD, standard deviation; SE, standard error.

^a Data are from the mixed‐effects model repeated measurement analyses. The model included treatment group and visit as fixed effects, the baseline value as a covariate, and treatment group‐by‐visit and baseline‐by‐visit as interaction terms, with an unstructured covariance matrix.

^b Adjusted using graphic approach to control the overall type I error rate for multiple comparisons; 95% CIs were not adjusted for multiple comparisons.

Safety monitored throughout the atogepant clinical trials has been consistent in short‐term and long‐term studies. The percentage of participants reporting treatment‐emergent adverse events (TEAEs) has been similar across atogepant treatment groups and placebo groups. The most common TEAEs associated with atogepant have been upper respiratory tract infection, constipation, nausea, urinary tract infection, and fatigue, which were reported primarily as mild to moderate in severity. ¹⁸ , ¹⁹ Transaminase elevations greater than three times the upper limit of normal have also been similar across atogepant treatment groups and placebo. ¹⁸ Transient elevations temporally associated with atogepant use resolved following discontinuation of atogepant. Hypersensitivity reactions have been reported, including anaphylaxis, dyspnea, rash, pruritus, urticaria, and facial edema. ¹³ If a serious or severe hypersensitivity reaction occurs, atogepant should be discontinued. In the four long‐term safety studies, 1662 participants were treated with atogepant 60 mg q.d. for up to 3 years.

CURRENT AND FUTURE CLINICAL DEVELOPMENTS IN MIGRAINE

CGRP‐targeting therapeutics work quickly. The efficacy of gepants has been demonstrated within 2‐h of a migraine attack for acute treatment or as early as 1 day for preventive treatment. ²² The time to onset of effect for gepants has greatly modified the treatment paradigm for migraine, whereas previously, non‐migraine‐specific medications required weeks to titrate medications for potential safety/tolerability issues and have a slower onset of action. Now, an assessment of a patient as a responder following treatment with a gepant can be obtained within a couple of days to a week at the relevant efficacious dose. Current efforts aim to predict nonresponders and super‐responders for all modalities of CGRP‐targeting therapeutics. ⁵ In some cases, dose‐escalation with mAbs improves patient response, suggesting that some patients require a higher level of CGRP blockade. Furthermore, real‐world evidence, clinical trials, and observational studies currently aim to understand preventive combination treatment strategies for patients with an insufficient response by combining drugs with different mechanisms and peripherally acting CGRP therapeutics with centrally acting non‐migraine‐specific drugs. For example, the combination of atogepant with onabotulinumtoxin A (NCT05216263) is currently being evaluated. Studies are also currently evaluating CGRP mAb switching between a CGRP receptor mAb and a CGRP ligand mAb. ⁵ These questions arise from the fundamental differences in the mechanism of action of these drugs; however, recent studies have also revealed differences in the physiological response to these drugs. Functional magnetic resonance imaging in patients with migraine treated with erenumab or galcanezumab demonstrated that these mAbs elicit different trigeminal nociceptive brain responses (i.e., galcanezumab decreases hypothalamic activation more in responders). ²³ Differences in C‐ and Aδ‐meningeal nociceptor inhibition have also been observed in a cortical spreading depression rat model following treatment with fremanezumab, onabotulinumtoxinA, and atogepant. ²⁴ Collectively, the advent of CGRP‐targeting therapeutics raises many questions that are leading to new opportunities in understanding migraine pathophysiology.

Finally, migraine is a highly complex neurological disease and our understanding of what initiates a migraine attack and much of the pathophysiology remains unclear. Advances in preclinical and human models that allow careful control and monitoring of various end points in experimentally induced migraine and associated changes with treatments are providing evidence for other signaling pathways involved in migraine neurobiology. ²⁵ In addition to CGRP, nitric oxide, pituitary adenylate cyclase‐activating polypeptide, and vasoactive intestinal peptide have been observed to induce migraine‐like attacks in humans. ²⁵ A recent study in a human provocation model has demonstrated that increasing cAMP with cilostazol during CGRP blockade can induce a migraine attack through CGRP‐independent pathways. ²⁶ Thus, although CGRP‐targeted therapies have significantly advanced migraine treatment, patients with migraine requiring newer therapeutic modalities still exist, suggesting the need for a better understanding of the disease to explore additional mechanisms for intervention.

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.

Boinpally R, Shebley M, Trugman JM. Atogepant: Mechanism of action, clinical and translational science. Clin Transl Sci. 2024;17:e13707. doi: 10.1111/cts.13707

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