Atogepant (DB16098): A Comprehensive Monograph on a Novel Oral CGRP Receptor Antagonist for Migraine Prophylaxis

Executive Summary

Atogepant is a second-generation, orally administered, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, also known as a gepant, specifically developed and approved for the preventive treatment of both episodic and chronic migraine in adults.[1] Marketed under the brand names Qulipta and Aquipta, it represents a significant evolution in migraine prophylaxis, offering a targeted mechanism of action within a convenient once-daily oral formulation.[1]

The primary mechanism of action of Atogepant involves its function as a highly potent and selective competitive antagonist of the CGRP receptor. By blocking the binding of the CGRP neuropeptide, Atogepant effectively inhibits the downstream signaling cascades responsible for the neurogenic inflammation, vasodilation, and nociceptive signal transmission that are central to migraine pathophysiology.[6] Its therapeutic activity is believed to be primarily mediated at peripheral sites, with evidence suggesting limited penetration of the blood-brain barrier.[9]

The clinical efficacy of Atogepant has been robustly established through a comprehensive clinical development program, most notably the pivotal Phase 3 trials: ADVANCE (for episodic migraine), PROGRESS (for chronic migraine), and ELEVATE (for treatment-refractory episodic migraine). Across these studies, Atogepant demonstrated statistically significant and clinically meaningful reductions in mean monthly migraine days (MMDs), monthly headache days (MHDs), and the use of acute medication compared to placebo.[1] This efficacy extends across the full spectrum of migraine frequency and has been proven in patient populations who have previously failed multiple other preventive treatments. A key clinical feature is its rapid onset of action, with benefits observed within the first week of treatment, which are sustained over long-term administration.[10]

Atogepant is generally well-tolerated, with a favorable safety profile. The most commonly reported treatment-emergent adverse events include mild-to-moderate nausea, constipation, and fatigue or somnolence, which typically do not lead to treatment discontinuation.[1] Critically, Atogepant has demonstrated an excellent hepatic safety profile, showing no evidence of the drug-induced liver injury that halted the development of first-generation gepants.[6] Long-term, open-label extension studies have further confirmed this safety profile, with no new safety signals identified after more than a year of continuous use.[12]

As the first oral CGRP antagonist developed exclusively for migraine prevention, Atogepant occupies a unique position in the therapeutic landscape. It provides a distinct alternative to the injectable CGRP monoclonal antibodies (mAbs) and older, non-specific oral preventive medications. Its oral route of administration, coupled with a relatively short pharmacokinetic half-life, offers flexibility and may be preferred by patients averse to injections or those for whom a rapid washout period is desirable.[2]

Introduction to Atogepant and the Role of CGRP in Migraine Pathophysiology

Migraine as a Complex Neurological Disorder

Migraine is a prevalent and highly debilitating neurological disease that extends far beyond the common perception of a simple headache. It is characterized by recurrent attacks of moderate-to-severe, often pulsating, head pain, frequently accompanied by a constellation of neurological symptoms, including photophobia (sensitivity to light), phonophobia (sensitivity to sound), nausea, and vomiting.[7] For a subset of patients, attacks are preceded or accompanied by transient neurological symptoms known as aura. The condition imposes a significant burden on individuals, affecting their ability to perform daily activities at work, school, and home, and has a profound negative impact on overall quality of life.[18] The societal and economic costs are substantial, making migraine one of the leading causes of disability worldwide, particularly among women.[17] For decades, the management of frequent migraine has relied on preventive medications repurposed from other therapeutic areas, such as anti-epileptics and beta-blockers, which are often associated with limited efficacy and problematic side effects, leading to high rates of discontinuation and a persistent unmet need for targeted, well-tolerated therapies.[2]

The Calcitonin Gene-Related Peptide (CGRP) Pathway

The modern era of migraine therapy has been defined by the elucidation of the critical role of calcitonin gene-related peptide (CGRP) in the disease's pathophysiology.[7] CGRP is a 37-amino acid neuropeptide that is widely expressed throughout the central and peripheral nervous systems, with particularly high concentrations in the trigeminal ganglia.[6] A compelling body of evidence has established CGRP as a key mediator of migraine pain. During a migraine attack, CGRP is released from the nerve endings of sensory trigeminal ganglion neurons that innervate the meningeal blood vessels.[7] This release triggers a cascade of events within the trigeminovascular system, including potent vasodilation of cranial blood vessels, neurogenic inflammation, and the transmission of pain signals from the meninges to the brainstem and higher cortical regions.[2]

The validation of CGRP as a therapeutic target is supported by several key clinical observations: CGRP levels are elevated in the blood during migraine attacks; intravenous infusion of CGRP can reliably trigger migraine-like attacks in susceptible individuals; and blockade of the CGRP pathway provides therapeutic benefit.[6]

The Evolution of CGRP-Targeted Therapies

The discovery of CGRP's central role in migraine precipitated a paradigm shift in drug development, moving away from repurposed, non-specific agents toward therapies specifically designed to modulate this pathway.[7] This has led to the emergence of two distinct classes of CGRP-targeted medications. The first class comprises large-molecule monoclonal antibodies (mAbs), which are administered via subcutaneous injection or intravenous infusion and work by binding either to the CGRP ligand itself or to its receptor, thereby preventing receptor activation.[23] The second class consists of small-molecule CGRP receptor antagonists, colloquially known as "gepants," which are orally administered and act as competitive antagonists at the CGRP receptor.[25]

Atogepant: A Second-Generation Oral CGRP Receptor Antagonist

Atogepant belongs to the gepant class and is distinguished as a second-generation molecule developed specifically for the preventive treatment of migraine.[1] Originally discovered by Merck (as MK-8031) and subsequently developed and commercialized by Allergan and its parent company, AbbVie (as AGN-241689), Atogepant was engineered to provide a durable prophylactic effect suitable for once-daily oral dosing.[1] Its development marks a significant milestone, as it was the first and remains the only oral CGRP antagonist specifically developed and approved for the preventive treatment of both episodic and chronic migraine, offering a novel therapeutic modality for a broad range of patients.[2]

Table 1: Atogepant Drug Profile Summary

Characteristic	Detail
Generic Name	Atogepant
DrugBank ID	DB16098
Type	Small Molecule
CAS Number	1374248-81-3
Drug Class	Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist (Gepant)
Indication	Preventive treatment of episodic and chronic migraine in adults
Commercial Brand Names	Qulipta (USA, Canada), Aquipta (EU)
Developer	AbbVie (originally discovered by Merck)
Data sourced from.1

Physicochemical Properties and Formulation

Chemical Identity and Structure

Atogepant is a synthetic organic small molecule with a complex polycyclic structure. Its definitive chemical properties are as follows:

• IUPAC Name: (3′S)-1′,2′,5,7-tetrahydro-N--2′-oxo-spiro[6H-cyclopenta[b]pyridine-6,3′-[3H]pyrrolo[2,3-b]pyridine]-3-carboxamide.[4]
• Synonyms: AGN-241689, MK-8031.[2]
• Chemical Formula: C29​H23​F6​N5​O3​.[1]
• Molar Mass: 603.525 g·mol⁻¹.[1]

Key Structural Features and Structure-Safety Relationship

The molecular architecture of Atogepant is intricate, containing four chiral centers and a unique spirocyclic core.[32] A defining feature is the (3'S)-2-azaspiro[4.4]nonan-1-one (spiroazaindane) motif, which is linked via an amide bond to a heavily functionalized piperidine-2-one ring. This piperidinone ring is substituted with a 6-(R)-methyl group and a 5-(R)-2,3,6-trifluorophenyl group, while the ring nitrogen is masked with a 2,2,2-trifluoroethyl group.[32]

These specific structural modifications are not arbitrary; they represent a rational drug design approach aimed at optimizing both potency and safety. A critical lesson from the history of gepant development was the failure of the first-generation compound, telcagepant, which was abandoned due to several instances of clinically apparent, drug-induced liver injury (DILI).[6] Subsequent research indicated that the formation of reactive metabolites was a likely cause. Atogepant was therefore deliberately engineered to circumvent this liability.[27] The specific 2,3,6-trifluorophenyl substitution pattern is believed to be a key factor in this improved safety profile. This fluorination not only provided a fourfold increase in binding affinity compared to its predecessor ubrogepant but is also thought to be responsible for alleviating the hepatotoxicity associated with telcagepant by altering the molecule's metabolic profile and reducing the potential for reactive metabolite formation.[32] This deliberate chemical engineering underscores Atogepant's status as a "second-generation" gepant, designed with a structure-safety relationship in mind to overcome the critical safety hurdles of earlier compounds.

Physical Properties and Formulation

• Physical Form: Atogepant is a solid at room temperature.[30]
• Solubility: It is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and methanol.[30]
• Formulation: For clinical use, Atogepant is formulated as immediate-release oral tablets.[6]
• Dosage Strengths: It is commercially available in three strengths: 10 mg, 30 mg, and 60 mg tablets.[6]
• The 10 mg tablet is a white to off-white, round biconvex tablet debossed with “A” and “10” on one side.[13]
• The 30 mg tablet is a white to off-white, oval biconvex tablet debossed with “A30” on one side.[13]
• The 60 mg tablet is a white to off-white, oval biconvex tablet debossed with “A60” on one side.[13]

Nonclinical and Clinical Pharmacology

Mechanism of Action

Atogepant exerts its therapeutic effect as a potent, selective, and competitive antagonist of the calcitonin gene-related peptide type 1 receptor (CGRPr).[2] The CGRPr is a G-protein-coupled receptor complex composed of the calcitonin receptor-like receptor (CLR) and a receptor activity-modifying protein 1 (RAMP1).[8] Atogepant binds to this receptor with high affinity, physically occupying the binding site and preventing the endogenous CGRP neuropeptide from docking and initiating its signaling cascade.[2] By blocking CGRP-mediated signaling, Atogepant inhibits the key downstream events implicated in migraine pathogenesis, including the activation of adenylyl cyclase and protein kinase A, which ultimately prevents CGRP-induced vasodilation, neurogenic inflammation, and nociceptive transmission in the trigeminovascular system.[9]

Recent research has provided a more granular understanding of its effects on meningeal nociceptors. Studies have shown that Atogepant does not completely abolish the activation of all sensory nerve fibers in the meninges. Instead, it exhibits a preferential inhibitory effect on the activation and subsequent sensitization of high-threshold (HT) trigeminovascular neurons. This effect is attributed to its stronger influence on thinly myelinated Aδ fibers. While it is less effective at preventing the initial activation of wide dynamic range (WDR) neurons, which are associated with unmyelinated C fibers, it still successfully prevents their sensitization.[20] This differential activity suggests a nuanced mechanism that may contribute to its prophylactic efficacy by dampening the hyper-responsive state of the trigeminal system.

The primary site of action for Atogepant is believed to be peripheral. Its molecular properties, including a large polar surface area, and its pharmacokinetic profile, characterized by a high apparent volume of distribution, suggest limited passive diffusion across the blood-brain barrier (BBB).[9] The clinical efficacy of Atogepant and other CGRP-targeted therapies with minimal BBB penetration provides strong evidence that blockade of peripheral CGRP receptors is sufficient to control both the pain and the associated central symptoms of migraine, such as photophobia and phonophobia.[9]

Pharmacodynamics

Atogepant is characterized by its exceptional potency and selectivity.

• Potency and Affinity: In vitro assays have demonstrated its high affinity for the human CGRP receptor, with a half-maximal inhibitory concentration (IC50​) of 0.026 nM.[8] This indicates that very low concentrations of the drug are required to achieve significant receptor blockade.
• Selectivity: Atogepant is highly selective for the CGRP receptor. Its affinity for other related receptors in the calcitonin family is substantially lower, with IC50​ values that are over 10,000-fold higher for the adrenomedullin receptors (AM1, AM2) and the calcitonin (CT) receptor, and 92-fold higher for the amylin receptor 1 (AMY1).[8] This high degree of selectivity ensures that its therapeutic action is targeted specifically to the CGRP pathway, minimizing the potential for off-target effects.

Pharmacokinetics (ADME Profile)

The pharmacokinetic profile of Atogepant supports its use as a once-daily oral medication for migraine prevention.

Table 2: Summary of Pharmacokinetic Parameters

Parameter	Value	Source(s)
Time to Peak Plasma Concentration (Tmax​)	~2–3 hours	2
Apparent Terminal Elimination Half-life (t1/2​)	~11 hours	9
Apparent Volume of Distribution (Vz​/F)	~292 L	8
Plasma Protein Binding	~95–98%	37
Primary Metabolism Pathway	Cytochrome P450 (CYP) 3A4	6
Primary Elimination Route	Hepatic metabolism and biliary secretion	27

• Absorption: Following oral administration, Atogepant is rapidly absorbed, reaching peak plasma concentrations (Tmax​) in approximately 2 to 3 hours.[2] Its systemic exposure increases in a dose-proportional manner up to doses of 170 mg/day, which is well above the maximum recommended clinical dose.[9] A key practical advantage is that its pharmacokinetics are not significantly affected by co-administration with food, allowing patients to take the medication without dietary restrictions.[2]
• Distribution: Atogepant has a large apparent volume of distribution (Vz​/F of ~292 L), indicating extensive distribution into tissues.[8] It is also highly bound to plasma proteins, with a bound fraction of approximately 95-98%.[37]
• Metabolism: The primary route of metabolism for Atogepant is through the hepatic cytochrome P450 system, predominantly via the CYP3A4 isoenzyme, with a minor contribution from CYP2D6.[6] The parent drug and a glucuronide conjugate metabolite are the most prevalent circulating components in plasma.[9] This significant reliance on CYP3A4 metabolism is the basis for several clinically important drug-drug interactions.
• Excretion: Atogepant is eliminated from the body primarily through hepatic metabolism followed by biliary secretion.[27] Studies have shown no evidence of significant drug accumulation with repeated once-daily dosing, indicating that a steady state is reached quickly and maintained effectively.[27]

Clinical Efficacy in Migraine Prophylaxis

The efficacy of Atogepant for the preventive treatment of migraine has been established through a robust clinical development program, featuring three large, multicenter, randomized, double-blind, placebo-controlled Phase 3 trials. These trials—ADVANCE, PROGRESS, and ELEVATE—were designed to evaluate its utility across the full spectrum of migraine, from episodic to chronic, including in patients with a history of multiple treatment failures.

Table 3: Overview of Pivotal Phase 3 Clinical Trials (ADVANCE, PROGRESS, ELEVATE)

Trial Name (NCT ID)	Phase	Population	Key Inclusion Criteria	Interventions	Primary Endpoint	Key Result vs. Placebo (60 mg dose)
ADVANCE (NCT03777059)	3	Episodic Migraine (EM)	Adults with 4–14 monthly migraine days (MMDs)	Atogepant 10, 30, 60 mg QD; Placebo	Change from baseline in mean MMDs over 12 weeks	-4.2 days vs. -2.5 days (p < 0.0001)
PROGRESS (NCT03855137)	3	Chronic Migraine (CM)	Adults with ≥15 monthly headache days (≥8 MMDs)	Atogepant 60 mg QD, 30 mg BID; Placebo	Change from baseline in mean MMDs over 12 weeks	Statistically significant reduction (p=0.0024)
ELEVATE (NCT04740827)	3b	Treatment-Refractory EM	Adults with EM and documented failure of 2–4 prior oral preventive classes	Atogepant 60 mg QD; Placebo	Change from baseline in mean MMDs over 12 weeks	-4.2 days vs. -1.9 days (p < 0.0001)
Data sourced from.3

Review of Pivotal Phase 3 Trials

• ADVANCE (Episodic Migraine): The ADVANCE trial enrolled 910 participants with a history of episodic migraine (4 to 14 MMDs) and randomized them to receive once-daily atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks.[10] The trial successfully met its primary endpoint, with all three doses of atogepant demonstrating a statistically significant and clinically meaningful reduction in mean MMDs compared to placebo. For the 60 mg dose, patients experienced a mean reduction of 4.2 days from a baseline of 7.8 MMDs, compared to a 2.5-day reduction in the placebo group.[13]
• PROGRESS (Chronic Migraine): The PROGRESS trial was pivotal in establishing Atogepant's efficacy in the more severe end of the migraine spectrum. It enrolled 778 participants with chronic migraine, defined as experiencing 15 or more headache days per month, of which at least 8 were migraine days.[10] Participants were randomized to receive atogepant 60 mg once daily, atogepant 30 mg twice daily, or placebo. The 60 mg once-daily dose met the primary endpoint, showing a significant reduction in mean MMDs from a high baseline of approximately 19 days.[3] The success of this trial was instrumental in securing the expanded FDA indication for chronic migraine.[3]
• ELEVATE (Treatment-Refractory Episodic Migraine): The ELEVATE trial specifically addressed a critical unmet need by enrolling patients with episodic migraine who had previously failed to respond to or tolerate two to four different classes of conventional oral preventive medications.[10] In this difficult-to-treat population, atogepant 60 mg once daily again demonstrated clear superiority over placebo, reducing MMDs by a mean of 4.2 days compared to a 1.9-day reduction for placebo.[42] This provides strong evidence of its efficacy even in patients who are refractory to other therapies.

Analysis of Efficacy Endpoints

Across the clinical program, Atogepant consistently demonstrated robust effects on key measures of migraine burden.

• Reduction in Migraine and Headache Days: The primary outcome in all pivotal trials was the reduction in MMDs. Atogepant consistently produced statistically significant reductions in both MMDs and total monthly headache days (MHDs) compared to placebo.[1]
• Responder Rates: A clinically important measure of success is the proportion of patients who experience a substantial reduction in migraine frequency. In the ADVANCE trial, 61% of participants in the 60 mg group achieved a 50% or greater reduction in MMDs over the 12-week period, compared to only 29% in the placebo group.[13] Similar high responder rates were observed in the PROGRESS and ELEVATE trials, with a significant proportion of patients also achieving ≥75% and even 100% reduction in MMDs.[43]
• Reduction in Acute Medication Use: Treatment with Atogepant led to a significant decrease in the number of days per month that patients required acute or "rescue" medications to treat migraine attacks.[1] This is a crucial secondary endpoint, as it reflects a reduced reliance on abortive therapies and a lower risk of developing medication overuse headache.

Patient-Reported Outcomes and Functional Improvement

Beyond simply reducing headache frequency, Atogepant has been shown to improve patients' daily lives and overall quality of life. Using validated patient-reported outcome measures, the trials demonstrated significant benefits. Treatment with Atogepant resulted in statistically significant improvements in scores on the Migraine-Specific Quality-of-Life Questionnaire (MSQ), particularly in the Role Function-Restrictive domain, which measures the extent to which migraine limits daily social and work-related activities.[11] Similarly, significant improvements were seen in the Activity Impairment in Migraine-Diary (AIM-D) scores, indicating a reduction in physical impairment and an enhanced ability to perform daily activities.[11]

Long-Term and Rapid Onset of Efficacy

• Rapid Onset: A distinguishing feature of Atogepant is its rapid onset of prophylactic effect. In the pivotal trials, a statistically significant reduction in the proportion of participants experiencing a migraine day was observed as early as the first day after the initial dose.[10] The reduction in weekly migraine days was also significant within the first four weeks of treatment, providing patients with early and noticeable relief.[10] This rapid feedback is a significant departure from many traditional oral preventives, which can take weeks or even months to show a therapeutic effect and often require slow dose titration. The high discontinuation rates seen with older medications, often between 35% and 50%, are frequently attributed to a lack of perceived efficacy or intolerable side effects during this initial period.[44] The ability of Atogepant to deliver a detectable clinical benefit within the first week may fundamentally alter the patient experience. This early validation of treatment effectiveness can foster greater patient engagement and confidence, potentially enhancing long-term adherence and improving overall outcomes beyond what is measured by traditional 12-week endpoints.[47]
• Sustained Efficacy: The benefits of Atogepant are not transient. Data from an ongoing 156-week open-label extension study provide evidence of its durable efficacy. An interim analysis conducted after 48 weeks of treatment showed that the initial improvements were maintained. Patients experienced an average reduction of 8.5 monthly migraine days, and approximately 70% of participants sustained at least a 50% reduction in their MMDs throughout the 48-week period.[12]

Safety and Tolerability Profile

Atogepant has demonstrated a favorable and consistent safety and tolerability profile across its extensive clinical trial program, including in long-term extension studies.

Table 4: Incidence of Common Adverse Events (≥2%) vs. Placebo in Pooled 12-Week Studies

Adverse Event	Placebo (N=663) %	Atogepant 10 mg (N=314) %	Atogepant 30 mg (N=411) %	Atogepant 60 mg (N=678) %
Nausea	3	5	6	9
Constipation	2	6	6	8
Fatigue/Somnolence	4	4	4	5
Decreased Appetite	<1	2	1	3
Dizziness	2	2	2	3
Data sourced from.13

Comprehensive Review of Adverse Events

• Most Common AEs: The most frequently reported treatment-emergent adverse events are gastrointestinal in nature, primarily nausea and constipation, along with fatigue or somnolence.[1] As shown in Table 4, the incidence of nausea appears to be dose-related. These events are typically mild to moderate in severity and have been associated with very low rates of treatment discontinuation, generally less than 1% for any single adverse event.[14]
• Weight Decrease: Across the 12-week placebo-controlled studies, a dose-dependent proportion of patients experienced a body weight decrease of at least 7%. This was observed in 5.3% of patients taking the 60 mg dose, compared to 3.8% for the 10 mg dose and 2.5% for placebo.[13]

Hepatic Safety Assessment

A critical aspect of Atogepant's safety profile is its lack of hepatotoxicity, a key differentiator from the first-generation gepant, telcagepant. In the large, preregistration controlled trials involving several thousand patients, there was no difference in the rate of mild-to-moderate serum aminotransferase elevations between Atogepant-treated groups and placebo recipients (1.0% vs 1.8%).[6] Crucially, there have been no reports of clinically apparent liver injury or cases meeting Hy's Law criteria attributed to Atogepant in either the clinical trials or post-marketing experience.[6] Following a thorough review of the safety data, the European Medicines Agency (EMA) was reassured about the medicine's liver safety profile, concluding that its benefits outweigh its risks.[33] This favorable hepatic profile is a testament to the successful rational drug design aimed at mitigating the risks observed with earlier compounds in its class.

Serious Adverse Events and Special Warnings

• Hypersensitivity Reactions: Although rare, severe hypersensitivity reactions, including anaphylaxis and dyspnea, have been reported. These reactions can occur days after administration. Consequently, Atogepant is contraindicated in patients with a known history of hypersensitivity to the drug or any of its components.[6]
• Hypertension and Raynaud's Phenomenon: As part of a class-wide observation for CGRP antagonists, postmarketing reports have noted the potential for development of new-onset hypertension or worsening of pre-existing hypertension, as well as the development or worsening of Raynaud's phenomenon.[13]

Long-Term Safety Data

The safety profile of Atogepant has been further characterized in long-term studies, which have confirmed its tolerability with continuous use.

• 52-Week Study (NCT03700320): A 52-week, open-label trial demonstrated a safety profile consistent with the shorter-term studies. The most common adverse events (≥5%) were upper respiratory tract infection (10.3%), constipation (7.2%), nausea (6.3%), and urinary tract infection (5.2%). Serious adverse events occurred in 4.4% of participants, but none were deemed related to the study drug by investigators.[44]
• 156-Week Extension Study (NCT04686136): An interim analysis of this ongoing long-term extension study, conducted after all participants had completed at least 48 weeks of treatment, continued to support the known safety profile of Atogepant. No new safety signals were identified. In this longer-term cohort, the most common adverse events (≥5%) were COVID-19 (28.7%), nasopharyngitis (10.9%), and constipation (8.2%).[12]

Dosing, Administration, and Special Populations

The dosing of Atogepant requires careful consideration of the migraine subtype being treated, as well as potential drug-drug interactions and patient-specific factors such as organ function.

Recommended Dosing Regimens

• Episodic Migraine: For the preventive treatment of episodic migraine, the recommended dosage is 10 mg, 30 mg, or 60 mg taken orally once daily.[13] The choice of dose allows for flexibility based on individual patient response and tolerability.
• Chronic Migraine: For the preventive treatment of chronic migraine, the recommended dosage is 60 mg taken orally once daily.[13]

Atogepant can be taken with or without food, and no dose titration is required at initiation.13

Table 5: Recommended Dosage Adjustments for Drug Interactions and Organ Impairment

Condition / Concomitant Drug Class	Recommended Dosage (Episodic Migraine)	Recommended Dosage (Chronic Migraine)
Standard Dosing	10 mg, 30 mg, or 60 mg once daily	60 mg once daily
Strong CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)	10 mg once daily	Avoid use
Strong, Moderate, or Weak CYP3A4 Inducers (e.g., rifampin, carbamazepine, St. John's Wort)	30 mg or 60 mg once daily	Avoid use
OATP Inhibitors (e.g., cyclosporine)	10 mg or 30 mg once daily	30 mg once daily
Severe Renal Impairment (CLcr​ <30 mL/min) or ESRD	10 mg once daily	Avoid use
Severe Hepatic Impairment	Avoid use	Avoid use
Data sourced from.13

Clinically Significant Drug-Drug Interactions

Due to its primary metabolism by CYP3A4, Atogepant is susceptible to significant drug-drug interactions.

• CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors substantially increases the systemic exposure of Atogepant. The dosage must be reduced to 10 mg once daily for episodic migraine. This combination should be avoided entirely in patients with chronic migraine.[13]
• CYP3A4 Inducers: Co-administration with strong, moderate, or weak CYP3A4 inducers can significantly reduce Atogepant plasma concentrations, potentially compromising its efficacy. For patients with episodic migraine, a higher dose of 30 mg or 60 mg once daily is recommended. This combination should be avoided in patients with chronic migraine.[13]
• OATP Inhibitors: Concomitant use with inhibitors of organic anion transporting polypeptides (OATP) can also increase Atogepant exposure. Dosage adjustments are required as detailed in Table 5.[13]

Guidelines for Use in Special Populations

• Renal Impairment: No dosage adjustment is necessary for patients with mild or moderate renal impairment. However, in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (ESRD), the dosage for episodic migraine should be reduced to 10 mg once daily. Atogepant should be avoided in chronic migraine patients with severe renal impairment.[2]
• Hepatic Impairment: While no dose adjustment is required for patients with mild or moderate hepatic impairment, Atogepant has not been studied in patients with severe hepatic impairment and its use should be avoided in this population.[2]
• Pregnancy and Lactation: There are no adequate data on the developmental risk associated with the use of Atogepant in pregnant women, and it is not recommended during pregnancy or for women of childbearing potential who are not using contraception.[41] Based on data from animal studies, it is presumed that Atogepant can pass into breast milk, and therefore its use during lactation is not recommended.[32]

Regulatory and Development History

Timeline of Development

Atogepant was originally discovered by Merck & Co., where it was designated as MK-8031. Its development was later advanced by Allergan, and subsequently AbbVie following its acquisition of Allergan, under the development code AGN-241689.[4] It was specifically engineered as a second-generation gepant with properties suitable for once-daily prophylactic dosing.

Global Regulatory Milestones

Atogepant has achieved regulatory approval in several major jurisdictions, solidifying its role as a key therapy in migraine prevention.

• U.S. Food and Drug Administration (FDA):
• Initial Approval: On September 28, 2021, the FDA approved Qulipta (atogepant) for the preventive treatment of episodic migraine in adults. This marked the first approval of an oral CGRP receptor antagonist specifically developed for migraine prevention.[2]
• Expanded Indication: On April 17, 2023, the FDA granted an expanded indication for Qulipta to include the preventive treatment of chronic migraine. This decision made Atogepant the first and only oral gepant approved to prevent both episodic and chronic migraine, covering the full frequency spectrum of the disease.[3]
• European Medicines Agency (EMA):
• MAA Submission: AbbVie submitted the Marketing Authorization Application (MAA) to the EMA on July 18, 2022, seeking approval for the prophylaxis of migraine in adults with at least four migraine days per month.[55]
• Approval: On August 11, 2023, the European Commission granted marketing authorization for Aquipta (atogepant) for this indication, making it the first once-daily oral gepant approved for migraine prophylaxis in the European Union.[2]
• Other Jurisdictions: Atogepant also received approval from Health Canada in December 2022 for the prevention of episodic migraine in adults.[2] It is approved in the UK for preventing episodic and chronic migraine in adults who have at least four migraine days per month and have failed at least three prior preventive treatments.[1]

Comparative Analysis and Place in Therapy

Atogepant's entry into the market has significantly broadened the therapeutic options for migraine prevention. Its unique profile as a once-daily oral CGRP antagonist necessitates a comparative analysis against other gepants and the class of CGRP monoclonal antibodies (mAbs) to define its optimal place in therapy.

Table 6: Comparative Profile of Atogepant vs. Other CGRP-Targeted Migraine Preventives

Medication (Brand Name)	Class	Target	Indication (Preventive)	Administration	Dosing Frequency	Common AEs
Atogepant (Qulipta)	Gepant	CGRP Receptor	Episodic & Chronic Migraine	Oral Tablet	Once Daily	Nausea, Constipation, Fatigue
Rimegepant (Nurtec ODT)	Gepant	CGRP Receptor	Episodic Migraine	Oral Disintegrating Tablet	Every Other Day	Nausea, Stomach Upset
Erenumab (Aimovig)	mAb	CGRP Receptor	Episodic & Chronic Migraine	Subcutaneous Injection	Once Monthly	Injection Site Reactions, Constipation
Fremanezumab (Ajovy)	mAb	CGRP Ligand	Episodic & Chronic Migraine	Subcutaneous Injection	Monthly or Quarterly	Injection Site Reactions
Galcanezumab (Emgality)	mAb	CGRP Ligand	Episodic & Chronic Migraine	Subcutaneous Injection	Once Monthly	Injection Site Reactions
Eptinezumab (Vyepti)	mAb	CGRP Ligand	Episodic & Chronic Migraine	Intravenous Infusion	Once Quarterly	Nasopharyngitis, Hypersensitivity
Data sourced from.24

Atogepant vs. Other Gepants

Within the gepant class, Atogepant is distinguished by its exclusive focus on prevention.

• Differentiation by Indication: While Atogepant is indicated solely for preventive use, rimegepant holds dual approval for both the acute treatment of migraine attacks and the preventive treatment of episodic migraine. Ubrogepant is approved only for acute treatment.[56] This positions Atogepant as the dedicated daily oral prophylactic agent in the class, designed for sustained, long-term receptor blockade.
• Dosing and Side Effects: For prevention, Atogepant is administered once daily, whereas rimegepant is taken every other day.[57] This difference in dosing frequency may influence patient preference. In terms of tolerability, clinical trial data suggest a higher incidence of constipation and nausea with Atogepant compared to rimegepant, which may be a deciding factor for some patients.[58]

Atogepant vs. CGRP Monoclonal Antibodies (mAbs)

The choice between Atogepant and a CGRP mAb is often guided by patient preference regarding administration route and pharmacokinetic properties.

• Administration and Pharmacokinetics: This represents the most significant difference. Atogepant is an oral pill taken daily, offering a familiar administration route for patients accustomed to oral medications. Its short half-life of approximately 11 hours allows for a rapid washout period, which can be advantageous for patients who experience intolerable side effects or are planning a pregnancy.[15] In contrast, mAbs are long-acting biologics administered as subcutaneous injections (monthly or quarterly) or intravenous infusions (quarterly).[25] This infrequent dosing is a major convenience for many patients but also represents a longer-term commitment, as the drug remains in the system for months.[16]
• Efficacy: While no large-scale, direct head-to-head trials have been published comparing Atogepant to the mAbs, network meta-analyses and indirect comparisons have been conducted to estimate their relative efficacy.[25] These analyses generally suggest that the efficacy of Atogepant is comparable to that of the mAbs in terms of reducing MMDs and achieving ≥50% responder rates.[62] One network meta-analysis identified daily atogepant 60 mg, monthly fremanezumab 225 mg, and monthly erenumab 140 mg as being among the most effective CGRP-targeted preventive interventions.[65]
• Safety and Tolerability: The adverse event profiles are distinct. Atogepant's primary side effects are gastrointestinal (nausea, constipation) and fatigue.[58] The subcutaneously injected mAbs are most commonly associated with injection-site reactions (e.g., pain, redness, swelling). Constipation is also a known side effect of erenumab, the only mAb that targets the CGRP receptor directly, similar to Atogepant.[66]

Patient Preferences and Real-World Evidence

• Patient Preferences: The decision between an oral daily pill and an infrequent injection is highly individualized. Discrete-choice experiments have shown that while some patients strongly prefer an oral formulation to avoid needles, others prioritize the convenience of not having to remember a daily medication.[16] However, these studies also consistently find that the most important driver of treatment preference is efficacy—specifically, the chance of achieving a ≥50% reduction in migraine days. Attributes like a rapid onset of action and a reduced impact on daily activities are also highly valued, often more so than the route of administration itself.[67]
• Real-World Evidence (RWE): As Atogepant becomes more widely used, real-world data are emerging that complement the findings from randomized controlled trials (RCTs). These studies confirm its effectiveness, safety, and rapid onset of action in routine clinical practice, often in more complex patient populations with multiple comorbidities and prior treatment failures who would have been excluded from pivotal RCTs.[11] Furthermore, RWE is beginning to support the use of combination therapy. A retrospective chart review demonstrated that adding Atogepant to an existing regimen of onabotulinumtoxinA for chronic migraine provided a significant additional reduction in monthly headache days, with no new safety signals identified.[11]
• Treatment Switching: An analysis of a large U.S. claims database provided an interesting real-world perspective on treatment persistence. The study found that patients newly initiating a CGRP mAb were significantly more likely to switch to a different branded preventive treatment within one year compared to patients initiating Atogepant (21.1% vs. 13.4%). This suggests that patients may have better satisfaction or persistence with the daily oral therapy in a real-world setting.[73]

Conclusion and Future Directions

Synthesis of Atogepant's Profile

Atogepant has established itself as a cornerstone in the modern preventive treatment of migraine. It successfully combines the targeted mechanism of CGRP receptor antagonism with the convenience and familiarity of a once-daily oral tablet. Its robust efficacy across the full spectrum of migraine—from low-frequency episodic to high-frequency chronic, including treatment-refractory cases—is well-documented. This is complemented by a favorable safety profile, most notably its lack of hepatotoxicity, and a rapid onset of action that provides early therapeutic feedback to patients. Atogepant fills a critical niche in the treatment paradigm, offering an effective alternative for patients who prefer an oral medication, have an aversion to injections, or for whom the pharmacokinetic properties of a short-half-life drug are advantageous. It represents a significant advancement, providing a highly effective, well-tolerated, and specifically designed oral option for migraine prophylaxis.

Knowledge Gaps and Future Research

Despite its successful development and launch, several areas warrant further investigation to fully characterize Atogepant's role and optimize its use.

• Pediatric Use: Migraine is also prevalent and debilitating in children and adolescents. Currently, Atogepant is only approved for adults. Ongoing clinical trials are actively recruiting pediatric patients (ages 6-17) to evaluate its safety and efficacy in this younger population, which could lead to a critical expansion of its indication.[74]
• Direct Comparative Trials: The current therapeutic landscape for CGRP-targeted preventives lacks direct, head-to-head randomized controlled trials. While network meta-analyses provide valuable estimates, prospective, randomized studies directly comparing Atogepant to preventive rimegepant and to the various CGRP monoclonal antibodies are needed to definitively establish their relative efficacy, tolerability, and long-term persistence rates.[25]
• Long-Term Safety and Pharmacovigilance: The ongoing 156-week extension study is providing crucial long-term safety data. Continued pharmacovigilance and real-world safety monitoring will be essential to identify any rare or delayed adverse events that may only become apparent with widespread, long-term use in diverse populations.[76]
• Combination Therapy: The promising real-world evidence for combining Atogepant with onabotulinumtoxinA should be validated in prospective, controlled clinical trials. Further research is also needed to explore the safety and efficacy of combining Atogepant with other CGRP-targeted therapies, such as an acute-treatment gepant or even a CGRP mAb, to determine if a dual-blockade strategy can provide additional benefit for the most refractory patients.[11]

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