Zavegepant (Zavzpret): A Comprehensive Monograph on a Novel Intranasal CGRP Receptor Antagonist for the Acute Treatment of Migraine

1.0 Executive Summary & Introduction to CGRP Antagonism in Migraine Therapy

1.1 Executive Summary

Zavegepant, marketed under the brand name Zavzpret®, is a third-generation, small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist approved for the acute treatment of migraine with or without aura in adults.[1] Developed by Pfizer following its acquisition of Biohaven Pharmaceuticals, Zavegepant represents a significant innovation in migraine therapeutics as the first and only "gepant" class medication formulated for intranasal administration.[1] This unique delivery system is designed to provide rapid onset of action, with clinical trials demonstrating pain relief as early as 15 minutes post-dose.[6] Its mechanism of action, which targets the well-established CGRP pathway in migraine pathophysiology, offers a valuable alternative to traditional therapies, particularly for patients who experience significant nausea and vomiting or who have contraindications to triptans.[8] With a robust clinical profile demonstrating efficacy and a favorable safety and tolerability record, Zavegepant is positioned to address key unmet needs in the management of acute migraine attacks.[6]

1.2 The Pathophysiological Role of CGRP in Migraine

The development of Zavegepant and its therapeutic class is rooted in decades of research elucidating the central role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine.[10] CGRP is a 37-amino acid neuropeptide that is widely distributed throughout the central and peripheral nervous systems. In the context of migraine, it is of paramount importance within the trigeminovascular system.[8] During a migraine attack, activation of the trigeminal ganglion leads to the release of CGRP from sensory nerve endings that innervate the meningeal blood vessels.[8]

Once released, CGRP acts as a potent vasodilator and a key modulator of nociceptive (pain) signaling.[8] It binds to its receptors on the smooth muscle cells of dural and pial arteries, causing vasodilation, and also acts on various cells within the trigeminal system to promote a state of neurogenic inflammation and peripheral and central sensitization. This cascade of events is believed to be directly responsible for the severe, throbbing headache characteristic of migraine, as well as associated symptoms like photophobia (light sensitivity) and phonophobia (sound sensitivity).[8] The discovery that CGRP levels are elevated in the jugular vein blood of patients during a migraine attack, and that these levels normalize with effective treatment, provided the foundational evidence for targeting this pathway for therapeutic intervention.[10]

1.3 The Evolution of "Gepants": A New Era in Migraine Treatment

The targeted inhibition of the CGRP pathway gave rise to a new class of small-molecule CGRP receptor antagonists, colloquially known as "gepants".[3] The first generation of these drugs, such as olcegepant (intravenous) and telcagepant (oral), demonstrated clinical proof-of-concept by effectively treating acute migraine attacks.[3] However, their development was halted due to formulation challenges (olcegepant) or signals of liver toxicity (hepatotoxicity) with daily dosing (telcagepant), which precluded their use for preventive therapy.[3]

These initial setbacks led to the development of second- and third-generation gepants, which were structurally optimized to retain high affinity for the CGRP receptor while eliminating the chemical liabilities associated with hepatotoxicity. This effort culminated in the successful approval of oral agents like ubrogepant and rimegepant for acute treatment, and later, rimegepant for preventive treatment.[3] Zavegepant is a member of this successful third generation of gepants, characterized by high selectivity and a favorable safety profile.[4] A key clinical advantage of the gepant class is that, unlike triptans and other older acute medications, CGRP signal-blocking therapies have not been associated with medication overuse headache (MOH) or rebound headaches, a common and debilitating complication of frequent acute medication use.[9]

1.4 Zavegepant: A Unique Position as the First Intranasal Gepant

Zavegepant distinguishes itself within this modern therapeutic class as the first and only CGRP receptor antagonist to be formulated and approved as a nasal spray.[4] This formulation was not an incidental choice but a deliberate strategic decision to overcome well-known clinical barriers in acute migraine treatment. A significant portion of individuals with migraine experience severe nausea and vomiting during an attack, which can make the administration of oral medications difficult or impossible.[4] Furthermore, a common but often overlooked symptom of migraine is gastroparesis, a delay in stomach emptying that can significantly impair or slow the absorption of oral drugs, reducing their efficacy and delaying the onset of relief.[15]

By delivering the medication directly onto the highly vascularized nasal mucosa, the intranasal route bypasses the gastrointestinal tract entirely, ensuring drug absorption is not compromised by these common migraine symptoms. This approach offers a needle-free, non-oral alternative for patients who require rapid relief or for whom oral therapies are suboptimal.[15] Therefore, Zavegepant was engineered not merely as another effective gepant, but as a specific solution for a defined patient population with unmet needs, positioning it as a complementary and valuable tool alongside existing oral CGRP antagonists.

2.0 Chemical Profile and Pharmaceutical Formulation

2.1 Systematic Identification

To ensure precise identification across scientific literature and databases, Zavegepant is cataloged with a comprehensive set of identifiers:

• Generic Name: Zavegepant [1]
• Brand Name: Zavzpret® [1]
• Developmental Codes: BHV-3500, BMS-742413 [1]
• DrugBank ID: DB15688 [1]
• CAS Number: 1337918-83-8 (for the free base); 1414976-20-7 (for the hydrochloride salt) [1]
• PubChem CID: 53472683 [1]
• Other Key Identifiers:
• UNII: ODU3ZAZ94J [1]
• KEGG: D11898 [1]
• ChEMBL: CHEMBL2397415 [1]

2.2 Structural and Physicochemical Properties

Zavegepant is classified as a small molecule drug with a complex chemical architecture.

• Drug Type: Small Molecule [1]
• IUPAC Name: N--1-oxopropan-2-yl]-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide.[1]
• Chemical Formula: C36​H46​N8​O3​ (free base); C36​H46​N8​O3​⋅HCl (hydrochloride salt).[17]
• Molecular Weight: 638.82 g/mol (free base); 675.28 g/mol (hydrochloride salt).[17]
• Chemical Structure & Identifiers: The molecule's structure is defined by several key moieties, including indazole, piperazine, piperidine, and quinolone groups.[8] Its unique structure is further defined by the following standard chemical identifiers:
• InChI: InChI=1S/C36H46N8O3/c1−24−19−25(20−28−23−37−40−33(24)28)21−32(35(46)43−17−15−42(16−18−43)29−9−11−41(2)12−10−29)39−36(47)44−13−7−26(8−14−44)30−22−27−5−3−4−6−31(27)38−34(30)45/h3−6,19−20,22−23,26,29,32H,7−18,21H2,1−2H3,(H,37,40)(H,38,45)(H,39,47)/t32−/m1/s1.[1]
• InChIKey: JJVAPHYEOZSKJZ-JGCGQSQUSA-N.[1]
• SMILES: CC1=CC(=CC2=C1NN=C2)C[C@H](C(=O)N3CCN(CC3)C4CCN(CC4)C)NC(=O)N5CCC(CC5)C6=CC7=CC=CC=C7NC6=O.[8]
• Physical Description: The active pharmaceutical ingredient used in the final formulation is zavegepant hydrochloride, which is a white to off-white powder. It has two pKa values of 4.8 and 8.8.[17] A critical physicochemical property is its high solubility; it is described as being "freely soluble in water".[17]

The high water solubility of zavegepant hydrochloride is a key molecular feature that enables its unique formulation. Intranasal delivery requires the active drug to be dissolved at a therapeutic concentration within the small volume of an aqueous solution that can be delivered in a single spray. Many complex small molecules suffer from poor aqueous solubility, which would necessitate complex formulations with potentially irritating co-solvents. The intrinsic high solubility of zavegepant hydrochloride allows for a relatively simple, well-tolerated aqueous solution, making the intranasal route a feasible and attractive development path.[8] Thus, the success of Zavzpret is as much a product of pharmaceutical chemistry as it is of pharmacology.

2.3 Zavzpret® Nasal Spray Formulation

The final marketed product, Zavzpret, is a pre-filled, single-use device designed for ease of use during a migraine attack.

• Dosage Form: Nasal Spray.[1]
• Strength and Delivery: Each unit-dose device is formulated to deliver a single 10 mg spray of zavegepant into one nostril. This dose is equivalent to 10.6 mg of the zavegepant hydrochloride salt.[17]
• Excipients: The drug is delivered in a buffered aqueous solution containing inactive ingredients necessary for stability and administration. These include dextrose, succinic acid, hydrochloric acid, and sodium hydroxide in water for injection.[17]

3.0 Comprehensive Pharmacological Profile

3.1 Mechanism of Action

Zavegepant exerts its therapeutic effect through a highly specific and targeted mechanism. It is a high-affinity, selective antagonist of the calcitonin gene-related peptide (CGRP) receptor.[4] The drug competitively binds to this receptor, physically blocking the endogenous CGRP neuropeptide from docking and initiating its downstream signaling pathways.[3] This blockade is believed to reverse the CGRP-mediated effects that drive a migraine attack, namely the vasodilation of intracranial and meningeal arteries and the transmission of pain signals within the trigeminovascular system.[8] As a third-generation gepant, Zavegepant is characterized by its high selectivity and structural uniqueness, which contribute to both its efficacy and its favorable safety profile, notably the absence of the hepatotoxicity concerns that plagued earlier compounds.[4]

3.2 Pharmacodynamics

Pharmacodynamic studies have been conducted to characterize the physiological effects of Zavegepant in humans, with a focus on cardiovascular safety.

• Cardiac Electrophysiology: A thorough QT study was conducted to assess the drug's potential to affect cardiac repolarization. At doses up to 40 mg, four times the recommended clinical dose, Zavegepant did not prolong the QT interval to any clinically relevant extent.[17] This is a critical safety finding that alleviates concerns about proarrhythmic potential.
• Hemodynamic Effects: To assess potential vascular interactions, Zavegepant was co-administered with sumatriptan, a triptan-class migraine drug known to cause vasoconstriction. The study found no clinically significant differences in resting blood pressure when the two drugs were given together compared to sumatriptan alone.[17] This suggests Zavegepant does not potentiate the vasoconstrictive effects of triptans and supports its use as an alternative for patients with cardiovascular contraindications to triptans.
• Clinical Effect Relationship: As is common for many neurological medications, the prescribing information notes that the precise relationship between the pharmacodynamic activity of receptor blockade and the mechanism by which Zavegepant exerts its clinical effects is unknown.[17]

3.3 Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion - ADME)

The pharmacokinetic profile of Zavegepant is uniquely suited to its role as an acute migraine therapy, characterized by rapid absorption and efficient clearance.

• Absorption: Following intranasal administration, Zavegepant is rapidly absorbed from the nasal mucosa. Peak plasma concentrations (Tmax​) are achieved in approximately 30 minutes.[6] This rapid absorption is a key advantage over oral gepants, which typically have a Tmax​ of around 1.5 hours.[20] The absolute bioavailability of the intranasal dose is low, at approximately 5%.[17] Pharmacokinetics are slightly less than dose-proportional up to 40 mg, and studies of once-daily dosing for 14 days showed no evidence of drug accumulation.[17]
• Distribution: Zavegepant is extensively distributed throughout the body. It is highly bound to plasma proteins (approximately 90%), and its mean apparent volume of distribution (Vd​) is very large at approximately 1774 L, indicating significant partitioning into tissues outside of the plasma.[17]
• Metabolism: In vitro studies indicate that Zavegepant is primarily metabolized by the cytochrome P450 enzyme CYP3A4, with a minor contribution from CYP2D6.[17] However, metabolism appears to be a minor pathway for its elimination. Following an intravenous dose of radiolabeled drug, the parent (unchanged) Zavegepant was the most prevalent circulating component in plasma, accounting for approximately 90% of the drug-related material. No major metabolites (defined as those constituting more than 10% of parent drug exposure) were detected in plasma.[17]
• Excretion: The primary route of elimination for Zavegepant is biliary/fecal excretion. After a single intravenous dose, approximately 80% of the dose was recovered as unchanged drug in the feces, while about 11% was recovered as unchanged drug in the urine.[17] The effective half-life ( t1/2​) after a 10 mg nasal spray dose is 6.55 hours, and the mean apparent clearance is 266 L/h.[17]

The pharmacokinetic properties of Zavegepant align almost perfectly with the ideal profile for an abortive medication. The ultra-rapid Tmax​ of 30 minutes facilitates a fast onset of clinical action, which is paramount for patients seeking immediate relief from debilitating migraine pain. This is coupled with a relatively short half-life of about 6.5 hours and a lack of drug accumulation, ensuring that the drug is cleared efficiently from the body. This "fast-on, fast-off" profile minimizes the potential for prolonged side effects and simplifies its use as an on-demand therapy. The fact that the parent drug is the primary active moiety, with no major active metabolites, further contributes to a predictable and straightforward pharmacological effect. While the 5% bioavailability may seem low, it is clearly sufficient to achieve therapeutic concentrations and produce a robust clinical effect, representing an effective trade-off for the benefits of rapid, non-oral absorption.

Table 1: Summary of Key Pharmacokinetic Parameters of Intranasal Zavegepant (10 mg)

Parameter	Value	Source Snippets
Time to Peak Plasma Concentration (Tmax​)	~30 minutes	6
Absolute Bioavailability	~5%	17
Plasma Protein Binding	~90%	17
Apparent Volume of Distribution (Vd​)	~1774 L	17
Primary Metabolizing Enzymes	CYP3A4 (major), CYP2D6 (minor)	17
Effective Half-Life (t1/2​)	6.55 hours	17
Apparent Clearance	266 L/h	17
Route of Excretion (as unchanged drug)	~80% Feces, ~11% Urine (after IV dose)	17

4.0 Clinical Efficacy and Performance in Pivotal Trials

The clinical development program for Zavegepant was designed to rigorously establish its efficacy and safety, culminating in two pivotal, large-scale, randomized, placebo-controlled trials.

4.1 Dose-Finding and Optimization (Phase 2/3 Trial - NCT03872453)

The first pivotal study served as a dose-ranging trial to identify the optimal dose of intranasal Zavegepant for acute migraine treatment.

• Study Design: This Phase 2/3 trial (NCT03872453) was a randomized, double-blind, placebo-controlled study in which 1,581 participants were analyzed for efficacy. Patients were randomized to treat a single migraine attack of moderate to severe intensity with one of three doses of Zavegepant nasal spray (5 mg, 10 mg, or 20 mg) or a matching placebo.[4]
• Co-Primary Endpoints: The trial's success was measured by two co-primary efficacy endpoints: freedom from pain at 2 hours post-dose, and freedom from the patient's self-identified most bothersome symptom (MBS), chosen from photophobia, phonophobia, or nausea, also at 2 hours post-dose.[4]
• Efficacy Results: The results demonstrated a clear dose-response relationship. Both the 10 mg and 20 mg doses of Zavegepant were statistically superior to placebo on both co-primary endpoints.[4]
• Pain Freedom at 2 hours: The percentage of patients achieving complete pain freedom was 22.5% for the 10 mg dose (p=0.0113) and 23.1% for the 20 mg dose (p=0.0055), compared to just 15.5% for placebo.[4]
• MBS Freedom at 2 hours: The percentage of patients free from their most bothersome symptom was 41.9% for the 10 mg dose (p=0.0155) and 42.5% for the 20 mg dose (p=0.0094), compared to 33.7% for placebo.[12]
• The 5 mg dose failed to demonstrate a statistically significant difference from placebo on these primary endpoints.[4]
• Conclusion: This trial successfully established the efficacy of Zavegepant. Given the similar efficacy between the 10 mg and 20 mg doses, the 10 mg dose was selected as the optimal dose to carry forward into the confirmatory Phase 3 trial, balancing robust efficacy with the lowest effective exposure.[6]

4.2 Confirmatory Phase 3 Evidence (Pivotal Trial - NCT04571060)

The second pivotal study (NCT04571060) was a large Phase 3 trial designed to confirm the efficacy and safety of the selected 10 mg dose. The results of this trial were a cornerstone of the New Drug Application (NDA) submitted to the FDA.

• Study Design: This was a randomized, double-blind, placebo-controlled trial involving 1,405 adult participants with a history of 2 to 8 moderate or severe migraine attacks per month. Participants were randomized to self-administer a single 10 mg dose of Zavegepant nasal spray or placebo to treat one qualifying migraine attack. The efficacy analysis was conducted on 1,269 participants.[6]
• Performance on Co-Primary Endpoints: Zavegepant 10 mg demonstrated highly statistically significant superiority over placebo on both regulatory co-primary endpoints at 2 hours post-dose.[6]
• Pain Freedom at 2 hours: 24% of patients in the Zavegepant group were pain-free at 2 hours, compared to 15% in the placebo group (p<0.0001).[6]
• MBS Freedom at 2 hours: 40% of patients in the Zavegepant group were free from their most bothersome symptom at 2 hours, compared to 31% in the placebo group (p=0.0012).[6]

4.3 Onset, Durability, and Breadth of Efficacy (Analysis of Secondary Endpoints)

A key part of Zavegepant's clinical value proposition is its speed of onset, a feature directly linked to its intranasal formulation and rapid pharmacokinetics. The clinical trial program was deliberately designed to capture this benefit by including several prespecified, very early secondary endpoints. This hypothesis-driven approach, which sought to clinically validate the advantages predicted by the drug's pharmacokinetic profile, was highly successful.

• Rapid Onset of Action: The trial demonstrated that Zavegepant provides relief significantly faster than placebo.
• Pain Relief at 15 minutes: A statistically significant separation from placebo was observed for pain relief (defined as a reduction from moderate/severe pain to mild or no pain) at the very first timepoint measured, 15 minutes post-dose (15.9% for Zavegepant vs. 8.0% for placebo; p<0.0001).[6]
• Return to Normal Function at 30 minutes: Patients treated with Zavegepant were also able to return to normal function significantly earlier, with a statistically significant benefit seen at 30 minutes post-dose (10.5% vs. 6.1%; p=0.0059).[6]
• Sustained Efficacy: The therapeutic benefits of Zavegepant were shown to be durable over time. The drug was statistically superior to placebo on endpoints measuring sustained pain relief and sustained pain freedom from 2 to 48 hours post-dose, indicating that the initial relief is maintained for a majority of patients.[6]
• Breadth of Effect: The robustness of Zavegepant's efficacy was underscored by its performance across a wide range of endpoints. In the pivotal NCT04571060 trial, Zavegepant demonstrated superiority to placebo on a total of 15 prespecified primary and secondary outcome measures, highlighting a comprehensive and consistent treatment effect.[11] Furthermore, a pooled analysis of both pivotal trials confirmed its efficacy and tolerability specifically in women, who represent over 80% of the study population and the majority of migraine sufferers.[25]

The successful demonstration of efficacy at these early time points is not a fortuitous finding but rather the clinical confirmation of a benefit predicted by the drug's fundamental pharmacokinetic properties. The seamless narrative—from the rapid 30-minute Tmax​ observed in Phase 1 studies to the statistically significant pain relief at 15 minutes in Phase 3—provides compelling evidence of a sophisticated and successful drug development strategy.

Table 2: Summary of Efficacy Outcomes from Pivotal Phase 3 Trial (NCT04571060)

Endpoint	Time Point	Zavegepant 10 mg	Placebo	p-value	Source Snippets
Co-Primary: Pain Freedom	2 hours	23.6%	14.9%	<0.0001	6
Co-Primary: MBS Freedom	2 hours	39.6%	31.1%	0.0012	6
Secondary: Pain Relief	15 minutes	15.9%	8.0%	<0.0001	6
Secondary: Pain Relief	2 hours	58.7%	49.7%	0.0012	6
Secondary: Return to Normal Function	30 minutes	10.5%	6.1%	0.0059	6
Secondary: Return to Normal Function	2 hours	35.8%	25.6%	0.0001	6
Secondary: Sustained Pain Relief	2-48 hours	36.1%	29.6%	0.013	6

5.0 Safety, Tolerability, and Risk Management

The safety and tolerability of Zavegepant were extensively evaluated throughout its clinical development program, demonstrating a favorable profile consistent with the third-generation gepant class.

5.1 Integrated Analysis of Adverse Events

Data from two pivotal, randomized, double-blind, placebo-controlled trials, which included 1,023 patients treated with a 10 mg dose of Zavegepant, form the basis of the primary safety assessment.[18]

• Most Common Adverse Events (AEs): The most frequently reported adverse events were generally mild, transient, and related to the intranasal route of administration or the inherent taste of the molecule.[6] The AEs reported in at least 2% of patients and at a higher rate than placebo were:
• Taste Disorders: This category, including dysgeusia (altered taste) and ageusia (loss of taste), was the most common AE, reported by 18% of patients on Zavegepant compared to 4% on placebo.[11]
• Nausea: Reported by 4% of patients on Zavegepant versus 1% on placebo.[11]
• Nasal Discomfort: Reported by 3% of patients on Zavegepant versus 1% on placebo.[11]
• Vomiting: Reported by 2% of patients on Zavegepant versus less than 1% on placebo.[11]
• Severity and Seriousness: The vast majority of these adverse events were characterized as mild or moderate in intensity and typically resolved without intervention.[4] Importantly, no treatment-related serious adverse events were reported in the pivotal trials, and there were no deaths.[6]
• Hepatotoxicity: Consistent with other third-generation gepants, the Zavegepant clinical program revealed no signal of hepatotoxicity. Liver enzyme monitoring did not identify any cases of drug-induced liver injury, a critical safety feature that distinguishes this class from earlier-generation compounds.[4]

5.2 Long-Term Safety Evaluation

To assess safety with repeated use over time, a one-year, open-label, long-term safety study was conducted in which 603 patients were treated with Zavegepant 10 mg as needed for migraine attacks.[27]

• Adverse Event Profile: The types of adverse events reported were consistent with those seen in the short-term placebo-controlled trials. As expected with longer exposure, the incidence rates were higher. Treatment-emergent AEs reported in at least 5% of subjects included dysgeusia (39.1%), nasal discomfort (10.3%), COVID-19 (7.5%), nausea (6.1%), nasal congestion (5.5%), throat irritation (5.5%), and back pain (5.3%).[28]
• Discontinuation Rate: Over the one-year study period, 6.8% of participants discontinued treatment due to adverse events. Notably, despite being the most common AE, dysgeusia led to discontinuation in only 1.5% of patients, suggesting it was generally well-tolerated.[28]
• Serious AEs: Seven serious adverse events were reported during the study, none of which were considered to be related to Zavegepant by the investigators.[28]

5.3 Contraindications, Warnings, and Drug Interactions

The FDA-approved prescribing information outlines specific risk management guidance for Zavegepant.

• Contraindications: Zavegepant is contraindicated in patients with a known history of hypersensitivity to zavegepant or any of its components.[11]
• Warnings and Precautions: Cases of hypersensitivity reactions, including facial swelling and urticaria (hives), have occurred in clinical studies. The label warns that if a hypersensitivity reaction occurs, Zavegepant should be discontinued immediately and appropriate medical therapy initiated.[7]
• Drug-Drug Interactions: Zavegepant is a substrate for certain drug transporters and metabolizing enzymes, leading to potential interactions:
• Transporter Inhibitors: Zavegepant is a substrate of the organic anion transporting polypeptide 1B3 (OATP1B3) and the sodium taurocholate co-transporting polypeptide (NTCP). Co-administration with drugs that inhibit these transporters (e.g., cyclosporine, rifampin, clarithromycin, erythromycin) may significantly increase Zavegepant plasma concentrations and should be avoided.[3]
• Intranasal Decongestants: The use of intranasal decongestants may affect the absorption of Zavegepant. Their use should be avoided if possible. If concomitant use is necessary, the decongestant should be administered at least one hour after Zavegepant administration.[3]

5.4 Use in Specific Patient Populations

Recommendations for use in specific populations are based on available data and pharmacokinetic principles.

• Renal Impairment: No dosage adjustment is necessary for patients with mild to moderate renal impairment. However, Zavegepant has not been studied in patients with severe renal impairment (creatinine clearance, CrCl<30 mL/min), and its use should be avoided in this population.[11]
• Hepatic Impairment: No dosage adjustment is needed for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The drug has not been studied in patients with severe hepatic impairment (Child-Pugh C), and its use should be avoided in this population.[11]
• Pediatric and Geriatric Use: The safety and effectiveness of Zavegepant have not been established in pediatric patients.[7] While clinical studies did not identify specific problems limiting its usefulness in the elderly, the number of geriatric participants was insufficient to determine if they respond differently from younger adults.[16]
• Pregnancy and Lactation: There are no adequate and well-controlled studies of Zavegepant use in pregnant or breastfeeding women. The potential risks and benefits must be carefully weighed.[16]

6.0 Development History and Regulatory Approval

The path of Zavegepant from a chemical compound to a marketed therapy is a compelling narrative of intellectual property licensing, focused clinical development by a nimble biotech, and eventual acquisition by a pharmaceutical giant.

6.1 Corporate Development Trajectory: From Big Pharma IP to Biotech Engine to Blockbuster Acquisition

The journey of Zavegepant illustrates a modern paradigm in pharmaceutical development.

• Origins at Bristol-Myers Squibb: The foundational intellectual property for Zavegepant (then known as BMS-742413) and its sister compound, rimegepant, originated within the research and development programs of Bristol-Myers Squibb (BMS).[21]
• Licensing and Development by Biohaven: In July 2016, a newly formed biotechnology company, Biohaven Pharmaceutical, executed a pivotal strategic move by licensing the exclusive worldwide rights to develop and commercialize BMS's CGRP antagonist portfolio. This portfolio, including Zavegepant, became the cornerstone of Biohaven's pipeline and corporate strategy.[29] Biohaven successfully advanced the compounds through rigorous clinical trials, focusing on demonstrating their efficacy and safety.
• Strategic Collaboration with Pfizer: As Biohaven achieved clinical and commercial success with rimegepant (Nurtec ODT), the value of its CGRP franchise grew substantially. In November 2021, this attracted the attention of Pfizer, leading to a major strategic collaboration. Under this agreement, Pfizer acquired the rights to commercialize rimegepant and Zavegepant outside of the United States, while Biohaven retained U.S. rights and continued to lead global research and development. The deal included a significant upfront payment and a $350 million equity investment by Pfizer into Biohaven.[29]
• Full Acquisition by Pfizer: The collaboration served as a prelude to a much larger transaction. Recognizing the immense potential of the entire CGRP platform, including the market leadership of Nurtec ODT and the highly differentiated profile of the soon-to-be-approved intranasal Zavegepant, Pfizer moved to acquire Biohaven outright. The acquisition, valued at approximately $11.6 billion, was completed in October 2022.[5]

This acquisition was not merely for a single drug but for a dominant position in the large and growing global migraine market. The successful Phase 3 results for Zavegepant, which demonstrated a unique, rapid-onset profile in a patient-friendly formulation, significantly de-risked Biohaven's pipeline and acted as a powerful catalyst for the acquisition. The story of Zavegepant is thus a prime example of how a well-differentiated pipeline asset with strong clinical data can create enormous strategic value, ultimately reshaping a major pharmaceutical company's portfolio.

6.2 Regulatory Pathway and Approval

Zavegepant's clinical and regulatory timeline was efficient and milestone-driven.

• Clinical Development: The foundation for approval was built upon the positive results from the Phase 2/3 dose-ranging study (NCT03872453) and the confirmatory Phase 3 pivotal trial (NCT04571060).[14] While other potential indications such as asthma were briefly explored and terminated (NCT04987944), the development program remained sharply focused on the acute treatment of migraine.[34]
• NDA Submission and Review: Following the positive topline results from the second pivotal trial in late 2021, Biohaven prepared and submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA). The NDA was formally accepted for review in May 2022.[32]
• FDA Approval: On March 9, 2023, the FDA granted approval for Zavegepant, to be marketed as Zavzpret, for the acute treatment of migraine with or without aura in adults.[1]
• Commercial Launch: Following the approval, Pfizer announced that Zavzpret was anticipated to become available in U.S. pharmacies in July 2023, marking its entry into the market.[11]

7.0 Synthesis and Expert Clinical Perspective

7.1 Comparative Positioning in the Migraine Armamentarium

Zavegepant (Zavzpret) enters a dynamic and increasingly sophisticated landscape of acute migraine treatments. Its clinical value is best understood by its positioning relative to other established and novel therapies.

• vs. Oral Gepants (Rimegepant, Ubrogepant): The primary and most significant differentiator is the intranasal route of administration and the consequent pharmacokinetic profile. Zavegepant's time to peak plasma concentration (Tmax​) of approximately 30 minutes provides a tangible advantage in speed of onset compared to the approximate 1.5-hour Tmax​ of its oral counterparts.[20] This makes Zavegepant a compelling option for patients who experience rapidly escalating migraine attacks where every minute to relief counts. It is not necessarily a replacement for oral gepants but rather a complementary tool for specific clinical scenarios demanding ultra-rapid action.
• vs. Triptans: For decades, triptans have been the standard of care for moderate to severe migraine. However, their vasoconstrictive mechanism of action precludes their use in patients with or at high risk for cardiovascular, cerebrovascular, or peripheral vascular disease.[4] Zavegepant, with its targeted CGRP receptor antagonism and demonstrated lack of clinically relevant vasoconstrictive effects, provides a first-line, highly effective alternative for this significant patient population.[9] Furthermore, the well-documented issue of medication overuse headache (MOH) associated with frequent triptan use is not a known concern with the gepant class, offering another critical advantage for patients with frequent migraines.[9]

7.2 The Clinical Value of Intranasal Delivery

The formulation of Zavegepant as a nasal spray is central to its clinical utility and addresses long-standing challenges in acute migraine care.

• Addressing Gastrointestinal Symptoms: Migraine is a systemic neurological disorder, and associated symptoms are often as debilitating as the head pain itself. Severe nausea and vomiting can make taking an oral tablet untenable, while migraine-induced gastroparesis can render it ineffective.[4] By bypassing the gastrointestinal system entirely, the intranasal route ensures reliable and rapid drug absorption, irrespective of the patient's GI status. This makes Zavegepant an invaluable option for the large subset of migraine sufferers for whom oral medications are poorly tolerated or unreliable.
• Patient Preference and Convenience: For patients seeking a non-oral route of administration, Zavegepant offers a convenient, portable, and needle-free alternative to subcutaneous injections.[15] The single-use, pre-filled device is designed for simple, on-the-go administration, empowering patients to treat an attack effectively at its onset.

7.3 Concluding Assessment and Future Outlook

Zavegepant (Zavzpret) is a landmark achievement in migraine therapeutics, representing the successful convergence of a targeted pharmacological mechanism with a patient-centric drug delivery technology. It is the first CGRP receptor antagonist nasal spray, a formulation that directly addresses the unmet needs of patients who require ultra-rapid relief and those whose attacks are accompanied by severe gastrointestinal distress. Its clinical development program has robustly demonstrated rapid, durable, and broad efficacy, complemented by a favorable safety and tolerability profile that aligns with the high standards of its therapeutic class.

The future for the Zavegepant molecule appears promising and extends beyond its current indication. Clinical development of an oral formulation of Zavegepant is currently underway, with a focus on the preventive treatment of migraine.[5] This lifecycle management strategy, if successful, could establish Zavegepant as a versatile therapeutic agent, available in two distinct formulations tailored for different clinical purposes: an intranasal spray for acute, rapid-onset relief and an oral tablet for prophylaxis. This potential for a dual-formulation, dual-indication franchise further solidifies the strategic value of Zavegepant within Pfizer's comprehensive migraine portfolio and promises to offer even more tailored treatment options for individuals living with this debilitating neurological disease.

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