Lasmiditan: A Breakthrough for Migraine Treatment – Dr Debjyoti Dutta MD. FIPP.

What is Lasmiditan? 

• Lasmiditan is a novel medication specifically designed to alleviate symptoms associated with migraine headaches. 

• Unlike traditional migraine treatments, which often include triptans (such as sumatriptan), Lasmiditan belongs to a different class of drugs called serotonin (5-HT1F) receptor agonists. 

• It works by targeting the serotonin receptors in the brain, ultimately reducing the intensity of migraines. 

Lasmiditan represents a significant advancement in the management of acute migraine episodes in adults. Approved by the U.S. Food and Drug Administration (FDA) in October 2019 and subsequently launched in February 2020, Lasmiditan offers a novel approach to treating migraines with or without aura, addressing a crucial medical need for those afflicted by this debilitating condition. 

Unlike traditional migraine treatments, Lasmiditan is not intended for prevention but rather for the active treatment of migraine attacks as they occur. Administered orally, it quickly alleviates migraine symptoms, providing relief from pain and associated discomfort. 

Developed by Eli Lilly, Lasmiditan is recognized as a first-in-class medication by the FDA, signifying its unique mechanism of action compared to existing therapies. By targeting specific receptors involved in the migraine pathway, Lasmiditan offers a promising option for individuals seeking effective relief from migraine symptoms, including pain, sensory disturbances, and visual disturbances. 

Although Lasmiditan demonstrates efficacy in mitigating migraine symptoms, it may induce certain side effects such as sleepiness, dizziness, tiredness, and numbness. Despite these potential adverse effects, its approval and availability mark a significant milestone in migraine treatment, providing patients with a valuable alternative for managing acute migraine episodes and improving their quality of life. 

Mechanism of Action of Lasmiditan: 

Lasmiditan operates as a serotonin receptor agonist, specifically targeting the 5-HT1F receptor subtype. This selective binding is akin to the mechanism of action of LY-334,370, although the latter proved unsuccessful in clinical trials. Unlike many other migraine medications, Lasmiditan's action is focused solely on the 5-HT1F receptor subtype, distinguishing it from triptans which typically interact with multiple serotonin receptor subtypes, including 5-HT1B and 5-HT1D. 

The 5-HT1F receptor subtype has been implicated in the pathophysiology of migraine, making it a key target for therapeutic intervention. By selectively activating this receptor subtype, Lasmiditan modulates the release of neurotransmitters and dampens neuronal activity associated with migraine attacks. Importantly, Lasmiditan's unique pharmacological profile may result in fewer side effects related to vasoconstriction compared to triptans. This reduced risk is particularly advantageous for individuals with underlying conditions such as ischemic heart disease, Raynaud's phenomenon, or those recovering from a myocardial infarction. 

Although triptans have historically been effective in managing migraine symptoms, their potential for vasoconstriction-related adverse effects has limited their use in certain patient populations. Lasmiditan's distinct mechanism of action offers a promising alternative for individuals seeking migraine relief without the associated cardiovascular risks. Through its targeted modulation of serotonin receptors, Lasmiditan represents a significant advancement in the treatment of acute migraine episodes, providing effective symptom relief with a potentially improved safety profile. 

Dosing in Adult for Lasmiditan: 

• The recommended dosage of Lasmiditan is 50 mg, 100 mg, or 200 mg, to be taken orally, as needed for the treatment of migraine. 

• It is important not to exceed more than one dose within a 24-hour period. 

• Tablets should be administered whole, without breaking or crushing them. 

 Adverse Effects of Lasmiditan: 

1. Driving Impairment: Lasmiditan poses a risk of driving impairment, necessitating caution in activities requiring alertness and coordination. Individuals are advised against driving or operating machinery for a minimum of eight hours after taking Lasmiditan, regardless of how they feel post-medication. 

1. Central Nervous System (CNS) Depression: Lasmiditan induces CNS depression, leading to symptoms such as dizziness and sedation. This effect can impair cognitive function and motor skills, affecting daily activities and tasks that require mental clarity and physical coordination. 

1. Interaction with Alcohol and CNS Depressants: Lasmiditan should be used cautiously in combination with alcohol or other CNS depressants due to the potential for additive effects. Concurrent use may exacerbate CNS depression, heightening the risk of dizziness, sedation, and impaired cognitive function. 

1. Rare but Serious Adverse effect – Serotonin Syndrome  

Overall, while Lasmiditan offers effective relief from migraine symptoms, its adverse effects necessitate careful consideration and adherence to safety precautions, particularly regarding activities that demand cognitive and motor proficiency.

Drug Interaction of Lasmiditan: 

Medications that interact with Lasmiditan: 

1. Aripiprazole 

1. Isotretinoin 

1. Amphetamine / Dextroamphetamine 

1. Zolpidem 

1. Citalopram 

1. Loperamide 

1. Topiramate 

1. Sertraline 

History of Lasmiditan: 

1. Discovery and Licensing: Lasmiditan was initially discovered by Eli Lilly and Company. Subsequently, the drug's rights were licensed to CoLucid Pharmaceuticals in 2006. However, in 2017, Eli Lilly repurchased the drug's intellectual property by acquiring CoLucid Pharmaceuticals. This strategic move allowed Eli Lilly to regain control over Lasmiditan's development and commercialization. The drug is protected by patents until 2031, securing its exclusivity in the market. 

1. Clinical Trials: Phase II clinical trials for Lasmiditan were conducted to determine optimal dosing regimens. These trials, completed in 2007 for an intravenous formulation and in early 2010 for an oral formulation, aimed to establish the safety and efficacy of the drug in treating migraine episodes. Following promising results from Phase II trials, Eli Lilly submitted a new drug application to the U.S. Food and Drug Administration (FDA) in November 2018, seeking approval for Lasmiditan's marketing and distribution. 

1. Phase III Clinical Trials: Lasmiditan underwent three Phase III clinical trials to further evaluate its effectiveness and safety profile. The SPARTAN trial compared Lasmiditan with placebo across multiple dosage strengths, while the SAMURAI trial focused on specific dosage comparisons against placebo. Additionally, the GLADIATOR study, an open-label trial, investigated Lasmiditan's efficacy in subjects previously exposed to the drug in prior trials. 

1. FDA Approval: Lasmiditan received FDA approval in October 2019, marking a significant milestone in migraine treatment. The approval was based on data from two pivotal clinical trials involving a total of 4439 subjects with migraine headaches, conducted across 224 sites in the United States, the United Kingdom, and Germany. The drug demonstrated efficacy in relieving migraine symptoms, meeting both primary and secondary endpoints in clinical trials. 

1. Schedule V Classification: Following FDA approval, Lasmiditan was classified under Schedule V of the Controlled Substances Act in January 2020. This classification reflects the drug's low potential for abuse or dependence relative to other controlled substances, underscoring its safety profile for therapeutic use in migraine management. 

Legal Status of Lasmiditan: 

Regulatory Approvals: 

1. United States Food and Drug Administration (USFDA): 

• Lasmiditan received approval from the USFDA in 2019. 

• This marked a significant milestone, as it provided an alternative treatment option for individuals who either couldn’t tolerate or didn’t respond well to triptans. 

1. Drug Controller General of India (DCGI): 

• In India, Lasmiditan has also received regulatory approval. 

• This means that individuals suffering from migraines in India now have access to this innovative medication. 

1. European Union (EU): In June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the granting of marketing authorization for the medicinal product Rayvow, developed for the treatment of migraine. The applicant for this authorization is Eli Lilly Nederland B.V. Subsequently, Rayvow received approval for medical use in the European Union in August 2022. This approval allows for the marketing and distribution of Rayvow as a treatment option for migraine within the EU. 

1. Canada: Lasmiditan has not been approved for use in Canada. Eli Lilly Canada Inc., the drug sponsor, filed a New Drug Submission in February 2020 seeking approval for Lasmiditan's marketing and distribution in Canada. However, before Health Canada issued a final decision, the submission was cancelled by Eli Lilly Canada Inc. in January 2021. Despite Health Canada completing its review of the submission without finding any deficiencies in the data provided, disagreement arose between Health Canada and Eli Lilly regarding the interpretation and wording of cardiovascular data in the product monograph. As a result, the drug sponsor opted to withdraw their submission, leading to the absence of approval for Lasmiditan's use in Canada at present.