−Removed: We are a commercial-stage, pharmaceutical company focused on developing and commercializing innovative therapies for patients living with rare neurological diseases as well as patients living with other neurological diseases who have unmet medical needs.
−Removed: Our product, WAKIX (pitolisant), is a first-in-class molecule with a novel mechanism of action (“MOA”) specifically designed to increase histamine signaling in the brain by binding to H 3 receptors.
−Removed: In August 2019, WAKIX was approved by the U.S.
−Removed: Food and Drug Administration (the “FDA”) for the treatment of excessive daytime sleepiness (“EDS”) in adult patients with narcolepsy, and its U.S.
−Removed: commercial launch was initiated in November 2019.
−Removed: In October 2020, WAKIX was approved by the FDA for the treatment of cataplexy in adult patients with narcolepsy.
−Removed: WAKIX is the first-and-only approved product for patients with narcolepsy that is not scheduled as a controlled substance by the U.S.
−Removed: Drug Enforcement Administration (the “DEA”).
−Removed: We believe that pitolisant’s ability to regulate histamine gives it the potential to provide therapeutic benefit in other rare neurological diseases that are mediated through H 3 receptors and histamine signaling.
−Removed: We are taking a mechanism-based approach to managing the life cycle of pitolisant and identified idiopathic hypersomnia (“IH”), another central disorder of hypersomnolence like narcolepsy, as our next potential new indication for pitolisant.
−Removed: We received orphan drug designation by the FDA for IH in September 2023 and Fast Track Designation in November 2023.
−Removed: In April 2022, we initiated a Phase 3 registrational trial, the INTUNE Study, to evaluate the efficacy and safety of pitolisant in adult patients with IH.
−Removed: We completed enrollment in the INTUNE study in May 2023 and we announced topline data in October 2023.
−Removed: While the primary endpoint did not meet statistical significance, we believe the totality of the data showed favorable numerical trends for pitolisant in the treatment of adult patients with IH and we have scheduled a meeting with the FDA for March 2024 to discuss the path forward for IH.
−Removed: We are focusing our development efforts on other rare neurological disorders in which EDS is a prominent symptom, including Prader-Willi Syndrome (“PWS”) and myotonic dystrophy, otherwise known as dystrophia myotonica (“DM”).
−Removed: Based on the positive signals from the Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS and other key symptoms in patients with PWS, an end-of-phase 2 meeting with the FDA was held in June 2023.
−Removed: We believe we aligned with the FDA on the proposed Phase 3 registrational study design for further investigation of pitolisant as a potential treatment to address the unmet medical need for children, adolescents and adults with PWS experiencing EDS, for which there is currently no approved treatment.
−Removed: In October 2023, we received FDA alignment regarding the protocol for the Phase 3 TEMPO study in patients with PWS, which we believe will satisfy the requirements for both the registrational trial and one of the two requirements for pediatric exclusivity for pitolisant, with the other requirement being data in pediatric narcolepsy.
−Removed: In February 2024, the FDA granted Orphan Drug designation to pitolisant for the treatment of PWS.
−Removed: We expect to initiate the Phase 3 study in the first quarter of 2024.
−Removed: In June 2021, we initiated a Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS, fatigue and cognitive dysfunction in adult patients with DM1 and announced positive topline results from this trial in the fourth quarter of 2023 in which clinically meaningful improvements were demonstrated in EDS and fatigue, and the safety profile was consistent with the established safety profile of pitolisant.
−Removed: Our partner, Bioprojet completed a Phase 3 trial in pediatric patients with narcolepsy and submitted the trial data to the European Medicines Agency (the “EMA”) seeking approval for a pediatric narcolepsy indication.
−Removed: On January 26, 2023, Bioprojet received a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (“CHMP”) and in March 2023, the EMA granted approval for the marketing authorization of WAKIX for the treatment of narcolepsy in children
−Removed: Based on the data from the positive Phase 3 trial conducted by Bioprojet, we submitted an sNDA for pediatric narcolepsy in December 2023.
−Removed: On February 21, 2024, we announced that the FDA has granted priority review of our pediatric narcolepsy sNDA and has set a Prescription Drug User Fee Act (“PDUFA”), or target action date, of June 21, 2024.
−Removed: We remain committed to obtaining pediatric exclusivity for WAKIX.
−Removed: We also seek to expand our pipeline through the acquisition of additional assets that focus on addressing the unmet needs of patients living with rare neurological diseases as well as patients living with other neurological diseases who have unmet medical needs.
−Removed: We are targeting assets that will allow us to further leverage the expertise and infrastructure that we have successfully built at Harmony so we can optimize the benefit of internal synergies.
−Removed: Consistent with this objective, in July 2022, we entered into a License and Commercialization Agreement (the “2022 LCA”) with Bioprojet whereby we obtained exclusive rights to manufacture, use and commercialize one or more new products based on pitolisant in the United States and Latin America, with the potential to add additional indications and formulations upon the agreement of both parties.
−Removed: We have made progress in the development of two formulations, Next Gen 1 (“NG1”) and Next Gen 2 (“NG2”).
−Removed: Both formulations entered clinical studies in the fourth quarter of 2023, and we anticipate data in the first half of 2024.
−Removed: In addition, on October 10, 2023, the Company completed a tender offer to acquire all of the outstanding shares of common stock (the “Zynerba Acquisition”) of Zynerba Pharmaceuticals, Inc.
−Removed: (together with its subsidiary, Zynerba Pharmaceutical Pty, Ltd., “Zynerba”) for $60.0 million, and incurred transaction related costs of approximately $2.6 million.
−Removed: Zynerba is a clinical-stage pharmaceutical company focused on innovative pharmaceutically produced transdermal cannabidiol therapies for orphan neuropsychiatric disorders, including Fragile X syndrome (“FXS”).
−Removed: The phase 3 RECONNECT registration study in FXS is ongoing.
−Removed: In August 2021, we acquired HBS-102, a Melanin-concentrating hormone receptor 1 (MCHR1) antagonist previously developed as CSTI-100/ALB-127258(a)/ALB-127258 (the “Compound”), along with intellectual property and other assets related to the development, manufacture, and commercialization of the Compound from ConSynance Therapeutics, Inc.
−Removed: In connection with the acquisition, we made an upfront payment of $3.5 million and will be required to make certain payments upon the achievement of certain development milestones, regulatory milestones, and sales milestones and pay ongoing royalties upon commercialization.
−Removed: We acquired full development and commercialization rights for HBS-102 globally, but we have provided an indication-limited grant-back license to ConSynance for the development and commercialization of the Compound in Greater China.
−Removed: We are conducting a preclinical proof-of-concept study to assess the effect of HBS-102 on hyperphagia, weight gain and other metabolic parameters in a mouse model of PWS and are also conducting a thirteen-week toxicology study.
−Removed: We anticipate data from both studies in the first half of 2024.
+Added: At Harmony, we are cultivating a differentiated neuroscience company, rooted in innovation and driven by a commitment to addressing the unmet needs of patients living with neurological diseases.
+Added: To date, we have focused on rare neurological diseases with a growing portfolio now spanning sleep/wake, neurobehavioral, and rare epilepsy, and we are harnessing scientific insights and pioneering approaches to advance meaningful treatments that help patients thrive.
+Added: Our lead product, WAKIX® (pitolisant) (“WAKIX”), is a first-in-class therapy with a novel mechanism of action designed to enhance histamine signaling in the brain by binding to H 3 receptors.
+Added: Since its initial FDA approval in 2019 for excessive daytime sleepiness (“EDS”) in adult patients with narcolepsy and subsequent approvals for cataplexy in adult patients in 2020 and EDS in pediatric patients six years and older in 2024, WAKIX has continued to reshape the treatment landscape for narcolepsy and remains the only FDA-approved treatment for narcolepsy that is not scheduled as a controlled substance by the U.S.
+Added: Drug Enforcement Administration (“DEA”).
+Added: Beyond narcolepsy, we have taken a mechanistic-based approach to expanding the reach of pitolisant, identifying idiopathic hypersomnia (“IH”) as a potential next indication in its lifecycle.
+Added: In the fourth quarter of 2024, we submitted a supplemental New Drug Application (“sNDA”) for pitolisant in IH based on a comprehensive evaluation of data from our INTUNE study and additional sources.
+Added: In February 2025, we received a Refusal to File letter from the FDA for pitolisant in IH.
+Added: We are also advancing late-stage clinical programs exploring pitolisant in Prader-Willi syndrome (“PWS”) and myotonic dystrophy type 1 (“DM1”) and continue to grow our impact in other rare neurological diseases.
+Added: In July 2022, we entered into the 2022 LCA with Bioprojet whereby we obtained exclusive rights to manufacture, develop and commercialize one or more next generation pitolisant based products in the United States and Latin America.
+Added: Two of the next generation formulations, pitolisant Gastro-Resistant (“pitolisant GR”) and pitolisant High-Dose (“pitolisant HD”) are currently in clinical development.
+Added: Along with nurturing the growth of our original pipeline, our innovation strategy includes targeted business development that strengthens our foundation and strategically extends our patient reach as we look to expand our portfolio to new diseases beyond histaminergic science.
+Added: In October 2023, we acquired Zynerba Pharmaceuticals, Inc.
+Added: (“Zynerba”), adding global rights to develop, manufacture and commercialize ZYN-002, a pharmaceutically manufactured 100% synthetic, patent protected permeation enhanced cannabidiol gel , to our neurobehavioral franchise.
+Added: With a Phase 3 registrational trial underway for Fragile X syndrome (“FXS”) and plans to initiate a Phase 3 registrational trial in 22q deletion syndrome (“22q”) in 2025, we are poised to deliver new treatment possibilities for patients with neurobehavioral conditions.
+Added: In April 2024, we expanded into orexin science through a sublicense agreement with Bioprojet for an orexin 2 receptor agonist (“BP1.15205”) in preclinical development for narcolepsy and other potential indications.
+Added: Under the sublicense agreement we obtained the exclusive right to develop, manufacture and commercialize BP1.15205 in the United States and Latin American territories, which are rights originally licensed from Teijin Pharma, the innovator of BP1.15205.
+Added: We further broadened our portfolio into rare epilepsy with the acquisition of Epygenix Therapeutics, Inc., adding global rights to develop, manufacture and commercialize EPX-100, a serotonin (5HT-2) receptor agonist , and EPX-200, a selective 5HT-2C agonist.
+Added: EPX-100 is in Phase 3 registrational trials for Dravet Syndrome (“DS”) and Lennox-Gastaut Syndrome (“LGS”), and EPX-200 is in the pre-IND phase for developmental and epileptic encephalopathies (“DEEs”).
+Added: Our innovative portfolio of assets reflects our dedication to novel science, innovative therapies and excellence in delivering these treatments to patients with serious medical conditions who have few or no available options.
+Added: Our operations are conducted by our wholly owned subsidiaries, Harmony Biosciences, LLC and Harmony Biosciences Management, Inc., formerly known as Zynerba prior to July 1, 2024 .
+Added: Commercial Product
+Added: Sleep/Wake Franchise
+Added: WAKIX (pitolisant).
Pitolisant was developed by Bioprojet and approved by the EMA in 2016 for the treatment of narcolepsy in adult patients with or without cataplexy and in 2021 for the treatment of EDS in adult patients with obstructive sleep apnea.
1 unchanged sentence
Pitolisant was granted Orphan Drug designation for the treatment of narcolepsy by the FDA in 2010.
−Removed: It received Breakthrough Therapy designation for the treatment of cataplexy in patients with narcolepsy and Fast Track status for the treatment of EDS and cataplexy in patients with narcolepsy in April 2018.
−Removed: Our operations are conducted by our wholly owned subsidiaries, Harmony Biosciences, LLC, which was formed in May 2017 and Zynerba.
−Removed: Narcolepsy Market Overview
−Removed: Narcolepsy is a rare, chronic and debilitating neurological disorder of sleep-wake state instability that is estimated to affect approximately 170,000 Americans, with fewer than 50% diagnosed.
−Removed: Narcolepsy is characterized by EDS, which is present in all patients with narcolepsy and is the primary reason why patients seek treatment.
−Removed: EDS is the inability to stay awake or alert throughout the day, including an irrepressible need for sleep, with lapses into drowsiness or sleep, which has a significant impact on a patient’s ability to function.
−Removed: Additional symptoms of narcolepsy may include cataplexy (which is characterized by sudden and transient episodes of muscle weakness accompanied by full conscious awareness), hallucinations, sleep paralysis and disrupted nighttime sleep.
−Removed: In most patients, narcolepsy is caused by the loss of orexin/hypocretin, a neuropeptide in the brain that, along with histamine, works to support sleep-wake state stability.
−Removed: This disorder affects men and women equally, with typical symptom onset in adolescence or young adulthood;
−Removed: however, it can take up to a decade after onset of symptoms to be properly diagnosed.
−Removed: narcolepsy market had an approximate net sales value of $2.5 billion in 2022.
−Removed: The market is expected to continue to grow based on several factors, including, but
−Removed: not limited to, the introduction of new innovative therapies that offer novel mechanisms of action resulting in improved safety/tolerability profiles while delivering clinically meaningful efficacy, additional investment in education, increased rates of diagnosis, and population growth.
−Removed: Prior to the FDA’s approval of WAKIX in 2019, there were six approved medications to treat patients with narcolepsy, all of which are scheduled as controlled substances, and no new therapies had been approved for narcolepsy patients in the United States since 2007.
−Removed: These medications included Xyrem (sodium oxybate), Provigil (modafinil), Nuvigil (armodafinil), Ritalin (methylphenidate), Adderall (amphetamine salts) and Sunosi (solriamfetol).
−Removed: Following the approval of WAKIX, in July 2020 the FDA approved a new lower sodium formulation of Xyrem called Xywav, followed by generic versions of sodium oxybate in January 2023 and July 2023, as well as a once-nightly version of sodium oxybate (Lumryz) in June 2023.
−Removed: These approved drugs are prescribed in accordance with their individual labels for indications covering narcolepsy, cataplexy and/or EDS related to narcolepsy, and have demonstrated the ability to improve the lives of the patients suffering from these symptoms.
−Removed: In addition, Xywav was approved in August 2021 for the treatment of IH in adults.
−Removed: Other prescription drugs are used off-label for the treatment of either EDS or cataplexy in patients with narcolepsy, including stimulants for EDS and antidepressants for cataplexy.
−Removed: Despite the benefits provided by the available medications, according to the American Academy of Sleep Medicine (“AASM”), traditional stimulants, wake-promoting agents and sodium oxybate, at best, provide only moderate improvement in narcolepsy symptoms and side effects may limit their use.
−Removed: Some of the current therapies have significant side effects (such as increased heart rate and blood pressure) and boxed warnings due to the risk of respiratory depression, abuse, dependence and diversion.
−Removed: These therapies also have the potential for rebound and withdrawal symptoms.
−Removed: The Voice of the Patient report from the FDA’s patient-focused drug development initiative, published in 2014, concluded that, based on the overall benefit-risk assessment of current medications, there is a continued need for additional effective and tolerable treatment options for patients with narcolepsy.
−Removed: In a retrospective electronic chart review conducted by Rush University Medical Center from June 2011 to December 2018, over 75% (73 out of 97 respondents) of patients with narcolepsy reported at least one residual symptom while on their current treatment.
−Removed: In a third-party survey that we commissioned prior to the commercialization of WAKIX, of the 200 patients with narcolepsy who were surveyed, 86% (173 out of 200 respondents) of patients reported narcolepsy is a life changing disorder and 93% (157 out of 169 respondents) expressed frustration with current treatment options, while 31 patients were not on treatment and, as such, did not provide a response to this question.
−Removed: The main drivers of patients’ dissatisfaction were side effects and tolerability, loss of efficacy over time and concerns about abuse and dependence with current therapies.
−Removed: In market research sponsored by us prior to the commercial release of WAKIX, both patients and HCPs expressed frustration and dissatisfaction with then-existing therapies, reflecting current unmet medical needs.
−Removed: These unmet needs included, in order of importance, the availability of:
−Removed: (i) non-scheduled treatment options, (ii) more tolerable treatment regimens, (iii) more effective treatment options, (iv) novel MOAs beyond currently available therapies and (v) once-daily treatment options.
−Removed: Based on our market research, we believe the most significant unmet need identified was the availability of non-scheduled treatment options.
−Removed: Other than WAKIX, all drugs approved by the FDA for the treatment of narcolepsy, including stimulants, are scheduled as controlled substances by the DEA.
−Removed: Controlled substances have the potential for abuse, misuse, and diversion.
−Removed: In addition, these products also have the potential for the development of tolerance and withdrawal symptoms.
−Removed: Despite their inherent drawbacks, due to the limited number of treatment options, stimulants have historically been a primary treatment for people with narcolepsy.
−Removed: In addition to having the potential for abuse, all of the treatments approved for narcolepsy, except WAKIX, require a Risk Evaluation and Mitigation Strategy (“REMS”) program, which is required by the FDA for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.
−Removed: WAKIX (pitolisant) represents a novel approach to narcolepsy treatment.
+Added: It received Breakthrough Therapy designation for the treatment of cataplexy in patients with narcolepsy and Fast Track designation for the treatment of EDS and cataplexy in patients with narcolepsy in April 2018.
+Added: In August 2019, WAKIX was approved by the FDA for the treatment of EDS in adult patients with narcolepsy, and its U.S.
+Added: commercial launch was initiated in November 2019.
+Added: In October 2020, WAKIX was approved by the FDA for the treatment of cataplexy in adult patients with narcolepsy.
+Added: WAKIX represents a novel approach to narcolepsy treatment.
We believe that WAKIX offers a meaningfully differentiated product profile over current treatment options for the following reasons:
● First-in-class molecule with a novel MOA .
−Removed: WAKIX is the only selective H 3 receptor antagonist/inverse agonist approved by the FDA.
−Removed: It is approved for the treatment of EDS or cataplexy in adult patients with narcolepsy and is the only narcolepsy treatment that works primarily through histamine, a major wake-promoting neurotransmitter.
+Added: WAKIX is a first-in-class molecule with a novel mechanism of action (“MOA”) and is the only selective H 3 receptor antagonist/inverse agonist approved by the FDA.
Pitolisant is thought to work by regulating histamine, such that it activates wake-promoting neurons and inhibits sleep promoting neurons, which helps to stabilize states of sleep and wakefulness.
3 unchanged sentences
We believe one of the most significant unmet needs is the availability of non-scheduled treatment options.
−Removed: In a clinical trial, pitolisant demonstrated statistically significantly lower abuse potential compared to phentermine (a Schedule IV stimulant), consistent with its lack of abuse potential.
● WAKIX is not a stimulant.
−Removed: Stimulants are one of the most commonly prescribed treatments for patients with narcolepsy.
+Added: Stimulants are one of the most commonly prescribed treatments for patients with narcolepsy and have the potential for abuse so their use must be considered carefully by HCPs and patients.
Unlike stimulants, in clinical trials, WAKIX showed no evidence for the development of drug tolerance or withdrawal symptoms.
−Removed: Therefore, there is no need for patients to temporarily stop the medication to reset efficacy.
In addition, unlike stimulants, WAKIX does not increase dopamine levels in the brain’s reward center, which contributes to its lack of abuse potential.
−Removed: According to the National Sleep Foundation, stimulants have the potential for abuse, so their use must be considered carefully by patients and HCPs.
−Removed: WAKIX gives patients and HCPs a different therapeutic option.
● WAKIX can be used as monotherapy or administered concomitantly with other narcolepsy treatments.
5 unchanged sentences
We believe that once-daily dosing with WAKIX addresses this need and may help improve patient compliance with treatment.
−Removed: Our goal is to become a leading pharmaceutical company dedicated to developing and commercializing novel treatment options for patients living with rare neurological diseases and/or neurological diseases where we can leverage our existing infrastructure and expertise.
−Removed: The key elements of our corporate growth strategy are outlined below:
−Removed: ● Continued Growth of WAKIX in Adult Patients with Narcolepsy.
−Removed: o Continued Commercialization of WAKIX in the United States .
−Removed: We have assembled a team of approximately 250 professionals who possess comprehensive life sciences experience.
−Removed: We have also established a robust company infrastructure to execute on our core business and growth strategies.
−Removed: This team includes over 80 dedicated and experienced sales professionals who call on the approximately 9,500 HCPs who treat more than 90% of narcolepsy patients in the United States.
−Removed: In November 2019, we launched commercial sales of WAKIX in the United States.
−Removed: ● Advance the clinical development programs, extend the pitolisant franchise, expand the pipeline and diversify the product portfolio beyond sleep/wake disorders.
−Removed: o Pursue New Indications Beyond Narcolepsy.
−Removed: We believe that pitolisant’s novel MOA offers a portfolio in a product opportunity and has therapeutic potential in several other patient populations living with rare neurological diseases.
−Removed: We opened an IND for pitolisant for the treatment of IH in November 2021 and initiated a Phase 3 registrational trial, the INTUNE Study, in adult patients with IH in April 2022.
−Removed: We completed enrollment in the INTUNE study in May 2023 and we announced topline data in October 2023.
−Removed: While the primary endpoint did not meet statistical significance, we believe the totality of the data showed favorable numerical trends for pitolisant in the treatment of adult patients with IH.
−Removed: Pitolisant received Orphan Drug designation for IH by the FDA in September 2023 and Fast Track Designation in November 2023.
−Removed: We submitted a meeting request to the FDA in the fourth quarter of 2023 to discuss the path forward and we have scheduled a meeting with the FDA in March 2024.
−Removed: We opened an IND for pitolisant for the treatment of PWS in November 2019 and completed a Phase 1 PK clinical trial in pediatric patients with PWS in December 2019.
−Removed: We then initiated a long-term, open-label safety trial in those patients who participated in
−Removed: the Phase 1 PK trial.
−Removed: In December 2020, we initiated a Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS and other key symptoms in patients with PWS, and based on the positive signals from the data, an end-of-phase 2 meeting with the FDA was held in June 2023.
−Removed: We believe we aligned with the FDA on the proposed Phase 3 registration study design for further investigation of pitolisant as a potential treatment to address the unmet medical need for children, adolescents and adults with PWS experiencing EDS, for which there is currently no approved treatment.
−Removed: In October 2023, we received FDA alignment regarding the protocol for the Phase 3 TEMPO study in patients with PWS, which we believe will satisfy the requirements for both the registrational trial and one of the two requirements for pediatric exclusivity, with the other requirement being data in pediatric narcolepsy.
−Removed: In February 2024, the FDA granted Orphan Drug designation to pitolisant for the treatment of PWS.
−Removed: We expect to initiate the Phase 3 study in the first quarter of 2024.
−Removed: In June 2021, we initiated a Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS, fatigue and cognitive dysfunction in adult patients with DM1 and announced topline results from this trial in the fourth quarter of 2023 in which clinically meaningful improvements were demonstrated in EDS and fatigue, and the safety profile was consistent with the established safety profile of pitolisant.
−Removed: o Expand WAKIX Label in Narcolepsy .
−Removed: Building upon the EDS and cataplexy indications in adult patients with narcolepsy, we are working with our partner Bioprojet in gaining a pediatric indication for both EDS and cataplexy.
−Removed: Bioprojet completed a Phase 3 trial in pediatric patients with narcolepsy and submitted the data to the EMA seeking approval for a pediatric narcolepsy indication.
−Removed: On January 26, 2023, Bioprojet received a positive opinion from the EMA’s CHMP and in March 2023, EMA granted approval for the marketing authorization of WAKIX for the treatment of narcolepsy in children 6 and older.
−Removed: Based on the data from the positive Phase 3 trial conducted by Bioprojet, we submitted an sNDA for pediatric narcolepsy in December 2023.
−Removed: On February 21, 2024, we announced that the FDA has granted priority review of our pediatric narcolepsy sNDA and has set a PDUFA, or target action date, of June 21, 2024.
−Removed: o Pursue Pediatric Exclusivity .
−Removed: We continue to pursue pediatric exclusivity, and we recently received feedback from the FDA regarding our request for a pediatric written request (“PWR”).
−Removed: We plan to prepare a proposed pediatric study request (“PPSR”) for submission to the FDA in order to align with the agency, in pursuit of pediatric exclusivity for WAKIX.
−Removed: We remain committed to obtaining pediatric exclusivity for WAKIX and the submission of a pediatric sNDA in the fourth quarter of 2023 and the planned initiation of a Phase 3 study in PWS in the first quarter of 2024 are consistent with our efforts to obtain pediatric exclusivity.
−Removed: o Expand Pitolisant Franchise Potentially up to 2040 and Beyond .
−Removed: Pursuant to the 2022 LCA with Bioprojet, we have made progress in the development of two new formulations of pitolisant, NG1 and NG2.
−Removed: Both formulations entered into clinical studies in the fourth quarter of 2023 and we anticipate data in the first half of 2024.
−Removed: o Expand and Diversify our Product Portfolio .
−Removed: As we continue our commercial growth and advancement of our clinical development programs with pitolisant, a key component of our strategy is to expand our pipeline and diversify our portfolio beyond sleep/wake disorders by partnering, co-developing or acquiring assets focused on rare neurological diseases and/or other neurological diseases serving patients with unmet medical needs that are complementary to our existing research and development expertise and/or commercial footprint.
−Removed: Consistent with this objective, in October 2023, we acquired Zynerba, a clinical-stage pharmaceutical company focused on innovative pharmaceutically produced transdermal cannabidiol therapies for orphan neuropsychiatric disorders, including FXS.
−Removed: The phase 3 RECONNECT registration study in FXS is ongoing.
−Removed: ● Maintain disciplined capital allocation strategy to maximize shareholder value.
−Removed: o Execute on Businesses Development Opportunities .
−Removed: We believe that with our existing cash, cash equivalents and investments on hand as of December 31, 2023, we are well positioned to execute on any business development opportunity to build out a robust pipeline.
−Removed: o Share Repurchase Program .
−Removed: We continue to opportunistically execute our share repurchase program to return value to shareholders.
−Removed: Our Commercialization Strategy
−Removed: We launched WAKIX into the narcolepsy market in November 2019 and we continue to engage with HCPs, patients and payors through the focused commercialization strategy outlined below to optimize adoption of WAKIX in the marketplace:
−Removed: ● HCP Awareness and Adoption :
−Removed: To facilitate HCP awareness and adoption of WAKIX, we have deployed our dedicated, over 80-person sales team to educate a defined prescriber base of approximately 9,500 HCPs comprised of neurologists, pulmonologists, sleep specialists, psychiatrists and high-prescribing primary care physicians who specialize in or focus on sleep disorders.
−Removed: We believe these HCPs diagnose and treat more than 90% of the narcolepsy patients in the United States.
−Removed: We began our commercial HCP outreach in August 2019 following FDA approval of WAKIX for the treatment of EDS in adult patients with narcolepsy and our efforts continue following the approval of the cataplexy indication in October 2020.
−Removed: ● Patient Awareness :
−Removed: It is estimated that narcolepsy affects approximately 170,000 Americans with fewer than 50% diagnosed.
−Removed: Of those living with narcolepsy in the United States, it is estimated that fewer than 40,000 are on narcolepsy medications, which we believe indicates a significant unmet medical need.
−Removed: To drive patient awareness of WAKIX and its differentiated product profile, we have been communicating with the narcolepsy patient community and providing them with educational materials and information on WAKIX.
−Removed: ● Payor Coverage :
−Removed: Recognizing the importance of payor coverage, our field market access team has been engaging with national and regional payors over the past four plus years to educate them on the clinical data and value proposition of WAKIX.
−Removed: Through December 31, 2023, we have secured formulary access for more than 80% of all insured lives (Commercial, Medicare and Medicaid) in the United States.
−Removed: Within these covered lives, we have observed favorable access to WAKIX subsequent to the expanded approval of WAKIX for the treatment of cataplexy in adult patients with narcolepsy in October 2020.
−Removed: We believe the differentiating attributes of WAKIX that have facilitated and will continue to facilitate awareness, adoption, and coverage include:
−Removed: (i) it is a first-in-class molecule with a novel MOA, (ii) it is the first-and-only non-scheduled treatment approved for EDS or cataplexy in adult patients with narcolepsy, (iii) it is not a stimulant, (iv) it has broad clinical utility because it can be used as monotherapy or administered concomitantly with other narcolepsy treatments, and (v) it is a once-daily oral tablet administered in the morning upon wakening.
−Removed: In September 2021, the AASM updated its clinical practice guidelines on central disorders of hypersomnolence, which serve as evidence-based treatment guidelines for such disorders, giving WAKIX a strong recommendation for the treatment of both excessive daytime sleepiness and cataplexy in adult patients with narcolepsy.
+Added: narcolepsy market had an approximate net sales value of $2.9 billion in 2023.
+Added: The market is expected to continue to grow based on several factors, including, but not limited to, the introduction of new innovative therapies that offer novel mechanisms of action resulting in improved safety/tolerability profiles while delivering clinically meaningful efficacy, additional investment in education, increased rates of diagnosis, and population growth.
+Added: Net product revenue related to the sales of WAKIX was $714.7 million for the year ended December 31, 2024.
As of December 31, 2024, we continued to see growth in unique HCPs prescribing WAKIX since it became available in November 2019.
The average number of patients on WAKIX in the fourth quarter of 2024 was approximately 7,100.
−Removed: Additionally, as of December 31, 2023, we had secured formulary access for more than 80% of all insured lives (Commercial, Medicare and Medicaid) in the United States.
−Removed: Within these covered lives, we observed favorable access to WAKIX subsequent to the expanded approval of WAKIX for the treatment of cataplexy in adult patients with narcolepsy in October 2020.
Our Development Pipeline
Development Pipeline Chart
−Removed: Trial conducted by Bioprojet;
−Removed: received EMA approval on March 15, 2023.
−Removed: Develop Pitolisant in New Patient Populations in Pursuit of Additional Indications
−Removed: We believe that pitolisant’s ability to regulate histamine and histaminergic signaling gives it the potential to provide therapeutic benefit in other disorders that are mediated through the H 3 receptor and histamine signaling and offers a portfolio in a product opportunity with pitolisant.
−Removed: Histamine plays an important role in normal physiologic functioning beyond wakefulness in the areas of attention, vigilance, behavior and cognition.
−Removed: The presence of H 3 receptors in the hypothalamus, brainstem and cerebral cortex account for different functions, which could provide an opportunity for pitolisant to treat symptoms other than EDS in different disorders.
−Removed: In addition, H 3 receptors are located mainly in the CNS as opposed to other parts of the body outside the CNS, which contributes to its overall tolerability profile.
−Removed: This fact, along with pitolisant being highly selective for the H 3 receptor (as opposed to H 1 receptors, H 2 receptors and H 4 receptors), is the reason we
−Removed: believe in pitolisant’s unique MOA and its potential to improve symptoms in patients living with rare neurological diseases, in which impaired histamine signaling is part of the underlying pathophysiology.
−Removed: Role of histamine in normal physiologic functioning beyond wake promotion (e.g.
−Removed: attention, vigilance, behavior, cognition)
−Removed: Location of H 3 receptors in hypothalamus, brainstem, and cerebral cortex account for different functions (and potential symptoms in different disorders)
−Removed: Limited H 3 receptor populations outside the CNS
−Removed: We have continued to seek new indications in rare neurological disease patient populations that have EDS as a prominent symptom, along with other symptoms mediated by CNS histamine signaling.
−Removed: We opened an IND for pitolisant for the treatment of IH in November 2021 and initiated a Phase 3 registrational trial, the INTUNE Study, in April 2022.
−Removed: We completed enrollment in the INTUNE study in May 2023 and we announced topline data on October 11, 2023.
−Removed: While the primary endpoint did not meet statistical significance, we believe the totality of the data showed favorable numerical trends for pitolisant in the treatment of adult patients with IH.
−Removed: We submitted a meeting request to the FDA in the fourth quarter of 2023 to discuss the path forward and we anticipate a meeting with the FDA towards the end of the first quarter of 2024.
−Removed: We plan to interact with the FDA to determine next steps.
−Removed: We opened an IND for pitolisant for the treatment of PWS in November 2019 and completed a Phase 1 PK clinical trial in pediatric patients with PWS in December of 2019.
−Removed: We then initiated a long-term, open-label safety trial in those patients who participated in the Phase 1 PK trial.
−Removed: In December 2020, we initiated a Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS and other key symptoms in patients with PWS, including behavioral symptoms and cognitive impairment.
−Removed: Topline results from this clinical proof-of-concept trial were reported in November 2022 and showed a positive signal on improvement in the primary outcome related to EDS.
−Removed: An end-of-phase 2 meeting with the FDA was held in June 2023.
−Removed: We believe we aligned with the FDA on the proposed Phase 3 registration study design to support investigation of pitolisant as a potential treatment to address the unmet medical need for children, adolescents and adults with PWS experiencing EDS, for which there is currently no approved treatment.
−Removed: In October 2023, we received FDA alignment regarding the protocol for the Phase 3 TEMPO study in patients with PWS, which will satisfy the requirements for both the registrational trial and one of the requirements for pediatric exclusivity, with the other requirement being data in pediatric narcolepsy.
−Removed: In February 2024, the FDA granted Orphan Drug designation to pitolisant for the treatment of PWS.
−Removed: We expect to initiate the Phase 3 study in the first quarter of 2024.
−Removed: In June 2021, we initiated a Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS, fatigue and cognitive dysfunction in adult patients with DM1 and announced topline results from this trial in the fourth quarter of 2023 in which clinically meaningful improvements were demonstrated in EDS and fatigue, and the safety profile was consistent with the established safety profile of pitolisant.
+Added: Sleep/Wake Franchise
+Added: We believe that pitolisant’s ability to regulate histamine and histaminergic signaling gives it the potential to provide therapeutic benefit in other disorders that are mediated through the H 3 receptor and histamine signaling and offers a portfolio in a product opportunity.
+Added: We have continued to pursue label expansion of WAKIX in narcolepsy and seek new indications in rare neurological disease patient populations that have EDS as a prominent symptom, along with other symptoms mediated by CNS histamine signaling including:
Idiopathic Hypersomnia
−Removed: IH, like narcolepsy, is another central disorder of hypersomnolence resulting in sleep-wake state instability.
+Added: IH is a central disorder of hypersomnolence resulting in sleep-wake state instability.
It is a rare and chronic neurological disease that is characterized by EDS despite sufficient or even long sleep time.
−Removed: Sleep in patients with IH is not felt to be refreshing, no matter how much sleep they get.
−Removed: People living with IH experience significant EDS along with the symptoms of sleep inertia (prolonged difficulty waking up from sleep) and ‘brain fog’ (impaired cognition, attention, and alertness).
−Removed: Symptoms of IH often begin in the late teens or early twenties but patients often experience a long diagnostic journey and do not receive an accurate diagnosis until reaching their thirties.
Based on insurance claims data, the number of patients diagnosed with IH in the US ranges from 30,000 to 40,000.
−Removed: The Phase 3 double-blind, placebo controlled randomized withdrawal study evaluated the safety and efficacy of pitolisant compared with placebo in adult patients with IH (ages ≥18 years) The study consisted of an 8-week Open-Label Phase, which included a 6-week Dose Optimization Period followed by a 2-week Stable Dose Period.
−Removed: Patients determined to be responders at the end of the Stable Dose Period entered the Double-Blind Randomized Withdrawal Phase of the study for 4 weeks of blinded treatment with pitolisant (at the same dose administered in the Stable Dose Period) or matching placebo.
−Removed: The primary efficacy endpoint in the study was the change in the Epworth Sleepiness Scale (ESS) score from the end of the Stable Dose Period (Week 8) to the end of the 4-week Double-Blind Randomized Withdrawal Phase (Week 12) for pitolisant compared with placebo.
−Removed: Secondary efficacy endpoints evaluated the effect of pitolisant on other symptoms of IH, including overall burden of disease, sleep-related impairment, sleep inertia, and cognitive function.
−Removed: Patients who completed the trial are eligible to participate in an open-label extension phase to assess the long-term safety and effectiveness of pitolisant in adult patients with IH.
+Added: Pitolisant received orphan drug designation by the FDA for the treatment of IH in September 2023 and Fast Track designation for the treatment of IH in November 2023.
+Added: In April 2022, we initiated a Phase 3 registrational trial, the INTUNE Study, to evaluate the efficacy and safety of pitolisant in adult patients with IH.
We completed enrollment in the INTUNE study in May 2023 and we announced topline data in October 2023.
3 unchanged sentences
● Positive trends favoring pitolisant were also observed across additional prespecified endpoints including the IH Severity Scale, which approached statistical significance, as well as on the Sleep Inertia Questionnaire.
−Removed: Further data analyses are being conducted.
● Approximately 88% of patients in the Double-Blind Randomized Withdrawal Phase continued into a long-term extension study, which is ongoing.
−Removed: ● The safety and tolerability profile of pitolisant in adult patients with idiopathic hypersomnia was consistent with the established safety profile and no new safety signals were observed.
+Added: ● The safety and tolerability profile of pitolisant in adult patients with idiopathic hypersomnia was consistent with the established safety profile of pitolisant and no new safety signals were observed.
While the primary endpoint did not meet statistical significance, we believe the totality of the data showed favorable numerical trends for pitolisant in the treatment of adult patients with IH.
−Removed: We are currently analyzing the full data set and we have scheduled a meeting with the FDA for March 2024 to discuss the path forward for IH.
+Added: We met with the FDA in March 2024 to discuss the path forward for IH and submitted an sNDA during the fourth quarter of 2024 based on the totality of the data obtained from the INTUNE study and other sources.
+Added: In February 2025, we received a Refusal to File letter from the FDA for pitolisant in IH.
Prader-Willi Syndrome
−Removed: PWS is a rare genetic disorder caused by a loss of function of specific genes on chromosome 15 resulting in hypothalamic dysfunction and decreased levels of orexin/hypocretin in some patients with PWS.
+Added: PWS is a rare genetic disorder caused by a loss of function of specific genes on the long arm of chromosome 15 resulting in hypothalamic dysfunction.
The hypothalamus controls both sleep-wake states and hunger-satiety;
−Removed: therefore, two of the main symptoms in patients with PWS are EDS and hyperphagia.
−Removed: Other features include low muscle tone, short stature, behavioral problems and cognitive impairment.
−Removed: It is estimated that approximately 15,000 to 20,000 people in the United States suffer from PWS, and over half of those suffering from PWS experience EDS.
−Removed: We opened an IND for pitolisant for the treatment of PWS in November 2019 and completed a Phase 1 PK clinical trial in pediatric patients with PWS in December of 2019.
−Removed: We then initiated a long-term, open-label safety trial in those patients who participated in the Phase 1 PK trial.
+Added: therefore, two of the main symptoms in patients with PWS are hyperphagia and EDS.
+Added: It is estimated that approximately 15,000 to 20,000 people in the United States suffer from PWS, and over half of the patients living with PWS experience EDS.
In December 2020, we initiated a Phase 2 proof-of-concept clinical trial to evaluate pitolisant for the treatment of EDS and other key symptoms in patients with PWS, including behavioral symptoms and cognitive impairment.
Topline results from this clinical proof-of-concept trial were reported in November 2022 and showed a positive signal on improvement in the primary outcome related to EDS.
−Removed: PWS poses a heavy burden for both patients and caregivers and there are few therapeutic options available and no FDA-approved treatments for EDS in patients with PWS.
−Removed: Clinical development programs in PWS have focused on hyperphagia, with no other programs focusing on EDS or cognitive function.
−Removed: EDS is thought to have a negative effect on behavior and cognitive function and could exacerbate these symptoms in patients with PWS.
−Removed: In addition, impaired histamine
−Removed: signaling in the brain can contribute to behavioral symptoms and impaired cognition.
−Removed: We believe there is a compelling opportunity for the mechanism of action of pitolisant to impact the EDS component of this disorder as well as other symptoms, such as behavioral issues and cognitive impairment.
−Removed: We have collaborated with the Foundation for Prader-Willi Research (the “FPWR”) to advance our clinical program and underscore our commitment to this patient population.
−Removed: We are members of the FPWR Clinical Trials Consortium and are working with members of its Scientific Advisory Board to gain their insights for our development program.
−Removed: Progress to date includes (i) opening an IND for PWS in October 2019, (ii) completion of a Phase 1 PK trial in patients with PWS in December 2019, with patients actively rolling over into an open-label, long-term safety trial, and (iii) completion of a Phase 2 proof-of-concept signal detection clinical trial with topline data reported in November 2022.
−Removed: The Phase 2 proof-of-concept clinical trial was a randomized, double-blind, placebo-controlled study designed to assess the safety and efficacy of pitolisant in patients with PWS.
−Removed: This proof-of-concept study was not powered to demonstrate statistical significance and was designed for signal detection.
−Removed: The study included patients ages 6 to 65 years and patients were randomized 1:1:1 to low dose pitolisant, high dose pitolisant, or placebo treatment groups.
−Removed: Pitolisant dosing was based on three age cohorts (children 6 to < 12;
−Removed: adolescents 12 to < 18;
−Removed: and adults 18 to 65) and another objective of the study was to evaluate for a dose-response to pitolisant in patients with PWS.
−Removed: The primary endpoint of this study was the evaluation of EDS as measured by change from baseline to end of treatment (EOT) on the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) Parent/Caregiver Version.
−Removed: Topline study results include:
−Removed: ● 65 patients were enrolled in the trial, 91% of which completed treatment and all but one patient opted to continue into the open-label extension.
−Removed: ● Mean baseline ESS-CHAD (Parent/Caregiver Version) ranged from 14.7 to 15.7.
−Removed: ● Mean change from baseline to EOT on the ESS-CHAD Parent/Caregiver Version scores ranged from -3.7 to -5.5 across all age groups and treatment groups, representing a clinically meaningful change (which is defined as a ≥ 2-point improvement on this scale).
−Removed: ● In two of the three age groups (children and adults), there was a clinically meaningful difference (minimum of 2 points) between pitolisant and placebo, driven by the high dose pitolisant treatment group.
−Removed: ● In the adolescent age group, there was a high placebo response of a magnitude three times that seen in the other two age groups, which resulted in no clinically meaningful difference between pitolisant and placebo in this age group.
−Removed: ● A responder analysis (defined as an improvement on the ESS-CHAD Parent/Caregiver Version of ≥ 3-points or a score at EOT of ≤10 for this analysis) showed response rates of 70% in the high dose pitolisant group, 55.6% in the low dose pitolisant group, and 52.6% in the placebo group.
−Removed: ● Overall safety/tolerability profile was consistent with the known safety/tolerability profile of pitolisant.
−Removed: ● Adverse events were reported in 57% of patients on pitolisant and 65% of patients on placebo.
−Removed: ● Treatment-related adverse events were reported in 26% of patients on pitolisant and 30% of patients on placebo.
−Removed: ● There was one serious adverse event in a patient in the placebo treatment group.
−Removed: These results represent the initial topline data.
−Removed: Based on the positive signals from the data from our Phase 2 proof-of-concept signal detection clinical trial to evaluate pitolisant for the treatment of EDS and other key symptoms in patients with PWS, an end-of-phase 2 meeting with the FDA was held in June 2023.
−Removed: We believe we aligned with the FDA on the proposed Phase 3 study design to support
−Removed: further investigation of pitolisant as a potential treatment to address the unmet medical need for children, adolescents and adults with PWS experiencing EDS, for which there is currently no approved treatment.
−Removed: In October 2023, we received FDA alignment regarding the protocol for the Phase 3 TEMPO study in patients with PWS, which we believe will satisfy the requirements for both the registrational trial and one of the requirements for pediatric exclusivity, with the other being data in pediatric narcolepsy.
+Added: Based on the positive signals from our Phase 2 proof-of-concept signal detection clinical trial, an End-of-Phase 2 meeting with the FDA was held in June 2023.
+Added: We have aligned with the FDA on the proposed Phase 3 study design to support further investigation of pitolisant as a potential treatment to address the unmet medical need for children, adolescents and adults with PWS experiencing EDS, for which there is currently no approved treatment.
+Added: In October 2023, we received FDA feedback regarding our proposed study protocol for the Phase 3 TEMPO study in patients with PWS, which has the potential to serve as a registrational trial and will support our efforts to seek pediatric exclusivity for pitolisant.
In February 2024, the FDA granted Orphan Drug designation to pitolisant for the treatment of PWS.
−Removed: We expect to initiate the Phase 3 TEMPO study in the first quarter of 2024.
−Removed: Myotonic Dystrophy
−Removed: DM is a rare, multi-system genetic disease that affects the neuromuscular system as well as several other systems.
−Removed: The primary symptom in patients with DM is myotonia, which is an impairment in the ability of muscles to relax;
−Removed: progressive muscle weakness is another prominent symptom of the disorder.
−Removed: It is inherited in an autosomal dominant pattern and there are two main types:
−Removed: The underlying cause of DM1 is a mutation in the DMPK gene on chromosome 19.
−Removed: DM1 is the most common form of adult-onset muscular dystrophy and affects as many as 160,000 patients in the United States.
−Removed: EDS and fatigue are hallmark clinical characteristics in the majority of patients with DM1 and are referred to as the most frequent non-muscular symptoms in patients with DM1.
−Removed: EDS and fatigue occur in approximately 80% to 90% of patients with DM1.
−Removed: Cognitive impairment is also a prominent symptom in patients with DM1 and all of these symptoms are thought to be mediated through H 3 receptors and histaminergic pathways located throughout the CNS.
−Removed: DM2 is not as common as DM1 with an estimated prevalence of between 3,000 and 29,000 patients in the United States.
−Removed: The underlying cause of DM2 is a mutation in the CBNP gene on chromosome 3.
−Removed: Patients with DM1 and DM2 share similar phenotypes but disease onset is later in patients with DM2 and symptoms tend to be milder.
−Removed: There are currently no FDA-approved treatments for patients with DM, which represents a significant unmet medical need.
−Removed: The therapeutic application of pitolisant may provide benefits across the key symptoms of EDS and fatigue which are often among the chief complaints of patients with DM.
−Removed: In a survey of 451 DM1 patients, daytime sleepiness and fatigue were second only to muscle weakness in symptom prevalence and impact.
−Removed: Our clinical program is designed to demonstrate effect on measures of EDS and fatigue, as well as assess performance related to cognitive function, such as attention, vigilance and working memory.
−Removed: Progress to date includes working with key opinion leaders to develop the scientific rationale for the investigation of pitolisant in patients with DM, development of a Phase 2 clinical protocol, submission of an IND at the end of 2020, the opening of an IND in January 2021, and initiation of a Phase 2 proof-of-concept clinical trial in adult patients with DM1 in June of 2021.
−Removed: We announced topline results for the Phase 2 proof-of-concept clinical trial in the fourth quarter of 2023.
−Removed: The Phase 2 proof-of-concept clinical trial was a randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of pitolisant in adult patients with DM1 ages 18 to 65.
−Removed: It was not powered to demonstrate statistical significance and was designed for signal detection.
−Removed: Thirty patients were enrolled at 20 sites across the United States and Canada.
−Removed: Patients were randomized to low-dose pitolisant, high-dose pitolisant, or placebo in a 1:1:1 treatment ratio and titrated over three weeks up to their randomized dose, followed by eight weeks of stable dosing.
−Removed: The primary trial objective was to assess for improvement in EDS as measured by the Daytime Sleepiness Scale (DSS).
−Removed: Secondary endpoints include assessments of fatigue as well as specific measures of cognitive function using validated computer-based assessments.
−Removed: Clinician and patient global impression of disease severity using the CGI-S and PGI-S, respectively, were measured as well as disease-specific patient assessments of overall disease burden.
−Removed: Plasma samples were collected to generate pharmacokinetic data and a PK/PD analysis were performed.
−Removed: Patients who completed the trial are eligible to participate in an open-label extension phase to assess the long-term safety and effectiveness of pitolisant in adult patients with DM1.
−Removed: Topline study results include:
−Removed: ● Clinically meaningful improvements were demonstrated in EDS as measured by DSS, ESS, and Clinical Global Impression of Severity (CGI-S) of EDS.
−Removed: o On DSS, the mean change from baseline to end of double-blind period was -2.5 and -1.0 for the higher dose and lower dose pitolisant treatment groups, respectively, compared to -0.2 for placebo.
−Removed: o On ESS, the mean change from baseline to end of double-blind period was -4.88 for the higher dose pitolisant treatment group compared to -0.10 for placebo.
−Removed: o On CGI-S, the mean change from baseline to end of double-blind period was -0.9 for the higher dose pitolisant treatment group compared to -0.1 for placebo.
−Removed: ● Clinically meaningful improvements were demonstrated for fatigue as measured by the Fatigue Severity Scale (FSS).
−Removed: o On FSS, the mean change from baseline to end of double-blind period was -0.86 and -0.36 for the higher dose and lower dose pitolisant treatment groups, respectively, compared to -0.13 for placebo.
−Removed: ● A clear and consistent dose-response was demonstrated with the higher dose pitolisant group showing a greater response than the lower dose group across the study endpoints.
−Removed: ● Safety and tolerability profile in adult patients with DM1 was consistent with the established safety profile of pitolisant with no new safety signals detected and no serious adverse events reported.
−Removed: These results represent the initial topline data.
−Removed: The full dataset from this trial will include findings from other secondary outcomes, including the Myotonic Dystrophy Health Index (MDHI), cognitive functions, and the safety and effectiveness of pitolisant from the ongoing Open-Label Extension (OLE) Phase.
−Removed: We are currently evaluating the full data set and determining next steps.
−Removed: Label Expansion of WAKIX in Narcolepsy
−Removed: Pediatric Narcolepsy
−Removed: Approximately 5% of diagnosed narcolepsy patients (approximately 3,600 patients in the U.S.) are under the age of 18 years.
−Removed: Symptoms often have a more profound effect in children, resulting in reduced function and greater psychological impact.
−Removed: Until the fourth quarter of 2018, no treatments were approved for pediatric patients with narcolepsy, at which time Xyrem received an expanded indication for the treatment of cataplexy or EDS in patients seven years of age or older with narcolepsy.
−Removed: Xywav (low sodium formulation of Xyrem) received the same indication in July 2020.
−Removed: We are working with our partner Bioprojet in gaining a pediatric indication for both EDS and cataplexy.
−Removed: On January 26, 2023, Bioprojet received a positive opinion from the EMA’s CHMP and in March 2023, the EMA granted approval for the marketing authorization of WAKIX for the treatment of narcolepsy in children 6 and older.
−Removed: Based on the data from the positive Phase 3 trial conducted by Bioprojet, we submitted an sNDA for pediatric narcolepsy in December 2023.
−Removed: On February 21, 2024, we announced that the FDA has granted priority review of our pediatric narcolepsy sNDA and has set a PDUFA, or target action date, of June 21, 2024.
−Removed: Pediatric Exclusivity
+Added: We initiated the Phase 3 TEMPO study in the first quarter of 2024.
We remain committed to obtaining pediatric exclusivity for WAKIX.
−Removed: Our recent efforts regarding pediatric exclusivity include the submission of the pediatric sNDA and the planned initiation of a Phase 3 study in PWS in the first quarter of 2024.
−Removed: Expand Pitolisant Franchise Potentially up to 2040 and Beyond
−Removed: In July 2022, we entered into the 2022 LCA with Bioprojet whereby we obtained exclusive rights to manufacture, use and commercialize one or more new products based on pitolisant in the United States and Latin America, with the potential to add additional indications and formulations upon the agreement of both parties (see “Strategic Agreements” below).
+Added: The initiation of the PWS Phase 3 registrational trial, the TEMPO study, and the data in pediatric narcolepsy are supportive of our efforts in obtaining pediatric exclusivity for WAKIX.
+Added: Our partner, Bioprojet completed a Phase 3 trial in pediatric patients with narcolepsy and in March 2023, the EMA granted approval for the marketing authorization of WAKIX for the treatment of narcolepsy with or without cataplexy in children six and older.
+Added: Based on the data from the positive Phase 3 trial conducted by Bioprojet, we submitted an sNDA for pediatric narcolepsy in December 2023.
+Added: In June 2024, we announced that the FDA approved our sNDA for WAKIX for the treatment of EDS in pediatric patients six years of age and older with narcolepsy .
+Added: In addition, in June 2024, the FDA did not approve our sNDA seeking to expand the WAKIX label for the treatment of pediatric patients with cataplexy.
+Added: In October 2024, we held a Type A meeting with the FDA to discuss the pediatric cataplexy indication and believe we reached alignment on a path to sNDA resubmission, which is planned for the second quarter of 2025.
+Added: Myotonic Dystrophy Type 1
+Added: DM1, otherwise known as dystrophia myotonica, is the most common form of adult-onset muscular dystrophy and affects as many as 160,000 patients in the United States.
+Added: In addition to myotonia, a progressive muscle weakness which is the core symptom in patients with DM1, EDS and fatigue are hallmark clinical characteristics in patients with DM1 and occur in approximately 80% to 90% of patients.
+Added: There are currently no FDA-approved treatments for patients with DM1, which represents a significant unmet medical need.
+Added: We believe the therapeutic application of pitolisant may provide benefits across the key symptoms of EDS and fatigue which are often among the chief complaints of patients with DM1.
+Added: We opened an IND in January 2021 and initiated a Phase 2 proof-of-concept clinical trial in adult patients with DM1 in June of 2021.
+Added: The topline data were released in December 2023 and showed clinically meaningful improvements in EDS and fatigue, the two most prominent non-muscular symptoms in patients with DM1.
+Added: The safety and tolerability profile of pitolisant in adult patients with DM1 was consistent with the established safety profile of pitolisant with no new safety signals detected and no serious adverse events reported.
+Added: Next Gen Pitolisant Formulations:
+Added: Pitolisant Gastro-Resistant and Pitolisant High-Dose
+Added: In July 2022, we entered into the 2022 LCA with Bioprojet whereby we obtained exclusive rights to manufacture, develop and commercialize one or more new products based on pitolisant in the United States and Latin America, with the
+Added: potential to add additional indications and formulations upon the agreement of both parties (see “Strategic Agreements” below).
The 2022 LCA will expand our opportunity in narcolepsy, and potentially other indications mutually agreed upon by the parties.
−Removed: We have made progress in the development of two formulations, NG1 and NG2.
−Removed: Both formulations entered clinical studies in the fourth quarter of 2023 and we anticipate data in the first half of 2024 .
−Removed: Expansion and Diversification of our Product Portfolio
−Removed: On October 10, 2023, we completed a tender offer to acquire all of the outstanding shares of common stock of Zynerba, a clinical-stage pharmaceutical company focused on innovative pharmaceutically produced transdermal cannabidiol therapies for orphan neuropsychiatric disorders, including FXS and 22q.
−Removed: Zynerba’s lead candidate, ZYN002, is the first-and-only pharmaceutically manufactured synthetic cannabidiol.
−Removed: It is a non-euphoric cannabidiol formulated as a patent-protected permeation-enhanced gel for transdermal delivery through the skin and into the circulatory system.
−Removed: The product is manufactured through a synthetic process in a cGMP facility and is not extracted from the cannabis plant.
−Removed: ZYN002 does not contain THC, the compound that causes the euphoric effect of cannabis, and has the potential to be a nonscheduled product if approved.
−Removed: Cannabidiol, the active ingredient in ZYN002, has been granted orphan drug designation by the FDA and the EMA for the treatment of FXS and for the treatment of 22q deletion syndrome (“22q”).
−Removed: Additionally, ZYN002 has received FDA Fast Track designation for the treatment of behavioral symptoms in patients with FXS.
−Removed: ZYN002 has the potential to serve 80,000 U.S.
−Removed: patients who are diagnosed with FXS and another 80,000 diagnosed with 22q.
+Added: Pursuant to the 2022 LCA with Bioprojet, we have made progress in the development of two new formulations of pitolisant, pitolisant GR and pitolisant HD.
+Added: Both formulations entered into clinical studies in the fourth quarter of 2023.
+Added: We received data from the pitolisant GR pilot bioequivalence study, which supports further development of pitolisant GR.
+Added: We are on-track to initiate a pivotal bioequivalence study in the first quarter of 2025, with an anticipated data readout in the third quarter of 2025.
+Added: Our anticipated PDUFA date for pitolisant GR is in 2026.
+Added: We received data from the pitolisant HD pilot pharmacokinetics study in June 2024, which also supports advancing this development program toward Phase 3 registrational trials in narcolepsy and IH.
+Added: The formulation optimization and technical operations work is ongoing, with a goal to initiate a Phase 3 registrational study in the fourth quarter of 2025.
+Added: A Phase 1b study was conducted to evaluate the safety and tolerability of pitolisant at repeat doses of up to 180mg and the initial results are consistent with the known safety profile of pitolisant and support advancement of the pitolisant HD development program.
+Added: Our anticipated PDUFA date for pitolisant HD is in 2028.
+Added: Non-provisional patents have been filed for both of these formulations, with the potential for patent protection to the mid-2040’s.
+Added: In April 2024, we entered into a sublicense agreement with Bioprojet for BP1.15205, an orexin 2 receptor agonist for the treatment of narcolepsy and other potential indications (the “Sublicense”).
+Added: Under the Sublicense, we have obtained the exclusive right to develop, manufacture and commercialize BP1.15205 in the United States and Latin American territories, which are rights that Bioprojet originally licensed from Teijin Pharma, the innovator of BP1.15205.
+Added: We believe the pre-clinical data from BP1.15205 is promising and we plan to file an investigational medicinal product dossier (“IMPD”) with the European Medicines Agency (“EMA”) in mid-2025 and begin first-in-human studies in the second half of 2025.
+Added: In August 2021, we acquired HBS-102, a Melanin-concentrating hormone receptor type 1 (MCHR1) antagonist previously developed as CSTI-100/ALB-127258(a)/ALB-127258 (the “Compound”), along with intellectual property and other assets related to the development, manufacture, and commercialization of the Compound from ConSynance Therapeutics, Inc.
+Added: We acquired full development and commercialization rights for HBS-102 globally, but we have provided an indication-limited grant-back license to ConSynance for the development and commercialization of the Compound in Greater China.
+Added: We conducted a preclinical PoC study to assess the effect of HBS-102 on hyperphagia, weight gain and other metabolic parameters in a mouse model of PWS.
+Added: The final report was received during the third quarter of 2024 and the results are consistent with the expected results.
+Added: In addition, a 13-week toxicology study has been completed, and we believe the preliminary results are encouraging .
+Added: Neurobehavioral Franchise
+Added: We are currently seeking the following indications for our product candidate, ZYN-002, a pharmaceutically manufactured 100% synthetic, patent protected permeation enhanced cannabidiol gel:
+Added: Fragile X Syndrome
FXS is a rare genetic disorder that is the leading known cause of both inherited intellectual disability and autism spectrum disorder, affecting 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females.
1 unchanged sentence
There are approximately 80,000 people in the United States and approximately 121,000 people in the European Union and UK living with FXS.
+Added: The total addressable market in the United State alone is estimated to be approximately 25,000 people.
There is a significant unmet medical need in patients living with FXS as there are currently no FDA approved treatments for this disorder.
−Removed: FXS is caused by a mutation in FMR1, a gene which modulates a number of systems, including the endocannabinoid system, and most critically, codes for a protein called FMRP.
−Removed: The FMR1 mutation manifests as multiple repeats of a DNA segment, known as the CGG triplet repeat, resulting in deficiency or lack of FMRP.
−Removed: FMRP helps regulate the production of other proteins and plays a role in the development of synapses, which are critical for relaying nerve impulses, and in regulating synaptic plasticity.
−Removed: In people with full mutation of the FMR1 gene, the CGG segment is repeated more than 200 times, and in most cases causes the gene to not function.
−Removed: Methylation of the FMR1 gene also plays a role in determining functionality of the gene.
−Removed: In approximately 60% of patients with FXS, who have complete methylation of the FMR1 gene, no FMRP is produced, resulting in dysregulation of the systems modulated by FMRP.
−Removed: Based on the data from the Phase 2 CONNECT study, the Phase 3 registration study, RECONNECT, was designed to evaluate the safety and efficacy of ZYN002 in FXS.
−Removed: This study is currently ongoing and we are evaluating the timelines for the completion of the study.
−Removed: 22q is a disorder caused by a small missing piece of the 22nd chromosome.
+Added: ZYN-002 is currently in a Phase 3 registrational trial, the RECONNECT study, designed to evaluate the safety and efficacy of ZYN002 in FXS .
+Added: Topline data from our ZYN-002 Phase 3 study is anticipated in the third quarter of 2025.
+Added: ZYN-002 has patent protection for the treatment of FXS until 2038.
+Added: 22q Deletion Syndrome
+Added: 22q is a disorder caused by a small missing piece on the long arm of the 22nd chromosome.
The deletion occurs near the middle of the chromosome at a location designated q11.2.
−Removed: It is considered a mid-line condition, with physical symptoms including characteristic palate abnormalities, heart defects, immune dysfunction, and esophageal / GI issues, as well as debilitating neuropsychiatric and behavioral symptoms, including anxiety, social withdrawal, ADHD, cognitive impairment and autism spectrum disorder.
+Added: It is considered a mid-line condition, with physical
+Added: symptoms including characteristic palate abnormalities, heart defects, immune dysfunction, and esophageal / GI issues, as well as debilitating neuropsychiatric and behavioral symptoms, including anxiety, social withdrawal, ADHD, cognitive impairment and autism spectrum disorder.
It is estimated that 22q occurs in one in 4,000 live births, suggesting that there are approximately 80,000 people living with 22q in the United States and 129,000 people living with 22q in the European Union and the UK.
Patients with 22q deletion syndrome are managed by multidisciplinary care providers, and there are currently no FDA approved treatments for this disorder.
−Removed: An open-label phase 2 proof-of-concept study showed positive signals for ZYN002 in the treatment of behavioral symptoms associated with 22q.
−Removed: We are currently evaluating the data and are planning further development of ZYN002 in 22q.
−Removed: In August 2021, we acquired HBS-102 along with intellectual property and other assets related to the development, manufacture, and commercialization of the Compound from ConSynance Therapeutics, Inc.
−Removed: We acquired full development and commercialization rights globally, but we have provided a grant-back license to ConSynance for the development and commercialization of the Compound in Greater China.
−Removed: HBS-102 is a Melanin-concentrating hormone (“MCH”) receptor 1 (MCHR1) antagonist and a potential first-in-class molecule with a novel mechanism of action.
−Removed: MCH neurons are located in the hypothalamus and are involved in the regulation of feeding behavior, energy metabolism and control of REM sleep, among other centrally mediated functions.
−Removed: We are currently conducting a preclinical proof-of-concept study to assess the impact of HBS-102 on hyperphagia, weight gain, and other metabolic parameters in a knockout mouse model of PWS and are also conducting a thirteen-week toxicology study.
−Removed: We anticipate data from both studies in the first half of 2024.
+Added: An open-label phase 2 proof-of-concept study conducted by Zynerba showed positive signals for ZYN-002 in the treatment of behavioral symptoms associated with 22q.
+Added: We plan to initiate a Phase 3 registrational study in 22q deletion syndrome in 2025.
+Added: Rare Epilepsy Franchise
+Added: EPX-100 (clemizole hydrochloride).
+Added: EPX-100 is a serotonin (5HT-2) receptor agonist evaluated for DEEs, initially in DS and LGS, because of the established serotonergic mechanism of action in DEEs and based on the positive results from the zebra fish model.
+Added: Patients with DS and LGS often encounter severe refractory epilepsy and extreme co-morbidities or mortality without effective treatments, even with polypharmacy.
+Added: As such, there is a recognized need for improved treatment options for both conditions.
+Added: We believe the total addressable market for EPX-100 among patients with DS is approximately 5,000 people based on an estimated current DS prevalence of approximately 8,600 cases and approximately 7,000 diagnosed DS cases.
+Added: We believe the total addressable market for EPX-100 among patients with LGS is approximately 35,000 people based on an estimated current LGS prevalence of approximately 48,000 cases and 44,000 diagnosed LGS cases.
+Added: EPX-100 has been granted orphan drug designation by the FDA for treatment of both DS and LGS.
+Added: EPX-100 is currently in a Phase 3 registrational clinical trial for DS and we initiated sites for a Phase 3 registrational clinical trial in patients with LGS in the fourth quarter of 2024.
+Added: EPX-200 (liquid formulation of lorcaserin).
+Added: We are currently developing EPX-200, a selective 5HT-2C agonist for DEEs.
+Added: EPX-200 is currently in the pre-IND phase.
Our industry is highly competitive and subject to rapid and significant change as research provides a deeper understanding of rare neurological disorders, including narcolepsy, and as new therapies are developed.
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The key competitive factors affecting the success of WAKIX, and any other product candidates that we develop, if approved, are likely to be efficacy, safety, convenience, price, the level of generic competition and the availability of reimbursement from government and other third-party payors.
−Removed: WAKIX competes with currently FDA-approved products for the treatment of EDS or cataplexy in adult patients with narcolepsy, all of which are controlled substances.
+Added: WAKIX competes with currently FDA-approved products for the treatment of EDS or cataplexy in adult patients with narcolepsy and EDS in children six years and older with narcolepsy, all of which are controlled substances.
Jazz Pharmaceuticals’ Xyrem (sodium oxybate) is an FDA-approved product for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy.
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As of January 2023, Xyrem is now available as generic sodium oxybate – one version is marketed by Hikma Pharmaceuticals through their agreement with Jazz Pharmaceuticals (launched in January 2023), and the other version is marketed by Amneal Pharmaceuticals through their agreement with Jazz Pharmaceuticals (launched in July 2023).
−Removed: Other potential future competitive products are currently in development, including Axsome Therapeutics’ AXS-12 (reboxetine) product candidate, Suven Life Sciences’ SUVN-G3031 H3 inverse agonist product candidate, NLS Pharmaceutics mazindol ER product candidate and orexin 2 receptor agonist product candidates from Takeda, Jazz Pharmaceuticals/Sumitomo Pharma and Alkermes among others.
−Removed: We believe WAKIX offers a meaningfully differentiated product profile that is competitive with each of the products listed above, some of which are only approved for EDS while others (Xyrem, Xywav, Lumryz and generic sodium oxybate) are approved for the treatment of both EDS or cataplexy in patients with narcolepsy.
+Added: Other potential future competitive products are currently in development, including Axsome Therapeutics’ AXS-12 (reboxetine) product candidate, Suven Life Sciences’ SUVN-G3031 H3 inverse agonist product candidate, NLS Pharmaceutics mazindol ER product candidate and orexin 2 receptor agonist product candidates from Takeda, Jazz Pharmaceuticals/Sumitomo Pharma, Centessa and Alkermes among others.
+Added: We believe WAKIX offers a meaningfully differentiated product profile that is competitive with each of the products listed above, some of which are only approved for EDS while others (Xyrem, Xywav, Lumryz and generic sodium oxybate) are approved for the treatment of both EDS and cataplexy in patients with narcolepsy.
It should be noted that WAKIX has not been compared with these products in head-to-head clinical trials, but its non-scheduled status represents a distinct competitive advantage relative to those same products.
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Conversely, WAKIX is priced higher than other competitors such as Provigil (modafinil), Nuvigil, Sunosi (armodafinil) and certain generic competitors, such as methylphenidate and amphetamine, which may contribute to third-party payor preferences for those lower-priced treatment options relative to WAKIX.
+Added: There are currently no FDA approved therapies for PWS.
+Added: We are aware of several companies pursuing clinical development of therapies for PWS including, but not limited to, product candidates from Acadia Pharmaceuticals Inc., Soleno Therapeutics Inc., Rhythm Pharmaceuticals, Inc.
+Added: and Palobiofarma.
+Added: Additionally, for DM1, there are several companies pursuing clinical development of therapies including, but not limited to, product candidates from Avidity Biosciences, Inc., Vertex Pharmaceuticals, Inc., Entrada Therapeutic, Inc.
+Added: and PepGen, Inc.
+Added: There are currently no FDA approved therapies for FXS.
+Added: We are aware of several companies pursuing clinical development of therapies for FXS including, but not limited to, product candidates from Acadia Pharmaceuticals, Inc., Mirum Pharmaceuticals, Inc., Spinogenix Inc., Allos Pharma Inc.
+Added: and Connecta Therapeutics S.L.
+Added: Additionally, there are currently no FDA approved therapies for 22q.
+Added: We are aware of several companies pursing clinical development of therapies for 22q including, but not limited to, Nobias Therapeutics, Inc.’s product candidate.
+Added: There are multiple FDA approved therapies for the treatment of DS, LGS or both DS and LGS including, but not limited to, products from GW Pharmaceuticals, Ltd.
+Added: and Lunbeck, Inc.
+Added: for the treatment of DS and LGS, Biocodex for the treatment of DS and Eisai Co., Ltd.
+Added: for the treatment of LGS.
+Added: We are also aware of several companies pursuing clinical development of therapies including, but not limited to, product candidates from Supernus Pharmaceuticals, Inc.
+Added: for the treatment of DS and LGS, SK Life Science, Inc.
+Added: for the treatment of LGS and Stoke Therapeutics, Inc.
+Added: for the treatment of DS.
Manufacturing, Supply and Distribution
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● Inmar Rx Solutions, Inc., an advanced technology and data analytics company, specializes in reverse distribution of our product and manages our pharmaceutical returns and product recall, if needed.
−Removed: Customers and Suppliers
+Added: We depend on a single supplier of the active pharmaceutical ingredient (“API”) for our commercial product, WAKIX, and single API suppliers for each of our potential product candidates .
For the year ended December 31, 2024, three customers accounted for 100% of gross product revenue;
Caremark LLC accounted for 39% of gross product revenue;
−Removed: PANTHERx Specialty Pharmacy LLC accounted for 31% of gross product revenue;
−Removed: and Accredo Health Group, Inc.
+Added: Accredo Health Group, Inc.
accounted for 34% of gross product revenue;
−Removed: We also depend on a single source supplier for our product, product candidates and active pharmaceutical ingredient.
−Removed: Strategic Agreements
+Added: and PANTHERx Specialty Pharmacy LLC accounted for 27% of gross product revenue.
License and Commercialization Agreements with Bioprojet
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Bioprojet also granted us an exclusive license to use certain trademarks and trade names in connection with the commercialization of the product under the Bioprojet License Agreement.
−Removed: Under the 2017 LCA, we cannot, directly or indirectly, develop, market, sell, promote or file an NDA with respect to any product that would compete with pitolisant in the field.
We paid Bioprojet an initial license fee of $150.0 million, a milestone payment of $50.0 million upon FDA acceptance of the NDA in February 2019, and a milestone payment of $75.0 million plus an additional $2.0 million fee for approval of the NDA in November 2019.
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The final milestone payment of $40.0 million was paid to Bioprojet in March 2022 upon the attainment of aggregate net sales of WAKIX in the United States of $500.0 million subsequent to the date of NDA approval by the FDA.
−Removed: Pursuant to the 2017 LCA, we agreed to pay royalties on the net sales of the product at tiered royalty rates of 13% to 24% based on annual
−Removed: total net sales during the period commencing on first commercial sale of the product and ending on the latest of 10 years from first commercial sale of the product, expiration of all regulatory exclusivity, or expiration of the last Bioprojet patent covering the product.
+Added: Pursuant to the 2017 LCA, we agreed to pay royalties on the net sales of the product at tiered royalty rates of 13% to 24% based on annual total net sales during the period commencing on first commercial sale of the product and ending on the latest of 10 years from first commercial sale of the product, expiration of all regulatory exclusivity, or expiration of the last Bioprojet patent covering the product.
Such royalty payments are subject to reductions based on royalties paid to any third party in order for us to commercialize the product.
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In addition, certain payments will become due upon the achievement of development milestones for new indications and formulations as agreed upon by both parties.
−Removed: The 2022 LCA also requires a fixed trademark royalty and a tiered royalty based on net sales upon commercialization, payable to Bioprojet on a quarterly basis for 10 years from the first commercial sale of each new product, the expiration of all regulatory exclusivity, or the expiration of the last Bioprojet patent covering the products.
+Added: The 2022 LCA also requires a fixed trademark royalty and a tiered royalty based on net sales upon
+Added: commercialization, payable to Bioprojet on a quarterly basis for 10 years from the first commercial sale of each new product, the expiration of all regulatory exclusivity, or the expiration of the last Bioprojet patent covering the products.
The $30.0 million licensing fee was recorded in research and development expenses within the consolidated statement of operations and comprehensive income (loss) for the year ended December 31, 2022.
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In addition, we and Bioprojet have the right to terminate the 2022 LCA upon the other party’s insolvency.
+Added: In April 2024, we entered into the Sublicense with Bioprojet for BP1.15205 to be evaluated for the treatment of narcolepsy and other potential indications.
+Added: Under the Sublicense, we obtained the exclusive right to develop, manufacture and commercialize BP1.15205 in the United States and Latin American territories (the “Licensed Territories”), which are rights that Bioprojet originally licensed from Teijin Pharma, the innovator of BP115205.
+Added: BP1.15205 is currently in pre-clinical development with IMPD submission anticipated in mid-2025.
+Added: Under the Sublicense, we paid Bioprojet an upfront license fee of $25.5 million, which we recognized as an IPR&D charge recorded in research and development within the consolidated statements of operations and comprehensive income for the year ended December 31, 2024, and will also be obligated to pay up to $127.5 million upon achievement of development and regulatory milestones and up to $240.0 million upon achievement of sales-based milestones, as well as royalty rates in the mid-teens on any sales of product using BP1.15205 in the Licensed Territories.
Intellectual Property
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and foreign patents and applications relating to our technology, inventions, and improvements that are important to the development and implementation of our business.
−Removed: Our WAKIX patent portfolio is comprised of three U.S.
−Removed: patents exclusively licensed to us from Bioprojet under the 2017 LCA.
−Removed: 8,207,197, which has claims directed to a polymorph, i.e., a specific crystalline form, of pitolisant and, methods for preparing that polymorph of pitolisant, is expected to expire in March 2030 based on a granted request for patent term extension, but without taking into consideration any possible pediatric exclusivity.
+Added: Our WAKIX patent portfolio comprises of four U.S.
+Added: patents and a U.S.
+Added: patent application exclusively licensed to us from Bioprojet under the 2017 LCA.
+Added: 8,207,197, which has claims directed to the polymorph, i.e., a specific crystalline form, of pitolisant in WAKIX, and methods for preparing that polymorph of pitolisant, is expected to expire in March 2030 based on a granted request for patent term extension, and patent term adjustment, but without taking into consideration any possible pediatric exclusivity.
A second U.S.
−Removed: 8,486,947, has claims directed to methods of treating excessive daytime sleepiness by administering pitolisant, which is expected to expire in September 2029 without taking into consideration any possible patent term extension.
+Added: 8,486,947, has claims directed to methods of treating excessive daytime sleepiness by administering pitolisant, which is expected to expire in September 2029 based on patent term adjustment.
+Added: 12,145,916 has composition claims directed to a second polymorph of pitolisant, and is expected to expire in March 2044, not including any possible extension of patent term.
+Added: We also license three pending U.S.
+Added: patent applications from Bioprojet that claim the pitolisant GR and pitolisant HD formulations.
+Added: Any patents that are issued from these applications are expected to expire in October 2044, without taking into consideration any possible adjustments of patent terms.
+Added: Further, we filed a patent family that includes a pending Patent Cooperation Treaty (“PCT”) application, PCT/US2024/031835, and pending U.S.
+Added: Patent Application No.
+Added: 18/679,624, which claim methods of using pitolisant for treating EDS in subjects with PWS.
+Added: Any patent that issues from these applications is expected to expire in May 2044, not including any possible adjustment to patent term.
Our HBS-102 patent portfolio comprises three patent families.
The first patent family includes U.S.
−Removed: 8,637,501, which has claims to certain melanin-concentrating hormone (MCH-1) receptor antagonists as compositions of matter, as well as methods of making the antagonists, and methods of use for treating obesity, anxiety, and depression, and processes for preparing the compounds, which is expected to expire in April 2031 without taking into consideration any possible patent term extension.
+Added: 8,637,501, which has claims to certain melanin-concentrating hormone (MCH-1) receptor antagonists as compositions of matter, as well as methods of making the antagonists, and methods of use for treating obesity, anxiety, and depression, which is expected to expire in April 2031 based on patent term adjustment and without taking into consideration any possible patent term extension.
A second patent family comprises three issued U.S.
patents (Nos.
−Removed: and 9,650,378), and issued patents in Australia, Brazil, Canada, China, Germany, Spain, France, the United Kingdom, Israel, Italy, Japan, Korea, Mexico, and New Zealand.
−Removed: The patents have claims directed to certain human MCH-1 receptor-selective antagonists as compositions of matter, and are expected to expire in June 2031 (the ‘308 patent) and January
−Removed: 2029 (the ‘743 and ‘378 patents, as well as the international patents).
−Removed: The third patent family comprises a pending PCT application (WO2021/142395) and has claims directed to therapeutic combinations or formulations of drugs comprising triple monoamine reuptake inhibitors, MCH receptor 1 (MCHR1) antagonists, and diazoxide, and methods of treating or preventing hyperphagia, moderate to severe binge eating disorder, bulimia nervosa, and management of obesity.
+Added: and 9,650,378), and issued patents in Australia, Brazil, Canada, China, Germany, Spain, France, United Kingdom, Israel, Italy, Japan, Korea, Mexico, and New Zealand.
+Added: The patents have claims directed to certain human MCH-1 receptor-selective
+Added: antagonists as compositions of matter, and are expected to expire in June 2031 (the ‘308 patent) and January 2029 (the ‘743 and ‘378 patents, as well as the international patents).
+Added: The third patent family comprises pending applications in the United States., Europe, Japan, China, and Hong Kong which have claims directed to therapeutic combinations or formulations of drugs comprising a melanin-concentrating hormone (“MCH-1”) receptor antagonist, and methods of treating or preventing hyperphagia, moderate to severe binge eating disorder, bulimia nervosa, among other disorders, and management of obesity using an MCH-1 receptor agonist, and also has claims to certain MCH-1 receptor antagonists as compositions of matter.
+Added: Our EPX-100 patent family includes pending applications in the United States., Europe, Australia, Brazil, Canada, China, Hong Kong, Japan, Korea, and Eurasia.
+Added: Any patent that issues from this patent family is expected to expire in June 2042, without taking into consideration any possible patent term extension or adjustment.
The term of individual patents in our portfolio depends upon the legal term of patents in the countries in which they are obtained.
−Removed: In the United States, the patent term is 20 years from the earliest date of filing a non-provisional patent application.
+Added: In the United States, and in other foreign jurisdictions where we have sought patent protection, the patent term is 20 years from the earliest date of filing a non-provisional patent application.
The term of a U.S.
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The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions.
−Removed: Changes in either the patent laws or their interpretation in the United States may diminish our ability to protect our technology or product candidates and could affect the value of such intellectual property.
+Added: Changes in either the patent laws or their interpretation in the United States, or in other foreign jurisdictions where we have sought patent protection, may diminish our ability to protect our technology or product candidates and could affect the value of such intellectual property.
In particular, our ability to stop third parties from making, using, selling, offering to sell or importing products that infringe our intellectual property will depend in part on our success in enforcing patent claims that cover our technology, inventions and improvements.
−Removed: We cannot guarantee that patents will be granted with respect to any patent applications we may file in the future, nor can we be sure that any patents that may be granted to us in the future will be commercially useful in protecting our products, the methods of use or manufacture of those products.
+Added: We cannot guarantee that patents will be granted with respect to any patent applications we may file in the future, nor can we be sure that any patents that may be granted to us in the future will be commercially useful in protecting our products, the methods of use, or the manufacture of those products.
Moreover, issued patents do not guarantee the right to practice our technology in relation to the commercialization of our products.
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Where applicable, the agreements provide that all inventions to which the individual contributed as an inventor shall be assigned to us, and as such, will become our property.
−Removed: There can be no assurance, however, that these agreements will provide meaningful protection or adequate remedies for our trade secrets in the event of unauthorized use or disclosure of such information.
+Added: be no assurance, however, that these agreements will provide meaningful protection or adequate remedies for our trade secrets in the event of unauthorized use or disclosure of such information.
Further, we have in-licensed from Bioprojet the registered trademark product name “WAKIX” in the United States.
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Failure to comply with the applicable U.S.
−Removed: requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.
+Added: requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending NDAs or sNDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.
The process required by the FDA before a drug may be marketed in the United States generally involves the following:
−Removed: ● completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s Good Laboratory Practice (“GLP”) regulations and other applicable regulations;
+Added: ● completion of certain preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s Good Laboratory Practice (“GLP”) regulations and other applicable regulations;
● submission to the FDA of an IND which must become effective before human clinical trials may begin;
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An IND is a request for authorization from the FDA to administer an investigational drug product to humans.
−Removed: An IND will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the trial includes an efficacy
+Added: An IND will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the trial includes an efficacy evaluation.
Some preclinical testing may continue even after the IND is submitted.
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These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
−Removed: In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.
+Added: In certain instances, the FDA may mandate the performance of such Phase 4 clinical trials as a condition of approval of an NDA.
Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMPs.
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An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.
−Removed: A complete response letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional clinical trial or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing.
+Added: A complete response letter usually describes the specific deficiencies in the
+Added: NDA identified by the FDA and may require additional clinical data, such as an additional clinical trial or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing.
Even with the resubmission of the application with this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
−Removed: Even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.
+Added: Even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.
The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.
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Such off-label uses are common across medical specialties.
−Removed: Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances.
+Added: Physicians may believe that such off-label uses are the best treatment for many patients in
+Added: varied circumstances.
The FDA does not regulate the behavior of physicians in their choice of treatments.
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A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.
−Removed: During the exclusivity period, the FDA may not approve or even accept for review an
−Removed: abbreviated new drug application (“ANDA”) or an NDA submitted under Section 505(b)(2) (“505(b)(2) NDA”) submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.
+Added: During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application (“ANDA”) or an NDA submitted under Section 505(b)(2) (“505(b)(2) NDA”) submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval.
However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.
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A pharmaceutical product may be listed as Schedule II, III, IV or V, with Schedule II substances considered to present the highest risk of abuse and Schedule V substances the lowest relative risk of abuse among such substances.
−Removed: The FDA did not recommend that the DEA schedule WAKIX as a controlled substance, and WAKIX is therefore not scheduled as a controlled substance by the DEA.
+Added: The FDA did not recommend that the DEA schedule WAKIX as a controlled substance, and WAKIX is therefore not scheduled as a controlled substance by the DEA, however we are developing certain centrally acting product candidates that may have the potential for DEA scheduling, if approved .
Annual registration is required for any facility that manufactures, distributes, dispenses, imports or exports any controlled substance.
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These laws include U.S.
−Removed: federal and state anti-kickback and false claims laws, civil monetary penalties laws, consumer protection and transparency laws as well as similar foreign laws in the jurisdictions outside the U.S., including, without limitation, those laws described below.
+Added: federal and state anti-kickback and false claims laws, civil monetary penalties laws, consumer protection and transparency laws as well as similar foreign laws in the jurisdictions outside the United States, including, without limitation, those laws described below.
The federal Anti-Kickback Statute prohibits, among other things, individuals or entities from knowingly and willfully offering, paying, soliciting or receiving remuneration, directly or indirectly, overtly or covertly, in cash or in kind to induce or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs.
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federal and state health information privacy, security and data breach notification laws, which may govern the collection, use, disclosure and protection of health-related and other personal information.
−Removed: In the U.S., HIPAA imposes privacy, security and breach reporting obligations with respect to individually identifiable health information upon “covered entities” (health plans, health care clearinghouses and certain health care providers), and their respective business associates, individuals or entities that create, received, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity.
+Added: In the United States, HIPAA imposes privacy, security and breach reporting obligations with respect to individually identifiable health information upon “covered entities” (health plans, health care clearinghouses and certain health care providers), and their respective business associates, individuals or entities that create, received, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity.
HIPAA mandates the reporting of certain breaches of health information to the Department of Health and Human Services (“HHS”), affected individuals and if the breach is large enough, the media.
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The relationship between the United Kingdom and the European Union in relation to certain aspects of data protection law remains unclear, and it is unclear how United Kingdom data protection laws and regulations will develop in the medium to longer term, and how data transfers to and from the United Kingdom will be regulated in the long term.
−Removed: The European Commission has adopted an adequacy decision in favor of the United Kingdom, enabling data transfers from EU member states to the United Kingdom without additional safeguards.
+Added: The European Commission has adopted an adequacy decision in favor of the United Kingdom, enabling data transfers from EU member states to the United
+Added: Kingdom without additional safeguards.
However, the UK adequacy decision will automatically expire in June 2025 unless the European Commission re-assesses and renews or extends that decision.
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Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the FDA-approved products for a particular indication, or place products at certain formulary levels that result in lower reimbursement levels and higher cost-sharing obligation imposed on patients.
−Removed: One third-party payor’s decision to cover a particular medical product or service does not ensure that other payors will also provide coverage for the medical product or service and the level of coverage and reimbursement can differ significantly from payor
+Added: One third-party payor’s decision to cover a particular medical product or service does not ensure that other payors will also provide coverage for the medical product or service and the level of coverage and reimbursement can differ significantly from payor to payor.
As a result, the coverage determination process will often require us to provide scientific and clinical support for the use of our products to each payor separately and can be a time-consuming process, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.
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required collection of rebates for drugs paid by Medicaid managed care organizations;
−Removed: required manufacturers to participate in a coverage gap discount program, under which they must agree to offer point-of-sale discounts (increased to 70 percent pursuant to the Bipartisan Budget Act of 2018, effective as of January 1, 2019) off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
+Added: required manufacturers to participate in a coverage gap discount program, which was replaced by a new manufacturer discount program on January 1, 2025 (as discussed below), under which they were required to offer point-of-sale discounts (increased to 70 percent pursuant to the Bipartisan Budget Act of 2018, effective as of January 1, 2019) off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D;
imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs” to specified federal government programs, implemented a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected expanded the types of entities eligible for the 340B drug discount program;
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created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;
−Removed: and established a Center for Medicare and Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
+Added: and established a Center for
+Added: Medicare and Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.
Since its enactment, there have been judicial, executive and Congressional legislative challenges to certain aspects of the ACA.
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Thus, the ACA will remain in effect in its current form.
−Removed: Further, prior to the U.S.
−Removed: Supreme Court ruling, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.
−Removed: The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.
Other legislative changes have also been proposed and adopted since the ACA was enacted, including aggregate reductions of Medicare payments to providers, which was temporarily suspended from May 1, 2020 through March 31, 2022 under the Coronavirus Aid, Relief and Economic Security Act (“CARES Act”), and further reduced payments to several types of Medicare providers.
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The rebate was previously capped at 100% of a drug’s average manufacturer price.
−Removed: Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, review the relationship between
−Removed: pricing and manufacturer patient programs and reform government program reimbursement methodologies for pharmaceutical products in an attempt to control drug costs.
+Added: Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs and reform government program reimbursement methodologies for pharmaceutical products in an attempt to control drug costs.
Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures and, in some cases, mechanisms to encourage importation from other countries and bulk purchasing.
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Eligibility for the Medicare Part D Low-Income Subsidy Program was also expanded under the legislation, and it further delayed the implementation of the Trump Administration’s drug rebate rule to 2027.
+Added: While the IRA includes an exemption for orphan drugs with a single approved indication, rare disease therapies with multiple indications may become subject to Medicare price negotiations.
The IRA permits the Secretary of the Department of Health and Human Services, or HHS, to implement many of these provisions through guidance, as opposed to regulation, for the initial years.
−Removed: On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the drug price negotiation program is currently subject to legal challenges.
+Added: On August 15, 2024, HHS announced the agreed-upon prices for the first ten drugs that are subject to price negotiations, which take effect in January 2026.
+Added: HHS will select up to fifteen additional products covered under Part D for negotiation in 2025.
+Added: Each year thereafter, more Part B and Part D products will become subject to the HHS price negotiation program, although the program is currently subject to legal challenges.
For that and other reasons, it is currently unclear how the IRA will be effectuated, or the impact of the IRA on our business.
−Removed: We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our products or additional pricing pressures.
+Added: We expect that additional state and federal healthcare reform measures, particularly in light of the new presidential administration, will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our products or additional pricing pressures.
Our corporate headquarters are located at 630 W.
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Human Capital Management
−Removed: As of December 31, 2023, we have 246 full-time employees, 127 who are dedicated to commercial functions, which includes sales, marketing, market access, commercial operations, and insights, and 65 who are dedicated to research and development.
+Added: As of December 31, 2024, we had 268 full-time employees, 124 dedicated to commercial functions, which includes sales, marketing, market access, commercial operations, and insights, and 90 dedicated to research and development.
None of our employees are represented by labor unions or covered by collective bargaining agreements.
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We focus on providing our employees safe and healthy working conditions, and actively participate in the communities where we are located.
−Removed: In addition, we support philanthropic organizations, patient-focused associations, local and national charitable organizations, and areas of need across the country by providing monetary donations or supplying
−Removed: food, medical supplies and other resources.
−Removed: We collaborate with patient advocacy organizations to understand the needs of patients living with rare, neurological disorders including narcolepsy, and are committed to addressing those needs.
+Added: In addition, we support philanthropic organizations, patient-focused associations, local and national charitable organizations, and areas of need across the country by providing monetary donations or supplying food, medical supplies and other resources.
+Added: We collaborate with patient advocacy organizations to understand the needs of patients living with rare, neurological disorders, and are committed to addressing those needs.
Our environmental, social and governance (”ESG”) and social impact strategy is directed by our Board and overseen by management and a cross-functional executive team comprised of Legal, Compliance, Human Resources, Corporate Affairs and Investor Relations.
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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.