Avadel Pharmaceuticals Stock

Avadel Pharmaceuticals plc (Avadel) operates as a biopharmaceutical company.

The company’s lead product candidate, LUMRYZ, also known as FT218, is an investigational once-at-bedtime, extended-release formulation of sodium oxybate for the treatment of cataplexy or excessive daytime sleepiness (‘EDS’) in adults with narcolepsy. The company is primarily focused on obtaining final U.S. FDA approval of LUMRYZ and the launch of LUMRYZ, if approved.

Outside of the company’s lead product candidate, the company continues to evaluate opportunities to expand the company’s product portfolio.

LUMRYZ

LUMRYZ is an investigational once-at-bedtime formulation of sodium oxybate that uses the company’s proprietary drug-delivery technology for the treatment of cataplexy or EDS in adults with narcolepsy. Sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter gamma-aminobutyric acid. Immediate release sodium oxybate is approved in the U.S. for the treatment of cataplexy in narcolepsy as well as EDS in narcolepsy and is approved in Europe for the treatment of cataplexy in narcolepsy. Since 2002, sodium oxybate has only been available as an immediate-release formulation that must be taken twice nightly, first at bedtime, and then again 2.5 to 4 hours later.

On July 18, 2022, the FDA granted tentative approval to LUMRYZ for the treatment of cataplexy or EDS in adults with narcolepsy. Tentative approval indicates that LUMRYZ has met all required quality, safety, and efficacy standards necessary for approval in the U.S. as of the date that the tentative approval was granted, but that the drug cannot receive final FDA approval until expiry or other disposition of a third-party exclusivity period. That tentative approval was granted based on the FDA’s determination that the LUMRYZ label implicated the use code listed in FDA’s Orange Book for U.S. Patent No. 8731963 (the ‘REMS Patent’). The owner of the REMS Patent subsequently requested delisting of that patent from the Orange Book on February 28, 2023, and the company subsequently submitted an amendment to the FDA on March 1, 2023, requesting final FDA approval of the LUMRYZ NDA. The company is awaiting a final approval decision from the FDA. Based on typical target turnarounds for the FDA and information provided in the tentative approval letter with respect to minor amendments, the company anticipates timing for a final approval decision to be around early May of 2023. There can be no guarantee that the FDA will act within the anticipated timing.

The FDA’s tentative approval can be subject to change based on new information that may come to the FDA’s attention between such time as the tentative approval and potential final approval. The company cannot legally market LUMRYZ in the U.S. until final approval is granted by the FDA. In addition, if the FDA concludes that LUMRYZ is the same drug product as a previously approved product having unexpired orphan drug exclusivity (e.g., Xywav), the company would need to demonstrate that LUMRYZ is clinically superior to that previously approved product before the FDA grants final approval to the company’s NDA. If the FDA determines the previously approved product is not the same drug product for purposes of orphan drug exclusivity, then any unexpired orphan drug exclusivity would not be relevant to a final approval decision for LUMRYZ. In an effort to expedite the time between a potential final approval of LUMRYZ and product availability, the company is advancing its preparations for the commercial launch of LUMRYZ, which the company expects to occur late in the second quarter or sometime in the third quarter of 2023, subject to receiving final approval by the FDA. For example, on March 15, 2023, the company was notified by the FDA that the company is permitted to conduct certain pre-launch activities, including the importation of foreign manufactured product under the Pre-launch Activities Importation Request (‘PLAIR’) Program.

With respect to clinical data generated for LUMRYZ, the company conducted a Phase 3 clinical trial of LUMRYZ (the ‘REST-ON trial’), which was a randomized, double-blind, placebo-controlled study that enrolled 212 patients who received at least one dose of LUMRYZ or placebo, and was conducted in clinical sites in the U.S., Canada, Western Europe and Australia. The last patient’s last visit was completed at the end of the first quarter of 2020, and positive top line data from the REST-ON trial was announced on April 27, 2020. Patients who received 9 g of once-at-bedtime LUMRYZ, the highest dose administered in the trial, demonstrated statistically significant and clinically meaningful improvement compared to placebo across the three co-primary endpoints of the trial: maintenance of wakefulness test (‘MWT’), clinical global impression-improvement (‘CGI-I’), and mean weekly cataplexy attacks. The lower doses assessed, 6 g and 7.5 g, also demonstrated statistically significant and clinically meaningful improvement on all three co-primary endpoints compared to placebo. The company observed the 9 g dose of once-at-bedtime LUMRYZ to be generally well-tolerated. Adverse reactions commonly associated with sodium oxybate were observed in a small number of patients (nausea 1.3%, vomiting 5.2%, decreased appetite 2.6%, dizziness 5.2%, somnolence 3.9%, tremor 1.3% and enuresis 9%), and 3.9% of the patients who received 9 g of LUMRYZ discontinued the trial due to adverse reactions.

In January 2018, the FDA granted LUMRYZ orphan drug designation for the treatment of narcolepsy, which makes LUMRYZ potentially eligible for certain development and commercial incentives, including potential U.S. market exclusivity for up to seven years. Additionally, thirteen LUMRYZ-related U.S. patents have been issued, and there are additional patent applications in development and/or pending at the U.S. Patent and Trademark Office (‘USPTO’), as well as foreign patent offices.

In July 2020, the company announced that the first patient was dosed in the company’s open-label extension (‘OLE’)/switch study of LUMRYZ as a potential treatment for cataplexy or EDS in patients with narcolepsy (‘RESTORE’). The RESTORE study is examining the long-term safety and maintenance of efficacy of LUMRYZ in patients with narcolepsy who participated in the REST-ON study, as well as dosing and preference data for patients switching from twice-nightly sodium oxybate to once-at-bedtime LUMRYZ, regardless of whether they participated in REST-ON. In May 2021, inclusion criteria were expanded to allow for oxybate naïve patients to enter the study.

New secondary endpoints from the REST-ON trial were presented at the American Academy of Neurology, beginning April 17, 2021. The first poster described LUMRYZ improvements in disturbed nocturnal sleep (‘DNS’), defined in REST-ON as the number of shifts from stages N1, N2, N3, and rapid eye movement (‘REM’) sleep to wake and from stages N2, N3, and REM sleep to stage N1. LUMRYZ also decreased the number of nocturnal arousals as measured on polysomnography. Improvements in DNS were further supported by post-hoc analyses demonstrating increased time in deep sleep (N3, also known as slow wave sleep), and less time in N1. A second poster described the statistically significant improvements in the Epworth Sleepiness Scale (‘ESS’), both the quality of sleep and the refreshing nature of sleep, and a decrease in sleep paralysis. These clinically relevant improvements were observed for all doses, beginning at week 3, for the lowest 6 g dose, compared to placebo. LUMRYZ did not demonstrate significant improvement for hypnagogic hallucinations compared to placebo.

Additional data supportive of the efficacy findings in REST-ON were presented at the 35th Annual Meeting of the Associated Professional Sleep Societies, a joint meeting of the American Academy of Sleep Medicine and the Sleep Research Society, also known as SLEEP 2021, beginning June 10, 2021. New data included post-hoc analyses demonstrating endpoints improvements, regardless of concomitant stimulant use, in both narcolepsy Type 1 (‘NT1’) or Type 2 (‘NT2’). Additionally, a post-hoc analysis showed that LUMRYZ was associated with decreased body mass index compared to placebo, which may be relevant as people with narcolepsy often have co-morbid obesity. In August 2021, the primary results from the REST-ON trial were published by Kushida et al. in the journal SLEEP.

New data was presented at the American College of Chest Physicians annual meeting (‘CHEST’), beginning October 17, 2021, including additional post-hoc analyses from the REST-ON trial, demonstrating a greater proportion of patients receiving LUMRYZ experienced reductions in weekly cataplexy attacks and improvement in mean sleep latency compared to placebo, as well as the results of a discrete choice experiment, indicating that the overall driver of patient preference between sodium oxybate treatments is a once-at-bedtime, versus twice-nightly, formulation.

New data was presented at World Sleep 2022 Congress in March 2022, in Rome, Italy. A total of eight posters were presented, including five new post-hoc analyses from the REST-ON trial. Most notably, the post-hoc analyses showed that LUMRYZ demonstrated improvement in subjective measures of daytime sleepiness, sleep quality and refreshing nature of sleep as early as week 1 with the 4.5 g starting dose, with even greater improvement at week 2 soon after starting the 6 g dose compared to placebo. Additional post-hoc analyses, stratified by narcolepsy type, as well as concomitant stimulant use, or without stimulants, demonstrated positive results that are generally consistent with previously reported positive endpoints from REST-ON and add to the existing body of evidence for LUMRYZ.

In addition, the results of a discrete choice experiment (‘DCE’) were presented, which showed that once-at-bedtime dosing, when compared to twice-nightly dosing, was the most important attribute driving both patient and clinician preference for overall oxybate product choice, as well as patient quality of life and reduction of patient anxiety/stress; dosing frequency (twice-nightly versus once-at-bedtime) was also viewed as a more important attribute as compared to other attributes assessed, including sodium content. Accompanying the DCE was a background survey for both patients and clinicians, which showed that dosing frequency was noted as a significant stressor by both patients and clinicians. The World Sleep 2022 presentations also included the first presentation of an interim safety analysis from the ongoing RESTORE study, which showed that LUMRYZ has generally been well-tolerated, with some patients receiving therapy for more than 18 months.

In addition, interim data from RESTORE were presented demonstrating that a high proportion of patients switching from twice-nightly sodium oxybate formulations had difficulty in taking the second dose, with a high proportion (92.5%) stating a preference for the once-at-bedtime dosing regimen and that most participants (62%) switching from twice-nightly sodium oxybate formulations had a stable dose equal to their starting dose; participants not currently taking sodium oxybate formulations or oxybate naive reached a stable dose with 2–4 dose titrations within four weeks.

Additional peer-review publications have included a relative bioavailability pharmacokinetics (‘PK’) study and a Plain Language Summary of the primary REST-ON trial results.

LUMRYZ has the potential to demonstrate improved dosing compliance, safety and patient satisfaction over the current standards of care for cataplexy or EDS in patients with narcolepsy.

Drug Delivery Technologies

The company owns drug delivery technologies that address formulation challenges, potentially allowing the development of differentiated drug products for administration in various forms (e.g., capsules, tablets, sachets or liquid suspensions for oral use; or injectables for subcutaneous administration) that could be applied to a broad range of drugs (novel, already-marketed, or off-patent).

A brief discussion of each of the company’s drug delivery technologies is set forth below.

MICROPUMP. The company’s MICROPUMP technology allows for the development of modified release solid, oral dosage formulations of drugs. MICROPUMP-carvedilol and MICROPUMP-aspirin formulations have been approved in the U.S. Further, a version of the company’s MICROPUMP technology is being employed in the company’s investigational LUMRYZ product.

LIQUITIME. The company’s LIQUITIME technology allows for the development of modified release oral products in a liquid suspension formulation, which may make such formulations particularly well suited for children and/or patients having issues swallowing tablets or capsules. Although the company owns this technology, the company is not pursuing any commercial pharmaceutical drug development opportunities using it.

MEDUSA. The company’s MEDUSA technology allows for the development of modified-release injectable dosage formulations of drugs (e.g., peptides, polypeptides, proteins, and small molecules). Although the company owns this technology, the company is not pursuing any commercial pharmaceutical drug development opportunities using it.

Intellectual Property

LUMRYZ Patents: The company has been awarded thirteen LUMRYZ-related U.S. patents having expiry dates from mid-2037 to early-2042. The company has a number of additional LUMRYZ-related patent applications pending at the USPTO, as well as at non-U.S. patent offices.

Supplies and Manufacturing

LUMRYZ is subject to regulation by the U.S. Drug Enforcement Administration (‘DEA’) under the Controlled Substances Act (‘CSA’), and its manufacturing and distribution are highly restricted.

Government Regulation

The company’s drug candidates must be approved by the FDA through the NDA process before they may be legally marketed in the U.S. The company relies on third parties for the production of clinical and commercial quantities of the company’s approved drug and drug candidates in accordance with cGMP regulations.

History

The company was incorporated in 2015. It was formerly known as Flamel Technologies, S.A. and changed its name to Avadel Pharmaceuticals plc in 2017.