7 FDA Drug Decisions Anticipated Before the End of 2024

After a very busy first half of 2024 in the pharmaceutical pipeline, a number of high-interest and practice-implicative US Food and Drug Administration (FDA) decisions remain to close the year.

Here is a rundown of 7 PDUFAs that HCPLive is most highly anticipating to occur in through the rest of 2024.

Vonoprazan (VOQUENZA; Phathom Pharmaceuticals) – July 19

The investigational potassium-competitive acid blocker (PCAB) is seeking an indication as a daily treatment of heartburn associated non-erosive gastroesophageal reflux disease (NERD) in adult patients, on the support of the pivotal phase 3 PHALCON-NERD-301 trial.¹ As previously explained by HCPLive editorial advisory board member Taha Qazi, MD, gastroenterologist with the Cleveland Clinic, the novel treatment is a uniquely viable treatment for both patients with NERD and esophagitis.²

“An aspect of PCABs which differentiates them from guideline-recommended proton pump inhibitors (PPIs) are the need for dosing around meals, particular to PPIs only,” Qazi explained. “PCABs represent a novel mechanism for the management of erosive esophagitis and may hold promise for the management of other peptic conditions.”

Chamil Codipilly, MD, a gastroenterologist with the Mayo Clinic, additionally told HCPLive that a key differentiator between PCABs and PPIs is the fast-acting mechanism of the former versus the latter.³

“And while they’re newer than the PPIs and we don’t have great long-term safety data, they’ve been used in several Asian countries for a few years now and seem to be very safe,” Codipilly said. ““I think the next steps are going to be refining truly whether it’s something that can be taken as an as-needed basis…and I think another question is going to be the dosage.”

In topline results of PHALCON-NERD-301 reported by Phathom, 10 mg and 20 mg daily doses of vonoprazan provided statistically significant improved heartburn relief versus placebo over a 4-week span. Additionally, patients on either 10 mg or 20 mg daily vonoprazan each achieved 24-hour free heartburn on approximately 46% of the days in the trial, versus 27.5% among those receiving placebo (P <.0001).⁴

Nasuea was reported in approximately 3% of all patients treated with vonoprazan, versus just 0.4% of placebo-treated patients; no other adverse event was reported in more than 3% of treated patients, according to Phathom.

Seladelpar (Cymabay Therapeutics) – August 14

The cholestatic disease pipeline has been robust in recent years. Now, a selective, orally-active PPAR agonist is in line for FDA decision as a treatment of primary biliary cholangitis (PBC) in adults with or without cirrhosis, or with compensated cirrhosis inadequately treated with ursodeoxycholic acid (UDCA).

At the Digestive Diseases Week (DDW) 2024 Annual Meeting this May, data from the phase 3 ASSURE trial showed daily oral 10 mg seladelpar was associated with a 70.3% success rate of composite alkaline phosphatase (ALP) decrease of ≥15% from baseline and reduced total bilirubin levels at 12 months. More than one-third (37.2%) of treated patients achieved ALP normalization, and mean ALP change from baseline was -44.4 (-144.4 u/L).⁵

The investigational therapy additionally provided statistically significantly improved pruritus (itch) scores to patients with PBC—a pivotal symptomatic outcome for patients with cholestatic disease.

In an interview regarding the findings, study author Cynthia Levy, MD, professor of medicine in the division of digestive health and liver diseases and associate director of the Schiff Center for Liver Diseases at the University of Miami, explained that up to 4 in 10 patients with PBC are not adequately treated with primary treatment UDCA. Another 50% do not adequately respond to second-line treatment obeticholic acid. Seladelpar may be a game changer for patients with the rare liver disease.⁶

“Treatments that effectively address the debilitating pruritis and slow the disease progression could greatly improve the quality of life for those living with PBC,” Levy told HCPLive. “Robust, long-term data from current and ongoing clinical trials indicate that seladelpar has the potential to become a transformative therapy if approved for use in people living with PBC, bringing us closer to addressing the needs of patients living with this rare disease.”

Dupilumab (Dupixent; Sanofi & Regeneron) – September 15 & September 27

The Swiss army knife interleukin 4 and 13 (IL-4; IL-13) inhibitor—indicated to treat a variety of type 2 inflammation-based conditions including atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and eosinophilic esophagitis—is up for 2 more supplemental Biologics License Application (sBLA) decisions in September.

The first would be to indicate the biologic therapy as an add-on or maintenance option for adolescents with inadequately controlled CRSwNP, after receiving indication to treat adult patients with the chronic condition in June 2019.⁷ At the time, investigator Stella Lee, MD, director of Sino-Nasal Disorders & Allergy at the University of Pittsburgh, highlighted how 1 week of dupilumab dosing resolved decade-long losses of smell, taste or capability to adequately breathe in some patients.

“These patients suffer greatly from loss of smell, they can't breathe, they can't taste,” Lee said. “Their nose has taken over their lives—imagine if you had a cold that never went away, compounded by times 100.”

The data supporting the adolescent CRSwNP indication is extrapolated from the pivotal adult-indication SINUS-24 and SINUS-52 trials that which showed significantly improved nasal congestion and obstruction severity versus placebo at 24 weeks, as well as safety data derived from dupilumab’s previous indications to treat adolescent patients.⁸

The second anticipated indication for dupilumab this September will be for the treatment of adults with uncontrolled chronic obstructive pulmonary disease (COPD) and type 2 inflammation per eosinophil counts. The PDUFA was originally scheduled for late June, but moved to September due to an FDA request for additional efficacy analyses from the pivotal BOREAS and NOTUS trials.⁹

Study author Stephanie Christenson, MD, associate professor of medicine in the division of pulmonary, critical care, allergy and sleep medicine at the University of California, San Francisco, was recently featured on an HCPLive COPD pipeline discussion panel. There she explained how the presence of high eosinophils in patients with COPD is indicative of likely exacerbated disease—regardless of whether a patient is receiving maximum-dose triple-therapy inhaler regimens or not.¹⁰

“We are at least getting improvements in exacerbations and in (forced expiratory volume over 1 second)—and probably some improvement in symptoms as well—in these patients who are already on maximal therapy,” Christenson said. “I think it's pretty exciting that we're seeing such substantial improvements. I think it will be interesting to see, if this gets approved, how these patients look compared to what we see in asthma, where sometimes we get a biologic and it really changes people's lives.”

Christenson said type 2 inflammation is generally present in about 1 in 5 patients with COPD; an interesting development may be the establishment of real-world standards for eosinophil counts in dupilumab-eligible patients, relative to the levels used as inclusion criteria in the BOREAS and NOTUS trials.

Xanomeline-trospium (KarXT; Karuna Therapeutics) – September 26

As one expert explained to HCPLive, a “substantial proportion” of patients with schizophrenia still do not adequately respond to the first or even second antipsychotic therapies they receive.¹¹ KarXT, an investigational, dual M1/M4 muscarinic antipsychotic, may lead its class of emerging options that may provide resolution to this gap in schizophrenia care.

Earlier this year, findings from the phase 3, 52-week EMERGENT-4 open-lbael extension trial showed more than three-fourths of treated patients achieved a ≥30% improvement in schizophrenia symptoms per the Positive and Negative Syndrome Scale (PANSS) total score. Additionally, patients achieved a significant enough improvement in Clinical Global Impression-Severity (CGI-S) scores to shift average severity from “markedly ill” at baseline, to “moderately or mildly ill” at 1 year with KarXT.¹²

Interestingly, KarXT was additionally associated with weight loss—not weight gain—as treated patients reported a mean weight reduction of approximately 5.7 lbs over 32 weeks. In general, the safety profile of the investigational drug was very promising to lead investigator Rishi Kakar, MD, of Segal Trials—in particular relative to the bariatric and metabolic events generally associated with other schizophrenia therapies.

“Clinicians often have to decide a subtle balance between the effectiveness of a particular medication and then its safety profile long term,” Kakar said in an interview with HCPLive. “I always say that clinicians have to often decide: Am I doing more good than harm long-term as I prescribe these medications to our patients? So, I think KarXT, because of [its] unique mechanism of action, fits into that sort of treatment regimen.”

Epinephrine nasal spray (neffy; ARS Pharmaceuticals) – October 2

The novel administration option for the treatment of severe allergic reactions has had a lengthier path toward potential FDA approval. ARS Pharmaceuticals received a Complete Response Letter (CRL) for the nasally-administered epinephrine in September 2023; the agency request a new pharmacokinetic and pharmacodynamic trial comparing repeat doses of neffy versus an injection pen option for the treatment of allergen-induced allergic rhinitis conditions.¹³

Reaction to the delayed decision was generally surprise from many allergists, including Edwin Kim, MD, associate professor of pediatrics at the UNC School of Medicine and director of the UNC Food Allergy Initiative research group. Kim noted to HCPLive at the time that neffy’s application had already received a supporting vote from an FDA advisory committee.¹⁴

“I'm kind of reading between the lines here, but I don't get the sense that the FDA necessarily was just against a concept,” Kim said. “But if anything, it looked like they wanted some more data, some more reassurance on the actual medication doing what it's supposed to do. So, I'm still holding out hope because I think, if anything, the last few months has made it very clear that there is a lot of interest in a non-injection form of emergency epinephrine.”

That said, Kim acknowledged the severe risks associated with allergic reactions and anaphylaxes that which warrant “no margin for error” with an novel epinephrine option.¹⁵

“People need to have something that they know will work, and this early period will be really important for people to just get comfortable with it and build that trust with this new product,” Kim said. “The idea that this is given in the nose, of course, is going to be much more benign than a needle in your leg.”

Minocycline hydrochloride (DFD-29; Fortress Biotech) – November 4

Fortress’ 40 mg modified-release capsule therapy is up for potential use to treat inflammatory lesions and erythema in adults with rosacea. According to the company, approval this year would make DFD-29 the first oral, systemic therapy indicated to treat these common symptoms of rosacea.¹⁶

A pair of phase 3, randomized, double-blinded clinical trials showed the minocycline hydrochloride therapy demonstrated statistical superiority to doxycycline (Oracea) and placebo in treatment success and reduced total inflammatory lesion counts per Investigator’s Global Assessment (IGA).

Though minocycline is among the better formulations developed in the last decade for the treatment of rosacea to experts including Hilary Baldwin, MD, medical director of the Acne Treatment & Research Center in New York, consistent and adherent treatment regimens remain a hurdle for patients with the chronic skin disease. There’s hope that achieving more significant efficacy with emerging agents like minocycline will bring resolve and treatment satisfaction to patients with rosacea sooner than later.

“We have ample evidence now that if you go all the way to clear (skin), your chances of staying clear and being able to go on a drug holiday are much improved,” Baldwin said in an interview with HCPLive.¹⁷

References

1. ^{Brooks A. FDA Accepts NDA for Vonoprazan (Voquenza) in Non-Erosive GERD. HCPLive. Published December 7, 2023. https://www.hcplive.com/view/fda-accepts-nda-for-vonoprazan-voquenza-in-non-erosive-gerd}
2. ^{Qazi T. Qazi Corner, Edition 4: Vonoprazan, Etrasimod, SEQUENCE, and Celiac Guidelines. HCPLive. Published December 6, 2023. https://www.hcplive.com/view/qazi-corner-vonoprazan-etrasimod-sequence-celiac-guidelines}
3. ^{Kunzmann K. Chamil Codipilly, MD: Vonoprazan and PCABs for GERD. HCPLive. Published September 19, 2023. https://www.hcplive.com/view/chamil-codipilly-md-vonoprazan-pcabs-gerd}
4. ^{Phathom Pharmaceuticals. Phathom Pharmaceuticals Announces Positive Topline Results from Phase 3 PHALCON-NERD-301 Trial Evaluating Daily Dosing of Vonoprazan for Symptomatic Non-Erosive Gastroesophageal Reflux Disease (NERD). Press release. Published January 8, 2023. Accessed July 8, 2024. https://investors.phathompharma.com/news-releases/news-release-details/phathom-pharmaceuticals-announces-positive-topline-results-1}
5. ^{Iapoce C. ASSURE: Seladelpar Achieves Clinical Improvement in Primary Biliary Cholangitis. HCPLive. Published May 18, 2024. https://www.hcplive.com/view/assure-seladelapr-achieves-clinical-improvement-primary-biliary-cholangitis}
6. ^{Brooks A. Cynthia Levy, MD: Interim ASSURE Data Suggest Seladelpar Could Be “Transformative” in PBC. HCPLive. Published May 18, 2024. https://www.hcplive.com/view/cynthia-levy-md-interim-assure-data-suggest-seladelpar-could-be-transformative-in-pbc}
7. ^{Kunzmann K. FDA Approves Dupilumab for Severe CRSwNP. HCPLive. Published June 26, 2019. https://www.hcplive.com/view/fda-approves-dupilumab-severe-crswnp}
8. ^{Regeneron. DUPIXENT® (DUPILUMAB) SBLA ACCEPTED FOR FDA PRIORITY REVIEW FOR TREATMENT OF ADOLESCENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSWNP). Press release. Published May 13, 2024. Accessed July 6, 2024. https://investor.regeneron.com/news-releases/news-release-details/dupixentr-dupilumab-sbla-accepted-fda-priority-review-0}
9. ^{Kunzmann K. FDA Extends Dupilumab COPD Decision to September 2024. HCPLive. Published May 31, 2024. https://www.hcplive.com/view/fda-extends-dupilumab-copd-decision-september-2024}
10. ^{Mannino D, Anzueto A, Christenson S. COPD: New Therapy Breakthroughs: Episode 2. Projecting Dupilumab's Fit in COPD. HCPLive. Published June 27, 2024. https://www.hcplive.com/view/projecting-dupilumab-fit-in-copd}
11. ^{Kunzmann K. John Kane, MD: Shifts in Antipsychotics for Schizophrenia. HCPLive. Published May 5, 2024. https://www.hcplive.com/view/john-kane-md-antipsychotics-schizophrenia}
12. ^{Derman C. KarXT Effective in Improving Schizophrenia Symptoms at 52 Weeks. HCPLive. Published April 8, 2024. https://www.hcplive.com/view/karxt-effective-in-improving-schizophrenia-symptoms-at-52-weeks}
13. ^{Smith T. FDA Declines to Approve of Epinephrine Alternative to EpiPen, Requests Further Study. HCPLive. Published September 20, 2023. https://www.hcplive.com/view/fda-declines-to-approve-of-epinephrine-alternative-to-epipen-requests-further-study}
14. ^{Smith T. Edwin H. Kim, MD: Responding to FDA Decision Not to Approve ‘Neffy’ Treatment. HCPLive. Published September 26, 2023. https://www.hcplive.com/view/edwin-h-kim-md-responding-to-fda-decision-not-to-approve-neffy-treatment}
15. ^{Smith T. Edwin H. Kim, MD: Advantages, Challenges of Intranasal Epinephrine Spray Administration. HCPLive. Published September 19, 2023. https://www.hcplive.com/view/edwin-kim-md-advantages-challenges-intranasal-epinephrine-spray-administration}
16. ^{Fortress Biotech. Fortress Biotech Reports First Quarter 2024 Financial Results and Recent Corporate Highlights. Published May 15, 2024. Accessed July 6, 2024. https://www.fortressbiotech.com/investors/news-events/press-releases/detail/641/fortress-biotech-reports-first-quarter-2024-financial}
17. ^{Kunzmann K. Hilary Baldwin, MD: The Surge of Rosacea Treatment Options. HCPLive. Published June 23, 2023. https://www.hcplive.com/view/hilary-baldwin-md-surge-rosacea-treatment-options}