Coming off of a busy month, July is looking relatively quiet for the FDA, with only five big target action dates and one pivotal advisory committee meeting. Read below for more.
By July 7, the FDA is expected to release its verdict on Arcutis Biotherapeutics’ supplemental New Drug Application (sNDA), seeking approval for a 0.15% formulation of roflumilast cream for the treatment of atopic dermatitis in patients as young as 6 years.
Roflumilast is a topical inhibitor of the phosphodiesterase 4 (PDE4) enzyme, which plays a role in increasing the production of pro-inflammatory mediators while dampening the body’s anti-inflammatory mechanisms.
A 0.3% formulation of roflumilast is approved under the brand name Zoryve for the treatment of psoriasis in patients 6 years and older. The FDA in December 2023 expanded roflumilast’s indication, allowing its use for seborrheic dermatitis in patients aged 9 and above.
Arcutis is backing roflumilast’s atopic dermatitis application with data from three Phase III programs, including INTEGUMENT-1 and INTEGUMENT-2, two identical parallel-group, double-blinded and vehicle-controlled studies. The 0.15% roflumilast cream aced these two studies, hitting four-week success rates of 32.0% and 28.9%, respectively.
In January 2024, Arcutis released additional pooled analysis from these two trials, demonstrating that 91.5% of patients treated with 0.15% roflumilast saw an improvement in the Eczema Area and Severity Index, measured at 4 weeks.
Roflumilast’s data package also included a Phase II dose-ranging study and a Phase I pharmacokinetic trial.
Orexo AB is proposing its high-dose naloxone drug candidate OX124 as a nasal rescue treatment for opioid overdose. The FDA’s deadline for a decision is July 15.
Originally approved under the brand name Narcan, naloxone is a well-known treatment for opioid overdose. Currently available as an injectable and as a nasal spray, it works by competing with opioids for the same receptor sites, thereby undoing and dampening the drugs’ effects. Naloxone is effective at reversing the respiratory depression, hypotension and sedation often seen in patients who overdose on opioids.
Orexo’s investigational formulation of naloxone makes use of its “world-class drug delivery platform,” dubbed amorphOX, according to the company’s news release accompanying the acceptance of its NDA. Through amorphOX, Orexo delivers a powder formulation of naloxone that is rapidly absorbed, highly bioavailable and highly stable.
AmorphOX also makes naloxone more convenient and easier to use for patients, according to the company, making the product more robust to temperature changes. For instance, its efficacy is unaffected even if stored at freezing temperatures.
If approved, Orexo expects to kick off commercial activities in the second half of this year, with a broader retail launch scheduled in early 2025, CEO Nikolaj Sørensen said in a statement.
The FDA is reviewing Phathom Pharmaceuticals’ application to use its oral drug Voquezna (vonoprazan) for the treatment of heartburn associated with non-erosive gastroesophageal reflux disease (GERD). Its decision is due on July 19.
Afflicting around 38 million adults in the U.S., non-erosive GERD is the most common type of GERD and is characterized by reflux symptoms without mucosal erosions in the esophagus. Among its most common signs is episodic heartburn, which typically occurs at night. Patients with non-erosive GERD also suffer from regurgitation and chest pain and often have trouble swallowing.
Voquezna, a potassium-competitive acid blocker, works by suppressing acid secretion and acts with preference on parietal cells found in the stomach. This mechanism of action helped the drug win its first FDA approval in November 2023, allowing its use for the treatment of erosive GERD and the relief of heartburn in erosive GERD.
The NDA, which Phathom filed in September 2023, is backed by a randomized, placebo-controlled and double-blinded trial with 772 enrolled patients. Results showed that both the 10-mg and 20-mg doses of Voquezna aced the trial's primary endpoint, resulting in a 45% and 44% mean percentage of heartburn-free days over the 4-week treatment period, respectively, whereas this figure was only 28% in placebo comparators.
During the study’s 20-week extension phase, the mean percentage of heartburn-free days in the 10-mg and 20-mg treatment groups increased to 62% and 63%, respectively.
By July 27, the FDA is set to release its decision on Alpha Cognition’s NDA for ALPHA-1062, a next-generation acetylcholinesterase inhibitor being proposed for the treatment of mild-to-moderate Alzheimer’s disease.
Formulated as a delayed-release oral tablet, ALPHA-1062 is the prodrug of an already-approved acetylcholinesterase inhibitor, galantamine, according to Alpha Cognition. The candidate works through a similar pathway, boosting the activity of acetylcholine on nicotinic receptors and the cholinergic neurotransmission in the central nervous system, in turn inducing cognitive improvements.
Compared with galantamine, however, ALPHA-1062 promises a cleaner safety profile. It carries additional benzoyl ester moieties, which allow it to bypass acetylcholine receptors in the gastrointestinal nervous system, thereby avoiding the unwanted stimulation of local neurons and reducing side effects, according to Alpha Cognition’s website.
ALPHA-1062’s NDA, which the FDA accepted in December 2023, is supported by studies establishing the bioequivalence of the drug candidate to galantamine. If approved, ALPHA-1062 would be the second oral Alzheimer’s therapy in a decade, according to a February 2024 release from Alpha Cognition.
In February 2024, the FDA accepted Xspray Pharma’s NDA resubmission for Dasynoc (dasatinib), being proposed for the treatment of chronic myeloid leukemia. The regulator’s verdict is due on July 31.
According to Xspray’s news release alongside the NDA’s acceptance, Dasynoc is an “optimized version” of Bristol Myers Squibb’s dasatinib, which the pharma sells under the brand name Sprycel. For instance, Dasynoc is unaffected by stomach pH and can be used together with omeprazole, as per Xspray’s website. Dasynoc also has a more consistent uptake profile and can be given at lower doses than Sprycel.
In July 2023, the FDA rejected Xspray’s initial bid to win approval for Dasynoc. At the time, the regulator accepted the proposed brand name and did not identify deficiencies with the application’s stability and clinical data. Instead, the FDA requested additional information regarding Dasynoc’s dosing in order to avoid confusion among doctors and patients. The regulator also asked for more information regarding a third-party manufacturer.
In a February 2024 news release, CEO Per Andersson said that despite the initial rejection, Xspray remains “on track” to launch Dasynoc on September 1, if approved.
On July 25, the FDA’s Oncologic Drugs Advisory Committee will meet to discuss AstraZeneca’s supplemental Biologics License Application for its antibody therapy Imfinzi (durvalumab) for the treatment of resectable non-small cell lung cancer (NSCLC).
The panel of external experts will evaluate AstraZeneca’s application for neoadjuvant treatment with Imfinzi and chemotherapy, followed by Imfinzi monotherapy after surgery. The advisory committee will also evaluate whether the pharma should be required to justify Imfinzi treatment before and after surgery.
Imfinzi is a monoclonal antibody designed to target and block the PD-L1 protein, in turn inhibiting its downstream signaling cascade. This mechanism hampers cancer cells’ ability to weaken and evade the immune system, while also boosting the body’s innate anti-cancer activity.
The FDA first approved Imfinzi in May 2017 for the treatment of advanced bladder cancer. The treatment has since been indicated for several other cancers, including unresectable stage III NSCLC, biliary tract cancer, pancreatic cancer and advanced or recurrent endometrial cancer.
In April 2023, AstraZeneca published data from the Phase III AEGEAN study showing that neoadjuvant Imfinzi with chemotherapy, followed by maintenance Imfinzi monotherapy, significantly improved event-free survival in patients with resectable early-stage NSCLC versus chemotherapy alone. The Imfinzi-based regimen also resulted in a significantly higher pathologic complete response.
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Gilead Sciences encountered a major setback in late May when its antibody-drug conjugate Trodelvy failed to reach the primary endpoint in a confirmatory Phase III trial in patients with metastatic urothelial cancer. In addition to missing the mark in overall survival, Gilead reported a higher number of deaths in the Trodelvy arm of the study. However, Wall Street analysts are still optimistic when it comes to the drug’s blockbuster potential as a future cornerstone of Gilead’s oncology franchise.
TROPiCS-04 was the late-stage confirmatory trial meant to upgrade Trodelvy’s accelerated approval in previously-treated urothelial carcinoma (UC), which was granted by the FDA in 2021. The study compared Trodelvy to chemotherapy as a second-line treatment for patients with locally advanced or metastatic UC (mUC). The bottom line: the TROP2-directed antibody-drug conjugate (ADC) did not extend patients’ lives any better than chemotherapy.
Hartaj Singh, managing director and senior analyst at Oppenheimer, told BioSpace that while the TROPiCS-04 results were a “bummer” and “deflating” for Gilead, there are extenuating circumstances that must be taken into consideration. Singh said the mUC trial was designed by Immunomedics, which was acquired by Gilead in 2020 for $21 billion, and that issues with the design involve some patients’ “one-off events” that may have “tilted the odds against the trial.”
“I think that [Gilead] feel[s] that really nothing is altered about Trodelvy and that they’ll go to the regulators and . . . I would speculate that there’s a better than 50-50 chance the drug stays on the market for that [mUC] indication,” Singh said.
Trodelvy, which is also FDA-approved for the treatment of breast cancer, earlier this year also failed a Phase III trial in non-small cell lung cancer (NSCLC), missing its overall survival endpoint. While the back-to-back losing streak for the ADC is not encouraging, there are still paths forward for Trodelvy’s expansion in oncology.
At the recent American Society of Clinical Oncology (ASCO) annual meeting, Gilead presented further details of the data from the EVOKE-01 NSCLC trial. The results showed that Trodelvy, when put up against the chemotherapy docetaxel, demonstrated a median overall survival of 11.1 months versus 9.8 months for docetaxel.
Still, Gilead observed a more than three-month difference in median overall survival in a subgroup of patients, providing the company with the motivation to continue trialing efficacy in these patients.
A Jefferies analyst note to investors acknowledged there “continues to be a debate on the next steps with Trodelvy” and that a critical factor in the future will be whether Gilead can file for NSCLC in the second line.
“We think they will likely need to run another Phase III study, but we expect an update likely later this year after FDA discussions,” Jefferies analysts wrote. “If they are able to file for [second line plus] NSCLC in PD-1 refractory, we think this is all upside. Another option is they could focus their strategy on [first-line] given recent data looked good [with] 13 months [progression-free survival] for Trodelvy in PD-1 positive patients.”
The Jefferies analysts also commented that the EVOKE-01 data “remains debated” among doctors as the ADC appears efficacious in PD-1 refractory NSCLC. Still, it remains unclear how the FDA will perceive Gilead’s data and whether the regulator will require a new Phase III trial to confirm efficacy.
“If they are able to file on the subgroup analysis, this would certainly drive upside,” the analysts opined.
Despite Trodelvy’s recent NSCLC stumble, some data did go Gilead’s way at ASCO. The Phase II EVOKE-02 trial, which investigated the ADC in combination with Merck’s blockbuster cancer drug Keytruda in NSCLC, showed a median PFS of 13.1 months. Gilead also touted the results as supporting “promising activity” in squamous and non-squamous populations. Jefferies analysts noted that the EVOKE-02 results had an overall response rate better than PD-1 monotherapies and better than a PD-1-chemotherapy combination.
Even though Trodelvy this year has reported less-than-stellar results, Singh remains optimistic about the ADC’s future.
He said he has models for the drug reaching around $1 billion annually “soon” and $2 billion within a year or two. By comparison, Trodelvy pulled in $309 million in sales in the first quarter of 2024, a 39% increase versus the same period in 2023.
While there might be a “momentary downtick” in mUC sales, Singh pointed to the fact that the ADC is still a significant treatment in triple-negative and hormone receptor-positive HER2-negative breast cancer, an approval Gilead secured in early 2023.
“I’m happy people are bummed out about Trodelvy because expectations have come down so low,” Singh said. “Trodelvy is growing like 20%-plus every quarter. And if that continues, which we believe it will, then people are just going to be surprised to the upside.”
Psychedelic drug developers got a wake-up call when the FDA’s Psychopharmacologic Drugs Advisory Committee recommended against approving Lykos’ MDMA-assisted therapy to treat post-traumatic stress disorder. Now, companies in this space are scrutinizing their own protocols to ensure they don’t make the same mistakes.
“It’s really a shot over the bow,” Joe Tucker, CEO of Enveric Biosciences, a neuropsychiatric drug developer, told BioSpace. “The FDA gave guidance specifically on clinical trials involving psychedelic drugs one year ago. When I read it, I remember thinking, ‘The FDA is basically bending over backwards . . . to help.' To me, that says the FDA really wants companies in this sector to be successful.”
This desire, however, pales in the face of unsatisfying clinical safety and efficacy. And, based on its recommendation, it’s clear the advisory committee insists on conducting and evaluating clinical trials “the right way,” Tucker said.
Dan Karlin, chief medical officer of MindMed, which is developing an LSD therapeutic, agreed that the FDA seems open to psychedelic drugs in general. “Committee members didn’t necessarily seem biased against psychedelics, so much as they had real reservations around the methods MAPS [now Lykos] had employed,” Karlin told BioSpace.
At the Lykos adcomm meeting, committee members seemed to focus more on the clinical trial than the company’s midomafetamine (MDMA) drug itself. “I think the issue was a trial issue, and not a compound issue,” Pamela Tenaerts, chief scientific officer of Medable, which designs digital trial software, told BioSpace.
Lykos showed post-traumatic stress disorder (PTSD) symptoms declined substantially, but Tenaerts said “it did less of a good job [with] the things surrounding that endpoint.” As examples, she cited symptoms that weren’t recorded, a case of sexual misconduct and uncertainty over endpoints “because they didn’t track the positive side effects, like the euphoria.” Additionally, “there are indications of patients being told that maybe they were contributing to making history,” which may have affected their perceptions of their experiences, she said.
The adcomm pointed out several issues in the trials, to which Lykos responded. Despite working closely with the FDA under a Special Protocol Assessment, the FDA did not require data regarding cardiovascular and liver toxicity risks, and Lykos did not include such information in its filings.
The lack of this physiologic safety data wasn’t a make-or-break omission, though. “The safety profile is already known and MDMA is only dosed three times in therapy . . . so that kind of safety data can be recorded in post-marketing surveillance Phase IV trials,” Sam Clark, CEO of Terran Biosciences, which develops therapies for neurological and psychiatric diseases, told BioSpace. Additionally, “companies can [design] a comprehensive risk evaluation and mitigation program to mitigate safety risks.” Nonetheless, he said, that data should be collected and submitted going forward. “Future trials should include those labs.”
Data regarding the potential for abuse also was absent from Lykos’ regulatory filings.
Although Lykos recorded adverse events during trials, it generally didn’t record patients’ neutral or positive feelings, such as elevated moods or euphoria, according to the FDA briefing document. This “limits the assessment of abuse potential,” the FDA noted. “However, there is an extensive literature in both animals and humans and other available data . . . to inform the assessment.”
Relying on that data, however, proved inadequate for the committee. Clark and Karlin both recommend recording all acute experiences with the drug, whether they’re expected or unexpected, positive, negative or neutral, to generate more thorough data and, thus, more significant information. Recording positive experiences, Clark explained, is important because that data helps address criticism around expectation bias.
The Drug Enforcement Agency notes that MDMA acts as both a stimulant and a psychedelic. As Karlin explained, “MDMA is not a [classic] psychedelic. It’s an entactogen or empathogen.”
Unlike psychostimulants or hallucinogenics, MDMA promotes profound introspection rather than “trips,” according to research from the University of North Carolina at Chapel Hill.
The “profound alterations in mood, sensation, suggestibility and cognition” make these types of studies “nearly impossible to blind,” the FDA said in its briefing document. The agency recommended using niacin or other stimulants or low-dose MDMA, each of which Lykos rejected, arguing that those options could exacerbate anxiety or worsen PTSD symptoms, according to the same document.
But, Clark pointed out, “functional unblinding is not uncommon in drugs in psychiatric trials.” Therefore, the FDA eventually agreed, despite concerns, with Lykos’ plan to use an inactive placebo with psychotherapy as a control.
Alterations in mood, etc., pose a bigger issue than merely unblinding a study. Their occurrence means that such guided therapies are conducted alongside psychotherapy, which makes it difficult to determine whether results were caused by the drug or the psychotherapy, the FDA briefing document noted.
“No one has suggested that MDMA, in the absence of psychotherapy, would be an effective treatment,” Karlin underscored. “Psychotherapy research is hard to standardize. It’s hard to know how to do an appropriate control condition.” Lykos, he said, was “in a tough spot . . . because now you have two different interventions that are not well controlled and not really well-understood.”
Dose escalation studies can help differentiate between the effects of the drug and those of psychotherapy. “There could potentially be a dose-dependent response,” Clark said, which may resolve the issue of functional unblinding.
If drug-assisted psychotherapy is a part of a trial, companies should also clarify what “psychotherapy” means in that context. “In Lykos’ situation,” Tucker said, “it seemed there was a lot of variability in what psychotherapy meant, how it was administered and how it was monitored.”
The original thinking around psychedelics was that, as a patient, “You took a drug, had a hallucination, and psychotherapy helped you process it. That solved your trauma, and you were cured,” Tucker told BioSpace.
In the past five years, however, scientists have proposed an alternative mechanism called neuroplasticity. “In people with depression or anxiety, the prefrontal cortex has lost some of its ability to calm the amygdala,” Tucker said.
By enhancing the brain’s neuroplasticity, existing neurons make more connections with other neurons, he explained. This “strengthens the signaling from the prefrontal cortex (which governs logical thinking) to the amygdala (which governs emotions).” Under that theory, the hallucination is a side-effect, and the benefit is the increased neuroplasticity.
For biopharma, this makes psychiatric therapies more appealing, Tucker said. Enveric, as well as AbbVie and Gilgamesh—which announced a collaboration in May—are developing neuroplastogen molecules, which minimize the risk of hallucinations.
Sponsor and investigator bias was another issue for the Lykos adcomm. To minimize this, MindMed is working with “20 different clinical research sites to minimize bias [in its trials] . . . and to ensure results aren’t overweighted by one site or another,” Karlin said. Extremely rigorous site training also helps, as does meticulous oversight to ensure adherence to protocols.
MindMed and Lykos both use centralized independent raters to talk with patients about their treatments. “We use an off-site service to do the primary efficacy assessments,” Karlin said. Because they are not in the room during the sessions and are blinded to visit number, he suggests their assessments are more likely to be unbiased.
Given Lykos’ experience, Clark advised companies in this space to plan their trials meticulously to minimize the risk of encountering similar objections from future adcomms.
The ultimate goal, Karlin said, is “to develop the drug in such a way that people who would never in a million years today think about taking [psychedelic drugs] can have a medical and psychiatric evaluation and access an [effective] treatment."
