FDA Action Alert: ImmunityBio, Aquestive, XOMA and More

The FDA has only a handful of notable target action dates for the rest of April, including one for a rare immunodeficiency and another for a potentially first-in-class superagonist for bladder cancer.

Read below for more.

By April 23, the FDA is expected to release its verdict on ImmunityBio’s Biologics License Application (BLA) for its investigational IL-15 activator N-803, which is being proposed as a combination treatment with bacillus Calmette-Guérin (BCG) for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC).

IL-15 is an inflammatory cytokine that plays a central role in the development and function of natural killer T cells. N-803, also known as Anktiva (nogapendekin alfa inbakicept), consists of a mutant version of IL-15 bound to an IL-15 receptor fusion protein. This unique structure allows N-803 to stimulate CD8+ T cells and natural killer cells while avoiding the activation of regulatory T cells.

In terms of pharmacokinetics, N-803 can persist for a longer time in lymphoid tissues and has demonstrated stronger anti-tumor activity than native, non-complexed IL-15.

N-803’s application, which the FDA accepted in July 2022, is supported by data from the Phase II/III QUILT-3.032 trial, which combined N-803 with intravesical BCG in 190 patients. Results showed that the combo regimen elicited high levels of treatment response and better response duration versus FDA-approved comparators.

In May 2023, the FDA rejected N-803’s BLA, citing deficiencies during a pre-license inspection of a third-party manufacturer. The regulator considered ImmunityBio’s resubmission on October 2023 as complete.

Aquestive Therapeutics is developing Libervant (diazepam) buccal film as an acute treatment for intermittent, stereotypic episodes of frequent seizure activity in pediatric patients. The FDA’s decision is due on April 28.

Currently, the only approved treatment for this indication in children is Diastat (diazepam), which is delivered via a rectal gel system. Aquestive’s Libervant aims to provide a more convenient dosing option for these patients.

The FDA in August 2022 granted Libervant tentative approval, allowing its use in patients 12 years of age and above. The tentative approval suggests that Libervant has cleared the regulator’s efficacy and safety standards, but cannot yet enter the U.S. market due to the orphan drug market exclusivity of Valtoco (diazepam), a nasal spray product.

Under the orphan drug market block, Libervant will not be able to enter the market until January 2027.

At the time of its tentative approval, CEO Daniel Barber said the company believes Libervant “has the distinct advantage of being able to be readily administered when needed without regard to food, providing an important benefit to patients.”

“We believe Libervant, as an oral alternative to existing device-based products, will be well-received by this patient population, if approved with market access,” Barber said in a September 2023 press release accompanying the FDA’s acceptance of Libervant’s New Drug Application (NDA).

The FDA is set to release its verdict on Day One Biopharmaceuticals’ NDA for tovorafenib as a monotherapy for relapsed or progressive pediatric low-grade glioma (pLGG) on or before April 30.

Accounting for 30% to 50% of all central nervous system tumors, pLGG is the most common brain tumor in children, leading to vision loss and motor dysfunction, among other disease-related morbidities. There are currently no approved therapies for most patients with pLGG and most treatment options are associated with harsh side effects, some with potentially lifelong consequences.

Tovorafenib is an investigational and brain-penetrant type II RAF kinase blocker that targets and inhibits a key player in the MAPK signaling cascade. This mechanism of action allows tovorafenib to interfere with cancer cells’ hyperactive proliferation and unchecked growth, triggering cell death.

Day One is backing tovorafenib’s regulatory bid with data from the Phase II FIREFLY-1 study, an open-label study assessing the safety and efficacy of the candidate in 140 patients.

In September 2023, Day One posted updated data from FIREFLY-1, touting a 67% overall response rate and a 93% clinical benefit rate. Median duration of response was 16.6 months. As for safety, tovorafenib was generally well-tolerated, with most of its side effects being Grade 1 or Grade 2 in severity. The most common adverse events were change in hair color, fatigue and rashes.

XOMA and Day One entered into a partnership over tovorafenib in March 2021, when the biotech royalty aggregator paid $13.5 million upfront.

Neurocrine Biosciences is proposing a new sprinkle formulation of Ingrezza (valbenazine) for the oral treatment of tardive dyskinesia and chorea associated with Huntington’s disease. The FDA’s decision is due on April 30.

Ingrezza’s new oral granule formulation will come in 40-mg, 60-mg and 80-mg capsules, and is intended to be opened and sprinkled on soft foods before administration.

This new formulation will offer a more convenient dosing method to patients, “who have difficulty swallowing or simply prefer not to take whole capsules,” Neurocrine CMO Eiry Roberts said in a statement alongside the NDA’s acceptance.

Neurocrine’s NDA, which the FDA accepted in September 2023, is backed by data showing that the proposed oral granule sprinkle capsules of Ingrezza have a comparable bioequivalence and tolerability profile to its currently approved capsule formulation. The filing also has chemistry, manufacturing and controls information relevant to the FDA.

Ingrezza is a novel and selective blocker of the vesicular monoamine transporter 2, which regulates the uptake of monoamine from the cytoplasm to the synaptic vesicles. According to its label, the exact mechanism of action is still unclear.

The FDA first approved Ingrezza in 2017 for tardive dyskinesia, a motor syndrome that often arises as a side effect of antipsychotic medication and is characterized by uncontrollable and abnormal repetitive movements of the trunk, limbs and face. Ingrezza secured another regulatory nod in August 2023 for chorea in Huntington’s disease.

By April 30, the FDA is expected to release its verdict on X4 Pharmaceuticals’ NDA proposing its investigational CXCR4 receptor antagonist mavorixafor as a once-daily oral treatment for WHIM syndrome in patients aged 12 years and above.

WHIM syndrome—which stands for warts, hypogammaglobulinemia, infections and myelokathexis—is a rare and primary immunodeficiency that, aside from its namesake symptoms, is also characterized by low levels of neutrophils and lymphocytes, an elevated risk of lung disease, limited antibody production and a heightened risk of certain types of cancer.

WHIM syndrome is caused by the hyperactivation of the CXCR4/CXCL12 pathway, which in turn leads to the impaired mobilization and trafficking of white blood cells from the bone marrow. Mavorixafor addresses this underlying pathologic cause by blocking the CXCR4 receptor and disrupting its downstream signaling cascade.

X4 is backing its NDA with data from the pivotal Phase III 4WHIM trial, which found that compared with those who took a placebo, patients treated with mavorixafor saw a significant improvement in the time above threshold for absolute neutrophil count. The drug candidate likewise lowered the rate, severity and duration of infections.

Mavorixafor has previously won the FDA’s breakthrough therapy, fast track and rare pediatric disease designations for the treatment of WHIM syndrome. If approved, X4 will be eligible to receive a priority review voucher, which it can use to obtain priority review for a future drug application.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.