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.

ImmunityBio Eyes First IL-15 Superagonist Approval for NMIBC

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 Proposes Buccal Film for Pediatric Seizures

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).

Day One Positions XOMA-Partnered Tovorafenib as Monotherapy for Pediatric Glioma

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.

FDA to Decide on New Formulation for Neurocrine’s Ingrezza

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.

X4 Eyes WHIM Syndrome Approval for Oral CXCR4 Blocker

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.

https://www.biospace.com/article/fda-action-alert-immunitybio-aquestive-xoma-and-more/

Early Data Indicate Cell Therapies Could ‘Reset the Clock’ in Parkinson’s

 Could stem cell therapies make the Parkinsonian brain generate dopamine again? Some companies, including BlueRock Therapeutics and International Stem Cell Corporation, are banking on it.

Parkinson’s disease is currently treated with dopamine replacement agents, but the efficacy of these drugs is limited and they come with challenging side effects. Some in the stem cell field say these new therapies, though early-stage, could ultimately be a better, safer option.

In a March 2024 report, GlobalData touted the “early promise” of cell therapies to address the motor and non-motor symptoms of Parkinson’s disease with minimal adverse effects.

‘Resetting the Clock’

With more than 10 million people around the world living with Parkinson’s disease, the treatment market is currently valued at $5.56 billion and is expected to reach $6.63 billion by 2029.

A progressive disease of the nervous system, Parkinson’s is characterized by the degradation of neurons in the part of the brain that controls movement. The loss of these neurons slows the production of dopamine, leading to a combination of motor symptoms, including writhing movements, resting tremors and muscle stiffness, which can be lessened with levodopa and dopamine-agonists—drugs that behave like dopamine. The disease also brings non-motor symptoms, including depression, hyposmia, dysphasia and psychosis.

Levodopa is currently the “gold standard” treatment for Parkinson’s. Although it provides a dopamine kick, the drug is laden with severe adverse effects, including hallucinations, dyskinesia and loss of impulse control. These side effects can occur a dopamine response is stimulated in several parts of the brain through medication, Agnete Kirkeby, a stem cell scientist at Lund University and the University of Copenhagen, told BioSpace. Levodopa also provides only a small window of relief for patients, Kirkeby said.

In an emailed statement to BioSpace, GlobalData analysts Lorraine Palmer and Christie Wong said early clinical trials of stem cell transplantation in Parkinson’s have shown a reduction in motor and non-motor symptoms. “However, the subject size of these clinical trials have been small and were not powered to measure statistical significance,” they said, adding that large-scale, pivotal trials will be required to investigate how safely and how well the therapies work.

“Currently, there are no therapies which recover lost dopaminergic neurons so if cell therapies do end up meeting their hopes of replacing dopaminergic neurons,” they could be market changers, Palmer and Wong said.

During her postdoctoral days at Lund, Kirkeby, along with her supervisor, designed a method to grow transplantable dopamine cells from embryonic stem cells. “When we transplant the cells, we transplant [them] to a very particular region of the brain that is involved in motor control,” she explained. Kirkeby is currently leading a preclinical study of STEM-PD sponsored by Lund, a stem-cell therapy intended to replace lost dopamine neurons in the brains of Parkinson’s patients.

Cambridge, Mass.–based BlueRock Therapeutics, a Bayer subsidiary, is also developing a stem cell–based therapy, called bemdaneprocel. “You can think about it almost like you’re resetting the clock for those people who live with Parkinson’s disease by providing them cells, which have the potential to integrate and re-establish some of the neural networks and circuitry in that part of the brain,” Ahmed Enayetallah, head of development at BlueRock, told BioSpace.

Cell Therapies for Parkinson’s in the Pipeline

There are currently seven stem cell therapies for Parkinson’s disease in Phase I clinical trials or later. Three of these—sponsored by BlueRock, Celavie Biosciences and International Stem Cell Corporation—have completed and published results.

In the Phase I trial of bemdaneprocel, neuronal progenitor stem cells derived from donors were transplanted into 12 patients, whose progress was monitored for 18 months. During the first year, the patients were treated with immunosuppressive drugs. The cells survived and bemdaneprocel was tolerated by patients throughout the trial period, Enayetallah said, even after immunosuppression was discontinued.

The trial met multiple clinical endpoints and broadened the window at which the patients experienced relief from disease symptoms, he added. Unlike with current treatments, Enayetallah said, there were no reported cases of dyskinesia or other adverse events except gastrointestinal bleeding and seizure, which he attributed to the surgical procedure and not the therapy itself.

Having a one-time treatment for Parkinson’s disease would be a paradigm shift, Enayetallah said.

Another therapy, ISC-hpNSC, is in development by California-based International Stem Cell Corporation. Upon completion of a Phase I trial, patients’ ON-Time—a period where Parkinson’s medications like levodopa bring about good motor control—increased by 65% over two years, and OFF-Time decreased by 55% within the same period, the company reported in June 2021. The cells were well-tolerated with no serious adverse events.

With therapies such as these, Kirkeby said it is possible that the cells could overgrow and generate too many cells in the brain, but so far, neither trials of STEM-PD nor bemdaneprocel have recorded this adverse effect.

And while stem cell therapies are currently aimed at relieving the motor symptoms of Parkinson’s, Enayetallah said bemdaneprocel’s trial results hint at improved quality of life and psychiatric outcomes. Kirkeby also indicated that her lab is working on stem cell therapies that would target non-motor symptoms such as cognitive impairment.

Enayetallah noted that therapeutic development in Parkinson’s is “incredibly challenging” and plagued with the highest failure rates in drug development. However, he said, the results of BlueRock’s Phase I trial are a significant step toward bringing a “transformational therapy” to patients.

“Cell therapy in neurology is something that hasn’t been explored to that extent before. We’re paving the road here.”

https://www.biospace.com/article/early-data-indicate-cell-therapies-could-reset-the-clock-in-parkinson-s-/

5 Cell and Gene Therapy Decisions to Watch in 2024

 In 2023, cell and gene therapy saw an unprecedented surge with seven FDA approvals, and this year, an even greater number of these treatments could reach the market. So far in 2024, the regulator has given the green light to three new CGTs, and at least seven additional cell and gene therapy products are expected to receive approval by year’s end, according to a March report from the Alliance for Regenerative Medicine.

“All signs point to 2024 surpassing 2023 as a landmark year for cell and gene therapy,” David Barrett, CEO of the American Society of Gene & Cell Therapy (ASGCT), told BioSpace.

The first approval this year belonged to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which won the FDA’s nod in January for use in transfusion-dependent beta thalassemia. This followed the agency's December 2023 approval of Casgevy as one of the first two cell-based gene therapies to treat patients with sickle cell disease. It also represented the first FDA approval of a therapy using CRISPR/Cas9 technology. Then, in February, Iovance Biotherapeutics’ Amtagvi was approved as the first one-time cell therapy for a solid tumor and the first tumor-infiltrating lymphocytes therapy, for advanced melanoma patients who have worsened after being treated with certain other therapies failed. Finally, last month, the FDA greenlit Orchard Therapeutics’ Lenmeldy, which entered the U.S. market as the first gene therapy for children with metachromatic leukodystrophy, and the word’s most expensive drug, with a $4.25 million price tag. 

Looking forward, the FDA has upcoming PDUFA dates for several more novel CGTs, including a traditional in vivo gene therapy delivered via viral vector, a couple of gene-corrected cell therapies in which a patient’s cells are modified by gene therapy outside of the body and then reinfused, and a new CAR-T.

Two Q1 reports, from ASGCT and the Alliance for Regenerative Medicine, highlight some of these regulatory actions as potential catalysts for the sector, with approvals poised to propel the CGT space. The ASGCT report includes a list of noteworthy events in Q1 2024, while ARM’s report makes the case that 2024 could be a banner year for cell therapy.

Here, BioSpace reviews five products under regulatory review that were highlighted by both organizations.

Pfizer’s Beqvez

Indication: Hemophilia B

Therapy type: In vivo gene therapy

Action date: April 27

Later this month, the FDA will rule on Pfizer’s gene therapy for hemophilia B, Beqvez. This engineered version of the factor IX coagulation gene carried by an adeno-associated virus is administered via a single infusion.

Beqvez has been approved by Health Canada to treat adults with hemophilia B based on positive data from the Phase III BENEGENE-2 study, which showed a significant reduction in bleeding rate and infusion frequency.

The Big Picture

An FDA approval would put Pfizer in competition with CSL Behring, whose gene therapy Hemgenix, which is also administered via a single intravenous infusion, became the first FDA-approved gene therapy for hemophilia B in November 2022. Pricing details for Beqvez are not yet available, but Hemgenix costs $3.5 million per dose. Chris Boshoff, Pfizer’s chief oncology officer, told BioSpace the company aims to leverage its experience to ensure smooth market entry and efficient delivery to eligible patients.

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Abeona Therapeutics’ pz-cel

Indication: Recessive dystrophic epidermolysis bullosa

Therapy type: Gene-corrected cell therapy

Action date: May 25

Next up is Abeona Therapeutics’ pz-cel, which delivers a functional collagen-producing COL7A1 gene into a patient’s own skin cells using a retroviral vector, for the treatment of patients with recessive dystrophic epidermolysis bullosa (RDEB). RDEB, a rare connective tissue disorder, causes severe skin wounds, pain and life-threatening complications stemming from compromised immunity due to a deficiency in the COL7A1 gene, preventing the production of functional type VII collagen.

In November 2023, the FDA granted priority review to pz-cel based on clinical data from the Phase III VIITAL study and long-term results from a Phase I/IIa study, which demonstrated sustained wound healing and pain reduction.

The Big Picture

Ira Leiderman, managing director of healthcare at Cassel Salpeter, underscored the importance of evaluating therapeutic options against the rarity and impact of the disease. A positive decision on Abeona’s pz-cel will help address the high unmet need of RDEB patients and may lead to transformative interventions in this challenging rare genetic disorder, Leiderman told BioSpace.

If approved, pz-cel would follow Krystal Biotech’s Vyjuvek, the first gene therapy approved for recessive or dominant DEB in May 2023. Abeona said in March it is actively preparing for the potential U.S. launch of pz-cel, including discussions with treatment sites and payer engagement.

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Rocket Pharmaceuticals’ Kresladi

Indication: Leukocyte adhesion deficiency-1

Therapy type: Ex-vivo vector gene therapy

Action date: June 30

While Rocket Pharmaceuticals initially anticipated a decision on its gene therapy for leukocyte adhesion deficiency-I (LAD-I) by March, the FDA requested more review time and extended the deadline to June 30.

Severe LAD-I, a rare genetic disorder affecting children, is caused by mutations in the ITGB2 gene that lead to life-threatening infections. Without regular bone marrow transplants, survival beyond childhood is rare. Kresladi contains patient-derived hematopoietic stem cells genetically modified with a lentiviral vector to carry functional copies of the ITGB2 gene, crucial for leukocyte adhesion and infection-fighting.

In November 2023, the FDA accepted Rocket’s BLA for Kresladi with priority review, following positive efficacy and safety data from a global Phase I/II study, in which all nine LAD-I patients were alive 12 to 24 months post-infusion. Significant reductions in infection rates were observed compared to pre-treatment levels, along with the resolution of LAD-I–related skin lesions and restoration of wound healing capabilities.

Kresladi also holds the FDA’s Regenerative Medicine Advanced Therapy, Rare Pediatric, Fast Track and Orphan Drug designations.

The Big Picture

This marks Rocket’s inaugural product filing and is a notable advancement for patients, offering an alternative to bone marrow transplant, which carries significant risks and may not be readily accessible. Rocket is enhancing its commercial infrastructure in preparation for a potential product launch, including center initiation, channel strategies, education and payer engagement.

Rocket CEO Gaurav Shah told BioSpace the FDA is reallocating reviewers to focus on rare diseases and complex biologics, necessitating changes and a transition period. Shah noted that the delayed decision, based on the FDA’s request for clarity on chemistry, manufacturing and controls information submitted by Rocket, is common among CGTs and does not raise significant concerns beyond ensuring the regulator has sufficient resources for the approval process.

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Adaptimmune’s afami-cel

Indication: Advanced synovial sarcoma

Therapy type: T cell receptor therapy

Action date: August 4

Adaptimmune is gearing up for the potential launch of its inaugural product in the sarcoma franchise, afami-cel, intended for treating advanced synovial sarcoma, with a PDUFA date set for August 4. Afami-cel received FDA priority review in January.

Synovial sarcoma, which makes up 5% to 10% of soft tissue sarcomas, typically affects individuals under 30, with a five-year survival rate of 20% for metastatic cases. Recurrence is frequent, necessitating multiple lines of therapy and potential exhaustion of treatment options. Afami-cel is a single-dose engineered T cell receptor therapy targeting MAGE-A4-posititive tumor cells. The therapy’s clinical data from the SPEARHEAD-1 trial revealed that about 39% of patients experienced clinical responses, with a median response duration of around 12 months. Median overall survival was about 17 months, contrasting with historical data of less than 12 months for those who received two or more prior lines of therapy. Some 70% of responders to afami-cel were alive two years post-treatment.

The FDA granted afami-cel Orphan Drug Designation for the treatment of soft tissue sarcomas and Regenerative Medicine Advanced Therapy designation.

The Big Picture

If approved, afami-cel would become the first approved engineered T cell therapy for this type of cancer. In November 2023, the Investigational New Drug (IND) for another T cell therapy, lete-cel, was transferred from GSK to Adaptimmune for the pivotal IGNYTE-ESO clinical trial, following an interim analysis showing a 40% response rate in synovial sarcoma or myxoid/round cell liposarcoma patients.

Adaptimmune CEO Adrian Rawcliffe said that the clinical results from the pivotal trial position lete-cel as a complement to afami-cel, potentially allowing the company’s sarcoma franchise to significantly expand its reach. He noted that leveraging the same commercial infrastructure intended for afami-cel could facilitate the efficient delivery of lete-cel to the market. Afami-cel would become the first engineered T cell therapy for a solid tumor. The franchise, including both afami-cel and lete-cel, “is projected to deliver up to $400 million in U.S. peak year sales,” Rawcliffe said in March.

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Autolus Therapeutics’ obe-cel

Indication: B cell acute lymphoblastic leukemia

Therapy type: CAR-T cell therapy

Action date: November 16

In accepting Autolus Therapeutics’ BLA for its lead next-generation CAR-T therapy obe-cel for relapsed/refractory adult acute lymphoblastic leukemia (ALL) in January, the FDA set a PDUFA target action date of November 16.

Obe-cel, an investigational CD19 CAR-T cell therapy, is designed to enhance clinical activity and safety compared to existing therapies by incorporating a fast target binding off-rate, minimizing T cell activation. In December 2022, Autolus hailed the Phase II FELIX trial as a success, as interim analysis showcased an overall remission rate of 70% for obe-cel in leukemia patients. CAR-T cell concentration peaked and persisted at 75% in peripheral blood after a median of 166.5 days post-infusion. The trial also demonstrated positive safety findings. 

Obe-cel holds the FDA’s Orphan Drug and Regenerative Medicine Advanced Therapy status. Earlier this month, the company;’s obe-cel marketing application was accepted by the European Medicines Agency.

The Big Picture

The potential approval of a second cell therapy for solid tumors this year suggests breakthroughs in treating these cancers may be near, Stephen Majors, a spokesperson for the ARM, told BioSpace. There is an “increasing focus on solid tumors,” a previously elusive area for cell and gene therapy, he said.

A recent $250 million deal granted BioNTech access to obe-cel, with the partner to aid in the launch and development program expansion and receive royalties based on net sales. Autolus expects obe-cel peak sales to exceed $300 million.

Autolus could face competition from Gilead Sciences subsidiary Kite, which in 2021 gained FDA approval for its CAR-T therapy Tecartus, the first such treatment for ALL, achieving a 65% complete remission rate.

https://www.biospace.com/article/5-cell-and-gene-therapy-decisions-to-watch-in-2024/