On February 11, 2025 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, reported that the U.S. Food and Drug Administration (FDA) has approved GOMEKLI (mirdametinib), SpringWorks’ MEK inhibitor, for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection (Press release, SpringWorks Therapeutics, FEB 11, 2025, View Source [SID1234650177]). With the approval, SpringWorks was granted a rare pediatric disease priority review voucher (PRV) by the FDA.

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"The NF1-PN patient community has a great need for more treatment options. With today’s approval, we are honored to serve both adults and children with NF1-PN and provide them with a therapy that has the potential to shrink their tumors and offer meaningful symptomatic relief," said Saqib Islam, Chief Executive Officer of SpringWorks. "We are grateful to each clinical trial participant, their families, the investigators, and the patient advocacy groups involved in the journey towards making GOMEKLI available in the U.S. I am proud that we are delivering on our commitment to patients with devastating diseases with our company’s second FDA approval in less than 18 months."

NF1 is a genetic disorder that currently affects approximately 100,000 children and adults in the United States.2,3 Patients with NF1 have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PNs, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment.2,4 There are approximately 40,000 people in the United States living with NF1-PN, the majority of whom are adults that have not had an approved medicine until GOMEKLI.5 Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors, an aggressive and potentially fatal disease.6 Surgical removal can be challenging due to the infiltrative tumor growth pattern of plexiform neurofibromas along nerves, and up to approximately 85% of plexiform neurofibromas are considered not amenable to complete resection.7,8,9

"Patients with NF1-PN often face significant challenges with their health and have had limited treatment options to manage this devastating condition," said Christopher Moertel, M.D., Medical Director Pediatric Neuro-Oncology and Neurofibromatosis Programs and Kenneth and Betty Jayne Dahlberg Professor of Pediatrics, University of Minnesota, and lead investigator of the ReNeu trial. "It was very encouraging in the ReNeu trial to see that GOMEKLI provided deep and durable responses, with a manageable safety profile that enabled patients to stay on therapy. This approval represents an important advance, especially for adults who previously did not have an approved treatment."

GOMEKLI was approved under Priority Review and SpringWorks received a rare pediatric disease priority review voucher from the FDA. GOMEKLI was previously granted Orphan Drug and Fast Track designations for the treatment of NF1-PN.

The FDA approval of GOMEKLI is based on results from the Phase 2b ReNeu trial, which enrolled 114 patients with NF1-PN ≥2 years of age (58 adults and 56 pediatric patients).10 GOMEKLI met the primary endpoint of confirmed objective response rate (ORR), as assessed by blinded independent central review, demonstrating a 41% ORR (N= 24/ 58) in adults and 52% in children (N=29/56).10 Tumor volume reductions were deep and durable; the median best percentage change in target PN volume was -41% (range: -90 to 13%) in adults and -42% (range: -91 to 48%) in children.10 Eighty-eight percent of adults and 90% of children with a confirmed response had a response of at least 12 months duration, and 50% and 48%, respectively, had a response of at least 24 months duration.10 Patients in both cohorts also experienced early and sustained significant improvements from baseline in pain, and quality of life, as assessed across multiple patient-reported outcome tools.10

GOMEKLI demonstrated a manageable safety and tolerability profile.1 The most common adverse events (>25%) reported in adults receiving GOMEKLI were rash, diarrhea, nausea, musculoskeletal pain, vomiting and fatigue.1 The most common adverse events (>25%) occurring in children were rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.1 Please see additional Important Safety Information below, including Warnings & Precautions relating to ocular toxicity, left ventricular dysfunction, dermatologic adverse reactions, and embryo-fetal toxicity.

"We are excited to celebrate the extraordinary milestone of our partners and long-term friends at SpringWorks for the NF1-PN community. This FDA approval shows the power of collaboration to advance innovative science for drugs that may otherwise not have been taken forward," said Annette Bakker, Ph.D., Chief Executive Officer of the Children’s Tumor Foundation. "When industry, researchers, and organizations like ours driving treatment innovation join forces, scientific progress moves faster, and patients gain access to the therapies they need. Every treatment approval is hard-won, built on research, persistence, and partnership. Today, that work delivers a critical new option for NF patients of all ages."

"NF1-PN is a complex, devastating disease that affects not only individual patients, but entire families. Treatment advances are crucial to achieving better outcomes for patients and this FDA approval offers hope for NF patients and their families," said Kim Bischoff, Executive Director, NF Network.

SpringWorks is dedicated to helping patients with NF1-PN access GOMEKLI and to providing support throughout their treatment journey. The SpringWorks CareConnections program is a comprehensive patient support program that offers personalized support services and resources to eligible GOMEKLI patients, including insurance coverage information and access support, financial assistance and personalized educational and emotional support. Physicians and patients can contact 1-844-CARES-55 (1-844-227-3755) or visit www.springworkstxcares.com for more information.

GOMEKLI is available in 1 and 2 mg capsules and in a 1mg tablet for oral suspension, which dissolves easily in water. GOMEKLI is expected to be available through a specialty pharmacy and specialty distributor network in the United States within two weeks.

SpringWorks’ Marketing Authorization Application for mirdametinib for the treatment of children and adults with NF1-PN was validated by the European Medicines Agency (EMA) and is currently under review; a decision is expected from the European Commission in 2025.

About NF1-PN

Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.11,12 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and there are approximately 100,000 patients living with NF1 in the United States.2,3 The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment.13 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.14

NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.2,4,6 NF1-PNs are most often diagnosed in the first two decades of life.2 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.15,16

Surgical removal of these tumors can be challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.6 Up to approximately 85% of plexiform neurofibromas are considered not amenable to complete resection.7,8,9

About GOMEKLI (mirdametinib)

GOMEKLI is an oral, small molecule MEK inhibitor approved in the United States for the treatment of adult and pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic plexiform neurofibromas (PN) not amenable to complete resection.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Ocular Toxicity: GOMEKLI can cause ocular toxicity including retinal vein occlusion (RVO), retinal pigment epithelium detachment (RPED), and blurred vision. In the adult pooled safety population, ocular toxicity occurred in 28% of patients treated with GOMEKLI: 21% were Grade 1, 5% were Grade 2 and 1.3% were Grade 3. RVO occurred in 2.7%, RPED occurred in 1.3%, and blurred vision occurred in 9% of adult patients. In the pediatric pooled safety population, ocular toxicity occurred in 19% of patients: 17% were Grade 1 and 1.7% were Grade 2. Conduct comprehensive ophthalmic assessments prior to initiating GOMEKLI, at regular intervals during treatment, and to evaluate any new or worsening visual changes such as blurred vision. Continue, withhold, reduce the dose, or permanently discontinue GOMEKLI as clinically indicated.

Left Ventricular Dysfunction: GOMEKLI can cause left ventricular dysfunction. GOMEKLI has not been studied in patients with a history of clinically significant cardiac disease or LVEF <55% prior to initiation of treatment. In the ReNeu study, decreased LVEF of 10 to <20% occurred in 16% of adult patients treated with GOMEKLI. Five patients (9%) required dose interruption, one patient (1.7%) required a dose reduction, and one patient required permanent discontinuation of GOMEKLI. The median time to first onset of decreased LVEF in adult patients was 70 days. Decreased LVEF of 10 to <20% occurred in 25%, and decreased LVEF of ≥20% occurred in 1.8% of pediatric patients treated with GOMEKLI. One patient (1.8%) required dose interruption of GOMEKLI. The median time to first onset of decreased LVEF in pediatric patients was 132 days. All patients with decreased LVEF were identified during routine echocardiography, and decreased LVEF resolved in 75% of patients. Before initiating GOMEKLI, assess ejection fraction (EF) by echocardiogram. Monitor EF every 3 months during the first year and then as clinically indicated. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction.

Dermatologic Adverse Reactions: GOMEKLI can cause dermatologic adverse reactions including rash. The most frequent rashes included dermatitis acneiform, rash, eczema, maculo-papular rash and pustular rash. In the pooled adult safety population, rash occurred in 92% of patients treated with GOMEKLI and required permanent discontinuation in 11% of adult patients. In the pooled pediatric safety population, rash occurred in 72% of patients treated with GOMEKLI and resulted in permanent discontinuation of GOMEKLI in 3.4% of patients. Initiate supportive care at first signs of dermatologic adverse reactions. Withhold, reduce the dose, or permanently discontinue GOMEKLI based on severity of adverse reaction.

Embryo-Fetal Toxicity: GOMEKLI can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of GOMEKLI. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Also advise patients to use effective contraception during treatment with GOMEKLI and for 6 weeks after the last dose (females) or 3 months after the last dose (males).

ADVERSE REACTIONS

The most common adverse reactions (>25%) in adult patients were rash (90%), diarrhea (59%), nausea (52%), musculoskeletal pain (41%), vomiting (38%), and fatigue (29%). Serious adverse reactions occurred in 17% of adult patients who received GOMEKLI. The most common Grade 3 or 4 laboratory abnormality (>2%) was increased creatine phosphokinase.

The most common adverse reactions (>25%) in pediatric patients were rash (73%), diarrhea (55%), musculoskeletal pain (41%), abdominal pain (39%), vomiting (39%), headache (34%), paronychia (32%), left ventricular dysfunction (27%), and nausea (27%). Serious adverse reactions occurred in 14% of pediatric patients who received GOMEKLI. The most common Grade 3 or 4 laboratory abnormalities (>2%) were decreased neutrophil count and increased creatine phosphokinase.

USE IN SPECIFIC POPULATIONS

Pregnancy & Lactation. Verify the pregnancy status of patients of reproductive potential prior to initiating GOMEKLI. Due to the potential for adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with GOMEKLI and for 1 week after the last dose.

You are encouraged to report negative side effects of prescription drugs to the FDA. To report suspected adverse reactions, contact SpringWorks Therapeutics at 1-888-400-SWTX (1-888-400-7989) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see accompanying full Prescribing Information for more information.

On February 10, 2025 Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") reported additional follow-up results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) evaluating the efficacy and safety of PADCEV (enfortumab vedotin-ejfv), a Nectin-4 directed antibody-drug conjugate, plus KEYTRUDA (pembrolizumab), a PD-1 inhibitor, in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) (Press release, Seagen, FEB 10, 2025, View Source [SID1234650137]). The results showed a sustained overall survival (OS) and progression-free survival (PFS) benefit consistent with the findings of the primary analysis after an additional 12 months of follow-up (median follow-up of 29.1 months).1,2 These data will be presented during a rapid oral session (Abstract 664) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (ASCO GU) 2025 in San Francisco, CA, on February 14 at 4:10pm PT.

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Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302 Primary Investigator

"These latest findings from the EV-302 trial reaffirm the primary results, which demonstrated survival improvements for patients treated with enfortumab vedotin and pembrolizumab that were previously unprecedented in locally advanced or metastatic urothelial cancer. These data show that the potential survival benefit has become even more robust with extended follow up and further solidify the combination as standard of care."

Results showed enfortumab vedotin plus pembrolizumab reduced the risk of death by 49% versus chemotherapy (hazard ratio [HR] = 0.51, 95% confidence interval [CI], 0.43-0.61). The median OS was 33.8 months for the combination versus 15.9 months for chemotherapy. The OS benefit was observed in all prespecified subgroups, including cisplatin eligible and ineligible subgroups. Enfortumab vedotin plus pembrolizumab also reduced the risk of disease progression or death by 52% versus chemotherapy (HR = 0.48, 95% CI, 0.41-0.57). The median PFS was 12.5 months for the combination versus 6.3 months for chemotherapy. The safety profile was consistent with previous findings and no new safety concerns were identified.1

Please see Important Safety Information at the end of this press release, including BOXED WARNING for enfortumab vedotin.

In addition to longer follow-up data, an exploratory analysis evaluating treatment outcomes and safety profile in patients with confirmed complete response (cCR) will also be presented. Among patients evaluable for response, confirmed objective response rate (cORR) was 67.5% for enfortumab vedotin plus pembrolizumab compared to 44.2% for chemotherapy. Median duration of response (DOR) was 23.3 months (95% CI, 17.8-not estimable [NE]) for the combination and 7.0 months (95% CI, 6.2-9.0) for chemotherapy. A cCR was achieved in 30.4% of patients treated with enfortumab vedotin plus pembrolizumab and 14.5% of patients treated with chemotherapy. Median duration of cCR was not reached for the combination and 15.2 months (95% CI, 10.3-NE) for chemotherapy. In patients with cCR, grade ≥3 treatment-related adverse events occurred in 61.7% of patients in the enfortumab vedotin plus pembrolizumab arm compared to 71.9% in the chemotherapy arm. There were no treatment-related deaths in the cCR subgroup.1

Roger Dansey, M.D.​, Chief Oncology Officer, Pfizer

"Patients with bladder cancer can face a poor prognosis, particularly in the advanced stages, and until recently had few available treatment options. The updated EV-302 results show sustained long-term efficacy in a broad population that includes both cisplatin eligible and ineligible patients and reinforce this combination’s ability to reshape the urothelial cancer treatment landscape."

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas

"The combination of enfortumab vedotin and pembrolizumab was the first approval to offer an alternative to platinum-containing chemotherapy, which had been the standard of care for first-line locally advanced or metastatic urothelial cancer for decades. We are delighted that the additional follow-up results of the EV-302 trial show a durable benefit. These data represent yet another milestone in our long-standing commitment to helping patients around the world live longer and healthier lives."

Enfortumab vedotin plus pembrolizumab is approved for the treatment of adult patients with la/mUC in the United States, the European Union, Japan and a number of other countries around the world. Enfortumab vedotin is also approved as a single agent for the treatment of adult patients with la/mUC who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.

About EV-302

The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The study enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.4

The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Primary results from the EV-302 study were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in October 2023.

About PADCEV (enfortumab vedotin-ejfv)

PADCEV (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.5 Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4-expressing cells, followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).3

PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information

BOXED WARNING: SERIOUS SKIN REACTIONS

PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
Closely monitor patients for skin reactions.
Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
Indication

PADCEV , in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC).

PADCEV, as a single agent, is indicated for the treatment of adult patients with locally advanced or mUC who:

have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 70% (all grades) of the 564 patients treated with PADCEV in combination with pembrolizumab in clinical trials. When PADCEV was given in combination with pembrolizumab, the incidence of skin reactions, including severe events, occurred at a higher rate compared to PADCEV as a single agent. The majority of the skin reactions that occurred with combination therapy included maculo-papular rash, macular rash and papular rash. Grade 3-4 skin reactions occurred in 17% of patients (Grade 3: 16%, Grade 4: 1%), including maculo-papular rash, bullous dermatitis, dermatitis, exfoliative dermatitis, pemphigoid, rash, erythematous rash, macular rash, and papular rash. A fatal reaction of bullous dermatitis occurred in one patient (0.2%). The median time to onset of severe skin reactions was 1.7 months (range: 0.1 to 17.2 months). Skin reactions led to discontinuation of PADCEV in 6% of patients.

Skin reactions occurred in 58% (all grades) of the 720 patients treated with PADCEV as a single agent in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 34% had pruritus. Grade 3-4 skin reactions occurred in 14% of patients, including maculo-papular rash, erythematous rash, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. The median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 8 months). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=75), 24% of patients restarting at the same dose and 24% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 3.1% of patients.

Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. For persistent or recurrent Grade 2 skin reactions, consider withholding PADCEV until Grade ≤1. Withhold PADCEV and refer for specialized care for suspected SJS, TEN or for Grade 3 skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.

Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials of PADCEV as a single agent, 17% of the 720 patients treated with PADCEV developed hyperglycemia of any grade; 7% of patients developed Grade 3-4 hyperglycemia (Grade 3: 6.5%, Grade 4: 0.6%). Fatal events of hyperglycemia and DKA occurred in one patient each (0.1%). The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. The median time to onset of hyperglycemia was 0.5 months (range: 0 to 20 months). Hyperglycemia led to discontinuation of PADCEV in 0.7% of patients. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. Of the patients who initiated insulin therapy for treatment of hyperglycemia, 66% (23/35) discontinued insulin at the time of last evaluation. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.

Pneumonitis/Interstitial Lung Disease (ILD) Severe, life-threatening or fatal pneumonitis/ILD occurred in patients treated with PADCEV. When PADCEV was given in combination with pembrolizumab, 10% of the 564 patients treated with combination therapy had pneumonitis/ILD of any grade and 4% had Grade 3-4. A fatal event of pneumonitis/ILD occurred in two patients (0.4%). The incidence of pneumonitis/ILD, including severe events, occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of any grade pneumonitis/ILD was 4 months (range: 0.3 to 26 months).

In clinical trials of PADCEV as a single agent, 3% of the 720 patients treated with PADCEV had pneumonitis/ILD of any grade and 0.8% had Grade 3-4. The median time to onset of any grade pneumonitis/ILD was 2.9 months (range: 0.6 to 6 months).

Monitor patients for signs and symptoms indicative of pneumonitis/ILD such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop Grade 2 pneumonitis/ILD and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis/ILD.

Peripheral neuropathy (PN) When PADCEV was given in combination with pembrolizumab, 67% of the 564 patients treated with combination therapy had PN of any grade, 36% had Grade 2 neuropathy, and 7% had Grade 3 neuropathy. The incidence of PN occurred at a higher rate when PADCEV was given in combination with pembrolizumab compared to PADCEV as a single agent. The median time to onset of Grade ≥2 PN was 6 months (range: 0.3 to 25 months).

PN occurred in 53% of the 720 patients treated with PADCEV as a single agent in clinical trials including 38% with sensory neuropathy, 8% with muscular weakness and 7% with motor neuropathy. Thirty percent of patients experienced Grade 2 reactions and 5% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without preexisting PN. The median time to onset of Grade ≥2 PN was 4.9 months (range: 0.1 to 20 months). Neuropathy led to treatment discontinuation in 6% of patients.

Monitor patients for symptoms of new or worsening PN and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.

Ocular disorders were reported in 40% of the 384 patients treated with PADCEV as a single agent in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 30% of patients, and blurred vision occurred in 10% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.7 months (range: 0 to 30.6 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.

Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 720 patients treated with PADCEV as a single agent in clinical trials, 1% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.

ADVERSE REACTIONS

Most common adverse reactions, including laboratory abnormalities(≥20%) (PADCEV in combination with pembrolizumab) Increased aspartate aminotransferase (AST), increased creatinine, rash, increased glucose, PN, increased lipase, decreased lymphocytes, increased alanine aminotransferase (ALT), decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets.

Most common adverse reactions, including laboratory abnormalities (≥20%) (PADCEV monotherapy) Increased glucose, increased AST, decreased lymphocytes, increased creatinine, rash, fatigue, PN, decreased albumin, decreased hemoglobin, alopecia, decreased appetite, decreased neutrophils, decreased sodium, increased ALT, decreased phosphate, diarrhea, nausea, pruritus, increased urate, dry eye, dysgeusia, constipation, increased lipase, decreased weight, decreased platelets, abdominal pain, dry skin.

EV-302 Study: 440 patients with previously untreated la/mUC (PADCEV in combination with pembrolizumab)

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab. The most common serious adverse reactions (≥2%) were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Fatal adverse reactions occurred in 3.9% of patients treated with PADCEV in combination with pembrolizumab including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%).

Adverse reactions leading to discontinuation of PADCEV occurred in 35% of patients. The most common adverse reactions (≥2%) leading to discontinuation of PADCEV were PN (15%), rash (4.1%) and pneumonitis/ILD (2.3%). Adverse reactions leading to dose interruption of PADCEV occurred in 73% of patients. The most common adverse reactions (≥2%) leading to dose interruption of PADCEV were PN (22%), rash (16%), COVID-19 (10%), diarrhea (5%), pneumonitis/ILD (4.8%), fatigue (3.9%), hyperglycemia (3.6%), increased ALT (3%) and pruritus (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 42% of patients. The most common adverse reactions (≥2%) leading to dose reduction of PADCEV were rash (16%), PN (13%) and fatigue (2.7%).

EV-103 Study: 121 patients with previously untreated la/mUC who were not eligible for cisplatin-containing chemotherapy (PADCEV in combination with pembrolizumab)

Serious adverse reactions occurred in 50% of patients treated with PADCEV in combination with pembrolizumab; the most common (≥2%) were acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), sepsis (3.3%), pneumonia (3.3%), hematuria (3.3%), pneumonitis/ILD (3.3%), urinary retention (2.5%), diarrhea (2.5%), myasthenia gravis (2.5%), myositis (2.5%), anemia (2.5%), and hypotension (2.5%). Fatal adverse reactions occurred in 5% of patients treated with PADCEV in combination with pembrolizumab, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis/ILD (0.8%). Adverse reactions leading to discontinuation of PADCEV occurred in 36% of patients; the most common (≥2%)were PN (20%) and rash (6%). Adverse reactions leading to dose interruption of PADCEV occurred in 69% of patients; the most common (≥2%)were PN (18%), rash (12%), increased lipase (6%), pneumonitis/ILD (6%), diarrhea (4.1%), acute kidney injury (3.3%), increased ALT (3.3%), fatigue (3.3%), neutropenia (3.3%), urinary tract infection (3.3%), increased amylase (2.5%), anemia (2.5%), COVID-19 (2.5%), hyperglycemia (2.5%), and hypotension (2.5%). Adverse reactions leading to dose reduction of PADCEV occurred in 45% of patients; the most common (≥2%) were PN (17%), rash (12%), fatigue (5%), neutropenia (5%), and diarrhea (4.1%).

EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy (PADCEV monotherapy)

Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each), and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis/ILD, and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%), and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite, and fatigue (3% each).

EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for cisplatin-based chemotherapy (PADCEV monotherapy)

Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis, and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia, and pneumonitis/ILD (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), increased AST, and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%), and fatigue (7%).

DRUG INTERACTIONS

Effects of other drugs on PADCEV ( Dual P-gp and Strong CYP3A4 Inhibitors )

Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.

SPECIFIC POPULATIONS

Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for 3 weeks after the last dose.

Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.

On February 10, 2025 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage biotechnology company developing first-in-classi targeted and immune-mediated therapeutics to fight cancer, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track Designation (FTD) to amezalpat (TPST-1120), an oral, small molecule, selective PPAR⍺ antagonist for the treatment of patients with hepatocellular carcinoma (HCC) (Press release, Tempest Therapeutics, FEB 10, 2025, View Source [SID1234650138]).

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"We are thrilled to receive Fast Track designation from the FDA," said Sam Whiting, M.D., Ph.D., chief medical officer and head of R&D of Tempest. "This designation, following the Orphan Drug designation granted last month, reinforces the promise of amezalpat as a potential treatment option for patients affected by HCC. We look forward to working closely with the FDA and foreign regulatory agencies to develop amezalpat with the goal of bringing this promising therapy to patients."

This is the second regulatory designation granted to amezalpat. The company announced in January that the U.S. FDA granted amezalpat with Orphan Drug Designation (ODD) following positive data across multiple key study efficacy and safety endpoints in a global randomized Phase 1b/2 clinical study evaluating amezalpat plus standard-of-care atezolizumab and bevacizumab versus atezolizumab and bevacizumab alone in the first-line treatment of patients with unresectable or metastatic HCC. Notable positive outcomes of the randomized comparison include a six-month improvement in median overall survival (OS) with a hazard ratio (HR) of 0.65 for patients receiving the amezalpat combination therapy. In addition, a survival benefit from the addition of amezalpat was preserved in key sub-populations including PD-L1 negative disease, which is consistent with amezalpat’s proposed mechanism of action to target both the tumor cells directly and the patient’s immune system.

About Hepatocellular Carcinoma

HCC is an aggressive cancer with rising mortality and is projected to become the third leading cause of cancer death by 2030.ii Every year, more than 900,000 people worldwide are diagnosed with HCC.iii Incidence and mortality are highest in East Asia and are increasing in parts of Europe and the US.iv In the US, HCC represents the fastest-rising cause of cancer-related death. iii

Nine out of ten cases of HCC are caused by chronic liver disease, which includes chronic hepatitis B and C infection, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related liver disease (ALD) and cirrhosis resulting from these conditions.v

Even if diagnosed in the early stage, an estimated 70-80% of people with early-stage HCC experience disease recurrence following surgery.vi Early recurrence is associated with poorer prognosis and shorter survival. v,vii Tumor size, number of tumors, and portal vein invasion are associated with an increased risk of recurrence.vi

About Amezalpat

Amezalpat is an oral, small molecule, selective PPAR⍺ antagonist. Data suggests that amezalpat treats cancer by targeting tumor cells directly and by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In a global randomized phase 1b/2 study in first-line HCC patients, amezalpat in combination with atezolizumab and bevacizumab showed clinical superiority across multiple study endpoints, including overall survival in both the entire population and key subpopulations, when compared to patients receiving atezolizumab and bevacizumab alone, the standard of care. These randomized data were supported by additional positive results observed in the Phase 1 clinical trial in patients with heavily pretreated advanced solid tumors, including renal cell carcinoma and cholangiocarcinoma.

About Fast Track Designation

Fast Track designation is intended to help rapidly advance the development and review processes for promising therapeutic candidates for serious conditions that may fill an unmet medical need. Clinical programs with Fast Track designation may benefit from early and frequent communication with the FDA throughout the regulatory review process and may also be eligible for accelerated approval and priority review when relevant criteria are met.

On February 10, 2025 Beyond Air, Inc. (NASDAQ: XAIR) ("Beyond Air" or the "Company"), a commercial stage medical device and biopharmaceutical company focused on harnessing the power of nitric oxide (NO) to improve the lives of patients, reported its financial results for the fiscal third quarter ended December 31, 2024, and provided a corporate update (Press release, Beyond Air, FEB 10, 2025, View Source [SID1234650139]).

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"Our commercial team continues to make significant progress as we expand the number of U.S. hospitals utilizing LungFit PH. While this is the culmination of years of work, it was approximately nine months ago that we started to make significant headway in our commercial efforts with the fully updated system. We expect to continue generating double digit sequential quarterly revenue growth for the foreseeable future," said Steve Lisi, Chairman and Chief Executive Officer of Beyond Air.

"We ended calendar year 2024 on a high note with the receipt of CE Mark for LungFit PH in Europe, opening a significant portion of the global market outside of the U.S. for our current and future distribution partners to launch their commercial programs for LungFit PH. With the advantage of real-world customer experience and feedback from our U.S. program, combined with our distribution partners’ established sales teams and customer networks, we anticipate a faster commercial ramp-up in these regions compared to what we experienced in the U.S.," concluded Mr. Lisi.

Commercial Execution, Portfolio Highlights and Upcoming Milestones

LungFit PH Commercial Execution
Increased demand for LungFit PH:
A 34% increase in revenue for the quarter ended December 31, 2024, compared with the quarter ended September 30, 2024
Six new hospital starts in the U.S. in the quarter ended December 31, 2024
Received market authorization in Australia in January 2025 and expect to have regulatory approvals in eight countries covered under the partnership with Getz Healthcare by calendar year-end, with initial commercial shipments occurring in 2025.
Signed partnerships with two distributors in the Middle East in January 2025, with initial shipments expected in the 1H of calendar year 2025.
Pipeline Highlights
Received CE Mark for LungFit PH, which allows Beyond Air to market LungFit PH in the European Union and all other countries that recognize this certification.
Indications under CE Mark certification include:
The treatment of infants >34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation; and
The treatment of peri- and post-operative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0-17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function
CE Mark certification triggered a $1 million milestone payment, payable in the fiscal fourth quarter of 2025, from the Company’s Asia-Pacific partner, Getz Healthcare, the leading distributor of medical equipment, devices and consumables in Asia Pacific region – providing access to hospitals in Australia, New Zealand, Thailand, Philippines, Taiwan, Hong Kong, Malaysia, Pakistan, Singapore and Vietnam
Beyond Air will also receive double-digit royalty payments based on LungFit PH net sales by Getz Healthcare
Cardiac surgery PMA supplement review ongoing at FDA
Currently no FDA approved nitric oxide system is labeled for cardiac surgery
Approval should increase LungFit PH’s rate of market penetration
LungFit PH transport-ready PMA supplement submission to FDA anticipated in the coming months
Beyond Cancer – Solid Tumor Program

Clinical Development Execution
Phase 1a trial (monotherapy) – Part A of the trial evaluating ultra-high concentration Nitric Oxide (UNO) therapy in subjects with advanced, relapsed or refractory unresectable, primary or metastatic cutaneous and subcutaneous solid tumors at a dose of 25,000 ppm has been completed, and at the dose of 50,000 ppm is ongoing.
Phase 1b trial (combination therapy) – Received regulatory approval in Israel for Part B of the trial, which will assess the intratumoral administration of 25,000 ppm low volume (LV) Nitric Oxide (UNO) in patients with unresectable cutaneous or subcutaneous histologically confirmed primary or metastatic lesions, who have shown disease progression or prolonged stable disease (12 weeks) after receiving a single agent anti-PD-1 containing treatment. Topline data from the Phase 1b portion of the study are anticipated late in calendar 2025 or early-2026.
NeuroNOS – Autism Spectrum Disorder (ASD) Program

NeuroNOS appointed Professor Roger D. Kornberg to its Scientific Advisory Board (SAB). Dr. Kornberg was awarded the Nobel Prize in Chemistry in 2006 for his groundbreaking work in molecular biology and is a renowned leader in the field of eukaryotic gene transcription. Professor Kornberg will assist NeuroNOS in accelerating the development of treatments for ASD and potentially other neurological disorders.
Financial Results for the Fiscal Third Quarter Ended December 31, 2024

Revenues for the fiscal quarter ended December 31, 2024 were $1.1 million compared to $0.4 million for the fiscal quarter ended December 31, 2023 and $0.8 million for the previous quarter ended September 30, 2024.

Cost of revenue of $1.3 million was recognized for the three months ended December 31, 2024, compared to $0.7 million for the three months ended December 31, 2023. Cost of revenue exceeded revenue primarily driven by depreciation of LungFit devices and one-time upgrade costs to systems.

Research and development expenses for the three months ended December 31, 2024 were $3.0 million as compared to $6.8 million for the three months ended December 31, 2023. The decrease of $3.8 million was primarily attributed to a decrease in salaries, stock-based compensation and to a lesser extent from clinical and pre-clinical studies expenses.

Selling, general and administrative expenses for the three-month periods ended December 31, 2024 and 2023 were $7.7 million and $9.8 million, respectively. The decrease of $2.1 million was attributed primarily to a reduction in salaries and stock-based compensation cost.

Other expense for the three months ended December 31, 2024 was $2.4 million compared to $0.3 million for the three months ended December 31, 2023. The increase in other expense of $2.1 million was mainly due to a non-cash loss recorded upon the retirement of the Avenue Capital debt.

Cash burn in the fiscal quarter ended December 31, 2024, excluding the impacts of financing and the extinguishment of debt, was $7.6 million.

As of December 31, 2024, the Company reported cash, cash equivalents, and marketable securities of $10.9 million, and total debt outstanding of $11.8 million. Debt repayment does not begin until October 2026. The Company’s cash, cash equivalents, and marketable securities, along with its cash conservation strategy and anticipated revenue growth are expected to provide sufficient cash runway to support current operating plans well into calendar 2026.

Conference Call & Webcast
Monday, February 10th @ 4:30 PM ET

Domestic: 1-877-407-0784
International: 1-201-689-8560
Conference ID: 13750714
Webcast: A webcast of the live conference call can be accessed by visiting the Events section of the Company’s website (click here) or directly (click here). An online recording of the conference call will be available on the Company’s website or via the direct link an hour after the call.

On February 10, 2025 Convergent Therapeutics Inc., a clinical-stage biotechnology company focused on the development of next-generation radiopharmaceuticals for the treatment of cancer, reported clinical trial updates for its lead asset, CONV01-α (225Ac-J591), a prostate-specific membrane antigen (PSMA)-targeted monoclonal antibody linked to actinium-225 (225Ac) (Press release, Convergent Therapeutics, FEB 10, 2025, View Source;at-the-american-society-of-clinical-oncology-asco-genitourinary-cancers-symposium-2025-302372722.html [SID1234650140]). Data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium, which will take place February 13-15, 2025, in San Francisco, California.

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The first presentation, titled "Mature phase 1 follow up of alpha emitter 225Ac-J591 with 177Lu-PSMA-I&T in advanced prostate cancer," reported clinical follow-up of a Phase I dose-escalation trial exploring the addition of CONV01-α to 177Lu-PSMA-I&T, a PSMA-targeted beta emitting small molecule for the treatment of advanced prostate cancer. The study population presented included 18 patients (six at each dose level of CONV01-α) with progressive metastatic castration-resistant prostate cancer (mCRPC). Relatively low doses of CONV01-α were used.

Data showed that the median overall survival was 29.8 months, with 10 patients still alive at the time of submission. Five patients were free from PSA progression at one year including one patient progression-free at 34 months on no active therapy. A decline in prostate-specific antigen (PSA) levels was seen in 94% of patients, 64% of patients achieved a PSA50 and 28% achieved a PSA90 response. Additionally, circulating tumor cell count changes were seen, with 80% of evaluable patients converting from "unfavorable" to "favorable." High grade adverse events were rare.

"The impressive clinical activity is consistent with our pre-clinical data demonstrating that the antibody/ligand combination delivers a synergistic dose to tumor. Importantly, the synergistic tumor dose is achieved in the absence of additive toxicity due to the non-overlapping normal organ biodistribution of the ligand and antibody. This was also confirmed by the benign safety profile in the trial. The dosimetry and safety profile suggest the potential for additional cycles beyond the two cycles used in this trial. That the overall survival in this trial was double that of the Phase III VISION trial of 177Lu PSMA-617 further increases our enthusiasm for future trials of this combination," said Neil Bander, MD, Convergent’s Co-Founder and Chief Scientific Officer and Professor Emeritus of Urology at Weill Cornell Medicine.

The second presentation, titled "CONVERGE-01: Dosimetry, randomized dose optimization, dose escalation, and efficacy of Ac-225 rosopatamab tetraxetan in participants with PSMA-positive castration-resistant prostate cancer," is a "Trials in Progress" presentation of the three-part company sponsored Phase II trial evaluating the safety and efficacy of CONV01-α (225Ac-J591) monotherapy in patients with castration-resistant prostate cancer. Philip Kantoff, MD, Co-Founder and CEO said, "CONVERGE-01 is intended to confirm the high response rate and durability of CONV01-a monotherapy and solidify the path forward to our pivotal trial."

About CONV01-α
CONV01-α, Convergent’s alpha-emitting radioantibody, combines the precision and pharmacokinetics of antibodies with the tumor-killing potential of alpha-emitting radionuclides. Specifically, CONV01-α uses a humanized monoclonal antibody targeted at prostate-specific membrane antigen (PSMA), which is highly overexpressed in prostate cancer cells. Since PSMA is a validated target, several therapeutics are directed at this antigen, and CONV01-α is differentiated by its use of both an antibody and alpha emitter. CONV01-α is linked to a powerful radionuclide called Ac-225, which releases alpha particles that kill cancer cells through DNA double-strand breaks. Unlike other radioactive sources, alpha particles deliver high-energy radiation over very short distances, thereby minimizing radiation exposure to healthy neighboring cells and tissues. Pairing highly selective antibodies with such a powerful, yet precise, payload offers the ideal combination to treat many types of cancers. Convergent Therapeutics is currently enrolling into the CONVERGE-01 Phase II monotherapy trial to confirm the high response rate, durability and safety of CONV01-a pre and post radioligand beta.