Gilead To Discontinue Phase III ENHANCE Study of Magrolimab Plus Azacitidine in Higher-Risk MDS

Gilead Sciences, Inc. reported that the Phase III ENHANCE study in higher-risk myelodysplastic syndromes (MDS) has been halted due to futility based on a planned analysis. The safety data in this trial are consistent with the known magrolimab profile and adverse events encountered in this patient population. In individuals with MDS, Gilead suggests stopping magrolimab medication. Magrolimab is a potential first-in-class anti-CD47 immunotherapy with a clinical development program spanning ten potential indications, including ongoing trials in solid tumors and two pivotal trials: ENHANCE-2 in acute myeloid leukemia (AML) with TP53 mutations and ENHANCE-3 in first-line, unfit AML.

The Phase III randomized, double-blind research looked at magrolimab plus azacitidine as first-line therapy for higher-risk myelodysplastic syndromes (HR-MDS), a disease that hasn’t had a new class of medications approved in nearly 20 years. The trial included over 500 individuals who were randomly assigned to receive magrolimab in conjunction with azacitidine or azacitidine alone. Complete response and overall survival were the primary goals. Secondary outcomes included, among other things, length of response, transfusion independence, progression-free survival, and time to transition to acute myeloid leukemia.

“The health and well-being of our patients are our top priorities, and while this is disappointing news, it confirms the challenges of treating HR-MDS, where no new class of treatments have been approved in nearly 20 years,” said Merdad Parsey, MD, Ph.D., Chief Medical Officer, Gilead Sciences. “Gilead is deeply grateful to the patients, families, investigators, and advocacy community who contributed to this research as we learn more about magrolimab and explore its potential for treating other cancers.”

Gilead is collaborating with study scientists to determine the best next steps for patients enrolled in the ENHANCE trial. The data will be presented at a forthcoming medical symposium.

FDA Approveds VANFLYTA for Patients with Newly Diagnosed AML

Daiichi Sankyo’s VANFLYTA® (quizartinib) has been approved by the U.S. Food and Drug Administration (FDA) in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, as well as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed FLT3-ITD positive AML as detected by an FDA-approved test. VANFLYTA is not approved as a maintenance medication after allogeneic hematopoietic stem cell transplantation (HSCT); no improvement in overall survival has been documented with VANFLYTA in this setting. 

AML is one of the most common forms of adult leukemia, with an anticipated 20,380 new cases identified in the United States in 2023. Up to 37% of newly diagnosed AML patients have an FLT3 gene mutation, with roughly 80% of them being FLT3-ITD mutations, which accelerate cancer growth and contribute to a higher risk of relapse and a shorter overall survival. The five-year survival rate for patients with FLT3-ITD AML has been estimated to be around 20%.

VANFLYTA is the first and only FLT3 inhibitor approved by the FDA for FLT3-ITD positive AML and for all three phases of treatment for newly diagnosed AML (induction, consolidation, and maintenance in patients without transplant). In the coming weeks, VANFLYTA will be available by prescription in the United States. 

The FDA granted permission based on the findings of the QuANTUM-First trial, which was published in The Lancet.

5 In QuANTUM-First, VANFLYTA in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation, and continued as maintenance monotherapy after consolidation, resulted in a 22% reduction in the risk of death compared to standard chemotherapy alone (HR = 0.78 [95% CI: 0.62-0.98; 2-sided p=.0324]). While complete remission (CR) rates were comparable in both arms of the trial, the median duration of CR for patients receiving VANFLYTA was more than two and a half times longer at 38.6 months (95% CI: 21.9, NE) compared to 12.4 months for those receiving placebo plus standard chemotherapy alone (95% CI: 8.8-22.7).

“The approval of VANFLYTA represents a significant advancement in the treatment of patients with newly diagnosed FLT3-ITD positive AML, which is one of the most aggressive and difficult-to-treat subtypes,” said Harry P. Erba, MD, PhD, Professor of Medicine, Duke Cancer Institute’s Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy. “VANFLYTA added to standard chemotherapy and continued as maintenance resulted in longer remission and prolonged overall survival in the QuANTUM-First trial, and it will be a much-needed new treatment option that has the potential to change the way FLT3-ITD positive AML is treated.” 

FDA Awards Fast Track Designation to ARX517 for Metastatic Castration-Resistant Prostate Cancer

ARX517 has been granted fast track designation by the FDA for potential use as a treatment option in patients with metastatic castration-resistant prostate cancer (mCRPC) who have seen their condition worsen while on an androgen receptor (AR) pathway inhibitor.

ARX517 is an antibody-drug conjugate (ADC) that consists of a fully humanized monoclonal antibody targeting the prostate-specific membrane antigen (PSMA), linked to AS269. Once ARX517 attaches to PSMA on the cancer cells’ surface, the drug is taken inside the cells where it releases its payload, known as pAF-AS269, after lysosomal metabolism. Importantly, this agent has a consistent drug-to-antibody ratio and shares biophysical properties comparable to monoclonal antibodies. These unique features suggest that ARX517 has the potential to specifically kill cancer cells while minimizing adverse effects on healthy cells.

ARX517 is currently being investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) as part of the ongoing APEX-01 trial (NCT04662580), which is a phase 1/2 trial. Initial data from the trial, reported in February 2023, revealed promising results. When the ADC was administered at dose levels starting from 0.32 mg/kg, it led to a reduction in prostate-specific antigen (PSA) of over 30% in cohorts 2 to 5.

In cohort 6, which consisted of three patients receiving ARX517 at a higher dose of 2.0 mg/kg, all patients experienced substantial PSA reductions, exceeding 50%. Impressively, two of these patients achieved PSA reductions of more than 90%. Additionally, one patient from this group, who had soft tissue measurable disease, demonstrated a partial response to the treatment based on RECIST v1.1 criteria, as seen in their first scan after treatment. At the time of data release, three patients in cohort 7 had received the ADC, and no dose-limiting toxicities were observed.

The APEX-01 trial is an open-label study that involves both dose-escalation and dose-expansion stages. It is enrolling patients with mCRPC whose tumors have progressed despite having received two or more FDA-approved treatments for metastatic disease, including at least one AR receptor signaling inhibitor. Eligible patients must meet one of the following criteria: PSA progression with at least two rising PSA values, radiographic progression according to RECIST v1.1 criteria, or progressive disease indicated by the presence of new bone lesions. Additionally, patients must be at least 18 years old and have acceptable blood counts to participate in the trial.

Certain patients with specific medical conditions will be excluded from the research. In the phase 1 portion of the study, researchers examined increasing doses of ARX517 administered every 3 weeks. The primary endpoints included evaluating safety, tolerability, pharmacokinetics, and measuring the decline in prostate-specific antigen (PSA) levels and tumor shrinkage, with a 50% reduction in PSA levels indicating improved survival. The data released involved 22 patients treated with ARX517 across seven dosing cohorts, with doses ranging from 0.32 mg/kg to 2.4 mg/kg. Notably, no serious toxicities related to the ADC were observed, and the maximum tolerated dose had not been reached, indicating a positive safety profile.

Additionally, preclinical data presented at the 2023 AACR Annual Meeting demonstrated that ARX517 exhibited antitumor activity in both enzalutamide (Xtandi)-sensitive and -resistant models of the disease. In the enzalutamide-sensitive mouse model, when the ADC was administered at a dose of 3 mg/kg in combination with enzalutamide at 10 mg/kg, it resulted in a substantial tumor reduction of 86%. In a model that was resistant to enzalutamide, the administration of ARX517 at weekly doses of 3 mg/kg for 3 weeks inhibited tumor growth by 79%.

EMA Panel Rejects Mirati’s KRAS Drug Krazati

Mirati Therapeutics has faced a challenging realization that gaining approval from the U.S. FDA does not guarantee approval in other regions, as evidenced by the rejection of their flagship KRAS inhibitor, Krazati, by European regulators. On Friday, Mirati disclosed that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) had turned down the company’s application for conditional marketing authorization of Krazati, also known as adagrasib, for the treatment of patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). In response, Mirati expressed its disagreement with the CHMP’s decision and announced its intention to apply for a formal re-examination.

Previously considered inaccessible for drug targeting, the KRAS gene now has two FDA-approved therapies competing in the potentially lucrative cancer market in the United States. Amgen obtained accelerated approval for its KRAS inhibitor, Lumakras, in May 2021, and shortly after, Mirati entered the competition with its own KRAS inhibitor, Krazati, marking the biotech’s first commercial product in December.

While Amgen’s drug experienced a decline in sales in the U.S., Mirati’s Krazati surprised analysts with its performance in the first full quarter on the market, generating $6.3 million in revenue during the first three months of 2023.

Regarding the rejection of Krazati’s conditional marketing authorization application in the European Union, Mirati explained that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) acknowledged its positive risk-benefit profile but found that certain requirements for conditional approval were not met. Despite this setback, Mirati believes that Krazati still fulfills the conditions for conditional marketing authorization and offers a distinct clinical profile compared to the currently conditionally approved KRAS G12C inhibitor from Amgen.

Mirati highlighted several factors that set Krazati apart, including its safety profile, potential activity in the central nervous system, and compatibility with other cancer-fighting agents. The biotech remains determined to provide hope for patients in the European Union, with plans to continue supplying Krazati under early access in EU member states, even though the conditional marketing authorization has not been granted.

Mirati’s EU application is based on data from the phase 2 registration-enabling cohort of the Krystal-1 study, which demonstrated tumor shrinkage in 43% of previously-treated patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) who received Krazati at a dose of 600mg twice a day.

The rejection of the EU application will not impact Mirati’s ongoing clinical trials. Enrollment in the company’s confirmatory phase 3 trial for adagrasib (Krazati) is progressing as expected, and the biotech anticipates delivering progression-free survival and interim overall survival results in the first half of 2024. Despite the setback in the EU, Mirati has already begun providing Krazati to certain European patients upon individual requests from healthcare professionals.

Harmony Biosciences Announces Plans to Initiate Phase 3 Registrational Study of Pitolisant in Prader-Willi Syndrome

On July 20, 2023, Harmony Biosciences Holdings, Inc. (“Harmony”) (Nasdaq: HRMY) announced that it has successfully completed an End-of-Phase 2 meeting with FDA regarding its clinical development plan evaluating pitolisant as a potential treatment for excessive daytime sleepiness (EDS) in patients ages six and older with Prader-Willi syndrome (PWS). Harmony plans to initiate a Phase 3 registrational study in the fourth quarter of 2023. 

“We are pleased with the outcome of our End-of-Phase 2 meeting with the FDA as we prepare to initiate our Phase 3 registrational study, which aims to further investigate the efficacy and safety of pitolisant as a potential treatment for excessive daytime sleepiness in individuals with Prader-Willi syndrome. Building upon the encouraging data obtained from our Phase 2 signal detection study, we remain committed to advancing our development program for pitolisant in pursuit of a new indication in people with PWS, given the high unmet medical need in this population.”

Kumar Budur, MD, Chief Medical Officer at Harmony Biosciences

Based on a positive signal observed from the Phase 2 proof-of-concept study, Harmony aligned with the FDA on the proposed Phase 3 study design elements to support further investigation of pitolisant for children, adolescents, and adults with Prader-Willi Syndrome experiencing EDS. Pitolisant is marketed as WAKIX® in the U.S. and is FDA-approved to treat EDS or cataplexy in adult patients with narcolepsy. Pitolisant is not approved for use in patients with Prader-Willi Syndrome and is currently being evaluated as an investigational agent in this patient population.

Prader-Willi syndrome is an orphan/rare, genetic neurological disorder characterized by severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity (unless food intake is strictly controlled). Prader-Willi Syndrome is sometimes called Willi-Prader syndrome or Prader-Labhart-Willi syndrome. There are currently 15,000 – 20,000 people in the US living with Prader-Willi Syndrome, a genetic condition often diagnosed in childhood. More than half of patients experience EDS. Treatment of a child affected with Prader-Willi Syndrome involves the primary care physician and a multispecialty team that includes an ophthalmologist to evaluate for myopia and strabismus, a pediatric endocrinologist for consideration of growth hormone treatment, and a developmental pediatrician.

Belite Bio Completes Enrollment in Pivotal Global Phase 3 DRAGON Trial Evaluating Oral Tinlarebant for Stargardt Disease

On July 24, 2023, Belite Bio, Inc (NASDAQ: BLTE) (“Belite” or the “Company”) announced that enrollment of its pivotal global Phase 3 “DRAGON” trial for patients with Stargardt Disease (STGD1) has been completed. Tinlarebant (a/k/a LBS-008) is an oral, once-daily retinol-binding protein 4 (RBP4) antagonist designed to lower levels of ocular vitamin-A-based toxins implicated in STGD1, GA, or advanced Dry AMD. The visual cycle, which is reliant on the supply of vitamin A (retinol) to the eye, produces these toxins as a byproduct. The only protein used to transport retinol from the liver to the eye, serum retinol-binding protein 4 (RBP4), is reduced and maintained by tinlarebant. Tinlarebant lessens the production of these toxins by controlling the quantity of retinol that enters the eye. 

For the treatment of STGD1, tinlarebant has received Orphan Drug Designation, Fast Track Designation, and Rare Paediatric Disease Designation in the United States. The Phase 2 STGD1 study’s topline data for tilarebant are anticipated in the fourth quarter of 2023, and the Phase 3 DRAGON trial’s interim data are anticipated in the middle of 2024. The first patient will also be enrolled in the two-year Phase 3 study (PHOENIX) of tinlarebant in geographic atrophy (GA) in the third quarter of 2023, according to Belite.

“Completing enrollment of all 90 adolescent subjects across 11 countries worldwide in the Phase 3 DRAGON trial marks an important milestone for our late-stage program in STGD1. Importantly, we are pleased to see the embrace of this much needed therapeutic opportunity by the STGD1 patient community. The DRAGON trial has potential to be the first global Phase 3 clinical trial to demonstrate a treatment benefit in patients with STGD1, and we look forward to sharing the interim safety and efficacy data in mid-2024,” 

Dr. Tom Lin, CEO of Belite Bio

The pivotal Phase 3 DRAGON trial is a randomized, double-masked, placebo-controlled, global, and multi-center study, designed to evaluate the safety and efficacy of Tinlarebant in adolescent STGD1 patients. The DRAGON trial will be conducted globally across 11 countries, including the U.S., the United Kingdom, Germany, France, Belgium, Switzerland, the Netherlands, China, Hong Kong, Taiwan, and Australia. 90 patients have been enrolled in this study with a 2:1 randomization (active: placebo). The primary efficacy endpoint is slowing lesion growth rate, along with the assessment of safety and tolerability. Tinlarebant has been granted Fast Track Designation and Rare Pediatric Disease Designation in the U.S., and Orphan Drug Designation in both the U.S. and Europe for STGD1.

Stargardt disease is the most common form of inherited macular degeneration, affecting about 30,000 people in the US.  Moreover, the prevalence of Stargardt disease is estimated to be 1 in 8,000 to 10,000 individuals. Stargardt disease, causes blurring, or loss of central vision in both adults and children. The disease is caused by mutations in a retina-specific gene (ABCA4) which results in a massive accumulation of toxic vitamin A byproducts (known as “bisretinoids”) in the retina leading to retinal cell death and progressive loss of central vision. The fluorescent properties of bisretinoids and the development of retinal imaging systems have helped ophthalmologists identify and monitor disease progression. Currently, there are no FDA-approved treatments for STGD1. There is a high unmet medical need as there are currently no treatments available for Stargardt disease. Hence, new treatments are needed to slow the progression of the disease and maintain acuity for longer. Nevertheless, several emerging therapies are under investigation, which are expected to enter the market in the near future. Belite Bio intends to evaluate the safety and efficacy of Tinlarebant in GA patients in its Phase 3 study (PHOENIX).