FDA Approves Rytelo (imetelstat) for the Treatment of Adult Patients with Lower-Risk MDS with Transfusion-Dependent Anemia

Geron Corporation (Nasdaq: GERN), a commercial-stage biopharmaceutical company aiming to change lives by changing the course of blood cancer, today announced that the U.S. Food and Drug Administration (FDA) has approved Rytelo™ (imetelstat) for the treatment of adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent (TD) anemia requiring four or more red blood cell units over eight weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA).

“With the approval and availability of Rytelo, we believe eligible patients with lower-risk MDS can potentially experience meaningful clinical benefit, particularly the potential for greater than 24 weeks of freedom from the burden of red blood cell transfusions and symptomatic anemia,” said John A. Scarlett, M.D., Geron’s Chairman and Chief Executive Officer. “The approval of Rytelo as the first telomerase inhibitor is a testament to the power of our science and the passion of our people to innovate in the field of blood cancer. As we celebrate today’s momentous milestone, I would like to thank the patients and families, advocates, clinicians, study coordinators and site personnel, scientists, and Geron employees and collaborators past and present whose participation was integral to this achievement and to supporting our transformation into a commercial company.”

Lower-risk myelodysplastic syndromes (LR-MDS) is a blood cancer that often progresses to require increasingly intensified management of key symptoms such as anemia and resulting fatigue1. These symptomatic LR-MDS patients frequently become red blood cell transfusion dependent, which has been shown to be associated with short- and long-term clinical consequences that reduce quality of life and shorten survival2,3. There is a high unmet need for many LR-MDS patients, particularly those with characteristics having poorer prognosis. Current treatment options for those failing ESA are limited to select sub-populations and there is an unmet need for treatments that can provide extended and continuous red blood cell transfusion independence.

Approval Based on Results from IMerge Phase 3 Clinical Trial

“For patients with lower-risk MDS and anemia who are transfusion dependent, we have very few options today and often cycle through available therapies, making the approval of Rytelo potentially practice changing for us,” said Rami Komrokji, MD, Vice Chair, Malignant Hematology Department, Moffitt Cancer Center, who was an investigator of the pivotal IMerge clinical trial. “What is exciting about Rytelo is the totality of the clinical benefit across LR-MDS patients irrespective of ring sideroblast status or high transfusion burden, including sustained and durable transfusion independence and increases in hemoglobin levels, all within a well-characterized safety profile of generally manageable cytopenias. The treatment goal for patients with LR-MDS and anemia is transfusion-independence and before today, this wasn’t possible for many patients.”

The FDA approval of Rytelo is based on results from the IMerge Phase 3 clinical trial, published in The Lancet 4. The IMerge trial met its primary and key secondary endpoints, with Rytelo demonstrating significantly higher rates of red blood cell transfusion independence (RBC-TI) versus placebo for at least eight consecutive weeks (Rytelo 39.8% [95% CI 30.9–49.3]; placebo 15.0% [7.1–26.6]; p<0.001) and for at least 24 weeks (Rytelo 28.0% [95% CI 20.1-37.0]; placebo 3.3% [95% CI 0.4-11.5]; p<0.001). RBC-TI was durable and sustained in the Rytelo treated population, with a median RBC-TI duration for 8-week responders and 24-week responders of approximately 1 year and 1.5 years, respectively.

In an exploratory analysis of Rytelo-treated patients achieving ≥8-week RBC-TI, median increases in hemoglobin were 3.6 g/dL for Rytelo and 0.8 g/dL for placebo. Clinically meaningful efficacy results were observed across key MDS subgroups irrespective of ring sideroblast (RS) status, baseline transfusion burden and IPSS risk category.

In the IMerge trial, the safety profile of Rytelo was well-characterized with generally manageable and short-lived thrombocytopenia and neutropenia, which are familiar side effects for hematologists who are experienced with managing cytopenias. The most common Grade 3/4 adverse reactions were neutropenia (72%) and thrombocytopenia (65%), which lasted a median duration of less than two weeks, and in more than 80% of patients were resolved to Grade < 2 in under four weeks. Cytopenias were generally manageable with dose modifications. The intravenous administration of Rytelo every four weeks aligns to routine blood count monitoring for these patients.

The most common adverse reactions (incidence ≥10% with a difference between arms of >5% compared to placebo), including laboratory abnormalities, were decreased platelets (thrombocytopenia), decreased white blood cells, decreased neutrophils (neutropenia), increased aspartate aminotransferase (AST), increased alkaline phosphatase (ALP), increased alanine aminotransferase (ALT), fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache. Clinically relevant adverse reactions in < 5% of patients who received Rytelo included febrile neutropenia, sepsis, gastrointestinal hemorrhage, and hypertension.

REF: https://en.wikipedia.org/wiki/Imetelstat

FDA Approves Rytelo (imetelstat) for the Treatment of Adult Patients with Lower-Risk MDS with Transfusion-Dependent Anemia

FDA Approves Jaypirca (pirtobrutinib) for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma

Loxo@Lilly, the oncology unit of Eli Lilly and Company (NYSE: LLY),  announced the U.S. Food and Drug Administration (FDA) approved Jaypirca™ (pirtobrutinib, 100 mg & 50 mg tablets) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor. Jaypirca was approved under the FDA's Accelerated Approval pathway based on response rate from the open-label, single-arm, international, Phase 1/2 study, called the BRUIN trial.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Jaypirca, a highly selective kinase inhibitor, utilizes a novel binding mechanism and is the first and only FDA approved non-covalent (reversible) BTK inhibitor. Jaypirca can reestablish BTK inhibition in MCL patients previously treated with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and extend the benefit of targeting the BTK pathway.

"The approval of Jaypirca represents an important advance for patients with relapsed or refractory MCL, who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent BTK inhibitor," said Michael Wang, M.D., Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. "These data indicate that Jaypirca can provide efficacy in patients previously treated with a covalent BTK inhibitor, potentially extending the time patients may benefit from BTK inhibition therapy. Jaypirca offers a new approach to targeting the BTK pathway following treatment with a covalent BTK inhibitor and has the potential to meaningfully impact the treatment paradigm for relapsed and refractory MCL patients."

The labeling for Jaypirca contains warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, second primary malignancies, and embryo-fetal toxicity. See Important Safety Information below and full Prescribing Information for additional information, including dosing modifications.

"We are pleased to bring a meaningful new therapeutic option to patients with MCL that can reestablish the benefit of targeting the BTK pathway after receiving multiple prior therapies, including a covalent BTK inhibitor," said Jacob Van Naarden, chief executive officer, Loxo@Lilly. "We are grateful to the patients, investigators, and other members of the clinical care teams for their contributions. Our team has been committed to rapidly advancing the development of Jaypirca for patients with MCL, and we look forward to building on this milestone by continuing to bring forward important new treatments for people with hematologic malignancies."

The FDA approval is based on data from a subset of patients in the BRUIN Phase 1/2 trial. The assessment of efficacy was based on 120 patients with MCL treated with Jaypirca 200 mg once daily until disease progression or unacceptable toxicity. Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation or CAR T-cell therapy within 60 days were excluded. Patients had received a median of three prior lines of therapy (range: 1 to 9), with 93% having two or more prior lines; all patients received one or more prior lines of therapy containing a covalent BTK inhibitor. Eighty-three percent (83%) of patients discontinued their last BTK inhibitor due to refractory or progressive disease. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an independent review committee (IRC) using 2014 Lugano criteria.

Read More 

https://en.wikipedia.org/wiki/Pirtobrutinib#/media/File:Pirtobrutinib.svg

FDA Approves Jaypirca (pirtobrutinib) for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma

FDA Approves Recorlev (levoketoconazole) for the Treatment of Endogenous Hypercortisolemia in Adult Patients With Cushing’s Syndrome

Xeris Biopharma Holdings, Inc. (Nasdaq: XERS), announce  the U.S. Food and Drug Administration (FDA) approval of Recorlev® (levoketoconazole) for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

“We are thrilled with the FDA's approval of Recorlev as a safe and effective treatment option for patients with endogenous Cushing's syndrome. With this approval, Xeris’ experienced endocrinology-focused commercial organization can begin rapidly working to help address the needs of Cushing’s syndrome patients in the U.S. who are treated with prescription therapy,” said Paul R. Edick, Chairman and CEO of Xeris Biopharma. “Today’s announcement also reinforces the value that we saw in acquiring Strongbridge Biopharma’s attractive rare disease portfolio, which we believe will deliver compelling long-term value to our shareholders. We look forward to making Recorlev commercially available in the first quarter.”

The approval of Recorlev was based upon safety and efficacy data from two positive Phase 3 studies that evaluated a combined study population of 166 patients, which was representative of the adult drug-treated U.S. population with Cushing’s syndrome. The SONICS study met its primary and key secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without a dose increase. LOGICS, a double-blind, placebo-controlled randomized-withdrawal study that met its primary and key secondary endpoints, confirmed the efficacy and safety of Recorlev in normalizing and maintaining therapeutic response compared with placebo.

“Levoketoconazole (Recorlev) is an important and welcome new therapeutic option for clinicians to help manage patients with endogenous Cushing's syndrome, a severe, potentially life-threatening rare disease, if not appropriately treated, with multisystem signs and symptoms,” said Maria Fleseriu, M.D., FACE, professor of Medicine and Neurological Surgery and director of the Pituitary Center at Oregon Health Sciences University. “In prospective clinical studies, treatment with levoketoconazole was shown to be effective for reducing and normalizing cortisol.”

“Cushing’s syndrome is a rare disease that can be physically and emotionally devastating to the patient. Most patients endure years of symptoms prior to obtaining a diagnosis and are then faced with limited effective treatment options," said Leslie Edwin, president of the Cushing’s Support & Research Foundation. “Today we are excited to see that the long and complicated path of rare drug development has reached FDA approval on a new therapeutic option for our underserved Cushing's community. We are grateful that the researchers worked so diligently for so long to establish the safety and efficacy of this drug. Rare disease patients know the importance of sharing their complicated experiences as ‘expert witnesses’, and we thank Xeris for being an early adherent to this concept. We especially want to thank the clinical trial patients who made this progress possible.”

Xeris is committed to ensuring everyone who needs access to their therapies will receive it. Xeris has created Xeris CareConnection™ to provide a comprehensive program for patients and their caregivers throughout the treatment journey, including financial assistance, one-on-one support, and educational resources. Xeris CareConnection also supports healthcare professionals and their teams through education on access and reimbursement. To get started with Recorlev, reach out to Xeris CareConnection (available Monday–Friday from 8 a.m–7 p.m ET) at 1-844-444-RCLV (7258).

https://en.wikipedia.org/wiki/Levoketoconazole

https://reference.medscape.com/drug/recorlev-levoketoconazole-4000226

FDA Approves Dayvigo (lemborexant) for the Treatment of Insomnia in Adult Patients

In continuation of my update on lemborexant

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) today announced that the U.S. Food and Drug Administration (FDA) approved the new drug application for its in-house discovered and developed orexin receptor antagonist Dayvigo (lemborexant). Dayvigo was approved for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance in adults1. In the United States, Dayvigo will be commercially available in 5 mg and 10 mg tablets following scheduling by the U.S. Drug Enforcement Administration (DEA), which is expected to occur within 90 days.

The mechanism of action of lemborexant in the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to orexin receptors OX1R and OX2R is thought to suppress wake drive. Lemborexant binds to orexin receptors OX1R and OX2R and acts as a competitive antagonist with stronger inhibition effect to OX2R*.

The approval was based on the results of a clinical development program that included two pivotal Phase III studies (SUNRISE 2 and SUNRISE 1), which evaluated Dayvigo versus comparators for up to one month and Dayvigo versus placebo for six-months, respectively, in a total of about 2,000 adult patients with insomnia. From these studies results, Dayvigo demonstrated statistically significant superiorities on sleep onset and sleep maintenance compared to placebo in both subjective and objective evaluations.

Across SUNRISE 2 and SUNRISE 1, Dayvigo was not associated with rebound insomnia following treatment discontinuation, and there was no evidence of withdrawal effects following Dayvigo discontinuation at either dose. In addition, the development program included multiple safety studies evaluating effects on postural stability, cognition, driving performance and respiratory safety.

• SUNRISE 2 was a long-term (six month), randomized, double-blind, placebo-controlled, multi-center, trial in adult patients age 18 or older who met DSM-5** criteria for insomnia disorder. Patients were randomized to placebo (n=325), Dayvigo 5 mg (n=323), or Dayvigo 10 mg (n=323) once nightly. The primary efficacy endpoint was the mean change from baseline to end of treatment at six months for patient-reported (subjective) sleep onset latency (sSOL), defined as the estimated minutes from the time that the subject attempted to sleep until falling asleep. Pre-specified secondary efficacy endpoints were change from baseline to end of treatment at six months for patient reported sleep efficiency (sSE; defined as the proportion of time spent asleep during time in bed) and subjective sleep onset and sleep maintenance (sWASO; defined as the minutes of wake from the onset of persistent sleep until lights on). The primary and pre-specified secondary efficacy endpoints were measured using a Sleep Diary. In SUNRISE 2, Dayvigo 5 mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, sSOL, compared to placebo. Dayvigo 5 mg and 10 mg also showed statistically significant superiority in sSE and sWASO.1
• SUNRISE 1 was a short-term (one month), randomized, double-blind, placebo- and active-controlled, multi-center, parallel-group clinical trial in adult female subjects age 55 and older and male subjects 65 years and older who met DSM-5 criteria for insomnia disorder. Patients were randomized to placebo (n=208), Dayvigo 5 mg (n=266) or 10 mg (n=269) or active comparator (n=263) once nightly. The primary efficacy endpoint was the mean change in latency to persistent sleep (LPS; defined as the number of minutes from lights off to the first 10 consecutive minutes of non-wakefulness) from baseline to end of treatment (day 29/30), as measured by overnight polysomnography (PSG) monitoring. The pre-specified secondary efficacy endpoints in SUNRISE 1 were the mean change from baseline to end of treatment (day 29/30) in sleep efficiency (SE) and wake after sleep onset (WASO) measured by PSG. In SUNRISE 1, Dayvigo 5 mg and 10 mg demonstrated statistically significant superiority on the primary efficacy measure, LPS, compared to placebo. Dayvigo 5 mg and 10 mg demonstrated statistically significant improvement in SE and WASO compared to placebo.1
  The most common adverse reaction (reported in 5% or more of patients treated with Dayvigo and at least twice the rate of placebo) in SUNRISE 2 (the first 30 days) and SUNRISE 1 was somnolence (Dayvigo 10 mg, 10%; Dayvigo 5 mg, 7%; placebo, 1%).

https://en.wikipedia.org/wiki/Lemborexant