Oral Ulcer

A genetic medicine at the heart of a $387 million Kyowa Kirin acquisition has won FDA approval, a regulatory decision that makes the one-time treatment the first approved therapy for the rare inherited disorder metachromatic leukodystrophy (MLD). In the most severe form of MLD, babies develop normally only to rapidly lose the ability to walk, talk, and interact by the time they reach late infancy. Eventually, children with MLD deteriorate to a vegetative state, and most pass away within five years of the disease’s onset. The gene therapy, from Kyowa Kirin subsidiary Orchard Therapeutics, is already approved in Europe for treating early onset MLD in infants and children, marketed there under the brand name Libmeldy. The FDA decision announced Monday is similar, covering the treatment of late infantile or early juvenile forms of the disease in children who are not yet showing symptoms. The FDA nod also covers the treatment of children who have early juvenile MLD with early signs of symptoms. In the U.S., the therapy will be commercialized as Lenmeldy. “The FDA approval of Lenmeldy opens up tremendous new possibilities for children in the U.S. with early-onset MLD who previously had no treatment options beyond supportive and end-of-life care,” Orchard co-founder and CEO Bobby Gaspar said in a prepared statement. MLD is an inherited disease that leads to a deficiency of a key enzyme called arylsulfatase A (ARSA). Without enough of this enzyme, fatty substances build up in cells, causing damage to the central and peripheral nervous system. According to the FDA, an estimated one in every 40,000 individuals in the U.S. has MLD. Lenmeldy is made by collecting a patient’s own hematopoietic stem cells. In a lab, a functional copy of the ARSA gene is inserted into those cells. The genetically modified cells are then infused back into the patient, where they go to the bone marrow and multiply. Like other gene therapies, the infusion step is preceded by a pretreatment regimen in which chemotherapy is used to kill cells from the bone marrow so they can be replaced by the modified cells that make up Lenmeldy. The FDA approval is based on data from two single-arm, open label studies that evaluated Lenmeldy in 37 children. Study participants were compared to the natural history of untreated children. The main goal was to measure the time from birth to the first occurrence of loss of locomotion, the loss of the ability to sit without support, or death. Trial results showed that all children with pre-symptomatic late infantile MLD who were treated with the Orchard gene therapy were alive at age 6, compared to 58% of children in the natural history group. At age 5, 71% of treated children were able to walk without assistance. Furthermore, 85% of the treated children at age 5 had normal language and performance IQ scores, a measure that has not been reported in untreated children. The results in pre-symptomatic early juvenile MLD patients and early symptomatic early juvenile patients showed a slowing of motor and cognitive disease. The most common side effects reported from the clinical trial included fever, low white blood cell count, mouth sores, respiratory infections, and rash. The FDA said that after infusion with Lenmeldy, patients’ counts of neutrophils, a type of white blood cell, should be monitored. The FDA said patients should also be monitored for a delay in the recovery of platelet cells. In clinical trials, four patients had a delay in this platelet engraftment after day 60, and three of them required platelet transfusions until engraftment occurred. The FDA cautioned that Lenmeldy may lead to blood clots or brain swelling. The agency also said blood cancer is a risk associated with this therapy, though no cases have been seen in treated patients so far. Like other cell and gene therapies, the FDA is requiring that patients have lifelong monitoring for blood cancers. Lenmeldy originated in the labs of GSK. That program and others went to Orchard in 2018 via the $133.6 million acquisition of the pharmaceutical giant’s gene therapy portfolio. The transaction put GSK in line for milestone payments and royalties from sales of approved products. GSK may also purchase any priority review voucher that the FDA awards Orchard for a product approval in MLD or two other rare diseases. Such vouchers enable a company to speed up the regulatory review of another drug for a rare disease, but voucher recipients often sell them at prices topping $100 million. Orchard said Monday that Lenmeldy’s approval came with a priority review voucher and the voucher would be transferred to GSK per the terms of the original agreement. Orchard has not disclosed any financial specifics of this transaction, other than to say that the price would be set by an agreed upon formula. The company also said it would provide details later this week about Lenmeldy’s U.S. launch. Last fall, Kyowa Kirin announced an acquisition agreement for Orchard, a deal that adds gene therapy to its pipeline. The Japanese drugmaker completed the transaction in January, paying $16 for each of Orchard’s American depositary shares. The acquisition agreement includes a contingent value right putting Orchard shareholders in line for an additional $1 per share tied to Lenmeldy’s FDA approval. That payment will add another $90 million to the payout. Image: Getty Images

SILVER SPRING, Md., March 18, 2024 /PRNewswire/ -- Today, the U.S. Food and Drug Administration approved Lenmeldy (atidarsagene autotemcel), the first FDA-approved gene therapy indicated for the treatment of children with pre-symptomatic late infantile, pre-symptomatic early juvenile or early symptomatic early juvenile metachromatic leukodystrophy (MLD). Metachromatic leukodystrophy is a debilitating, rare genetic disease affecting the brain and nervous system. It is caused by a deficiency of an enzyme called arylsulfatase A (ARSA), leading to a buildup of sulfatides (fatty substances) in the cells. This buildup causes damage to the central and peripheral nervous system, manifesting with loss of motor and cognitive function and early death. It is estimated that MLD affects one in every 40,000 individuals in the United States. There is no cure for MLD, and treatment typically focuses on supportive care and symptom management. "This is the first FDA-approved treatment option for children who have this rare genetic disease," said Peter Marks, M.D., Ph.D., director of the FDA's Center for Biologics Evaluation and Research (CBER). "We remain committed to advancing scientific and regulatory principles that enable the efficient development and review of safe, effective and innovative products that have the potential to change patients' lives." Lenmeldy is a one-time, individualized single-dose infusion made from the patient's own hematopoietic (blood) stem cells (HSCs), which have been genetically modified to include functional copies of the ARSA gene. The stem cells are collected from the patient and modified by adding a functional copy of the ARSA gene. The modified stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow. The modified stem cells supply the body with myeloid (immune) cells that produce the ARSA enzyme, which helps break down the harmful build-up of sulfatides and may stop the progression of MLD. Prior to treatment, patients must undergo high-dose chemotherapy, a process that removes cells from the bone marrow so they can be replaced with the modified cells in Lenmeldy. "MLD is a devastating disease that profoundly affects the quality of life of patients and their families. Advancements in treatment options offer hope for improved outcomes and the potential to positively influence the trajectory of disease progression," said Nicole Verdun, M.D., director of the Office of Therapeutic Products in CBER. "This approval represents important progress in the advancement and availability of effective treatments, including gene therapies, for rare diseases." The safety and effectiveness of Lenmeldy was assessed based on data from 37 children who received Lenmeldy in two single-arm, open-label clinical trials and in an expanded access program. Children who received treatment with Lenmeldy were compared to untreated children (natural history). The primary efficacy endpoint was severe motor impairment-free survival, defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support or death. In children with MLD, treatment with Lenmeldy significantly reduced the risk of severe motor impairment or death compared with untreated children. All children with pre-symptomatic late infantile MLD who were treated with Lenmeldy were alive at 6 years of age, compared to only 58% of children in the natural history group. At 5 years of age, 71% of treated children were able to walk without assistance. Eighty five percent of the children treated had normal language and performance IQ scores, which has not been reported in untreated children. In addition, children with pre-symptomatic early juvenile and early symptomatic early juvenile MLD showed slowing of motor and/or cognitive disease. The most common side effects of Lenmeldy are fever and low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, fever, gastrointestinal infections and enlarged liver. After infusion with Lenmeldy, patients should be monitored for neutrophil counts and risk of delayed platelet engraftment until engraftment has been achieved. Treatment with Lenmeldy may be associated with formation of blood clots or a type of swelling of brain tissues known as encephalitis. There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in patients treated with Lenmeldy. Patients receiving this product should have lifelong monitoring for hematologic malignancies, including a complete blood count (with differential) annually and integration site analysis, as warranted, for at least 15 years after treatment. The application received Priority Review, Orphan Drug, Rare Pediatric Disease and Regenerative Medicine Advanced Therapy (RMAT) designations. The FDA granted approval of Lenmeldy to Orchard Therapeutics. Media Contact: Carly (Kempler) Pflaum, [email protected], 240-672-8872 The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation's food supply, cosmetics, dietary supplements, radiation-emitting electronic products, and for regulating tobacco products. SOURCE U.S. Food and Drug Administration

New Phase 2b results for amlitelimab support potential for best-in-class maintenance of response in atopic dermatitis Late-breaking data at AAD show sustained off-drug improvements of AD signs and symptoms with amlitelimab for 28 weeks The safety profile for patients dosed to 52 weeks was consistent with amlitelimab 24 weeks data showing it to be well-tolerated with no new safety concerns identified Durability of response supports quarterly dosing currently being investigated in Phase 3 pivotal program Sustained biomarker reduction suggests the modulation of immune response and durable disease control via the blockade of OX40L, a non-T cell depleting mechanism Amlitelimab is one of 12 potential blockbusters in Sanofi’s leading immunology pipeline, results for a Phase 2 asthma study expected in H2 2024 and three additional Phase 2 study starts expected by year-end March 11, 2024. Positive results from Part 2 of the investigational amlitelimab Phase 2b study STREAM-AD showed sustained improvement of signs and symptoms for 28 weeks in adults with moderate to severe AD who previously responded to amlitelimab and continued treatment. High responder rates were also observed in participants who were taken off amlitelimab. The safety profile was consistent with Part 1 of the study with amlitelimab being well-tolerated and no new safety concerns identified. These results were presented as part of a late-breaking session at the American Academy of Dermatology (AAD) 2024 Conference in San Diego and support the quarterly (every 12-week) dosing of amlitelimab 250 mg with 500 mg loading dose (LD) now being investigated in a larger Phase 3 clinical program (OCEANA). Director, Professor, Chair of Department of Dermatology and Allergy, University Hospital Schleswig-Holstein “Despite available treatment options, not all patients with moderate-to-severe atopic dermatitis respond sufficiently to these treatments, and many continue to suffer from skin lesions and symptoms such as persistent itch, which can have a high impact on their day-to-day lives. Results from this part of the study indicate amlitelimab’s potential for durable off-drug efficacy which supports the evaluation of a less frequent every 12-week dosing. This could offer an important benefit in the treatment of AD patients.” In the second part of the dose-ranging STREAM-AD study, responders to amlitelimab who achieved a 75% improvement in Eczema Area and Severity Index (EASI-75) score and/or Investigator Global Assessment (IGA) score of 0 or 1 during the 24-week treatment period (Part 1) were re-randomized to explore the maintenance of clinical response over an additional 28-week period with continued amlitelimab treatment or amlitelimab withdrawal. Across all dose arms, patients who continued amlitelimab treatment maintained high EASI-75 and/or IGA 0/1, IGA 0/1, and EASI-75 responder rates through 28 weeks. High responder rates were also demonstrated among patients who were taken off treatment. In 69.2% of patients with continued treatment with amlitelimab 250 mg Q4W with 500 mg loading dose (LD) vs 58.8% of patients withdrawn from treatment IGA 0/1 and/or EASI-75 response was maintained. An analysis including pooled dose-arms showed that IGA 0/1 response was maintained in 71.9% of patients with continued treatment vs 57% of patients withdrawn from treatment. In this analysis, EASI-75 response was maintained in 69% of patients with continued treatment vs. 61.6% of patients withdrawn from treatment. AD-related biomarkers remained reduced at Week 52 in both amlitelimab withdrawn and continuing groups, despite amlitelimab reaching negligible levels in serum. Reduction of TARC, eosinophils, and IL-22 observed at Week 24 was maintained during withdrawal as well as in patients continuing treatment to Week 52. These biomarker data suggest the modulation of inflammatory T cells via the blockade of OX40L and durable control of AD after amlitelimab withdrawal. Head of Global Development, Immunology and Inflammation, Sanofi “It’s unprecedented to see this type of durability of clinical response, which we believe could be very meaningful to patients and is the reason why we selected an every 12-week dosing regimen in the AD pivotal program. AD is a chronic, lifelong disease, which means we must strive to provide a portfolio of solutions to patients that matches their individual needs and puts as little burden on them as possible. We are also moving with speed in our exploration of amlitelimab's potential in 5 other chronic inflammatory diseases, including asthma, hidradenitis suppurativa, scleroderma, celiac disease, and alopecia. In addition, we are exploring 6 other innovative MOAs in 8 dermatologic indications underscoring our commitment to patients with high unmet medical needs.” The aggregated safety profile of amlitelimab in Part 2 of this study was consistent with that of Part 1, with amlitelimab being well-tolerated, and no new safety concerns were identified during the 28-week maintenance/withdrawal period. Overall rates of treatment-emergent adverse events (TEAEs) were 69.8% for continued amlitelimab treatment, 71.9% for the amlitelimab withdrawal-arm and 66.7% for placebo. TEAEs more commonly observed included headache (11.6% amlitelimab continuation, 3.9% amlitelimab withdrawal, 6.7% placebo), upper respiratory tract infection (9.3% amlitelimab continuation, 5.5% amlitelimab withdrawal, 20% placebo). No adverse events such as fever or chills, oral ulcers or conjunctivitis were observed across doses. Amlitelimab is a fully human non-T cell depleting monoclonal antibody that blocks OX40-Ligand, a key immune regulator, and has the potential to be a first- or best-in-class treatment for a range of immune-mediated diseases and inflammatory disorders, including moderate-to-severe atopic dermatitis (Phase 3), asthma (Phase 2), hidradenitis suppurativa (Phase 2), scleroderma, celiac disease, and alopecia (Phase 2 studies to be initiated in 2024). By targeting OX40-Ligand, amlitelimab aims to restore balance between pro-inflammatory and regulatory T cells. Amlitelimab is currently under clinical investigation, and its safety and efficacy have not been evaluated by any regulatory authority. STREAM-AD, a Phase 2b study, is a randomized double-blind, placebo-controlled study, evaluating amlitelimab in adult patients with moderate-to-severe atopic dermatitis whose disease was inadequately controlled with topical therapies or where such therapies were not advisable. This study is designed with two parts and is double-blind through both. Part 1 was a 24-week treatment period, and Part 2 was a 28-week maintenance/withdrawal period, which included clinical responders from Part 1, defined as participants achieving EASI-75 and/or IGA 0/1 at Week 24. Of 390 participants enrolled in Part 1, 190 entered Part 2. Participants were re-randomized 3:1 to withdraw treatment or continue pre-Week 24 subcutaneous Q4W dose (250mg with 500mg loading dose (LD), 250mg, 125mg, 62.5mg, placebo responders continuing placebo), and were followed to Week 52 for efficacy. The study enrolled 390 people in Australia, Bulgaria, Canada, Czechia, Germany, Hungary, Japan, Poland, Spain, Taiwan, the United Kingdom and the United States. We are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across some 100 countries, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions. The content above comes from the network. if any infringement, please contact us to modify.