Orchard Therapeutics Plc

Pictured: 3D rendering of human cells and DNA/iStock/iStock, anusorn nakdee 2023 was a banner year for cell and gene therapy, with seven FDA approvals, according to the Alliance for Regenerative Medicine. And the pace doesn’t appear to be slowing at all as the second quarter of this year gets underway. The advocacy group is anticipating an even bigger year for the CGT space in 2024, with a potential 17 approvals in the U.S. and EU combined, according to ARM’s annual Cell & Gene State of the Industry Briefing in January. “It seems like the FDA is really pushing forward with accelerated approvals for cell and gene therapies, and that’s quite encouraging to see,” Jack Allen, a senior research analyst at Baird, told BioSpace. “These can be quite expensive products to develop, and if we’re able to leverage abbreviated pathways to get them to market rapidly, I think that can really reignite enthusiasm for the space.” Allen noted that cell and gene therapy is somewhat de-risked by the fact that, in many instances, these treatments involve introducing the genetic sequence for a native functional protein. “I think there will be some bumps in the road as it relates to pressing forward rapidly with the technology,” he said, but “it seems like the FDA has buy-in and is willing to ride through some of those bumps.” Here, we take a closer look at six of the more notable cell and gene therapies approved during the past year—two of them under the FDA’s accelerated approval pathway—and preview some of the decisions on the horizon. Cell Therapies BMS’s Breyanzi Chronic lymphocytic leukemia and small lymphocytic leukemia On March 14, the FDA approved Bristol Myers Squibb’s Breyanzi as the first CAR T cell therapy for relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia. In the pivotal TRANSCEND 004 trial, Breyanzi elicited a complete response—something that is “basically unheard of” in patients with relapsed/refractory CLL, according to Rosanna Ricafort, vice president and head of late development hematology and cell therapy at BMS—in 20% of recipients, with responses lasting more than 35 months. The Big Picture In November 2023, the FDA launched an investigation into the “serious risk” of secondary malignancies in patients treated with BCMA- or CD19-directed autologous CAR T cell therapies. This led to the addition of a boxed warning to all six commercial CAR-T therapies at the time, including BMS’s Breyanzi. But industry leaders and the FDA itself have been supportive of CAR-T’s risk/benefit profile. Breyanzi’s approval in two more indications, along with the recommendation of FDA advisers to move Abecma and J&J’s Carvykti into earlier lines of treatment for multiple myeloma, have cemented this tone. Iovance’s Amtagvi Melanoma In one of the year’s most anticipated decisions, the FDA in February greenlit the first one-time cell therapy for a solid tumor, Iovance Biotherapeutics’ Amtagvi for unresectable or metastatic melanoma, under the accelerated approval pathway. Iovance is currently conducting a confirmatory study to verify the therapy’s benefit. The Big Picture Amtagvi is the first tumor-infiltrating lymphocytes (TIL) therapy, a treatment modality some experts say has advantages over CAR-T. While CAR Ts recognize only a small number of proteins on the surface of tumor cells, TILs can identify tumor targets derived from intra- or extracellular tumor proteins, Sammy Farah, CEO of Turnstone Biologics, told BioSpace. As of February 2023, there were more than 75 TIL immunotherapies in preclinical or clinical studies for various indications. Gene Therapies Orchard Therapeutics’ Lenmeldy Metachromatic leukodystrophy Last month, the FDA approved Orchard Therapeutics’ Lenmeldy as the first gene therapy for metachromatic leukodystrophy (MLD), a rare, degenerative disease characterized by loss of motor and cognitive function and early death. MLD is caused by a deficiency in the arylsulfatase-A (ARSA) gene, leading to a buildup of fatty substances in the cells. Lenmeldy is a single-dose infusion made from a patient’s own hematopoietic stem cells, which have been genetically modified to include functional copies of the ARSA gene. The Big Picture Lenmeldy joins a growing list of gene therapy firsts in pediatric diseases, including Sarepta’s Elevidys for Duchenne muscular dystrophy and bluebird bio’s Skysona for cerebral adrenoleukodystrophy. It is also the first FDA-approved treatment for MLD patients, “who previously had no treatment options beyond supportive and end-of-life care,” Orchard CEO Bobby Gaspar said in a statement. Vertex and CRISPR Therapeutics’ Casgevy Sickle cell disease, beta thalassemia Possibly the most celebrated approval of 2023 went to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which in December became the first-ever CRISPR-based gene editing therapy in the U.S., for sickle-cell disease (SCD). Just one month later, Casgevy was also approved for transfusion-dependent beta thalassemia, more than two months ahead of its PDUFA date. The Big Picture Casgevy’s SCD approval came just over a decade after the publication of the Nobel Prize-winning CRISPR-Cas9 technology—a timeline many industry experts have deemed faster than what would normally be expected of a new modality. But CRISPR is not without its risks. Researchers have cited cell toxicity and genomic instability as potential side effects, which could potentially trigger tumor development. Scientists are now working to improve on the technology with new modalities, including base editing and epigenetic editing. Bluebird bio’s Lyfgenia Sickle-cell disease While the historic nature of Casgevy’s approval won the day, bluebird bio’s Lyfgenia, a lentiviral gene therapy, also got the FDA’s nod for SCD on Dec. 8, 2023. Treatment with Lyfgenia led to the complete resolution of vaso-occlusive events 6 to 18 months after infusion, making it another promising option for patients. The Big Picture Allen said Lyfgenia may have a couple of advantages in the SCD market. “Both [therapies] are incredibly transformative in that they effectively eliminate sickle-cell disease–induced pain crises. Lyfgenia I think is quite interesting in that there’s a longer durability of data . . . and they also have some data in stroke patients, which I think is going to be differentiating in the commercial marketplaces” given the prevalence of stroke in SCD. Lyfgenia also has the upper hand over Casgevy in terms of developing the infrastructure needed to deliver treatment to patients. Sarepta’s Elevidys Duchenne muscular dystrophy In one of 2023’s more controversial decisions, the FDA approved Sarepta Therapeutics’ Elevidys as the first gene therapy for Duchenne muscular dystrophy (DMD). Elevidys missed the primary functional endpoint in a randomized trial but won accelerated approval based on data showing it increased the expression of the micro-dystrophin protein—a biomarker the agency determined is “reasonably likely to predict clinical benefit” in DMD patients 4 to 5 years of age. The FDA’s green light followed an adcomm meeting where its advisers narrowly recommended the gene therapy for approval. Then, just four months after the approval, Elevidys failed a confirmatory trial. The Big Picture Elevidys’ approval kicked off a wave of momentum in the DMD space. In October 2023, the FDA authorized Santhera Pharmaceuticals’ Agamree, and just last month, Italfarmaco won approval for Duvyzat, the first nonsteroidal drug approved to treat patients with all genetic variants of the disease. On the Horizon Rocket’s Kresladi Leukocyte adhesion deficiency-I Rocket Pharmaceuticals had expected a decision on its gene therapy Kresladi, in development for the rare disease leukocyte adhesion deficiency-I, in March, but the FDA pushed the date back to June 30, 2024 in order to allow for more review time. BMS’s Breyanzi Follicular lymphoma and mantle cell lymphoma It’s a big year for BMS’s Breyanzi, as the company is expecting the FDA to decide on the CAR T cell therapy as a treatment for patients with relapsed or refractory follicular lymphoma on May 23 and for those with relapsed or refractory mantle cell lymphoma who have been treated with a Bruton tyrosine kinase inhibitor therapy on May 31. Pfizer’s Beqvez Hemophilia B After winning approval in Canada in January, Pfizer’s adeno-associated virus-based gene therapy fidanacogene elaparvovec—marketed as Beqvez in Canada—has a PDUFA date in the second quarter of 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

An Akebia Therapeutics drug for a type of anemia has won FDA approval, a regulatory decision that comes nearly two years after the agency rejected the drug due to safety concerns. Safety remains a concern about the small molecule, vadadustat. The drug’s label carries a black box warning about an increased risk of death from a variety of cardiovascular complications. But the Akebia product, which will be branded as Vafseo, now introduces a new treatment option for the estimated 500,000 adults in the U.S who suffer from anemia due to chronic kidney disease (CKD). To use this drug, patients must have been receiving dialysis for at least three months. Anemia develops when there aren’t enough healthy red blood cells to carry oxygen to tissues in the body. It’s common in chronic kidney disease patients because their kidneys do not produce enough erythropoietin, a hormone that helps regulate red blood cell production. This anemia can be treated with erythropoietin-stimulating agents, engineered versions of the hormone administered as chronic injections. Akebia’s Vafseo offers more convenient oral dosing. This drug belongs to a class of drugs called hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors. By mimicking the effects of high altitude on the body, these drugs get the body to produce erythropoietin. When the FDA rejected this drug in 2022, it flagged cardiovascular risks and asked Akebia to run another clinical trial. Instead, the company resubmitted an application with additional post-marketing safety data from Japan, where the drug has been used since its approval there in 2020. Vafseo will compete against GSK’s Jesduvroq, which last year became the first FDA-approved oral medication for anemia caused by CKD. Jesduvroq is limited to patients who have been on dialysis for at least four months. Similar to Akebia’s drug, Jesduvroq’s label carries a black box warning for cardiovascular risks. Akebia said it will commercialize Vafseo in the U.S. with its established commercial team, which has renal experience and a relationship with CSL Vifor, the kidney disease-focused company that is the product of CSL Limited’s 2021 acquisition of Vifor Pharma. Here’s a recap of other recent regulatory news: —Winrevair, the pulmonary arterial hypertension (PAH) drug that was the centerpiece of an $11.3 billion Merck acquisition, won FDA approval. The PAH drugs already available treat symptoms. Winrevair is the first drug that addresses an underlying cause of this disorder affecting heart and lung function. —In other PAH news, the FDA approved Johnson & Johnson’s Opsynvi. This drug combines two older PAH drugs, macitentan and taladifil. Macitentan blocks the endothelin receptor while taladifil is a phosphodiesterase 5 inhibitor. Addressing both pathways requires patients to take multiple pills. Opsynvi is the first drug that combines both mechanisms in a single once-daily pill. —AstraZeneca’s drug Ultomiris added neuromyelitis optica spectrum disorder (NMOSD) as a new indication for the blockbuster drug. NMOSD is an autoimmune disease affecting the central nervous system, including the spine and optic nerves. Ultomiris blocks C5, a protein of the complement system, a part of the immune system. The drug has approvals for treating several other rare, complement system disorders. —Metabolic dysfunction-associated steatohepatitis (MASH), a fatty liver disease that affects as many as 7 million Americans, now has its first approved drug. The FDA gave the green light to Rezdiffra, a Madrigal Pharmaceuticals’ medication that posted clinical trial results showing it can reverse the liver scarring that is characteristic of the disorder. Madrigal’s once-daily pill carries an annual wholesale price of $47,400. —An Italfarmaco drug for Duchenne muscular dystrophy won FDA approval for treating all patients who have the inherited muscle-wasting disorder, regardless of the genetic variant driving their disease. Corticosteroids are a standard first-line therapy for Duchenne. The Italfarmaco drug, Duvyzat, is the first nonsteroidal therapy approved for the disease. —Orchard Therapeutics gene therapy Lenmeldy is now the first FDA-approved treatment for metachromatic leukodystrophy (MLD), a rare enzyme deficiency. Lenmeldy is made by modifying a patient’s hematopoietic stem cells to carry a functional gene that codes for the deficient enzyme. Orchard is now part of Japanese drugmaker Kyowa Kirin following a $387 million acquisition announced last year. —Regeneron Pharmaceuticals’ drug odronextamab was turned down by the FDA for two indications: follicular lymphoma and diffuse large B-cell lymphoma. According to Regeneron, the agency did not flag any safety, efficacy, or manufacturing issues for the bispecific antibody. The FDA told Regeneron it cannot resubmit applications until confirmatory studies are underway and completion timelines are agreed upon. Regeneron said it will share updates on enrollment and regulatory timelines later this year. The drug is still under regulatory review in Europe. —The FDA awarded full approval to AbbVie ovarian cancer drug Elahere. The antibody drug conjugate developed by ImmunoGen won accelerated approval in 2022. AbbVie acquired ImmunoGen last year in a $10.1 billion deal. —Invivyd antibody drug Pemgarda was granted emergency use authorization for prevention of Covid-19 in adults and adolescents with moderate-to-severe compromised immune systems. Other Covid-19 antibody drugs have had their authorizations revoked as they proved ineffective against new variants. Pemgarda comes from an Invivyd platform technology designed to address rapid viral evolution. —Idorsia Pharmaceuticals’ aprocitentan, brand name Tryviao, received FDA approval for treating hypertension when used in combination with other antihypertension drugs. The once-daily pill is designed to block the endothelin receptor. It’s the first approved high blood pressure drug with this mechanism of action. —Takeda Pharmaceutical drug Iclusig is now FDA approved for treating Philadelphia chromosome-positive acute lymphoblastic leukemia when used in combination with chemotherapy. The once-daily pill works by blocking enzymes associated with cancer growth. The accelerated approval adds to the list of indications for the drug, which is used to treat three types of leukemia. —The European Commission granted marketing authorization to Prevnar 20 for preventing pneumococcal disease in infants and children. The conjugate vaccine, which is designed to protect against the 20 circulating strains responsible for most pneumococcal infections, won European approval for adults in 2022. Prevnar 20 was first approved by the FDA for adults in 2021 and for children last year. —BeiGene cancer immunotherapy Tevimbra received a long-awaited FDA approval for treating adults with advanced esophageal squamous cell carcinoma. The FDA decision expected in 2022 was delayed by Covid-19. Though the drug received European Commission approval last year, BeiGene lost Novartis as a partner on the cancer therapy along the way. BeiGene said it expects Tevimbra, part of the class of drugs known as checkpoint inhibitors, will become available in the U.S. in the second half of this year. —Mirum Pharmaceuticals drug Livmarli landed FDA approval for treating pruritus, or severe itching, caused by the rare liver disease progressive familial intrahepatic cholestasis (PFIC). The approval cover patients age 5 and older. The company has also submitted an application seeking approval of a higher concentration formulation for treating younger PFIC patients. Livmarli was first approved by the FDA in 2021 as a treatment for pruritus caused by Alagille syndrome. Public domain image by Flickr user SciTechTrend

New investments in biopharma manufacturing by Novo Nordisk, Novartis and Merck KGaA; Kyowa Kirin's $4.25 million gene therapy; and BeiGene's belated PD-1 approval made our news this week. Three large pharma companies plan to expand their manufacturing footprints. Kyowa Kirin’s $4.25 million gene therapy set a new world pricing record. BeiGene’s PD-1 inhibitor finally crossed the FDA finish line after a 20-month delay. Plus more headlines. 1. Riding GLP-1 wave, Novo Nordisk lays out $560M to boost drug production in China Celebrating its 30th anniversary in China, Novo Nordisk unveiled a 4 billion yuan ($556 million) investment to expand its flagship factory in Tianjin. The project, which will improve the process for producing sterile drugs, has already kicked off and is expected to be complete in 2027. Novo’s obesity blockbuster, Wegovy, is expected to win approval in China later this year. 2. Novartis lays out $256M for antibody plant expansion in Singapore, plots 100 hires Novartis broke ground on a $256 million expansion of its biologics facility in Singapore. Like many other recent Novartis projects, the Singapore plant will feature digitalization and automation. The expanded site is expected to come online in 2026 and will create 100 new jobs. 3. Merck KGaA's MilliporeSigma drops €300M on Korean biologics plant with plans to create 300 new jobs Merck KGaA has chosen South Korea as the latest location to expand its life sciences service unit, MilliporeSigma. In the unit’s largest investment in the Asia-Pacific region to date, MilliporeSigma is pouring 300 million euros ($326 million) into a new bioprocessing plant in Daejeon. The project is expected to create 300 new jobs by the end of 2028. 4. After Kyowa Kirin buyout, Orchard scores FDA approval for first MLD gene therapy in the US Orchard sets new gene therapy price tag at $4.25M—the steepest of any drug Kyowa Kirin’s Orchard Therapeutics has won FDA approval for Lenmeldy, the first gene therapy for the rare central nervous system genetic disease metachromatic leukodystrophy. The product uses the patient’s own hematopoietic stem cells to deliver functional copies of the ARSA gene. Orchard has set the list price for the one-time therapy at $4.25 million, making it the most expensive drug in the world. 5. BeiGene finally snags FDA approval for PD-1 drug Tevimbra after long delay, Novartis breakup Twenty months after the FDA’s original target decision date, BeiGene’s PD-1 inhibitor Tevimbra finally won the go-ahead to treat post-chemo advanced esophageal squamous cell carcinoma. The company will launch the drug in the second half of the year, and its first-line application is awaiting an FDA verdict in July. 6. Despite early death concerns, FDA advisers back J&J and Legend's Carvykti and BMS' Abecma for earlier myeloma Eleven experts on the FDA’s Oncologic Drugs Advisory Committee voted unanimously in favor of Johnson & Johnson and Legend Biotech’s Carvykti in second-line multiple myeloma. Despite the agency’s concerns about an increased risk of death in the first few months of a clinical trial, the experts agreed that the CAR-T therapy’s benefits over a longer time frame outweigh the risks. 7. WuXi AppTec still sees sales growing and expansions rolling in 2024 despite concerns over US biosecurity bill WuXi AppTec doesn’t expect the draft BIOSECURE Act targeting it and other Chinese biotechs to materially affect its business in 2024. The company reported 2023 revenue at 40.34 billion yuan ($5.6 billion), including 65% from its customers in the U.S. For 2024, WuXi AppTec expects revenues to land within 38.3 billion yuan to 40.5 billion yuan, growing between 3% to 9% after excluding COVID projects. Other News of Note:  8. Takeda's Iclusig wins first-line FDA nod to treat rare Philadelphia chromosome-positive ALL 9. Hansoh, fresh from Big Pharma deal table, signs $690M ADC pact with Biotheus 10. Chinese biotech's MASH candidate reduces liver fat in phase 2 trial 11. Innovent's anti-VEGF drug matches Eylea in phase 2 eye disease trial