Orchard Therapeutics Outlines US Launch Plans for the Only Approved Therapy for Children With Early Onset Metachromatic Leukodystrophy

Orchard Therapeutics recently announced the details of its US commercial launch of Lenmeldy (atidarsagene autotemcel), formerly known as OTL-200, the first FDA-approved therapy for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile, (PSEJ), or early symptomatic early juvenile (ESEJ)—collectively referred to as early-onset—metachromatic leukodystrophy (MLD).

MLD is an ultra-rare, rapidly progressive, irreversible and ultimately fatal neurometabolic disease that affects approximately one in 100,000 live births, which is estimated to be fewer than 40 children annually in the US. It is caused by a mutation in the gene responsible for encoding the enzyme arylsulfatase A (ARSA) leading to neurological damage and developmental regression. In the most severe form of MLD, babies develop normally but in late infancy start to rapidly lose the ability to walk, talk and interact with the world around them. These children eventually deteriorate into a vegetative state, which may require 24-hour intensive care, and the majority pass away within five years of symptom onset, creating an enormous emotional and financial burden on the family. Prior to Lenmeldy, there were no treatment options in the U.S. for early-onset MLD beyond supportive and end-of-life care.

Lenmeldy aims to correct the underlying genetic cause of MLD by inserting one or more functional copies of the human ARSA gene ex vivo (outside the body) into the genome of a patient’s own hematopoietic stem cells (HSCs) using a lentiviral vector. The genetically repaired cells are infused back into the patient, where, once engrafted, they differentiate into multiple cell types, some of which migrate across the blood-brain barrier into the central nervous system and express the functional enzyme. 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. This approach has the potential to restore enzymatic function to stop or slow disease progression with a single treatment.

“Lenmeldy is truly a paradigm-shifting medicine and has the potential to stop or slow the progression of this devastating childhood disease with a single treatment, particularly when administered prior to the onset of symptoms,” said Bobby Gaspar, MD, PhD, co-founder and chief executive officer of Orchard Therapeutics. “We are committed to enabling broad, expedient and sustainable access to this important therapy for eligible patients with early-onset MLD in the US.”

“The launch of Lenmeldy in the US will build on our success delivering personalized gene therapies to eligible children with MLD throughout Europe and the Middle East by utilizing a similar commercial strategy and infrastructure,” added Frank Thomas, President and Chief Operating Officer of Orchard Therapeutics. “We are confident in the potential long-term clinical outcomes of Lenmeldy and will continue to work with public and private payers to structure outcomes-based and other types of innovative reimbursement models that appropriately balance the needs of patients and families for adequate access, health care systems for affordability, as well as support future research and development of treatments for ultra-rare diseases like MLD.”

The FDA approval of Lenmeldy is based on data from 37 pediatric patients with early onset MLD, enrolled in two single-arm, open-label clinical studies or treated under European expanded access frameworks, who received a one-time administration of the gene therapy and compared with natural history data. All treated patients were administered Lenmeldy and subsequently monitored at Ospedale San Raffaele in Milan, Italy.

All children with PSLI 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 and 85% of the children treated had normal language and performance IQ scores, which has not been reported in untreated children. In addition, children with PSEJ and ESEJ 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 type of treatment; however, no cases have been seen in patients treated with Lenmeldy. Patients receiving this therapy should have life-long 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. Please see below for additional details and Important Safety Information.

With more than 12 years of follow-up in the earliest treated patients (median of 6.76 years), Lenmeldy is launching with the longest duration of follow-up available at the time of approval for a gene therapy in the US to date.

Orchard Therapeutics has set the wholesale acquisition cost (WAC) of Lenmeldy in the US at $4.25 million which is reflective of the value the therapy may deliver to eligible patients and their families, as well the potential long-term impact treatment may have on overall healthcare utilization, minimization of productivity loss for caregivers, and life opportunities for patients. The WAC was determined following the completion of a comprehensive Health Technology Assessment (HTA) by the independent, non-profit organization, the Institute for Clinical and Economic Review (ICER) which determined the health benefit price benchmark (HBPB) for Lenmeldy to be up to $3.94 million at the $150,000 per Equal Value Life Year (evLY) threshold from a modified societal perspective.

“The value of Lenmeldy has been recognized by several HTA authorities around the world, including in the US by ICER, which determined Lenmeldy to have the highest value-based price for any treatment it has evaluated to date,” said Bennett Smith, Senior Vice President and General Manager of North America at Orchard Therapeutics. “MLD places an enormous emotional and economic burden on families and caregivers—who face substantial wage loss and added expenses each year as the disease progresses—all while dealing with the unquantifiable anguish of losing their child. HSC gene therapy has the potential to offer a transformative impact on devastating genetic diseases not well addressed by other therapeutic modalities, and we will continue to ensure society reaps the benefits from the anticipated value these therapies may deliver to eligible children and their families.”

Lenmeldy is launching with an unprecedented amount of follow-up data, providing support for the potential long-term durability of treatment effect. Recognizing the need to establish innovative payment structures for one-time durable therapies, Orchard Therapeutics is working collaboratively with commercial and government payers to offer outcomes- and value-based agreements intended to ensure timely access by sharing risk between the payer and manufacturer.

Lenmeldy is being made available to eligible patients through a network of Qualified Treatment Centers (QTCs) in key regions throughout the US to minimize the travel burden on patients and their families. Five treatment centers with specialized expertise in transplant and the treatment of neurometabolic diseases, like MLD, are being activated.

One of those centers, the M Health Fairview Masonic Children’s Hospital in Minnesota, is in the final stages of qualification. Several eligible children with MLD from the US have already been treated at the center on a compassionate use basis with drug product supplied by Orchard Therapeutics manufactured using commercial processes.

Four additional regional centers geographically dispersed throughout the US, including Children’s Healthcare of Atlanta, Children’s Hospital of Philadelphia, Texas Children’s Hospital, and UCSF Benioff Children’s Hospital San Francisco, are in the process of becoming fully qualified.

Orchard Therapeutics’ patient support program, Orchard Assist, will offer individualized support for eligible patients and their caregivers who enroll in the program throughout the treatment process. Experienced case managers with success supporting patients and their families with both private and public insurance are available to assist in accessing Lenmeldy. For more information, visit https://orchardassist.com.

As with many rare, life-threatening pediatric diseases, early detection and diagnosis is key to ensuring the best possible outcomes for patients, and Orchard Therapeutics supports efforts to expand newborn screening (NBS) for diseases like MLD which meet Wilson and Jungner criteria.

Currently, ten prospective NBS studies for MLD are active throughout the US, Europe, and the Middle East, with approximately 275,000 newborns screened to date. The data from these studies provide critical evidence to support applications for universal screening of MLD in the US and around the world.

Utilizing results from such studies, a multi-stakeholder working group is finalizing a nomination to add MLD to the US. Recommended Uniform Screening Panel (RUSP), a national guideline for NBS comprising a list of medical conditions for which the federal government recommends all newborns receive screening. States use the RUSP to help them decide which conditions to include in their NBS panels. Based on current timelines and assumptions, Orchard Therapeutics expects the nomination will be submitted in mid-year 2024.

MLD is a rare and life-threatening inherited disease of the body’s metabolic system estimated to occur in approximately one in every 100,000 live births based on existing literature. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity, and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at five years from onset is estimated at 50 percent and 44 percent at 10 years for juvenile patients.

Lenmeldy (atidarsagene autotemcel), formerly known as OTL-200, is the only approved therapy in the US for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD).