LibmeldyPre-symptomatic early onset (late infantile and early juvenile) metachromatic leukodystrophy (MLD)
New molecular entity
Development and Regulatory status
Mar 22Libmeldy dispersion for infusion available in the UK. Price for 1 infusion bag containing 2 million to 10 million cells/ml =£2875000.00 .
Mar 22NICE recommends use of atidarsagene .
Feb 22NHS England agrees a confidential deal with Orchard Therapeutics that will allow access to Libmeldy in the UK. List price is £2.8 million. The therapy has already been used commercially to treat two children in Germany and France, with a third child from the Middle East set to receive it in Italy .
Sep 21NICE will hold a second committee meeting in October to discuss Libmeldy .
Mar 21Be The Match BioTherapies expands their multi-year partnership with Orchard Therapeutics to include supply chain services in support of the upcoming commercial launch of Libmeldy. Be The Match BioTherapies will provide comprehensive support across the commercial supply chain for OTL 200, including support of the onboarding and training of apheresis centers, oversight of the autologous cell collection process and delivery of both harvested cells to the manufacturing site and gene corrected cells back to the qualified treatment center. Previously Be The Match BioTherapies supported cell collection for Orchard ’s clinical trials .
Mar 21FDA has also awarded OTL-200 Regenerative Medicine Advanced Therapy (RMAT) status .
Dec 20Has rare pediatric disease designation in US .
Dec 20Approved in EU and UK .
Nov 20US FDA has cleared the IND application for OTL-200 for MLD - the company have provided data on 39 pts including post-treatment follow-up data of up to 8 years. The company say this will help to determine a path to file a Biologics License Application for regulatory approval of OTL-200 in the U.S. The company also has applied for RMAT designation. 
Nov 20Orchard plans to file in the US and launch OTL-200 in Europe in H1 21 .
Oct 20Recommended for EU approval by CHMP - the full indication is "for the treatment of metachromatic leukodystrophy (MLD) characterized by biallelic mutations in the arysulfatase A (ARSA) gene leading to a reduction of the ARSA enzymatic activity: in children with late infantile or early juvenile forms, without clinical manifestations of the disease; in children with the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline.” It must be administered in a qualified treatment centre with experience in haematopoietic stem cell transplantation. 
Dec 19Filed in EU via centralised procedure. MAA will be reviewed under EMA´s accelerated assessment programme .
May 19following a positive MAA pre-submission meeting with the EMA, the planned submission has been brought forward to the first half of 2020; BLA submission in the US is expected about a year later .
Apr 19Orchard plans an MAA submission in 2020 followed by filing in the US .
Mar 19Has orphan drug status in EU .
Autologous gene therapy where CD34+ stem cells are taken from the patient and modified ex vivo using a lentiviral vector to insert a functional ARSA gene, then re-infused as a single dose after myeloablative therapy.
MLD is a rare and life threatening metabolic disorder caused by a mutation in the arylsulfatase-A (ARSA) gene . This leads to a deficiency in the ARSA enzyme, the accumulation of sulfatides and the progressive destruction of the myelin sheath in nerve cells. UK incidence is approximately 1 in 40,000 .
Pre-symptomatic early onset (late infantile and early juvenile) metachromatic leukodystrophy (MLD)
Trial or other data
Jul 21In draft guidance, Libmeldy is rejected for NHS use by NICE. The agency said that while there was evidence of a short-term benefit with Libmeldy (atidarsagene autotemcel or OTL-200), assumptions about its long-term effects are uncertain, making it unclear whether it will offer value for money to the NHS. The decision kicks off a comment period and further negotiations between the company, NICE and NHS England on the price of Libmeldy. Orchard has already offered a confidential discount on the therapy .
Oct 20Integrated clinical efficacy data for OTL 200 in metachromatic leukodystrophy reported by Orchard. The co-primary endpoints of the integrated efficacy analysis were Gross Motor Function Measure (GMFM) total score and ARSA activity, both evaluated at 2 years post-treatment. Results of this analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients. Data showed that pre-symptomatic late infantile (LI) and early juvenile (EJ) patients experienced significantly less deterioration in motor function at 2 years and 3 years post-treatment, vs. age and disease subtype-matched untreated patients (p=0.008). The mean difference between treated pre-symptomatic LI patients and age-matched untreated LI patients was 71.0% at year 2 and 79.8% at year 3. Similarly, the mean difference between treated pre-symptomatic EJ patients and age-matched untreated EJ patients was 52.4% at year 2 and 74.9% at year 3. A clear difference in GMFM total score was also noted between treated early-symptomatic EJ patients and age-matched untreated EJ patients (28.7% at year 2; p=0.350 and 43.9% at year 3; p=0.054). A statistically significant increase in ARSA activity in peripheral blood mononuclear cells was observed at 2 years post-treatment compared to pre-treatment in both pre-symptomatic patients (20.0-fold increase; p55) at chronological ages at which all 14 untreated comparator LI patients showed evidence of severe cognitive impairment (i.e. IQ/DQ below 55 and close to 0). Of the 10 surviving EJ patients, all 4 pre-symptomatic patients and 4 out of 6 early-symptomatic patients showed normal IQ/DQ throughout follow-up. In contrast, 11 out of 12 untreated EJ patients showed evidence of severe cognitive impairment during follow-up .
Oct 20The integrated analysis of results was based on data from 29 patients with early-onset MLD who were all treated with Libmeldy prepared as a fresh (non-cryopreserved) formulation: 20 patients were treated in the registrational study (NCT03392987; median 4 years follow-up); 9 patients were treated in expanded access programs (median 1.5 years follow-up). 16 patients had a diagnosis of LI MLD; 13 had a diagnosis of EJ MLD. At the time of treatment, 20 patients were deemed pre-symptomatic; 9 were deemed early-symptomatic. Clinical safety was evaluated in 35 patients with early-onset MLD: 29 patients from integrated efficacy analysis. 6 patients treated with the cryopreserved formulation of Libmeldy .
May 20PIII study (NCT03392987) has finished recruiting; timescales as originally planned .
Dec 19NCT03392987 - no UK trial sites 
Oct 19No other treatment is currently available apart from best supportive care. Allogeneic hematopoietic stem cell transplants in MLD patients show very limited benefit in patients with early-onset MLD .
Dec 18PIII study (NCT03392987) is recruiting .
Dec 17Open-label, PIII study to assess the safety and efficacy of GSK-2696274 in paediatric patients with pre-symptomatic early onset metachromatic leukodystrophy starts (NCT03392987). The single arm study intends to enrol approximately 10 patients in Italy. Primary outcome is change in Gross Motor Function Measure (GMFM) score at 24 months post gene-therapy. GMFM will evaluate subject´s ability to perform specific tasks in different positions. The scoring range is between 100 percent and 0 percent, with 0 percent corresponding to loss of all voluntary movement. Collection of these data is due to complete Aug 22 .