In late May, Novartis AG's Avexis Inc. unit gained FDA approval for Zolgensma (onasemnogene neparvovec) to treat spinal muscular atrophy, and other companies are looking to follow suit developing drugs to treat a variety of diseases of the central nervous system (CNS). (See BioWorld, May 28, 2019.)

"Gene therapy gets around many of the drug delivery challenges that have plagued other treatment modalities like small molecules. In part, that is because it's a one-time approach, and also it really enables you to target the tissue bed of interest, in some cases direct to the CNS," Shankar Ramaswamy, chief business officer at Axovant Gene Therapies Ltd., told BioWorld Insight.

Injecting directly into the CNS offers challenges, for sure, but finding the right vector and optimal route of administration has become part of early stage development work. Once optimized, the direct administration can be more effective since "the number of cells you need to transduce, and as a consequence, the total vector genomes you have to deliver are much more modest typically for CNS diseases and direct to CNS delivery as compared to systemic diseases that require transduction of every diseased cells throughout the body," Ramaswamy noted.


One of Axovant's lead therapies, AXO-Lenti-PD, to treat Parkinson's disease, expresses tyrosine hydroxylase, cyclohydrolase 1 and aromatic L-amino acid decarboxylase, which are needed for the synthesis of levodopa and dopamine. The lentivirus-based gene therapy is a reengineered version of Axovant's proof-of-concept treatment, Prosavin. By reordering the genes in the vector, Axovant was able to produce a five- to 10-fold increase in production of levodopa and dopamine.

In June, Axovant, of Basel, Switzerland, got its first look at six-month data from the phase II Sunrise-PD study for two patients treated with the low dose of AXO-Lenti-PD who had an average improvement from baseline in UPDRS III (motor) OFF score of 17 points, an improvement of 29% from baseline. UPDRS Part II (activities of daily living) OFF score improved by approximately 20 points, while UPDRS Part IV (complications of therapy) OFF score improved by 3 points on average. The treatment also helped patients reduce their use of levodopa by 21% from baseline as well as improving other measures of Parkinson's disease.

The first patient in mid-dose cohort was dosed in April 2019, setting up a data release in the fourth quarter of 2019. If the data continue to be positive, Axovant plans on eventually proceeding to part B of the study, which will compare the treatment to sham-treated patients, which is scheduled to kick off in 2020.

Likewise, Voyager Therapeutics Inc., of Cambridge, Mass., is trying to tackle Parkinson's disease with its gene therapy, VY-AADC, which expresses aromatic L-amino acid decarboxylase that converts levodopa to dopamine.

In a phase Ib study, combined results from the 10 patients in the two highest dosed cohorts showed an increase from baseline in good ON time, defined as on-time without troublesome dyskinesia, by 2.4 hours per day at 12 months and 2.6 hours per day at 18 months.

Voyager has advanced the therapy into the phase II Restore-1 study. Based on the enrollment criteria for the study, seven of the 10 patients in the phase Ib study could have been enrolled in Restore-1. Those patients had an average improvement in good ON time of 2.8 hours at 12 months and 2.5 hours at 18 months.

Letting the immune cells do the work

Orchard Therapeutics Ltd. is taking a different approach to express proteins in the CNS, using ex vivo autologous gene therapy of hematopoietic stem cells to treat a variety of neurometabolic diseases. Some of the transfected stem cells that are put back into the patient develop into microglia, which act as scavengers in the CNS. For diseases where a protein can be expressed by one cell and taken up by nerve cells, the microglia can act as a conduit to get the protein expressed in the CNS.

"We are overexpressing that gene — so a bone marrow transplant in which you would engraft someone else's hematopoietic stem cells doesn't work consistently because you're not making enough enzyme from wild type cells," Bobby Gaspar, chief scientific officer at Orchard, told BioWorld Insight.

Orchard's lead gene therapy for neurometabolic diseases, OTL-200, treats metachromatic leukodystrophy, an inherited disease where mutated arylsulfatase-A (ARSA) leads to the accumulation of sulfatides and the progressive destruction of the myelin sheath in nerve cells.

Expression of ARSA after treatment with OTL-200 in nine patients led to prevention of disease onset or halted disease progression compared with historical untreated patients with early-onset disease. In six of the patients, gross motor performance was similar to that of normally developing children. And eight patients had protection from CNS demyelination with at least three patients having amelioration of peripheral nervous system abnormalities, with signs of remyelination.

The registration study used a fresh formulation of transfected stem cells, but to make the treatment more widely available, Orchard is testing a cryopreserved version of the cells that can be transported to the patient. The company has already treated four patients in the comparator study and plans to file with the EMA in the first half of 2020.

Orchard is starting with the EMA first because London-based Glaxosmithkline plc, which originally developed the treatment, was in more advanced conversations about the approval process than it was with the FDA.

London-based Orchard is using the same ex vivo autologous gene therapy strategy to treat mucopolysaccharidosis (MPS), a series of diseases in which the body is unable to breakdown sugar molecules, resulting in a build-up in the brain and in other body tissues.

OTL-201 for MPS-IIIA is expected to enter a clinical study later this year. OTL-202 is in preclinical development for MPS-IIIB. And in May, Orchard licensed a clinical-stage gene therapy for MPS-I, which will be referred to as OTL-203, from San Raffaele Telethon Institute for Gene Therapy, a joint venture between Ospedale San Raffaele and Fondazione Telethon. As of data presented in April, two patients had been treated long enough to observe expression of alpha-L-iduronidase, the protein mutated in MPS-1 patients.