Orphan drug designation to APB-102

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FDA has granted orphan drug designation to APB-102, a gene therapy for SOD1 ALS

Familial ALS, which represents about 10% of all ALS cases, is inherited as a dominant trait. About 20% of these cases arise from mutations in the gene encoding cytosolic Cu/Zn superoxide dismutase 1 (SOD1 ). An estimated 12 to 23% of patients with familial ALS and 1 to 3% of patients with sporadic ALS carry a mutation in this gene; 185 mutations in SOD1 have been identified. So if ALS is a rare disease, each mutation of SOD1 is an extremely improbable case, roughly one out of 100,000,000!

An elusive disease

Multiple mechanisms have been proposed to explain why mutant SOD1 proteins are neurotoxic, including the observation that mutant SOD1 acquires toxicity via conformational instability, misfolding, and some degree of aggregation. In turn, this activates multiple adverse events that include the unfolded protein response, endoplasmic reticulum (ER) stress, mitochondrial damage, heightened cellular excitability, impaired axonal transport, and some elements of apoptotic and necrotic cell death. Some data suggest that misfolded mutant SOD1 protein can spread from cell to cell in a prion-like fashion. Additionally, it is proposed that mutant SOD1 can cause toxic misfolding of wild-type SOD1.

Toward a therapy for ALS

The therapeutic silencing of SOD1 has been pursued by many groups, using various modalities: antisense oligonucleotides (ASOs), RNA interference (RNAi), viral vector-delivered RNAi, and CRISPR-Cas9. From a clinical perspective, one of the major disadvantages of ASOs and small interfering RNAs is the repeated dosing of the patients, whereas rAAV-mediated gene therapy (including gene transfer and RNAi-based gene silencing) relies on a one-time dosing paradigm.

side effects

Technological improvements allow the ASO doses to be less frequent than in the past, for example, by nusinersen (Spinraza), a recently approved ASO developed as a treatment for spinal muscular atrophy (SMA) by Biogen and Ionis Pharmaceuticals. With this drug, a typical patient would receive three intrathecal doses yearly upon completion of the loading doses In contrast, as an example, AVXS-101, a gene therapy treatment developed by AveXis as a treatment for SMA type 1, has a therapeutic effect for up to 24 months after a single intravenous injection of a rAAV9 vector. However AVXS-101 has side effects like asymptomatic liver enzyme elevations. These types of adverse events have been observed with other gene therapy trials.

What did Apic Bio?

A potential therapy for SOD1 is to suppress the expression of the mutant gene, whatever its mutation. Indeed SOD1 has a role and suppressing its expression, even the mutant one, will create side effects. Apic Bio investigated silencing of SOD1, using an adeno-associated virus (AAV) encoding an artificial microRNA (miRNA) that targeted SOD1 .

In recent years, Apic Bio and others have investigated this strategy in depth using various modalities. Apic Bio have previously demonstrated the preclinical characterization of this approach in cynomolgus macaques (Macaca fascicularis ) using an AAV serotype for delivery that has been shown to be safe in clinical trials. They optimized AAV delivery to the spinal cord by preimplantation of a catheter and placement of the subject with head down at 30° during intrathecal infusion. Results demonstrated efficient delivery and effective silencing of the SOD1 gene in motor neurons. These results support the notion that gene therapy with an artificial miRNA targeting SOD1 is safe and merits further development for the treatment of mutant SOD1 -linked ALS. They selected a recombinant adeno-associated viral vector serotype rh.10 (rAAVrh.10) because of its excellent central nervous system (CNS) transduction and safety profile in nonhuman primates. The presence of GFP in their vectors caused mild liver toxicity, as previously described, and a cellular immune response in two of eight animals. The fact that the immune response is not detected in all the injected animals can be explained by the early sacrifice point (22 days).

Orphan drug designation

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to APB-102, a gene therapy soon to be in clinical development for the treatment of genetic SOD1 amyotrophic lateral sclerosis (ALS). The U.S. FDA Orphan Drug program provides orphan designation to novel drugs that are intended for the treatment of rare diseases (those affecting fewer than 200,000 people in the United States). The designation provides sponsors with development and commercial incentives including seven years of market exclusivity in the US, consultation by FDA on clinical study design, potential for expedited drug development, and certain fee exemptions and reductions.

What is next?

Having an orphan drug designation in ALS is not a so big deal, several dozens drugs got it for ALS and it was withdrawn a few years later by FDA, when it was obvious they were not efficient at all. The important thing is now to wait for clinical trials. For that Apic Bio needs money, so probably they will solicit investors. And in this perspective, having an orphan drug designation will help them a lot.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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