Argenx Nears Phase III In Myasthenia Gravis

The reporting of positive topline Phase II results for a modified antibody fragment, efgartigimod, in myasthenia gravis by the Netherlands-based antibody-engineering biotech, argenx, has added to a growing list of new therapeutic approaches for the disorder.

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Antibodies against acetylcholine receptors in neuromuscular junctions are a cause of myasthenia gravis

The administration of argenx SE's modified antibody fragment, efgartigimod (ARGX-113), as four weekly doses on top of the usual standard of care of corticosteroids and immunomodulators, has been associated with a clinically meaningful and significant improvement in MG-ADL scores in a Phase II clinical study in 24 patients with generalized myasthenia gravis.

The Phase II study "catapults ARGX-113 forward on its timeline to Phase III clinical trials," company CEO Tim Van Hauwermeiren told analysts in a call on Dec. 11. The data are "truly transformational for our company." In noting the good tolerability of the antibody fragment, he said the safety profile of efgartigimod was a key differentiator for the product in the FcRn antagonist space.

There's been a flurry of development activity in the myasthenia gravis sector during 2017. Alexion Pharmaceuticals Inc.'s Soliris (eculizumab) was approved by the US FDA on Oct. 23, 2017, for a subset of patients with the condition – in adult patients with generalized myasthenia gravis who are anti-acetylcholine receptor antibody-positive. Soliris was also approved for generalized myasthenia gravis in Europe in August. (Also see "Alexion Seizes On New Soliris Indication, Business Development For Growth" - Scrip, 26 Oct, 2017.)

A chronic autoimmune neuromuscular disease, myasthenia gravis causes weakness in the skeletal muscles, which are responsible for breathing and moving parts of the body, including the arms and legs. A variety of other therapeutic approaches are in clinical development for the disorder, according to Informa Pharma Intelligence's Biomedtracker database (see exhibit one).

The efgartigimod results in myasthenia gravis were announced on the same day the Euronext- and Nasdaq-listed company also revealed positive initial Phase I/II results for another compound, ARGX-110, in acute myeloid leukemia and cutaneous T-cell lymphoma, at the American Society of Hematology (ASH) meeting; the company then said it was launching a public offering of $150m of its American Depositary Shares (ADSs).

Positive Topline Phase II

Efgartigimod was compared with placebo in the Phase II myasthenia gravis study, and the product's positive effects were seen for at least six weeks after the end of the infusions, Van Hauwermeiren said. The Myasthenia Gravis Activity of Daily Living (MG-ADL) score, a measure of disease activity, showed a rapid and sustained benefit associated with efgartigimod administration – disease improvement was seen one week after the first infusion.

In the trial, 83% of patients had clinically meaningful improvements of two or more points on the MG-ADL score, while 75% of patients achieving significant improvements in MG-ADL scores for six weeks, compared with 25% of patients in the placebo-treated arm of the study.

Patients in the treatment arm had rapid and deep reductions in total IgG levels, and disease improvement correlated with reductions in pathogenic IgG levels, the company added. Disease improvement was seen on other clinical efficacy scales used as secondary endpoints – Quantitative Myasthenia Garvis (QMG), Myasthenia Gravis Composite (MGC), and Myasthenia Gravis Quality of Life (MG-QoL15) scores, and the drug was found to be well tolerated. Full details of the study are expected to be presented at a scientific conference next year.

Efgartigimod is the Fc portion of an IgG1 antibody modified by argenx's technology that blocks the usual metabolic recycling of antibodies by binding to the recycling receptor FcRn. This blockade leads to a rapid decline in circulating levels of IgG auto-immune antibodies. In myasthenia gravis, these antibodies are thought to bind to acetylcholine receptors at neuromuscular junctions, preventing neuromuscular transmission and the recruitment of complement, both leading to severe muscle weakness.

There are around 55,000 patients with severe generalized myasthenia gravis in the US, with limited treatment options, noted Van Hauwermeiren. Apart from the recently approved Soliris, there had been no innovation in this space in the past 40 years, he added.

Efgartigimod is also being evaluated in two other conditions, in immune thrombocytopenia (ITP) and in pemphigus vulgaris (PV), that are also characterized by pathogenic auto-antibodies, with early results from both studies expected in the second half of 2018.

Currently therapies for myasthenia gravis include pyridostigmine, acetylcholinesterase inhibitors, higher-dose corticosteroids, immunosuppressive agents, and five consecutive days of plasma exchange. But the industry is evaluating several new approaches to treat the disorder.

Exhibit 1. Selected Products In Development For Myasthenia Gravis

Source: Biomedtracker

Company	Product	Target	Phase
Alexion Pharmaceuticals Inc.	Soliris (eculizumab)	complement proteins	approved
CuraVac inc	CV-MG01	immune system	Phase II/III
Catalyst Pharmaceuticals Inc.	Firdapse (amifampridine phosphate)	potassium channels	Phase II/III
Alpha Cancer Technologies	ACT-101	immune system	Phase II
argenx SE	ARGX-113	Fc receptors	II
GlaxoSmithKline PLC	Benlysta (belimumab)	BLyS receptors	II
Novartis AG	CFZ533	CD40	II
Ra Pharmaceuticals Inc.	RA101495	complement	II
UCB SA	UCB7665	Fc receptors	II
Uni Pennsylvania	MG vaccine	acetylcholine	preclinical