Argenx SE’s later-stage effort with antibody fragment efgartigimod in generalized myasthenia gravis (gMG) was designed with guidance from the phase II trial that showed 75% of patients had a durable response of at least six weeks. The result “gave us the idea to set up for individualized dosing, or personalized medicine,” the firm’s chief operating officer, Keith Woods, told investors during a conference call. The neonatal Fc receptor (FcRn) binder delivered top-line findings as expected. “We’re going to continue to work through the data, but the long and short of it is, get a patient into response fast, get that response deep, and then dial in their customized interval,” he said.

Argenx, of Breda, the Netherlands, plans to submit a BLA by the end of this year for efgartigimod in gMG, with data included from the global phase III experiment in 167 adults that met its primary endpoint defined as percentage of responders on the Myasthenia Gravis Activities of Daily Living (MG-ADL) score among acetylcholine receptor-antibody positive (AChR-Ab+) gMG patients. Responders are defined as having at least a two-point improvement on the MG-ADL score for at least four consecutive weeks.

Enrolled patients had a confirmed gMG diagnosis and an MG-ADL total score of five or greater. Patients were on a stable dose of at least one gMG treatment before randomization, including acetylcholinesterase inhibitors, corticosteroids or nonsteroidal immunosuppressive drugs, and were required to remain on that stable dose throughout the primary trial. Patients were eligible to enroll in Adapt regardless of antibody status.

Participants were randomized in a 1-to-1 ratio to receive efgartigimod or placebo for a total of 26 weeks as part of the primary trial. The study was designed to enable an individualized treatment approach with an initial treatment cycle followed by a variable number of subsequent treatment cycles. Those consisted of four infusions of efgartigimod (10 mg/kg I.V.) or placebo at weekly intervals. Retreatment with additional treatment cycles was begun according to clinical response.

In Adapt, 67.7% of AChR-Ab+ patients treated with efgartigimod achieved the primary endpoint compared with 29.7% on placebo (p<0.0001). Also, 63.1% of AChR-Ab+ patients responded to efgartigimod compared with 14.1% on placebo on the Quantitative Myasthenia Gravis (QMG) score (p<0.0001), with responder here defined as having at least a three-point improvement on the QMG score for at least four consecutive weeks. Forty percent of efgartigimod-treated AChR-Ab+ patients achieved minimal symptom expression defined as MG-ADL scores of 0 (symptom free) or 1, compared to 11.1% treated with placebo. Efgartigimod was well-tolerated with a safety profile that was comparable to placebo, the company said. Argenx (NASDAQ:ARGX) closed at $212.12, up $54.16, or 34%.

Near best-case scenario

Secondary endpoints turned up favorable, too, with Adapt yielding statistically significant differences in the efgartigimod arm for AChR-Ab+ patients compared to placebo in MG-ADL responders in the overall population, including both AChR-Ab+ and AChR-antibody-negative patients (p<0.0001). Statistical significance was met in time on trial in clinically meaningful improvement (MG-ADL improvement ≥2) (p=0.0001), Argenx said. Fast onset of response on MG-ADL score (onset observed in first two weeks) (p=0.0004) also hit the mark, though time to qualify for the retreatment endpoint fell short.

In AChR-Ab+ patients who met the primary endpoint, the majority showed a sustained response, including 88.6% who achieved a response for at least six weeks, 56.8% for at least eight weeks and 34.1% for at least 12 weeks. Of AChR-Ab+ patients who received a second treatment cycle, 70.6% were MG-ADL responders compared to 25.6% of placebo patients. Ninety percent of patients enrolled in the Adapt trial continued to the Adapt-Plus open-label extension (OLE) study.

The percentage of efgartigimod responders on the MG-ADL score in the AChR-antibody-negative patient population was consistent with the AChR-Ab+ patient population, but a greater placebo response showed up in that cohort. Argenx said detailed data from Adapt, which was conducted in North America, Europe and Japan, will be submitted for presentation at a future medical meeting.

Meanwhile, “the magnitude and speed of response impressed” Piper Sandler analyst Edward Tenthoff, who said in a report that he is “confident in FDA approval and U.S. launch next year.” Argenx plans to file for clearance with Japan’s regulatory authorities, too, in the first half of 2021. He said Adapt’s data “support the therapeutic hypothesis of immunoglobulin G [IgG] lowering, de-risking other efgartigimod studies,” including two phase III trials in immune thrombocytopenic purpura, a registrational phase II effort in chronic inflammatory demyelinating polyneuropathy, and a planned phase III bid in pemphigus vulgaris, due to start by the end of 2020. Argenx ended the first quarter with about $1.4 billion in cash.

FcRn is an IgG and albumin-binding protein expressed on the cell surface of most hematopoietic, endothelial and epithelial cells. It recycles IgG antibodies by shuttling them away from lysosomal degradation, which keeps pathogenic antibody levels in IgG-mediated diseases. Blocking FcRn results in decreased total IgG for better outcomes.

Benefiting from the Adapt findings was New York-based Immunovant Inc., shares of which (NASDAQ:IMVT) closed at $22.87, up $2.86, or 14%. The company is developing FcRn MG player IMVT-1401, and phase IIa data from the Ascend-MG trial are due in the third quarter of this year. Double-blind Ascend is enrolling 21 AChR+ MG patients, randomized to either 340 mg or 680 mg IMVT-1401 by subcutaneous injection weekly or placebo for six weeks. The trial has a six-week OLE part testing 340 mg given every other week. The results will provide the first placebo-controlled data for IMVT-1401 in patients with IgG-mediated disease and, SVB Leerink’s Thomas Smith speculated in a report, “the first data points in MG that could allow for some level of cross-trial comparison.” Momenta Pharmaceuticals Inc., of Cambridge, Mass., expects top-line interim data from the phase II Vivacity-MG study with nipocalimab in the third quarter of this year. The candidate is a fully human FcRn aglycosylated IgG monoclonal antibody.

Cowen analyst Yaron Werber called the Adapt data “close to the best-case scenario,” adding in a report that the outcome represents “strong confirmation of the positive phase II results, reaffirms efgartigimod’s superior clinical efficacy” vs. late-stage rozanolixizumab from UCB SA, of Brussels, “and further cements [Argenx’s] lead as the top FcRn inhibitor in the space.”

No Comments