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Spring 2022 - Safety

Neonatal Fc Receptor Blockers for Myasthenia Gravis: The Concept Is Now Reality

WHILE THE underlying cause of generalized myasthenia gravis (gMG) remains unclear, its pathogenesis is relatively straightforward: IgG autoantibodies target the nicotinic acetylcholine receptor (AChR) or other components of the postsynaptic motor end plate, breaking down motor nerve signaling to the muscle. MG can variously manifest as dyspnea, dysphagia, ptosis and fatigable muscle weakness affecting the neck and limbs. Bouts of severe muscular weakness can worsen to myasthenic crisis, with potentially life-threatening airway obstruction or respiratory failure.

In part because of the heterogeneous individual patient responses to available MG treatments, as well as a dearth of prospective clinical trials, there is no universally accepted MG management guideline. While acetylcholinesterase inhibitors, corticosteroids and thymectomy are generally considered first-line therapies for MG, many patients additionally require proven immunosuppressive therapies (ISTs) such as azathioprine, cyclosporine/tacrolimus or mycophenolate mofetil, or immunomodulatory therapies, including intravenous immune globulin (IVIG) or plasma exchange (PLEX).

In 2017, Soliris (emicizumab), Alexion Pharmaceuticals’ complement inhibitor product, received its fourth approved indication for treatment of AChRantibody positive (AChR-Ab+) MG. Prompted by this drug’s exceedingly high annualized cost, a number of large U.S. health insurers have established restrictive coverage policies aligned with enrollment criteria for the pivotal study: failed treatment for at least one year with two or more ISTs (either in combination or as monotherapy), or failure on at least one IST and required chronic IVIG or therapeutic PLEX.1,2 Other insurers have gone further, requiring the patient to have tried and failed from three to as many as six conventional MG treatment options before they will agree to cover Soliris.2 Between these restrictive coverage policies and a boxed warning citing the risk of life-threatening or fatal meningococcal infections, adoption of this drug for the management of MG has been limited. But four years later, in December 2021, a far more widely anticipated new MG immunotherapy arrived with the announcement by Dutch-Belgian biotechnology firm argenx that it received U.S. Food and Drug Administration (FDA) marketing approval for VYVGART (efgartigimod) for the treatment of the approximately 85 percent of MG patients who test positive for anti-AChR antibodies. VYVGART is the first of an entirely new drug category called neonatal Fc receptor (FcRn) blockers, which selectively reduce circulating levels of all four IgG subclasses, but have no effect on IgA, IgD, IgE or IgM levels.

IG recycling diagram

VYVGART comprises a human immunoglobulin G1 (IgG1)-derived Fc fragment designed to avidly bind to endothelial cell FcRn. In doing so, VYVGART thwarts FcRn’s physiologic function: to protect IgG from cellular digestion and “recycle” it back into the bloodstream, thereby extending the halflife of IgG to around 19 days to 23 days. As illustrated graphically in Figure 1, FcRn normally forms a complex with the constant Fc region of IgG taken up into endothelial cells from the circulation, and internalizes that IgG into endosomes, which protects it from degradation by cellular lysosomes. The endosome migrates to the cellular surface, where by exocytosis, the intact IgG contained within it is released back into the circulation. By outcompeting IgG to bind to intracellular FcRn, the VYVGART IgG1-derived Fc fragment blocks the natural IgG recycling pathway, resulting in much-accelerated IgG degradation and a sharp decline in circulating IgG levels.

Guided by results from IgG pharmacokinetic studies (Figure 2), argenx settled on evaluating a dosing schedule of 10 mg/kg of VYVGART once weekly for four weeks, with a minimum 50-day cycle period before reevaluating whether and when to start the next four dose VYVGART infusion series. The mechanism of action by which the drug acts to reduce MG-related weakness and disability is simplicity itself: By inducing a sharp, sustained reduction in total IgG, VYVGART equally reduces levels of anti-AChR IgG autoantibodies interfering with normal motor nerve conduction to affected muscles.

Diagram of efgartigimod effect after infusion

Phase III ADAPT Trial Findings

In mid-2021, findings from argenx’s pivotal ADAPT study revealed just how effective this treatment strategy can be. A total of 167 gMG patients, 77 percent of whom who were AChRAb+, were randomized to receive four consecutive weekly infusions of 10 mg/kg of efgartigimod or placebo. To qualify for enrollment, at screening patients had to meet the following criteria:

• A Myasthenia Gravis Foundation of America (MGFA) clinical classification of class II (mild) to class IV (severe) weakness other than or in addition to ocular weakness;

• A Myasthenia Gravis Activities of Daily Living (MG-ADL) score of ≥5 on an 8-point scale, where a higher score represents more severe disease;

• On a stable dose of MG therapy that included AChE inhibitors, steroids or nonsteroidal immunosuppressive therapies, either alone or in combination; and

• A baseline IgG level of at least 6 g/L.

The primary endpoint, assessed in the 129 study participants who were AChRAb+, was treatment response defined as a ≥2-point improvement from baseline for ≥4 consecutive weeks, with initial improvement by week 4 during the first treatment cycle. Each subsequent treatment cycle could begin only if 50 days or more had elapsed following initiation of the previous treatment cycle and 1) the total MG-ADL score was ≥5 points or 2) improvement in responders dropped to less than a 2-point reduction compared to the start of the cycle. The study’s secondary endpoint was the Quantitative Myasthenia Gravis (QMG) score, a 13-item scale that measures ocular, bulbar, respiratory and limb function, where treatment response was defined as a minimum three-point improvement over baseline for four consecutive weeks.

After a single treatment cycle, 68 percent (44/65) of AChR-Ab+ patients in the VYVGART group were MG-ADL responders, compared to 30 percent (19/64) of control group patients (odds ratio, 4.95; 95% confidence interval, 2.21, 11.53; p<0.0001). The gap in response rate favoring VYVGART was even wider for QMG responders: 63 percent versus 14 percent (p<0.0001). After two treatment cycles, the response rate climbed to 79 percent, with nearly 90 percent of these responders experiencing a duration of response exceeding six weeks (Figure 3).

Table showing ADAP trial results

ADAPT study investigators also reported that 40 percent of AChR-Ab+ VYVGART group patients achieved minimal symptom expression at some point during their first treatment cycle, compared to just 11 percent in the placebo group. A further analysis revealed that about 45 percent of all VYVGART treated MG patients, regardless of their AChR antibody status, were able to go eight or more weeks without retreatment following the last first cycle infusion. While there are no specific contraindications for its use, the approved product labeling warns that VYVGART may increase the risk of infection. In the ADAPT study, 10 percent of VYVGART-treated patients developed urinary tract infections, versus 5 percent of placebo-treated patients. While not statistically significant, the respective rates of respiratory tract infection were 33 percent and 29 percent. Additionally, a higher frequency of patients who received VYVGART compared to placebo were observed to have below-normal levels of white blood cell counts (12 percent versus 5 percent), lymphocyte counts (28 percent versus 19 percent) and neutrophil counts (13 percent versus 6 percent). While the majority of infections and hematologic abnormalities were graded mild to moderate in severity, clinicians are advised to delay VYVGART administration in patients with an active infection until it is resolved, and to monitor patients on treatment for clinical signs and symptoms of infection.

Nevertheless, argenx has reported no instances of dose-limiting toxicities in more than 600 healthy volunteers and patients treated across multiple clinical trials, including more than 125 patients who received VYVGART therapy longer than one year.

Where Will VYVGART Therapy Fit?

Now that it has secured marketing approval, the next question is obvious: For which MG patients is VYVGART an appropriate treatment option? The answer is far from straightforward, as physicians must weigh the merits and drawbacks of numerous available therapies and consider the highly individual patient response to these treatments, either alone or in combinations. Because of its cost — about $225,000 per year for a typical MG patient, according to argenx CEO Tim Van Hauwermeiren3 — it would not be unexpected if many health insurers choose to design coverage policies requiring patients to have failed to adequately respond to first-line MG treatments, and possibly one or more secondline immunosuppressive drug options as well. But beyond that, it remains to be seen which and how many established treatment options a patient candidate will need to give a fair trial and fail before any given insurer agrees to authorize VYVGART coverage. Of particular interest will be how providers prioritize VYVGART in relation to two well-established immunomodulatory MG therapies: IVIG and PLEX. Both modalities are prescribed in a number of clinical circumstances, including:4

• Short-term treatment in MG patients with life-threatening signs such as respiratory insufficiency or dysphagia;

• When other treatments are insufficiently effective;

• Circumstances when a rapid response to treatment is needed; and

• Prior to initiating corticosteroids if deemed necessary to prevent or minimize exacerbations.

While IVIG and PLEX are considered to be similarly effective, expert consensus suggests PLEX is more effective and works more quickly in patients with impending or manifest myasthenic crisis.4 Further, as PLEX works by physically removing plasma containing pathologic IgG autoantibodies against AChR or other motor end-plate receptors, which in essence is the same mechanism as VYVGART, both approaches act by reducing circulating levels of pathogenic anti-AChR antibodies.*

Yet between PLEX and IVIG, the latter treatment is used far more widely as maintenance therapy for refractory MG. While generally safe, PLEX exposes patients to significant risks of hemodynamic complications, infusion line-related infections and vascular access problems. Additionally, because the PLEX procedure requires highly trained apheresis nurses, it is not always readily accessible, particularly in smaller and more rural communities.

Where VYVGART ultimately fits into the MG treatment armamentarium in relation to IVIG and immunosuppressive drug options should become clearer with further clinical investigation and handson experience. But from the outset, VYVGART seems well-positioned to supplant PLEX for treatment of refractory MG, particularly for patients at increased risk for procedure-related complications or who live in communities without convenient access to PLEX services.

SC Delivery and More Indications

On the heels of its pivotal study of IV-administered VYVGART, argenx’s Phase III ADAPT-SC study is currently investigating a subcutaneous (SC) delivery form that can be self-administered by the patient at home. To facilitate SC administration of 1,000 mg of efgartigimod per weekly infusion session, argenx has in-licensed Halozyme Therapeutics’ recombinant hyaluronidase, also called PH20.

As the IV formulation of VYVGART must be infused weekly, the convenience-based rationale for offering an SC efgartigimod formulation is compelling — more so even than the case for developing SC formulations of polyvalent human IG to relieve patients with primary immunodeficiency disorders of the inconvenience of clinic visits every three weeks to four weeks for their IVIG infusions.

With adjustments to the weekly SC dose to account for differences in pharmacokinetic parameters, there is every reason to expect argenx’s investigational SC formulation of efgartigimod will achieve similar MG-ADL and QMG responder rates in AChR-Ab+ MG patients.

Both IV and SC efgartigimod formulations are now being evaluated in separate trials for the treatment of immune thrombocytopenic purpura (ITP). But in clinical trials currently investigating efgartigimod for chronic inflammatory demyelinating polyneuropathy (CIDP) and pemphigus vulgaris indications, argenx has elected to test only the SC version. Table 1 summarizes the current status and expected readout timing of topline results from these trials.

A Promising Answer for a Clear Need

According to argenx’s market research, the average person with MG is managed on more than two current treatments, yet 60 percent of patients report poor well-being due to debilitating muscle weakness and fatigue. Fully half are diagnosed with depression or anxiety in addition to MG, and half report they have completely stopped working due to the impact of their disease.3

The obvious unmet need for effective new MG treatment options, coupled with the evidence of VYVGART’s effectiveness and its relatively benign adverse event profile, are encouraging signs for this novel therapy and its more convenient SC self-administered successor product, both for managing acute MG exacerbations and chronic weakness. Added to this are solid proof-of-concept data that argenx already has in hand for CIDP, pemphigus and ITP, and the company’s announced ambition to develop and launch up to a dozen other autoimmune IgG-mediated indications by 2025. From all appearances, argenx and its unique FcRn blocker are just getting started.

*One mechanism by which IVIG is thought to work against MG and certain other IgG antibody-mediated disorders is via saturation of FcRn receptors, reducing the recycling of endogenous anti-AChR antibodies and in turn lowering their circulating plasma levels.

References

  1. SOLIRIS (emicizumab). Full prescribing information, revised November 2020. Alexion Pharmaceuticals, Inc.
  2. Levine A and Chambers J. How might US health plans cover efgartigimod for generalized myasthenia gravis? Lessons from the SPEC Database. Tufts Medical Center: Center for the Evaluation of Value and Risk in Health. Accessed at cevr.tuftsmedicalcenter.org/news/2021/how-might-us-health-plans-cover-efgartigimod-for-generalized-myasthenia-gravis-lessons-from-the-spec-database.
  3. Van Hauwermeiren T. VYVGART Approval (investor call). Dec. 17, 2021. Accessed at www.argenx.com/investors/events-presentations.yy.
  4. Sanders DB, Wolfe GI, Benatar, M, et al. International consensus guidance for management of myasthenia gravis. Neurology 2016;87:419-25.
Keith Berman, MPH, MBA
Keith Berman, MPH, MBA, is the founder of Health Research Associates, providing reimbursement consulting, business development and market research services to biopharmaceutical, blood product and medical device manufacturers and suppliers. He also serves as editor of International Blood/Plasma News, a blood products industry newsletter.