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Summer 2023 - Vaccines

FcRn Antagonists: A Panoply of Autoimmune Disorders Now in the Development Pipeline

Specifically designed to blockade the physiologic IgG recycling function of endothelial cell neonatal crystallizable fragment receptor (FcRn), FcRn antagonists represent a new class of monoclonal antibody (mAb)-based drugs that have been shown to mediate a sharp, dose-dependent reduction in circulating IgG levels. Thanks to this unique immunomodulatory functionality, FcRn antagonists are now recognized as among the most promising — and intensively competitive — new therapeutic modalities to emerge in years.

One product recently secured U.S. Food and Drug Administration (FDA) approval for the treatment of generalized myasthenia gravis (gMG), a classic autoantibody-mediated neuromuscular disorder. In total, four investigational FcRn antagonists are currently being clinically evaluated as potential treatments for a remarkable range of mostly rare autoantibody-mediated neurological, hematological, rheumatologic, endocrinologic, dermatologic and renal disorders.

First identified for its role in the facilitated transport of IgG from mother to fetus or neonate (thus its name), FcRn complexes with the constant tail (Fc) region of endocytosed plasma IgG and internalizes it into recycling endosomes, thus protecting IgG from degradation by cellular lysosomes. Endosomal FcRn-bound IgG is rereleased into the circulation by exocytosis, while unbound IgG is trafficked to lysosomes for degradation (Figure).

Figure. 1) Endothelial Cell FcRn-Mediated Recycling of Plasma IgG and 2) Blockade of Plasma IgG Recycling by FcRn Antagonist (Anti-FcRn Antibody)

Figure. 1. Endothelial Cell FcRn-Mediated Recycling of Plasma IgG and 2. Blockade of Plasma IgG Recycling by FcRn Antagonist (Anti-FcRn Antibody)

In essence, FcRn rescues IgG from cellular catabolism, which accounts for the prolonged 19- to 23-day average IgG half-life in the circulation. The functionality of FcRn is also indiscriminate: The half-lives of both physiologic and pathogenic IgG antibodies are extended by this endothelial recycling mechanism.

FcRn antagonists are designed to outcompete IgG for the Fc receptor epitope on FcRn. As a result of this blockade of FcRn functionality, more IgG is degraded in lysosomes and less is protected within endosomes and recycled into the circulation. At clinically tested doses, FcRn antagonists can reduce circulating IgG — including pathogenic IgG autoantibodies — by as much as 80 percent or more.

While the FcRn-targeted mechanism of action is novel, the therapeutic principle of reducing pathophysiologic IgG levels to ameliorate disease symptoms or induce remission is not new at all: Therapeutic plasma exchange (TPE or PLEX), generally with five percent albumin replacement, has been used as first- or second-line therapy for decades to acutely reduce serum IgG levels in a diverse spectrum of disorders that are known or thought to be IgG-mediated.1 But serious clinical investigation of potential indications for TPE has never happened, largely due to challenges relating to vascular access, limited availability of equipment and trained nurse operators and, perhaps most importantly, a lack of adequate financial return potential to justify the large investments required to organize and conduct well-controlled trials.

None of these barriers apply with FcRn antagonists. As of early 2023, four well-financed drug developers are collectively investigating their proprietary FcRn antagonists for the treatment of at least 22 known or presumptive antibody-mediated autoimmune disorders (Table).

Table. Current Clinical Trials with Investigational and Approved FcRn Antagonists

Neurological/neuromuscular FcRn antagonist (sponsor) – Development status
Myasthenia gravis Efgartigimod SC (argenx) — Phase III completed1
Batoclimab SC (Immunovant) — Phase III
Nipocalimab IV (Janssen) — Phase III
Rozanolixizumab SC (UCB) — BLA accepted2
Chronic inflammatory demyelinating polyneuropathy (CIDP) Efgartigimod SC (argenx) — Phase III
Batoclimab SC (Immunovant) — Phase II
Nipocalimab IV (Janssen) — Phase II/III
Rozanolixizumab SC (UCB) — Phase II completed
Guillain-Barré syndrome Efgartigimod IV4 (argenx) — Phase II
Idiopathic inflammatory myopathies (myositis) Efgartigimod SC (argenx) — Phase II/III
Nipocalimab IV — Phase II
Autoimmune encephalitis3 Rozanolixizumab SC (UCB) — Phase II
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOG-AD) Rozanolixizumab SC (UCB) — Phase III
Post-COVID-19 postural orthostatic tachycardia syndrome (POTS) Efgartigimod IV4 (argenx) — Phase 2
Hematological
Primary immune thrombocytopenia (ITP) Efgartigimod SC (argenx) — Phase III
Rozanolixizumab SC (UCB) — Phase II completed
Warm autoimmune hemolytic anemia (wAIHA) Nipocalimab IV (Janssen) — Phase II/III
Hemolytic disease of the fetus and newborn (HDFN) Nipocalimab IV (Janssen) — Phase II/III
Rheumatologic
Sjögren’s syndrome Efgartigimod IV4 (argenx) — Phase II
Nipocalimab IV (Janssen) — Phase II
Systemic lupus erythematosus (SLE) Nipocalimab IV (Janssen) — Phase II
Rheumatoid arthritis Nipocalimab IV (Janssen) — Phase II
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis Efgartigimod (argenx) — Proof-of-concept trial pending
Severe fibromyalgia syndrome Rozanolixizumab (UCB) — Phase II
Dermatologic
Pemphigus vulgaris/foliaceus Efgartigimod SC (argenx) — Phase III
Bullous pemphigoid Efgartigimod SC (argenx) — Phase II/III
Endocrinological
Thyroid eye disease (TED) Efgartigimod (argenx) — Registrational trial pending
Batoclimab SC (Immunovant) — Phase III
Graves’ disease Batoclimab SC (Immunovant) — Phase II
Renal
Lupus nephritis Efgartigimod IV4 (argenx) — Phase II
Nipocalimab IV (Janssen) — Phase II
Membranous nephropathy Efgartigimod IV4 (argenx) — Phase II
Antibody-mediated renal allograft rejection Efgartigimod (argenx) — Proof-of-concept trial pending

BLA = biologics license application
IV = intravenous
SC = subcutaneous

1. Intravenously administered VYVGART (efgartigimod) received FDA approval for MG in December 2021.
2. LA decision by the FDA is expected in the second half of 2023.
3. Leucine-rich glioma inactivated 1 autoimmune encephalitis.
4. VYVGART (efgartigimod alfa-fcab) injection, for intravenous use.

Argenx (efgartigimod)

By now, most clinicians who manage gMG patients are familiar with argenx’ intravenously administered VYVGART (efgartigimod), approved for treatment of this indication in December 2021 and currently the only available FcRn antagonist. Efgartigimod is a human IgG1 fragment specifically engineered to increase its affinity to FcRn and thus outcompete endogenous IgG and prevent IgG recycling.

A more convenient self-administered subcutaneous (SC) delivery form of efgartigimod is currently being clinically evaluated in a 360-subject trial for the treatment of gMG. SC efgartigimod incorporates Halozyme Therapeutics’ patented recombinant human hyaluronidase (rHuPH20) enzyme, which is incorporated into a number of approved biologics to facilitate their dispersion and absorption in circumstances where rapid, high-volume SC infusion is desirable.

Intravenous or SC efgartigimod is additionally being tested for the treatment of a dozen other rare or uncommon autoimmune disorders, including chronic inflammatory demyelinating polyneuropathy (CIDP), immune thrombocytopenic purpura (ITP), pemphigus vulgaris or foliaceus, bullous pemphigoid, myositis, post-COVID-19 postural orthostatic tachycardia syndrome (PC-POTS), primary Sjögren’s syndrome, membranous nephropathy, thyroid eye disease (TED), lupus nephritis, ANCA-associated vasculitis, and antibody-mediated renal allograft rejection. The company anticipates data readouts from its late-stage CIDP, ITP and pemphigus trials later this year, and its myositis and bullous pemphigoid trials in 2024.

“Efgartigimod is a once-in-a-decade drug, the type of drug which builds companies,” argenx Chief Financial Officer Karl Gubitz told attendees at a recent investor conference. Numerous investors clearly agree with his assessment: Solely on the strength of efgartigimod’s anticipated commercial potential, to date this Dutch/Belgian biotechnology firm has raised more than $4.3 billion from offerings of equity securities, and currently boasts a market capitalization that exceeds $20 billion.

Janssen Pharmaceutical (nipocalimab)

This Johnson & Johnson company acquired nipocalimab, a fully human anti-FcRn IgG1 mAb, in its $6.5 billion acquisition of Momenta Pharmaceuticals in 2020. Janssen’s clinical development program is no less ambitious than that of argenx, with nipocalimab currently being clinically tested for the treatment of at least 10 rare autoimmune disorders, including gMG, CIDP, idiopathic inflammatory myopathies, Sjögren’s syndrome and warm autoimmune hemolytic anemia (wAIHA). Phase III trial results from the gMG and wAIHA studies are expected in the fourth quarter of 2023.

“We have seen in clinical trials that nipocalimab can remove [pathogenic autoantibody] IgG without interfering with cellular immunity or other antibodies such as IgM or IgA, which are important immune protectors,” said Janssen’s Senior Director and Global Compound Development Team Leader Hong Sun, MD, PhD.

In February, Janssen announced positive topline results from its proof-of-concept Phase II open-label clinical trial of once-weekly nipocalimab for the treatment of pregnant women at high risk for severe hemolytic disease of the fetus and newborn (HDFN); the trial met the primary endpoint, with the majority of pregnant patients who received nipocalimab achieving a live birth at ≥32 weeks of gestational age, without the need for risky intrauterine transfusion throughout their entire pregnancy.2

Janssen also believes its FcRn antagonist may be an effective treatment for selected subgroups of two other relatively common autoimmune disorders: rheumatoid arthritis (RA), which affects well over one million U.S. adults,3 and systemic lupus erythematosus (SLE), which is believed to affect more than 200,000 Americans.4 Results from its Phase II RA and SLE proof-of-concept trials are expected in the second half of 2023.

Immunovant (batoclimab and IMVT-1402)

This clinical-stage biopharmaceutical company has raised more than $900 million to develop its lead product batoclimab (IMVT-1401), a fully human IgG1-based FcRn antagonist. Expected to shortly follow batoclimab into the clinic is a second product (IMVT-1402), which has been engineered to minimize interference with albumin recycling.*

Of particular interest, Immunovant has initiated the first anti-FcRn treatment program targeting Grave’s disease. A significant share of the more than 100,000 persons diagnosed each year with Graves’ disease remain difficult to control and symptomatic with anti-thyroid drug (ATD) therapy. Other treatment options, including radioiodine and surgery, present their own significant risks, primarily the risk of hypothyroidism and fatigue. Pathogenic autoantibodies are the known etiologic agent in most cases, in particular autoantibodies causing overstimulation of the thyroid stimulating hormone receptor (TSHR).5

Graves’ patients on ATD therapy with elevated stimulatory TSHR antibodies and active disease are receiving weekly batoclimab over 24 weeks. The primary endpoint is the proportion of participants who achieve normalization of T3 and T4 with an ATD dose less than the baseline dose. Preliminary results from this Phase II trial are expected in the second half of 2023.

Clinical trials are additionally in progress to evaluate SC batoclimab for the treatment of CIDP, gMG and TED. A dose-dependent response was documented in a post-hoc analysis of findings from a placebo-controlled Phase IIb trial, with more than 40 percent of patients at the highest 680 mg weekly dose experiencing a ≥2 mm proptosis reduction in the study eye without a corresponding increase in proptosis of the nonstudy eye. Currently underway are a pair of Phase III trials in patients with moderate to severe TED, or Graves’ disease evidenced by positive anti-TSHR antibody titers, with initial findings expected in the first half of 2025.

Immunovant expects to release new topline results from its currently ongoing studies about every six months between the second half of 2023 and the first half of 2025. Subject to demonstration of favorable safety and IgG-lowering activity in Phase I trials, the company also plans to evaluate its second-generation, albumin-sparing FcRn antagonist (IMVT-1402) for treatment of several of these and potentially other indications.

UCB (rozanolixizumab; UCB7665)

With annual sales of $6 billion, this Belgian biopharmaceutical company is developing its own fully humanized IgG4 FcRn antagonist product, rozanolixizumab (UCB7665). Earlier this year, a biologics license application was submitted to FDA seeking approval for an SC delivery form of UCB7665 for the treatment of moderate to severe gMG, anchored by results from a randomized, double-blinded, placebo-controlled Phase III trial in 200 subjects enrolled at more than 90 sites in 17 countries. UCB is additionally enrolling 30 gMG patients in a study to evaluate two alternative methods of self-administering UCB7665 subcutaneously — by syringe driver or manual push.

The company has also recently completed a 43-subject Phase III trial evaluating the long-term safety, tolerability and efficacy of UCB7665 for the treatment of persistent or chronic ITP. A prior Phase II study documented good tolerability and clinically relevant improvements in platelet count (≥50 x 109/liter) in all UCB7665 dosage groups. “These data build on the growing body of evidence that targeting the FcRn pathway has the potential to treat people with rare IgG autoantibody-mediated diseases such as primary ITP,” said co-investigator and noted ITP research authority James Bussel, MD.6

In addition, UCB is investigating UCB7665 for the treatment of myelin oligodendrocyte glycoprotein (MOG) antibody disease (Phase III), as well as autoimmune encephalitis and severe fibromyalgia syndrome (both Phase II). Topline results from all three trials are expected in 2024.

Of all the prospective clinical uses for FcRn antagonists now in clinical development, fibromyalgia syndrome is particularly interesting because historically no clear underlying cause had been identified to explain the characteristic widespread musculoskeletal pain that is typically accompanied by fatigue, sleep, memory and mood issues. What is known is that fibromyalgia tends to run in families, and is sometimes triggered or aggravated by an infection or a traumatic physical or emotional event.

However, very recent research has identified a subset of fibromyalgia patients with elevated levels of anti-satellite glial cell IgG, and these antibodies appear to be associated with more severe fibromyalgia symptomology.7 UCB’s randomized, placebo-controlled, double-blind proof-of-concept fibromyalgia study incorporates a crossover design and will enroll a total of 60 subjects. The primary outcome measure is the average score on the Brief Pain Inventory short form after 12 weeks of treatment.

A Promising Future for FcRn Antagonists

In a recent review article, one apheresis therapy expert astutely described FcRn antagonists as “plasma exchange in a bottle.”8 As both treatment modalities act by acutely reducing titers of pathologic IgG, it is not surprising that FcRn antagonists are being investigated for a few clinical indications for which TPE is long-established as first- or second-line therapy, most notably gMG and CIDP.

But advancement of clinical research on FcRn antagonists is not constrained by the inherent limitations that have discouraged broader investigation of potential TPE uses. TPE is a roughly two-hour procedure involving the use of sophisticated equipment positioned in dedicated hospital spaces and operated by specially trained nurses. Vascular access is often challenging and can require surgical placement of ports. And perhaps the biggest barrier to TPE clinical research of the sophistication and scale needed to secure FDA approvals is a manufacturer revenue stream from sale of the enabling technology that simply cannot justify the very high cost of these trials.

The converse is true for FcRn antagonists, which are simple to administer in an outpatient setting (or may be self-administered by the patient at home), and whose potential to generate hundreds of millions or even billions of dollars in revenue can easily justify the large investments required to design, conduct and analyze clinical trial findings.

The impressive development pipelines of each of the four major competitors speak volumes about their belief that diseases mediated by pathophysiologic IgG autoantibodies, including many for which these “bad” autoantibodies haven’t yet been identified, can be effectively managed by simply reducing their circulating titers. The global medical community will soon learn if this confidence bears out in real-world results.


* In addition to IgG, FcRn complexes with circulating albumin to mediate albumin recycling.

References

  1. Connelly-Smith L, Alquist CR, Aqui NA, et al. Guidelines on the use of therapeutic apheresis in clinical practice — Evidence-based approach from the Writing Committee of the American Society for Apheresis: The Ninth Special Issue. J Clin Apher 2023 Apr;38(2):77-278.
  2. Janssen Global Services, LLC. Feb. 6, 2023. Accessed at www.janssen.com/janssen-reports-positive-topline-phase-2-results-nipocalimab-pregnant-individuals-high-risk-severe.
  3. Hunter TM, Boytsov NN, Zhang X, et al. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004-2014. Rheumatol Int 2017 Sep;37(9):1551-7.
  4. Izmirly PM, Parton H, Wang L, et al. Prevalence of SLE in the United States: Estimated from a meta-analysis of the CDC and National Lupus Registries. Arthritis Rheumatol 2021 Jun;73(6):991-6.
  5. Smith TJ. TSHR as a therapeutic target in Graves’ disease. Expert Opin Ther Targets 2017 Apr;2194):427-32.
  6. UCB. Final Phase II results for UCB’s rozanolixizumab in primary immune thrombocytopenia (ITP) published in Blood Advances (9/9/2020). Accessed at www.ucb.com/stories-media/Press-Releases/article/Final-Phase-II-Results-for-UCB-s-Rozanolixizumab-in-Primary-Immune-Thrombocytopenia-ITP-Published-in-Blood-Advances.
  7. Krock E, Morado-Urbina CE, Menezes J, et al. Fibromyalgia patients with elevated levels of antisatellite glia cell immunoglobulin G antibodies present with more severe symptoms. Pain 2023 Mar 22 (online ahead of print).
  8. Tran M. “Plasma exchange in a bottle:” An overview of efgartigimod for apheresis practitioners. J Clin Apher Oct;37(5):512-5.
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.