The next big tests for Argenx and its followers

Some believe that blocking FcRn has TNF-like potential, and J&J, Immunovant and UCB are all hot on Argenx’s heels.

Encouraging proof-of-concept data from Johnson & Johnson this month on nipocalimab in a rare autoimmune condition was the first of many readouts expected from this closely watched project this year. J&J is running one of the sector’s most extensive research programmes with a novel FcRn antagonist, a relatively new mechanism that comes with huge expectations.

Partly this is because blocking FcRn, which in turn dampens down IgG autoantibodies, might help treat a wide range of autoimmune conditions. Wells Fargo analysts recently asked whether the FcRn class might become bigger than the anti-TNFs, and grow to be worth more than $40bn. The valuation of the leading company in this space, Argenx, suggests that many believe this to be a distinct possibility.

Projects against FcRn, or neonatal Fc receptor, still have a lot to prove, however, in terms of safety and efficacy. The coming 12 months promises plenty of readouts.

Fast followers?

Argenx is leading this field with Vyvgart, an antibody fragment approved in myasthenia gravis and approaching regulators in immune thrombocytopenia and, pending positive data, in chronic inflammatory demyelinating polyneuropathy (CIDP). A hit in CIDP would be a huge win for the class and for the Belgian company. 

Its biggest rival, at least in terms of having the deepest pockets, is J&J. Having spent $6.5bn buying Momenta for nipocalimab in 2020, the pharma giant is now promising blockbuster potential.

Pivotal data are not due until 2024 and beyond, but this year will yield further proof-of-concept readouts, following the toplining of the Unity trial in pregnant adults at high risk of severe haemolytic disease of the foetus and newborn. HDFN occurs when the blood types of a pregnant woman and her foetus are incompatible.

Still, the big focus is on a phase 2 trial in rheumatoid arthritis, which is the first proper test of FcRn targeting in this potentially large setting. The study enriches for patients with autoantibodies and is in a TNF-refractory population.

The trial’s primary endpoint is change from baseline in DAS28-CRP at week 12. Wells Fargo analysts reckon the efficacy bar is a profile similar to Abbvie’s Rinvoq, with a delta of around -1.3 between placebo and treatment. A cleaner safety profile for nipocalimab would also be a big win.

Catalysts on the horizon for the FcRn mechanism
Setting Trial details/event Timing
Argenx and Vyvgart (IV approved, subcutaneous under review) 
CIDP Phase 3 Adhere trial (subcu) Q2'23
MG US approval of subcutaneous formulation Pdufa Jun 20, 2023
PV Phase 3 Address trial (subcu) H2'23
ITP Phase 3 Advance-SC  H2'23
PC-POTS Proof of concept phase 2 Q4'23
J&J and nipcocalimab (IV in ph3, subcutaneous in early development)
HDFN Open-label phase 2 Toplined positive Feb 2023
RA Proof-of-concept phase 2 H2'23
SLE Proof-of-concept phase 2 H2'23
wAIHA  Phase 2/3 Q4'23
MG  Phase 3 Q4'23
UCB and rozanolixizumab (subcutaneous infusion under review) 
MG  Potential US/EU approvals Q2'23
Immunovant and batoclimab (subcutaneous in ph3)
Graves' disease  Initial phase 2 results (trial not started) H2'23
MG China phase 3 (run by Harbour Biomed) H2'23
Immunovant and IMVT-1402 (subcutaneous in preclinical) 
TBC  Initial phase 1 data Mid-2023
Note: CIDP = chronic inflammatory demyelinating polyneuropathy; HDFN = haemolytic disease of the foetus and newborn; ITP = immune thrombocytopenia; MG = myasthenia gravis; PC-POTS = post-COVID-19 postural orthostatic tachycardia syndrome; PV = pemphigus vulgaris; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; wAIHA = warm autoimmune haemolytic anaemia. Source: Evaluate Pharma, & company communications.

UCB is likely to be the next to market later this year with rozanolixizumab, in MG. However, in MG the group seems to be prioritising a C5-targeted project, zilucoplan, which comes with a more convenient subcutaneous delivery than rozanolixizumab, which is available only as a subcutaneous infusion.

This formulation, and the poorest side-effect profile of the FcRn class, means rozanolixizumab is considered the least competitive in this field. A different scaffold to the other full MAbs in the FcRn pipeline might be at the root of the problem, Wells Fargo analysts suggest.

Perhaps this is why UCB is only pushing forward in rare, niche conditions where none of the other FcRn players is working, for now at least. An example is leucine-rich glioma inactivated 1 autoimmune encephalitis, where phase 2 data should emerge in 2024.

Safety and convenience

Immunovant is also in the FcRn queue with batoclimab, though global pivotal data, in MG, are not due until 2024 and in other settings even later; a pivotal MG study run by its China partner, Harbour Biomed, should emerge later this year. Other than early results in Graves' disease, initial readout from a potentially pivotal phase 2b CIDP trial due early next year is the next big catalyst for batoclimab.

The company is also poised to move into the clinic with a back-up designed to overcome a batoclimab toxicity finding. A hike in LDL cholesterol was detected in a thyroid eye disease trial, a result of the MAb's effect on albumin.

Albumin reduction has also been detected with UCB and J&J’s projects, and is one of the biggest concerns with the FcRn MAbs. More phase 3 data are needed to determine whether safety signals, in the shape of LDL increases, will follow. Vyvgart has not shown any impact on albumin.

While this potential toxicity is casting something of a shadow over Immunovant's projects the group is at least pushing forward with subcutaneous formulations. This could become an important differentiator versus IV candidates, particularly J&J's nipocalimab. J&J has said little about its subcutaneous efforts, which are presumably early, while Argenx is awaiting a delayed FDA decision on its subcutaneous project.

But while improving convenience is helpful, it is more important that these next few clinical readouts confirm the FcRn class's efficacy, and score full marks on safety. Otherwise hopes of TNF-like market sizes can be put to bed.

“Our diligence suggests 20-90% of patients with 'traditional' autoimmune diseases such as ulcerative colitis, Crohn's disease, multiple sclerosis, lupus and others could have disease driven partly or entirely by auto-antibodies where anti-FcRn therapies could be developed,” Wells Fargo wrote recently.

That huge range shows that there is much still to be learned about the potential of this mechanism. But, if nipocalimab impresses in RA, watch the value of all of these FcRn assets balloon.

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