Pathway covered: FcRN
Companies mentioned: Immunovant, Momenta/JNJ, Alexion, Argenix
Immunovant stock (NASDAQ: IMVT) got hammered earlier this month on news of a clinical hold in its phase 2b trial for IMVT-1401, a treatment for thyroid eye disease (Graves Disease). The company said it voluntarily decided to pause dosing “out of an abundance of caution,” due to elevated total cholesterol. Apparently, cholesterol levels were not measured in the earlier Phase 1/2 trials. The company was hammered again 2 days ago when they released earnings, noting that a second trial in Warm AutoImmune Hemolytic Anemia (WAIHA) was also stopped. This is a bundle of bad news at several levels.
Level 1 – The drug.
IMVT-1401 is an anti-FcRN antibody, designed to prevent IgG from recycling through FcRN-mediated cell internalization and re-release. This is a heavily prosecuted target in disease indications, like Graves, that are thought to be driven by pathogenic autoantibodies. The thinking is pretty straightforward – preventing recycling of IgG will cause a drop in the entire antibody pool, including the pathogenic ones.
Here is some of the activity ongoing in this space:
One can appreciate pretty quickly that these programs are tightly focused on just a handful of rare diseases. IMVT-1401 is Immunovant’s only drug, and so a delay here could become a critical issue in the face of robust competition.
Level 2 – The target.
As noted, FcRN recycles IgG by binding and shunting the bound IgG through the endosomal pathway, thereby avoiding the lysosomal pathway that would break down the IgG rather than release it intact. A second protein uses the same trick – albumin. Notably, the IgG and albumin binding sites on FcRN are distinct, and anti-FcRN antibodies that block IgG uptake do not necessarily block albumin binding.
But IMVT-1401 from Immunovant appears to block both IgG and albumin, as does Nipocalimab from Momenta/JNJ. In their 2020 10-K, Immunovant revealed drops in serum albumin to the lower range of normal in their Phase 1 studies: “Dose-dependent and reversible albumin reductions were observed in the single-ascending and multiple-ascending dose cohorts … Mean reduction in albumin levels at day 28 were 20% in the 340 mg multiple-dose cohort, and 31% in the 680 mg multiple-dose cohort. For subjects in the 340 mg and 680 mg cohorts, the mean albumin levels at day 28 were 37.5 g/L and 32.4 g/L, respectively (normal range 36-51 g/L). These reductions were not associated with any AEs or clinical symptoms and did not lead to any study discontinuations.”
Why is this important?
Albumin is a globular protein with many functions – one function is to bind (non-specifically) to lipids in blood, including cholesterol and its fractions (HDL and LDL). Therefore, reduction in the total albumin concentration in blood can result in a change in the amount of cholesterol held within cells versus released into circulation (cholesterol efflux). This causes circulating cholesterol to rise. Indeed, low serum albumin is itself considered a risk factor for cardiovascular disease and stroke. Notably, albumin reduction to even lower levels (below 25 g/L) were reported by Momenta in their Nipocalimab clinical trials (corporate deck dated November 2019, Appendix) but we have not had reports of an impact on total cholesterol with this drug.
One thing to consider in passing is that Momenta claims their anti-FcRN specifically binds the IgG binding site and does not bind the albumin. This suggests that specificity may not be enough here to prevent an impact on albumin levels and, potentially, increase cholesterol. That would be a worst-case scenario- a drug class effect. As Jacob Pleith wrote a few weeks ago, “Immunovant’s decision yesterday to pause clinical trials of IMVT-1401 … sent ripples through the anti-FcRn space..”. In response to the Immunovant hold, Argenix quickly noted that they measured total cholesterol, HDL and LDL in two separate trials of Efgartigimod and saw no impact. So yes, the news caused ripples.
Level 3 – The indication.
A reasonable conclusion is that the problem is indication-specific, and indeed this was the assumption made until the announcement this week that the WAIHA trial was also paused along with the Graves Disease trial.
Graves is a thyroid condition and is associated with elevated cholesterol levels itself. Therefore, the combination of a drug effect on top of the disease effect causes concern. The measured increases were modest – LDL-C increased by ~ 65% in the 680mg dose, ~40% at the 340mg dose, and ~25% in the 255mg dose – but this was after only 12 weeks of treatment, in an indication that would likely require life-long chronic dosing. One might just shrug and say “pravastatin is free” so just give them statins and get on with it. That’s not a bad proposition for these patients.
All of this would make sense: the drug decreased circulating albumin, causing cholesterol to rise, in patients already at cardiovascular risk … but why stop the WAIHA trial? We have to await more data from the competing programs in other diseases to fully understand what is happening,
In the meantime, a prediction: the hold is in place while the company gets its regulatory ducks in a row, which is a smart de-risking move, then that hold will be lifted.