FcRn Inhibitors to Treat Autoimmune Conditions
June 2020 (click here to download)
Many, but not all, autoimmune diseases are caused by the presence of antibodies against certain cells and tissues (“auto-antibodies”). These auto-antibodies bind to their targets and solicit the immune system to attack the cells and tissues to which they are bound.
A significant portion of auto-antibody-mediated autoimmune diseases are caused by immunoglobulin-G (aka IgG) auto-antibodies. Historical strategies to treat autoimmune diseases caused by IgGs have focused on the use of chronic steroids to mute the immune system, however, steroids are associated with a high side-effect burden. Another strategy that is effective, but inconvenient, is called plasmapheresis. Plasmapheresis is a semi-invasive procedure in which IgGs are externally filtered from the bloodstream.
The Manager, and others, have hypothesised that inhibition of FcRn (aka neonatal Fc receptor) might be effective in depleting IgG auto-antibodies, and in doing so might also ameliorate IgG-mediated auto-immune disease (see Exhibit A).
Exhibit A: How Targeting FcRn Depletes Autoantibodies
On 26th May 2020, the first definitive results were released that confirm the Manager’s hypothesis. Phase 3 results were released from a randomised, controlled study evaluating the effect of FcRn inhibition versus placebo in patients with myasthenia gravis, a disease characterised by auto-antibodies that destroy neuro-muscular signalling. The results confirmed what we had previously believed: that FcRn inhibition would safely deplete IgG antibodies and lead to amelioration of disease.
Although substantial evidence already existed supporting the safety and effectiveness of FcRn inhibition, this first ever positive phase 3 result for an FcRn inhibitor paves the way for what the Manager expects to be a string of favourable, mid-to-late stage studies that support numerous approvals for the FcRn inhibitor class over the coming years.
There are three stand-alone companies that have leading FcRn inhibitors, and their aggregate market value is approximately $15b. The markets to be addressed by the FcRn class are numerous and the Manager expects the aggregate addressable market by the class to be VERY large (>$10bn; see Exhibit B below). The Manager has its opinions on which companies are best positioned for various scenarios, and it has expectations for how other treatment modalities will impact uptake of the FcRn class, but ultimately the Manager thinks all three will work and become real drugs. In this context, the Manager thinks there remains meaningful value to be unlocked as these molecules progress through clinical development and ultimately get to market.
Source: Alex Munns of Driehaus Capital Management LLC.
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