Thread by @GuiRamosMD

A New Year, New Therapies! An #IBD #medtwitter #tweetorial

As a late ring into the New Year, let’s explore Novel #IBD Agents coming to practice!

Our Aims:
1️⃣ Understand the Nomenclature
2️⃣ Revise Currently Available Drugs
3️⃣ Discuss Mechanisms & Adverse Events of Novel Agents

First, do we even know what are we treating ⁉️

Studies 🔬 within each one of these four key elements have unveiled pathways involved in #IBD pathogenesis.

Some of which are amendable for potential therapeutic intervention…

In summary...

It takes a genetically susceptible host 🧬 to be exposed to a specific environmental agent 🦠 that, through a weakened intestinal barrier ⚔️, will lead to an exaggerated Immune activation🔥, responsible for the phenotypes we see in clinical practice!

As most of the clinical findings are a consequence of Excessive Immune Response, most #IBD therapies target the Immune System, as classically exemplified by different Biologic agents!

But wait, are all IBD therapies “Biologics”?

Not necessarily! When discussing Novel Therapies we usually referring to two medication classes:

🍎BIOLOGICS: Proteins (Antibodies) from animals or cell lines. Usually Parenteral.

🍊SMALL MOLECULE INHIBITORS: Synthetic Drugs. Usually PO.

Any clues to recognizing which is which?
Pay attention to the END of their names!

tofacit-INIB (Kinase Inhibitor);
ozan-IMOD (Immunomodulator).

Biologic Names are a bit more complex. Let’s break it down:
1. Prefix – 2. Target Site – 3. Source – 4. Class

A few examples:
Inf (Prefix) – LI (Immune System) – XI (Chimeric) – MAB (monoclonal antibody)

USTE – KIN (Interleukin) – U (Human) – mab

BONUS POINTS
🐭 Chimeric = The Antibody’s Fc is Murine & the Variable Region (Fab) Human.
🧑🏻‍🎤“Humanized” = if the Fab amino acids are >85% similar to human.

This is ❌ the same as Immunogenicity! Eg. ADA is more immunogenic than Vedo 🤷🏻‍♂️ Mech of Action is also important!

👴🏼 Old but Gold 💰

Before we start talking about what’s New, let’s quickly review the oldies with a twist in the end!

This excellent table by @bruce_sands1 on Available meds for treating #crohnsdisease & #ulcerativecolitis

🧓🏼 Old is the new New? 👶🏻

Existing therapies have new SubCut formulations! Both Vedolizumab & the Infliximab Biosimilar CT-P13!

Simplifying the mode of administration may decrease costs and make these therapies more accessible (and convenient) to patients!

🌟 Now it’s time for the real New! 🌟

This is a Summary of all the mechanisms of action of Current and Novel #IBD Therapies!

😱 Don’t run away just yet! Hold with me, it will be clear soon!

Let’s go from the OUTSIDE IN…

1️⃣ LYMPH NODE (LN)
Sphingosine-1-phosphate receptor (S1PR) modulators:

S1PR allow Tcells to leave LN. Tcells can momentarily “turn-off” these receptors in order to stay in the LN to communicate with other immune cells.

We explore that mechanism, “trapping” Tcells in the LN!

Eg. Ozanimod (S1P1,5), Etrasimod (S1P1,4,5)

🤢 PROBLEM 🤢
S1PR are common and modulate different functions!
Hence, we may see numerous side effects due to nonspecific binding to other receptors!

Eg: Bradycardia, AV Block (S1P2,3); Hypertension (S1P2,3)

2️⃣ LEUKOCYTE MIGRATION – Endothelium
- SHP647:
mab against MADCAM-1 in endothelial cells, which is a4b7 binding partner!

🤔 Curiosity 🤔
Pts w PSC have aberrant MADCAM-1 expression in the liver. Good to keep in mind for the PSC-IBD population as these agents become available!

3️⃣ LEUKOCYTE MIGRATION – Tcells
- Etrolizumab:
mab agains Beta-7 subunit

Like Vedo, prevents cells from 🚪entering the mucosa (α4β7) but ALSO inhibits 📌retention (αϵβ7), by blocking αϵ integrin/e-cadherin in the gut epithelium.

‼️Interesting ‼️

Patients with Higher expression of aE integrin or Granzyme A (characteristic enzyme of αϵβ7+ lymphocytes) have demonstrated better response to Etro.

May be a good way to decide who to start this drug in, huh? #PrecisionMedicine

4️⃣ EXTRACELLULAR TARGETS – IL23
Eg. Mirikizumab; Brazikumab; Risankizumab; Tindrakizumab; Guselkumab
IgG4, IgG2, IgG1 (x3) antibodies (respectively).

Ustekinumab ❌p40, shared by IL-12/IL-23. Most beneficial effects of this inhibition, however, have been attributed to 🚫IL-23!

✴️ The New Kids on the Block aim specifically at IL-23 by targeting the p19.​ ✴️

There might be an extra benefit of targeting exclusively IL23:
In 🐁 models, selective ❌ IL23 is protective against Colorectal Cancer compared to blocking IL12, which can be cancer inducing.

5️⃣ INTRACELLULAR TARGETS – Janus Kinase Inhibitors
Killing 🐦🐦 with 🌰

JAK are enzymes linked to cytokine receptors, responsible for transmitting the membrane signals through the cytoplasm to the nucleus.

⚠️Highly effective, but the MOA comes with issues ⚠️
Other molecules also use JAK for signaling, leading to undesired AE.

New therapies (Filgotinib -JAK1, Upacitinib-JAK1) are more specific to avoid AEs!

6️⃣ INTRANUCLEAR TARGETS – microRNA
We’re now 🔍 into the nucleus!

ABX464 Phase 1 results were presented @DDWMeeting last year!
This small molecule promotes miRNA124 Expression, which in turn has anti-inflammatory properties!

Looking forward to seeing how future trials!

7️⃣ CELLULAR THERAPY – Stem Cells
Let’s add some fresh blood🩸to the game!

Stem Cells are being studied for penetrating CD. These cells have immunomodulatory properties & can differentiate into bone, cartilage and fat for repair!

Optimal delivery💉 method is yet to be defined!

8️⃣ CELLULAR THERAPY – Regulatory T Cells

🥉Last but not least, the use of autologous Regulatory T cells (expanded in-vitro prior to being re-injected in patient) is currently on early stages of development!

gut.bmj.com/content/early/…

🛸 FUTURE PERSPECTIVES 🚀
The arsenal for #IBD treatment is getting bigger every year!
And there is more coming 💩🦠

Future studies should focus on understanding How to choose the right therapy for the right Patient!

I hope this was helpful! Thanks for hanging in with me!