DLV-2026-002 Tier 2 dossier Public excerpt - 2 of 7 sections May 2026 refresh

TPO Receptor Agonists vs FcRn Inhibitors in Immune Thrombocytopenia

Mechanistic distinction, clinical signal comparison, and the off-treatment durability gap. Indication scope: 2L+ adult chronic ITP. May 2026 refresh incorporates Wayrilz (rilzabrutinib) FDA approval (2025-08-29) as a third mechanistic class.

Hematology Medical Affairs / MSL Phase 2-3 RCT data Mechanism analysis May 2026 refresh

Section 1 - Executive summary

Different problems, no class superiority on durability

Central thesis - council-reviewed - May 2026 refresh

TPO receptor agonists, FcRn inhibitors, and (since 2025-08-29) the BTK inhibitor rilzabrutinib solve different biological problems in ITP, but none has been demonstrated to modify the underlying autoimmune disease.

TPO-RAs achieve superior on-treatment response by overcoming platelet destruction at the production level. FcRn inhibitors reduce the destruction signal (pathogenic IgG) more directly, with lower clinical efficacy and uncharacterised off-treatment durability. Rilzabrutinib (Wayrilz, FDA-approved August 2025) acts upstream on B-cell signalling and macrophage FcγR activation - LUNA 3 shows 23% durable response vs 0% placebo. The decisive cross-class question - which mechanism enables durable remission off therapy - remains open for both FcRn inhibitors and BTKi.

79%

Eltrombopag response RAISE Phase 3 [RCT]

22%

Efgartigimod sustained ADVANCE IV [RCT]

30.5%

TPO-RA off-treatment remission (TAPER) [Prospective single-arm Phase II]

N/D

FcRn off-treatment durability - not published

Evidence tier system used throughout this dossier

RCTRandomised controlled trial. Highest evidence.
IndirectMechanistic inference or cross-trial comparison. No head-to-head RCT.
RWEReal-world evidence. Hypothesis-generating.
EditorialAnalytical interpretation. Not a published conclusion.

No head-to-head RCT between TPO-RAs and FcRn inhibitors exists. All cross-class comparisons in this dossier are Indirect.

1.1 Key findings at a glance

Domain	TPO-RAs	FcRn inhibitors	Rilzabrutinib (BTKi)	Verdict
Mechanism layer	Downstream - stimulates platelet production	Upstream - increases IgG catabolism, reducing circulating pathogenic IgG	Dual - B-cell BTK + macrophage FcγR signalling	Three distinct targets
On-treatment response	38-79% RCT	5-22% RCT	64% initial 12w response RCT	TPO-RA + BTKi lead
Durable response (per-trial primary endpoint)	52% continuous response ≥25w on-treatment (EXTEND OLE) RCT	22% sustained platelet response ≥4 of last 6w (ADVANCE IV) RCT	23% ≥50×10⁹/L on ≥8 of last 12w, vs 0% pbo (LUNA 3) RCT	Three distinct endpoints; not directly comparable
Time to response	1-2 weeks RCT	7-8 days RCT	15 days (responders) RCT	FcRn fastest
Off-treatment remission	30.5% (TAPER) Prospective single-arm Phase II	Not published	Not published; OLE ongoing	Data gap - FcRn, BTKi
ADA formation	Minimal (oral small molecule) Indirect	Rozanolixizumab 71-75% RCT	N/A (oral small molecule) Indirect	TPO-RA, BTKi advantage
Disease modification	Not proven Editorial	Not proven Editorial	Not proven Editorial	No class proven

Table 1.1 - Summary comparison. All cross-class comparisons are Indirect (no head-to-head RCT exists). The "Durable response" row spans three incommensurable primary endpoints (EXTEND continuous ≥25w on-treatment; ADVANCE IV ≥4 of last 6w; LUNA 3 ≥8 of last 12w). Numbers are not directly comparable. Rilzabrutinib column added May 2026 following Wayrilz FDA approval (NDA 219685, 2025-08-29).

Section 3 - Clinical signal comparison (excerpt)

Agent-level trial data and durability asymmetry

3.1 Agent-level trial data

Agent	Class	Key trial	Primary endpoint	Response	Evidence
TPO receptor agonists
Eltrombopag	TPO-RA	RAISE (Ph 3)	≥50×10⁹/L at least once (6mo)	79% (vs 28% pbo, p<0.0001)	RCT
Eltrombopag	TPO-RA	EXTEND (Ph 3 OLE)	Continuous response ≥25w on-treatment	52%	RCT
Eltrombopag	TPO-RA	TAPER (Ph 2, NCT03524612)	Sustained response off treatment through Month 12	32/105 (30.5%)	Prospective single-arm Phase II
Romiplostim	TPO-RA	Kuter 2008 (Ph 3)	Durable response ≥50×10⁹/L for ≥6/8w	38-61%* (vs 0-5% pbo)	RCT
Avatrombopag	TPO-RA	Ph 3 (NCT01438840)	Cumulative weeks ≥50×10⁹/L without rescue	65.6% at Day 8 (vs 0% pbo)	RCT
FcRn inhibitors
Efgartigimod	FcRn	ADVANCE IV (Ph 3)	Sustained ≥50×10⁹/L for ≥4 of last 6 weeks	22% (vs 5% pbo, p=0.032)	RCT
Rozanolixizumab	FcRn	TP0003 (Ph 3, terminated)	Durable ≥50×10⁹/L for ≥8/12w	19% (4/21)	RCT Underpowered
Rozanolixizumab	FcRn	TP0006 (Ph 3, terminated)	Durable ≥50×10⁹/L for ≥8/12w	5% (1/20)	RCT Underpowered
Nipocalimab	FcRn	-	-	No ITP trial registered on ClinicalTrials.gov (May 2026)	No data
BTK inhibitors (third class, added May 2026)
Rilzabrutinib (Wayrilz)	BTKi	LUNA 3 (Ph 3, NCT04562766)	Durable platelet response ≥50×10⁹/L ≥8/12w	23% (rilzabrutinib) vs 0% pbo	RCT
Rilzabrutinib (Wayrilz)	BTKi	LUNA 3 - 12w initial	Platelet response (any)	64% rilzabrutinib; rescue 33% vs 58% pbo	RCT

*38% splenectomised, 61% non-splenectomised. Rozanolixizumab trials terminated early at 30-40% of planned enrolment - formally underpowered. Rilzabrutinib FDA-approved as Wayrilz (NDA 219685) on 2025-08-29 for persistent or chronic ITP with insufficient response to prior therapy; LUNA 3 is the pivotal trial. All cross-class comparisons are Indirect.

3.4 Durability: the decisive asymmetry

Durability is the lens through which both classes must ultimately be judged. The data are strikingly asymmetric - not because one class is clearly superior, but because the comparison cannot yet be made.

Metric	TPO-RAs	FcRn inhibitors
On-treatment "continuous response"	52% (EXTEND, ≥25w) - on-treatment only RCT	22% (ADVANCE IV, ≥4/6w) - on-treatment only RCT
Off-treatment remission (published)	32/105 patients (30.5%) achieved protocol-defined sustained response off treatment through Month 12 after eltrombopag tapering and discontinuation, maintaining platelets ≥30×10⁹/L without bleeding or rescue therapy (TAPER) Prospective single-arm Phase II	Not published in any Phase 3 ITP trial No data
Relapse kinetics post-cessation	Gradual; 70% relapse within 2-4 weeks RWE	Likely rapid (IgG rebounds 3-5w post-dose); not formally measured Indirect
Re-treatment response maintained?	Yes - ~70-80% re-respond (REPEAT trial) RCT	Unknown - not studied No data
Data maturity	15+ years Phase 3 + RWE RCT+RWE	<3 years Phase 3 data; OLE ongoing RCT

Table 3.4 - Durability comparison. Off-treatment remission is the only unambiguous measure. For FcRn inhibitors, this metric is currently unpublished.

MSL positioning statements - durability question

Three scenarios, three exact statements. Each is defensible at the evidence-tier shown and stays on label.

Scenario 1. Hematologist asks: "Which class gives more durable response?"

Statement. "On-treatment, TPO-RAs show 38-79% response (RAISE, Kuter 2008) versus 5-22% for FcRn inhibitors (ADVANCE IV, TP0003/6). Off-treatment response after eltrombopag tapering was prospectively evaluated in the single-arm Phase II TAPER study (32/105, 30.5%, through Month 12). Because the study had no control arm, spontaneous remission and treatment effect cannot be separated conclusively. Comparable prospective post-discontinuation evidence for FcRn inhibitors was not identified at the May 2026 snapshot." Prospective single-arm Phase II

Scenario 2. Competitor MSL cites TAPER off-treatment remission as a class superiority claim.

Statement. "TAPER is a single-arm Phase II study; it establishes a prospectively measured off-treatment outcome for eltrombopag specifically, not a randomized superiority claim, and does not generalise across the TPO-RA class - romiplostim has not demonstrated equivalent off-treatment data. FcRn inhibitors target a different mechanistic layer (increased catabolism of pathogenic IgG), and their durability question is open, not unfavourable." Prospective single-arm Phase II Indirect

Scenario 3. Hematologist asks: "Why use FcRn before durability is proven?"

Statement. "FcRn inhibition addresses the upstream destruction signal - lowering pathogenic IgG, which is the proximate driver of platelet loss in ITP. On-treatment, the response is fast (7-8 days) and biologically targeted. The off-treatment durability question is the next data readout, not a contradiction of the mechanism." Editorial

Scenario 4 (May 2026 addition). Hematologist asks: "Where does Wayrilz (rilzabrutinib) fit relative to TPO-RA and FcRn?"

Statement. "Wayrilz was FDA-approved on 2025-08-29 (NDA 219685) for persistent or chronic ITP after insufficient response to prior therapy. The pivotal trial is LUNA 3 (NCT04562766): 23% durable response ≥50×10⁹/L for ≥8 of 12 weeks vs 0% placebo. It acts on two layers simultaneously - BTK in B cells and macrophage FcγR signalling - distinct from TPO-RA (platelet production) and FcRn (IgG catabolism). Initial 12-week response is 64%; durable response is 23%. Off-treatment durability has not yet been published. Cross-class durability comparisons remain Indirect and currently lack a head-to-head RCT." RCT Indirect

Off-label boundary. Claiming FcRn-class or BTKi-class equivalence to TPO-RA durability is not yet supportable. ADVANCE next (NCT06544499) and the rilzabrutinib OLE are the next data gates; until then, the open-question framing above is the scientifically defensible position.

Not shown in this public excerpt

The full report (23 pages, 7 sections) additionally contains:

Section 2 - Mechanistic framework. Why upstream mechanism ≠ disease modification. Treg/Th17 logic. Re-baseline kinetics. BTKi dual-mechanism rationale (B-cell signalling + macrophage FcγR) added May 2026.
Section 4 - Endpoint and interpretation critique. Why the ≥50×10⁹/L platelet threshold conflates hemostatic rescue with disease modification. Continuous dosing bias. Underpowered Phase 3 reliability scoring. ADA formation. LUNA 3 endpoint construction (8/12-week durable response) compared with ADVANCE IV (4/6 of last 6 weeks).
Section 5 - MSL strategic positioning. Evidence-based talking points, what MSLs cannot claim without data, hematologist objection handling. Wayrilz launch positioning (third class, 2L+ label) added May 2026.
Section 6 - Forward signals (refreshed May 2026).
- Argenx ADVANCE next (NCT06544499) - RECRUITING since 2024-10; n=69; primary completion 2028-06. First Phase 3 efgartigimod IV trial designed with explicit off-treatment durability assessment.
- Efgartigimod IV long-term (NCT04225156) - COMPLETED 2026-03-11; n=101; data readout pending. Could address the FcRn durability gap.
- Efgartigimod SC (PH20, NCT04687072) - COMPLETED 2023; supports SC formulation differentiation vs IV (convenience play).
- Rilzabrutinib post-approval (NCT07007962) - new Sanofi single-arm Phase 3 in 2L+ ITP, RECRUITING since 2025-10; n=60; supports real-world label generalisation.
- Iptacopan (NCT05086744) - TERMINATED 2023-09; complement-inhibitor strategy in ITP currently paused. Removes Novartis as a near-term class entrant.
- Povetacicept (RUBY-4, NCT05757570) - Alpine/Vertex BAFF/APRIL Phase 1/2 ACTIVE; ITP cohort within autoimmune-cytopenia basket; primary completion 2026-07.
- Pediatric efgartigimod (NCT07194850) - Phase 2/3 RECRUITING since 2025-10; argenx pediatric label expansion.
Section 7 - References. Full citation list, ClinicalTrials.gov IDs (CT.gov pull dated 2026-05-28), EMA/FDA label cross-references including NDA 219685 (Wayrilz).

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DLV-2026-002 - Tier 2 dossier - May 2026 refresh (originally published April 2026).
Correction - 10 August 2026: TAPER was previously misclassified as randomized and linked to the wrong publication. It is a prospective, single-arm, open-label Phase II study (NCT03524612; Cooper et al., Am J Hematol. 2024; PMID 38014779). The 30.5% result is unchanged but is now described using the study's protocol-defined Month 12 endpoint. Related evidence labels and comparative language have been revised.
Sources cited in this excerpt: RAISE (Cheng et al., Lancet 2011), EXTEND (Saleh et al., Blood 2013), TAPER (Cooper N et al., Am J Hematol 2024;99(1):57-67. PMID 38014779. DOI 10.1002/ajh.27131. NCT03524612), Kuter 2008 (Lancet), ADVANCE IV (Broome et al., Lancet 2023), TP0003/TP0006 (Robak et al., Blood Adv 2020), LUNA 3 (Sanofi/Principia, AJMC commentary 2025-10-09), Wayrilz FDA label NDA 219685 (approved 2025-08-29). ClinicalTrials.gov registry pull dated 2026-05-28: NCT04562766 (LUNA 3), NCT04188379 (ADVANCE IV), NCT06544499 (ADVANCE next), NCT04687072 (efgartigimod SC), NCT04225156 (efgartigimod IV OLE), NCT07007962 (rilzabrutinib post-approval), NCT01438840 (avatrombopag), NCT04200456 / NCT04224688 (rozanolixizumab, terminated), NCT05086744 (iptacopan, terminated), NCT05757570 (povetacicept RUBY-4), NCT03524612 (TAPER). Mechanistic interpretation and editorial framing are explicitly tagged.

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