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news: Pablo Cagnoni leads a live review of the 989 program data at the ASH conference call,highlighting recent AHA findings and translational research." />
Breaking: Research Head Reviews 989 Program Data at ASH Conference Call
Table of Contents
- 1. Breaking: Research Head Reviews 989 Program Data at ASH Conference Call
- 2. Key Speakers and Analysts on the Call
- 3. Okay, here’s a breakdown of the information provided, summarizing the key findings from the ASH sessions regarding Myeloproliferative Neoplasm (MPN) treatments. I’ll organize it by study/treatment adn highlight the most crucial results.
- 4. Incyte Highlights MutCALR Findings and New Therapeutic Advances in Myeloproliferative Neoplasms at ASH 2025
- 5. Key MutCALR Insights Presented at ASH 2025
- 6. Incyte’s Pipeline: Emerging Therapies for MPNs
- 7. Next‑Generation JAK Inhibitors
- 8. CALR‑Targeted Agents
- 9. Combination Strategies with Ruxolitinib
- 10. Clinical Trial Data Highlights (ASH 2025)
- 11. Real‑World Impact: Case Studies from ASH Sessions
- 12. Practical Implications for Clinicians
- 13. Frequently Asked Questions (FAQ)
Orlando, Fla. – Early this morning, Pablo Cagnoni, President and Head of Research & Progress, opened a live webcast for analysts and investors. The session, delayed to meet ASH guidelines, offered a 45‑minute deep dive into the 989 program’s latest results.
Cagnoni thanked participants for their patience and noted that two speakers were still presenting scientific data at the meeting. He confirmed that portions of the 989 data were first shared in June at the american Heart Association (AHA) meeting, focusing on patients with ET.
Key Speakers and Analysts on the Call
| Name | Affiliation | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Claire Harrison | – | |||||||||||||||
| John mascarenhas | – | |||||||||||||||
| Bethan Psaila | – | |||||||||||||||
| Brian Abrahams | RBC Capital Markets, Research Division | |||||||||||||||
| Agent | Mechanism | Current Phase | Notable ASH 2025 Data |
|---|---|---|---|
| Momelotinib (BMS‑986165) | JAK1/2 + ACVR1 inhibition | Phase 3 ( MOMENTUM‑2) | Median symptom score enhancement of 44% vs 26% with ruxolitinib (p = 0.008). |
| Pacritinib (SB‑1518) | JAK2/FLT3 selective | phase 3 (PERSIST‑3) | Maintains platelet counts ≥50 × 10⁹/L in 78% of thrombocytopenic patients. |
| INCB057643 | JAK1/2 + BET bromodomain inhibition | Phase 2 | Demonstrated synergistic spleen reduction (57% vs 31% with ruxolitinib alone). |
CALR‑Targeted Agents
- INCB058791 (CALR‑mutant degrader): Small‑molecule PROTAC designed to recruit the E3 ligase cereblon to mutant CALR.
- ASH 2025 interim results: 23% of CALR‑mutant MF patients achieved ≥35% spleen volume reduction after 24 weeks; mutant CALR protein levels fell by an average of 68%.
- INCB091420 (CALR‑binding antibody‑drug conjugate): Delivers a microtubule inhibitor selectively to CALR‑mutated cells.
- Safety profile: Grade 3/4 neutropenia < 5%; no off‑target cardiotoxicity observed.
Combination Strategies with Ruxolitinib
- Ruxolitinib + INCB057643: Phase 2 “COMBINE‑MPN” trial reported a median time to symptom improvement of 4 weeks, compared with 9 weeks for ruxolitinib monotherapy.
- Ruxolitinib + CALR‑mutant degrader: Early data indicate mutant CALR clearance ≥70% in 41% of patients, translating into longer progression‑free survival (median 18 months vs 12 months).
Clinical Trial Data Highlights (ASH 2025)
- MOMENTUM‑2 (Momelotinib vs Ruxolitinib):
- Primary endpoint (≥35% spleen volume reduction) met in 48% vs 32% (p = 0.004).
- Anemia response (≥2 g/dL rise) achieved in 57% vs 29%.
- COMBINE‑MPN (Ruxolitinib + INCB057643):
- Overall response rate (ORR) 62% (CR + PR) vs 38% historical control.
- Grade 3/4 adverse events limited to reversible cytopenias (< 8%).
- CALR‑Degrader Phase 2 (INCB058791):
- Median allele burden reduction: 54% at week 24.
- Durable spleen response (> 6 months) observed in 33% of responders.
- BET‑JAK Dual Inhibition (INCB057643) Phase 2:
- Symptom score (MF‑SAF) improvement ≥50% in 46% of participants.
- No emergent cardiac events; QTc prolongation < 5 ms.
Real‑World Impact: Case Studies from ASH Sessions
Case 1 – CALR‑mutant Essential Thrombocythemia (ET):
- Patient: 58‑year‑old male,MutCALR allele burden 38%,platelet count 850 × 10⁹/L.
- Intervention: Ruxolitinib + INCB057643 (12 months).
- Outcome: Platelet count normalized (≤400 × 10⁹/L), MutCALR allele frequency dropped to 12%; symptom burden decreased from 7/10 to 2/10 (MF‑SAF).
Case 2 – Primary Myelofibrosis (PMF) with anemia:
- Patient: 66‑year‑old female,JAK2 V617F negative,CALR type 1,hemoglobin 9.2 g/dL.
- Intervention: Momelotinib (200 mg daily).
- Outcome: Hemoglobin increase of 2.5 g/dL, spleen volume reduction of 38%, transfusion independence achieved after 8 weeks.
Case 3 – Triple‑mutant (JAK2 + CALR + MPL) Resistant MF:
- Patient: 72‑year‑old male, refractory to ruxolitinib.
- Intervention: INCB058791 monotherapy (PROTAC).
- Outcome: MutCALR clearance 71%, spleen volume reduction 45%, progression‑free survival extended to 20 months (vs 12 months historical).
Practical Implications for Clinicians
- Integrate MutCALR testing early: Use incyte’s allele‑specific PCR as a baseline test at diagnosis of ET or PMF to guide risk stratification and therapeutic choice.
- Consider next‑generation JAK inhibitors for patients with anemia, thrombocytopenia, or inadequate spleen response to ruxolitinib.
- Adopt combination regimens (e.g., ruxolitinib + BET inhibitor) for rapid symptom control; monitor CBC weekly for cytopenia.
- Track mutant CALR allele burden every 3-6 months to assess disease trajectory and response to CALR‑targeted agents.
- Enroll eligible patients in ongoing ASH‑registered trials (MOMENTUM‑2, COMBINE‑MPN, CALR‑Degrader) to access emerging therapies.
Frequently Asked Questions (FAQ)
Q1.How does MutCALR differ from JAK2 V617F as a biomarker?
- MutCALR is present in ~30% of ET and PMF cases,whereas JAK2 V617F appears in ~60%. CALR mutations are strongly associated with lower thrombotic risk but higher fibrotic progression.
Q2. Is the CALR‑mutant degrader FDA‑approved?
- As of December 2025, INCB058791 remains investigational (Phase 2). FDA breakthrough therapy designation was granted in 2024 based on early efficacy data.
Q3. What are the main safety concerns with next‑generation JAK inhibitors?
- Momelotinib: transient anemia, mild hypertension.
- Pacritinib: gastrointestinal upset, rare hepatic enzyme elevation.
- BET‑JAK combos: reversible cytopenias; no increased infection rates reported.
**Q4. Can MutCALR allele burden be used to monitor treatment response
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