On May 14, 2020 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that three abstracts relating to the MANIFEST clinical trial of CPI-0610 in myelofibrosis were published online in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting (Press release, Constellation Pharmaceuticals, MAY 14, 2020, View Source [SID1234557982]). The abstracts include an analysis of data from 157 patients based on a data cutoff of January 9, 2020. An upcoming presentation of posters at EHA (Free EHA Whitepaper) on June 12 will reflect an analysis of a larger patient population based on a later data cutoff. Constellation expects to present 12-week data in about 50 first-line patients and 24-week data in 25-30 first-line patients and 70-80 second-line patients at the EHA (Free EHA Whitepaper) meeting.

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"The data from the abstracts include 35% reductions in spleen volume (SVR35), 50% improvement in Total Symptom Scores (TSS50), hemoglobin improvements, conversions to transfusion independence in transfusion-dependent (TD) patients, and bone marrow fibrosis improvements," said Claire Harrison, D.M., Professor of Haematology, and Clinical Director, Guy’s and St Thomas’ NHS Foundation Trust, and a MANIFEST investigator. "Evidence of clinical activity was seen both as monotherapy and in combination with ruxolitinib. If these preliminary data are confirmed in further testing, CPI-0610 may have the potential for disease modification and could become part of a new standard of care in myelofibrosis."

Data Highlights

Arm 3 (1L) – CPI-0610 + ruxolitinib in JAK-inhibitor-naïve patients

21 of 29 evaluable patients (72%) achieved SVR35 at 12 weeks
Of 15 patients evaluable for SVR at week 24, 14 completed 24 weeks of treatment (one discontinued), with 10 patients (67%) achieving SVR35
The median spleen volume change in those 14 patients was 54% at 24 weeks
TSS50 responses at 12 and 24 weeks were 56% (15 of 27 evaluable patients) and 79% (11 of 14 evaluable patients), respectively
5 of 11 (46%) patients evaluable for bone marrow fibrosis had a >1 grade improvement at 24 weeks
Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients

2 of 10 (20%) and 4 of 11 (36%) evaluable non-transfusion-dependent (non-TD) patients achieved SVR35 (the primary endpoint for cohort 1B) and TSS50, respectively, at 24 weeks
3 of 10 (30%) evaluable non-TD patients had a >1 grade improvement in bone marrow fibrosis at 24 weeks
13 of 22 (59%) evaluable non-TD patients had > 1.5 g/dL increase in hemoglobin
2 of 6 (33%) evaluable TD patients converted to transfusion independence (the primary endpoint for cohort 1A)
No evaluable TD patients achieved SVR35 or TSS50 at 24 weeks
Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients

7 of 19 (37%) evaluable TD patients converted to TI (the primary endpoint for cohort 2A)
3 of 18 (17%) and 10 of 18 (56%) evaluable TD patients achieved SVR35 and TSS50, respectively, at 24 weeks
9 of 14 (64%) evaluable TD patients had a > 1 grade improvement in bone marrow fibrosis at 24 weeks
No evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 2B) and 4 of 13 (31%) evaluable non-TD patients achieved TSS50 at 24 weeks
Safety

CPI-0610 in MANIFEST, both as monotherapy and in combination with ruxolitinib and in both JAK-inhibitor-naïve and JAK-inhibitor-experienced and -ineligible patients, was generally well tolerated.

Among the most common treatment-emergent adverse events (AEs) for CPI-0610 monotherapy in 43 safety-evaluable patients in Arm 1, those that were ≥ Grade 3 were thrombocytopenia (14.0%), anemia (7.0%), and diarrhea (4.7%). Two patients discontinued treatment because of AEs (blood creatinine increase, fatigue, and pleuritic pain). There were no Grade 5 AEs.

Among the most common treatment-emergent AEs in 61 safety-evaluable patients in Arm 2, those that were ≥ Grade 3 were thrombocytopenia (21.3%), anemia (8.2%), diarrhea (4.9%), infections (4.9%), nausea (1.6%), abdominal pain (1.6%), and vomiting (1.6%). Seven patients discontinued treatment due to AEs, including three previously reported Grade 5 AEs.

Among the most common treatment-emergent AEs in 53 safety-evaluable patients in Arm 3, those that were ≥ Grade 3 were anemia (15.1%), thrombocytopenia (5.7%), infections (3.8%), and dyspnea (3.8%). Two patients discontinued treatment due to AEs (infections); one of them was Grade 5 within 30 days of treatment discontinuation.

For further details, please see the EHA (Free EHA Whitepaper) abstracts in the Investors and Media/Other Presentations section of Constellation’s website, View Source

EHA Poster Presentations

TITLE: CPI-0610, A Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, in Combination with Ruxolitinib, in JAK Inhibitor Treatment Naive Myelofibrosis Patients: Update of MANIFEST Phase 2 Study (Submission ID: EHA (Free EHA Whitepaper)-2731, Final Abstract Code: EP1084)

TITLE: CPI-0610, A Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, as Monotherapy in Advanced Myelofibrosis Patients Refractory/Intolerant to JAK Inhibitor: Update from Phase 2 MANIFEST Study (Submission ID: EHA (Free EHA Whitepaper)-3245, Final Abstract Code: EP1091)

TITLE: CPI-0610, Bromodomain and Extraterminal Domain Protein (BET) Inhibitor, as "Add-on" to Ruxolitinib (Rux), in Advanced Myelofibrosis Patients with Suboptimal Response: Update of MANIFEST Phase 2 Study (Submission ID: EHA (Free EHA Whitepaper)-2790, Final Abstract Code: EP1083)

Session: Myeloproliferative Neoplasms—Clinical

Date and Time: June 12, 2020, 8:30 AM CEST/2:30 AM EDT

Investor Event

Constellation will host a virtual investor meeting and conference call to discuss these interim data on June 12. Details will be announced later.

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of CPI-0610 in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation is also evaluating CPI-0610, either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to TI for 12 consecutive weeks. The primary endpoint for the patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.