On December 9, 2019 Constellation Pharmaceuticals, Inc., a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported an update of preliminary data from the MANIFEST clinical trial in oral and poster presentations at the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) in Orlando (Press release, Constellation Pharmaceuticals, DEC 9, 2019, View Source [SID1234552110]).

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MANIFEST is an open-label Phase 2 clinical trial of the Company’s bromodomain and extra-terminal domain (BET) protein inhibitor CPI-0610 in patients with myelofibrosis (MF). Arm 3 is evaluating CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve MF patients. Arms 1 and 2 are studying CPI-0610 as a monotherapy or in combination with ruxolitinib in ruxolitinib-resistant or -intolerant MF patients.

The updated preliminary data presented at ASH (Free ASH Whitepaper) showed signs of clinical activity for CPI-0610 similar to that previously reported at the annual meetings of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) and the European Hematology Association (EHA) (Free EHA Whitepaper) and in the ASH (Free ASH Whitepaper) abstracts. The preliminary data included data on additional patients and showed evidence of activity across a broad range of myelofibrosis parameters in both JAK-inhibitor-naïve and ruxolitinib-resistant or -intolerant patients.

"If trends in preliminary data from MANIFEST in JAK-inhibitor-naïve patients are confirmed with further study, CPI-0610 has the potential to transform the standard of care in these patients," said Claire Harrison, D.M., Professor of Haematology, and Clinical Director, Guy’s and St Thomas’ NHS Foundation Trust, and a MANIFEST investigator.

"Preliminary data from MANIFEST in ruxolitinib-resistant or -intolerant patients are encouraging, suggesting the potential opportunity for a differentiated treatment option in such patients," said John Mascarenhas, M.D., Associate Professor, the Icahn School of Medicine at Mount Sinai, and a MANIFEST investigator.

The presentations at ASH (Free ASH Whitepaper) reflect data as of an October 17, 2019, data cutoff, updating preliminary data presented in ASH (Free ASH Whitepaper) abstracts published on November 6, 2019, as of a June 27, 2019, data cutoff.

Below are highlights of the presentations at ASH (Free ASH Whitepaper):

JAK-Inhibitor-Naïve Patients (Arm 3)

SVR35: Twelve out of 15 (80%) evaluable JAK-inhibitor-naïve patients experienced SVR35 at 12 weeks. The median percent change in spleen volume reduction was -49.7%.
TSS50: Ten out of 14 (71%) evaluable patients achieved at least a 50% improvement in Total Symptom Score (TSS50) at 12 weeks. The median percent change in TSS at 12 weeks was -60.3%.
Ruxolitinib-Resistant or -Intolerant Patients (Arms 1 and 2)

CPI-0610 Add-on to Ruxolitinib in Transfusion-Dependent Patients (Cohort 2A)

SVR35: At 24 weeks, SVR35 was achieved in 3 out of 12 (25%) evaluable patients, with a median percent change of -24.9%. An SVR35 at any time (best response) was achieved in 5 out of 17 (29%) evaluable patients, with a best median percent change of -21.2%.
SVR: At 24 weeks, 11 out of 12 (92%) evaluable patients had a spleen volume reduction.
TSS50: At 24 weeks, TSS50 was achieved in 7 out of 13 (54%) evaluable patients, with a median percent change of -58.8%. A TSS50 at any time (best response) was achieved in 13 out of 17 (76.5%) evaluable patients, with a median best change of -71.0%.
TD to TI: Conversion from transfusion dependence (TD) to transfusion independence (TI) occurred in 6 out of 14 (43%) evaluable patients with at least 24 weeks of treatment.
Other Ruxolitinib-Resistant or -Intolerant Patients (Cohorts 1A, 1B, and 2B)

SVR35: None of the patients in these cohorts achieved SVR35 at 24 weeks. An SVR35 at any time (best response) was achieved in 1 out of 4 evaluable patients in cohort 1A.
SVR: Nine out of 13 (69%) evaluable patients in Cohort 2B, 1 out of 2 (50%) evaluable patients in Cohort 1A, and 5 out of 7 (71%) evaluable patients in Cohort 1B achieved a spleen volume reduction at 24 weeks. The median reductions were -10.9%, -3.2%, and -26.0%, respectively.
TSS50: Five out of 13 (38%) evaluable patients in Cohort 2B, 0 out of 1 evaluable patient in Cohort 1A, and 3 out of 5 (60%) evaluable patients in Cohort 1B achieved a TSS50 at 24 weeks. Median reductions were -44.1%, -18.4%, and -53.5%, respectively.
TD to TI: Zero out of 2 TD patients in cohort 1A with at least 24 weeks of treatment converted to TI.
Additional Data Supporting Possible Disease Modification

Hemoglobin Improvement: Six out of 11 (55%) evaluable patients treated with CPI-0610 monotherapy and 2 out of 15 (13%) evaluable patients treated with CPI-0610 + ruxolitinib achieved at least a 1.5 g/dL improvement in hemoglobin without receiving a blood transfusion in the 12 weeks prior to assessment.
Bone Marrow Fibrosis Score Improvement: Twelve out of 32 (38%) evaluable patients in Arms 1 and 2, including 7 out 11 (63%) evaluable patients in Cohort 2A, achieved at least a one-grade improvement in bone marrow fibrosis score. Ten out of 12 improvements occurred within the first six months of treatment.
Safety

CPI-0610 in combination with ruxolitinib in JAK-inhibitor-naïve patients (Arm 3) was generally well tolerated. No adverse events led to study discontinuation. Three patients (10%) had ≥ Grade 3 anemia. One patient (3.3%) had Grade 4 thrombocytopenia, which was reversible. The most common non-hematologic adverse events were diarrhea, nausea, dizziness, and muscle spasms, which were primarily Grade 1/2.
CPI-0610 as monotherapy or in combination with ruxolitinib in ruxolitinib-refractory or -intolerant patients (Arms 1 and 2) was generally well tolerated. The most common hematologic adverse event was thrombocytopenia. Nine patients (10%) had ≥ Grade 3 thrombocytopenia, none of which were serious adverse events. These nine patients included two (5.6%) in Arm 1 and seven (12.9%) in Arm 2. The most common non-hematologic adverse events, primarily Grade 1/2, were diarrhea, nausea, cough, fatigue, vomiting, and upper respiratory tract infection. Eight out of 90 (8.9%) patients reported Grade 4 adverse events, all of which resolved. Of these eight, four (11.1%) occurred in Arm 1, of which three required dose interruption and one (rash) was considered related to CPI-0610, and four (7.4%) occurred in Arm 2, none required dose reduction and one (anemia) was considered related to the combination therapy. One ruxolitinib-resistant or -intolerant patient (1.1%) discontinued due to serious adverse event(s), which were reported as unlikely to have been related to CPI-0610. Three out of 90 (3.3%) ruxolitinib-resistant or -intolerant patients, all in Arm 2, reported Grade 5 adverse events—acute kidney injury, traumatic subdural hematoma (fall due to tripping), and brain stem hemorrhage (no concomitant thrombocytopenia)—none of which were considered by Constellation to be related to CPI-0610.
Orphan Drug Designation

The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to CPI-0610 for the treatment of MF on November 20, 2019.
The FDA Orphan Drug Designation program provides orphan status to drugs and biologics that are defined as those intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. Under specified conditions, this designation may provide companies a seven-year marketing exclusivity period, as well as certain incentives, including federal grants, tax credits, and a waiver of Prescription Drug User Fee Act (PDUFA) filing fees.
Future Plans

Constellation continues to enroll patients in MANIFEST. As a result of encouraging preliminary data, Constellation expanded Arm 3 of MANIFEST for JAK-inhibitor-naïve patients from 43 to up to 101 patients. The Company also expanded Cohort 2A, for TD ruxolitinib-resistant or -intolerant patients adding CPI-0610 to ruxolitinib, from 16 to up to 60 patients.
Constellation has started planning for a randomized, active-controlled, pivotal Phase 3 clinical trial studying the combination of CPI-0610 and ruxolitinib versus ruxolitinib and placebo in JAK-inhibitor-naïve patients with MF. The Company expects this clinical trial to start in 2020.
Investor Event

Constellation will host an analyst/investor event and webcast today at 12:30 PM EST in Salon 2 at the Rosen Centre Hotel in Orlando in conjunction with the annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper). The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source Analysts and investors may also access the event and participate in the live question-and-answer session by dialing (877) 473-2077 (domestic) or (661) 378-9662 (international) and referring to conference ID 7892044. A replay of the call will be available at (855) 859-2056, (404) 537-3406, or (800) 585-8367.
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 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.