On June 12, 2020 Sorrento Therapeutics, Inc. (Nasdaq: SRNE, "Sorrento") reported that it prepaid in full its outstanding term loans on June 12, 2020 (Press release, Sorrento Therapeutics, JUN 12, 2020, View Source [SID1234561058]).

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The prepaid debt, comprised of an initial $100 million term loan and an additional $20 million term loan from certain funds affiliated with Oaktree Capital Management, L.P., was obtained pursuant to a Term Loan Agreement entered into in November 2018.

On June 12, 2020 AstraZeneca reported that Detailed results from both the Phase II ACE-CL-001 trial and the pivotal Phase III ASCEND trial showed the long-term efficacy and tolerability of Calquence (acalabrutinib) in chronic lymphocytic leukaemia (CLL), one of the most common types of adult leukaemia.1,2,3 (Press release, AstraZeneca, JUN 12, 2020, View Source [SID1234561024])

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The results will be presented during the Virtual Edition of the 25th European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress, 11 to 14 June 2020.

In the single-arm ACE-CL-001 trial, 86% of CLL patients treated with Calquence as a 1st-line monotherapy remained on treatment at a median follow up of more than four years. The trial showed an overall response rate of 97% (7% complete response; 90% partial response) and a 100% overall response rate in subgroups of patients with high-risk disease characteristics, including genomic aberrations (17p deletion and TP53 mutation), immunoglobulin mutation status (unmutated IGHV), and complex karyotype. Safety findings showed no new long-term issues.1,4

In the final analysis of ASCEND, an estimated 82% of patients with relapsed or refractory CLL treated with Calquence remained alive and free from disease progression at 18 months compared with 48% of patients on rituximab combined with idelalisib or bendamustine.2 The trial previously met the primary endpoint of Independent Review Committee-assessed progression-free survival at the interim analysis.5

Richard R. Furman, Director of the CLL Research Center, Weill Cornell Medicine said: "These data demonstrate no new safety concerns for acalabrutinib, confirming its ability to safely provide meaningful, long-term clinical benefit for patients with treatment-naive and relapsed or refractory disease. The safety profile of acalabrutinib makes treatment to progression an important and plausible option for patients."

José Baselga, Executive Vice President, Oncology R&D said: "These long-term data reaffirm that Calquence delivers a durable response with a favourable safety profile for chronic lymphocytic leukaemia patients. Patients with chronic lymphocytic leukaemia are typically 70 years or older with comorbidities and often require treatment over a long time, making the sustained safety and efficacy profile highly relevant to their quality of life."

Results from the Phase II ACE-CL-001 trial informed the development of the pivotal Phase III ELEVATE TN trial, which, along with findings from the Phase III ASCEND trial, formed the basis for the US approval of Calquence for the treatment of patients with CLL or small lymphocytic lymphoma (SLL).

Calquence in previously untreated CLL: 4.4-year follow-up from Phase II trial (abstract #S163)

The Phase II ACE-CL-001 trial investigated safety and efficacy of Calquence (100mg twice-daily [n=62] or 200mg once-daily [n=37]) in previously untreated patients with CLL.1 On 1 May 2015, patients receiving the 200mg dosing regimen were switched to the 100mg regimen.1

Key data from the Calquence Phase II ACE-CL-001 trial1

Calquence Phase II ACE-CL-001 trial table
CI, confidence interval; CR, complete response; DoR, duration of response; EFS, event free survival; TTR, time to response; NR, not reached; ORR, overall response rate; PR, partial response

Response rates were 100% in each subgroup of patients with high-risk disease characteristics (unmutated IGHV [n=57], 17p deletion [n=9], TP53 mutation [n=9], and complex karyotype [n=12]), and reduction in lymph node disease was noted in all patients tested (n=97).1

At the time of data cut-off, 85 (86%) patients receiving Calquence remained on treatment. Six patients discontinued treatment due to adverse events (AEs) and three patients discontinued for progressive disease (PD). No patient discontinued Calquence due to bleeding events, hypertension, or atrial fibrillation. Incidence of AEs generally diminished with time on the trial. The most common AEs (≥40%) of any grade in the trial were diarrhoea (52%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%). All-grade and Grade ≥3 events of clinical interest included infection (84% and 15%, respectively), bleeding events (66%, 3%), hypertension (22%, 11%), leukopenia (9%, 9%), and thrombocytopenia (3%, 1%). Atrial fibrillation (all grades) occurred in 5% of patients with Grade ≥3 occurring in 2%. Second primary malignancies (SPM) excluding non-melanoma skin (all grades) occurred in 11% of patients.1 Serious adverse events (SAEs) were reported in 38% of patients. SAEs occurring in more than two patients included pneumonia (n=4) and sepsis (n=3).1

Final results of Calquence Phase III ASCEND trial in relapsed or refractory CLL (abstract #S159)

ASCEND was a global, randomised, multicentre, open-label, Phase III trial that investigated the efficacy and safety of Calquence (100mg twice-daily) versus investigator’s choice of rituximab combined with idelalisib (IdR) or bendamustine (BR) in patients with relapsed or refractory CLL.2

Key data from the final analysis of the Calquence Phase III ASCEND trial2

Calquence Phase III ASCEND trial table
BR, rituximab in combination with bendamustine; CI, confidence interval, DoR, duration of response; HR, hazard ratio; IdR, rituximab in combination with idelalisib; INV, investigator; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival

Sixteen per cent of patients on Calquence, 56% of patients on IdR, and 17% of patients on BR discontinued treatment because of AEs. Common AEs occurring in greater than 15% of patients of any grade in the Calquence arm of the trial included headache (22%), neutropenia (21%), diarrhoea (20%), upper respiratory tract infection (20%), cough (16%), and anaemia (16%). Events of clinical interest for Calquence versus controls included atrial fibrillation (all grade, 6% and 3%, respectively), major haemorrhage (all grade, 3% in both arms), infections (Grade ≥3, 20% and 25%, respectively), and SPM excluding non-melanoma skin cancer (all grade, 5% and 2%, respectively). SAEs (any grade) occurred in 33% of patients receiving Calquence, 56% of IdR patients, and 26% of BR patients.2

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is one of the most common types of leukaemia in adults, with an estimated 105,000 new cases globally in 2016 and 21,040 new cases in the US in 2020, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.3,6,7,8 In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections.3 As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets.3 This could result in anaemia, infection, and bleeding.3 B-cell receptor signalling through Bruton’s tyrosine kinase is one of the essential growth pathways for CLL.

Calquence

Calquence (acalabrutinib) is a next-generation, selective inhibitor of Bruton’s tyrosine kinase (BTK). Calquence binds covalently to BTK, thereby inhibiting its activity.4,9 In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.4

Calquence is approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) in nine countries and for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy in 14 countries. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 23 company-sponsored clinical trials. Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström macroglobulinaemia, follicular lymphoma, and other haematologic malignancies.

AstraZeneca in haematology

Leveraging its strength in oncology, AstraZeneca has established haematology as one of four key oncology disease areas of focus. The Company’s haematology franchise includes two US FDA-approved medicines and a robust global development programme for a broad portfolio of potential blood cancer treatments. Acerta Pharma serves as AstraZeneca’s haematology research and development arm. AstraZeneca partners with like-minded science-led companies to advance the discovery and development of therapies to address unmet need.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On June 12, 2020 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved an expanded indication for GARDASIL 9 for the prevention of oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58 (Press release, Merck & Co, JUN 12, 2020, View Source [SID1234561059]). The oropharyngeal and head and neck cancer indication is approved under accelerated approval based on effectiveness in preventing HPV-related anogenital disease. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The trial is currently underway.

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"At Merck, working to help prevent certain HPV-related cancers has been a priority for more than two decades," said Dr. Alain Luxembourg, director, clinical research, Merck Research Laboratories. "Today’s approval for the prevention of HPV-related oropharyngeal and other head and neck cancers represents an important step in Merck’s mission to help reduce the number of men and women affected by certain HPV-related cancers."

GARDASIL 9 is a vaccine indicated in females 9 through 45 years of age for the prevention of cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by human papillomavirus (HPV) Types 16, 18, 31, 33, 45, 52, and 58; cervical, vulvar, vaginal, and anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.

GARDASIL 9 is indicated in males 9 through 45 years of age for the prevention of anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58; anal precancerous or dysplastic lesions caused by HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV Types 6 and 11.

GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant].

Both men and women can be at risk for HPV-attributable oropharyngeal cancer; however, this cancer affects men five times more than women.1 For most people, HPV clears on its own. But, for those who don’t clear the virus, it can cause certain cancers. Oropharyngeal cancer can arise as a result of HPV infection in the oropharynx, which includes the soft palate, side and back wall of the throat, tonsils, and back one-third of the tongue. According to a recent model published by the U.S. Centers for Disease Control and Prevention (CDC), HPV-attributable oropharyngeal cancer has surpassed cervical cancer as the most prevalent type of HPV-related cancer in the U.S.1

1 The CDC analyzed data from the U.S. Cancer Statistics (USCS) to assess the incidence of HPV-associated cancers and to estimate the annual number of cancers caused by HPV, overall and by state, during 2012 to 2016.

The estimated number of HPV-attributable cancers was calculated by multiplying the average number of HPV-associated cancers by the percentage of HPV-attributable cancers diagnosed from 1993 to 2005, before HPV vaccination was available in the U.S.

The detection of HPV DNA in an HPV study is not enough to determine that HPV caused the cancer.

Not all cervical and oropharyngeal cancers are caused by HPV.

Important Information About GARDASIL 9

GARDASIL 9 does not eliminate the necessity for vaccine recipients to undergo screening for cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers as recommended by a healthcare provider.

GARDASIL 9 has not been demonstrated to provide protection against diseases caused by:

HPV types not covered by the vaccine
HPV types to which a person has previously been exposed through sexual activity
Not all vulvar, vaginal, anal, oropharyngeal and other head and neck cancers are caused by HPV, and GARDASIL 9 protects only against those vulvar, vaginal, anal, oropharyngeal and other head and neck cancers caused by HPV Types 16, 18, 31, 33, 45, 52, and 58.

GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) is not a treatment for external genital lesions; cervical, vulvar, vaginal, anal, oropharyngeal and other head and neck cancers; or cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), vaginal intraepithelial neoplasia (VaIN), or anal intraepithelial neoplasia (AIN).

Vaccination with GARDASIL 9 may not result in protection in all vaccine recipients.

Select Safety Information for GARDASIL 9

GARDASIL 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of GARDASIL 9 or GARDASIL [Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Recombinant].

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following HPV vaccination. When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion.

Safety and effectiveness of GARDASIL 9 have not been established in pregnant women.

The most common (≥10%) local and systemic adverse reactions in females were injection-site pain, swelling, erythema, and headache. The most common (≥10%) local and systemic reactions in males were injection-site pain, swelling, and erythema.

The duration of immunity of GARDASIL 9 has not been established.

Dosage and Administration for GARDASIL 9

GARDASIL 9 should be administered intramuscularly in the deltoid or anterolateral area of the thigh.

For individuals 9 through 14 years of age, GARDASIL 9 can be administered using a 2-dose or 3-dose schedule. For the 2-dose schedule, the second dose should be administered 6-12 months after the first dose. If the second dose is administered less than 5 months after the first dose, a third dose should be given at least 4 months after the second dose. For the 3-dose schedule, GARDASIL 9 should be administered at 0, 2 months, and 6 months.
For individuals 15 through 45 years of age, GARDASIL 9 is administered using a 3-dose schedule at 0, 2 months, and 6 months.
About HPV and HPV-related Cancers and Diseases

According to the CDC, an estimated 14 million new HPV infections occur every year in the United States. HPV is so common that 80% of people who are sexually active get HPV at some point in their life. For most people, HPV clears on its own; but for those who don’t clear the virus, it could cause certain cancers and diseases. There is no way to know which people who have HPV will develop cancer or other health problems. GARDASIL9 (Human Papillomavirus 9-valent Vaccine, Recombinant) helps protect against seven HPV types that cause the majority of HPV-related cancers in the United States. Persistent HPV infection can also lead to pre-cancerous lesions that may require additional follow-up procedures. With the exception of cervical cancer, there is no routinely recommended screening for the detection of HPV-related cancers.

On June 12, 2020 ALX Oncology Holdings Inc., a clinical-stage immuno-oncology company developing therapies that block the CD47 checkpoint pathway, reported preliminary results from the fully enrolled ALX148 plus rituximab combination cohort of the Phase 1 clinical program at the 25th Annual Congress of EHA (Free EHA Whitepaper) [abstract #EP1247] (Press release, ALX Oncology, JUN 12, 2020, View Source [SID1234561060]). As of April 1, 2020, 33 patients with relapsed or refractory non-Hodgkin Lymphoma (NHL) were administered ALX148 at 10 or 15 mg/kg once per week (QW) in combination with a standard rituximab regimen. The following key results were observed in response-evaluable subjects:

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ALX148 in combination with a standard regimen of rituximab is well tolerated with no maximum tolerated dose reached. The maximum administered dose is 15 mg/kg QW (molar equivalent to 30 mg/kg QW an antibody) with no exposure-dependent cytopenia observed across the exposure range evaluated.
ALX148 10mg/kg plus rituximab (n=22): In all subjects, an overall objective response rate (ORR) of 40.9% and median progression-free survival (mPFS) of 7.4 months were observed.
In patients with aggressive NHL (n=15) an ORR of 33.3% and median duration of response (mDOR) of 5.6 months were observed.
In patients with indolent NHL (n=7) an ORR of 57.1% was observed and mDOR was not reached.
Three patients achieved complete response.
ALX148 15mg/kg plus rituximab (n=11): In all subjects, an ORR of 54.6% was observed and mPFS was not reached.
In patients with aggressive NHL (n=7) an ORR of 42.9% was observed and mDOR was not reached.
In patients with indolent NHL (n=4) an ORR of 75% was observed and mDOR was not reached.
Two patients achieved complete response.
ALX148 demonstrates linear pharmacokinetics at 10 mg/kg and 15 mg/kg QW with near complete peripheral CD47 target occupancy in combination with rituximab at both dose levels.
"With no exposure-dependent cytopenias observed, and a greater response rate observed in the higher dosing cohort of heavily pre-treated subjects with NHL, we believe this study provides compelling evidence for the potential of ALX148 in treating hematologic malignancies," said Sophia Randolph, M.D., Ph.D., Chief Medical Officer of ALX Oncology. "The higher ALX148 exposure levels observed in subjects with objective responses is encouraging evidence for the pharmacologic activity of ALX148 and supports higher dose administration in future trials for patients with cancer."

On June 12, 2020 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST) reported that three posters relating to the MANIFEST clinical trial of CPI-0610 in myelofibrosis (MF) were published online in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting (Press release, Constellation Pharmaceuticals, JUN 12, 2020, View Source [SID1234561026]). The data in these posters are based on a data cutoff of April 17, 2020, and reflect an analysis of clinical activity in 51 first-line (1L) and 73 second-line (2L) patients.

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"I’m encouraged that the initial signals of activity with CPI-0610, such as spleen and symptom responses, that were presented last December at ASH (Free ASH Whitepaper) continue to be observed in a larger dataset presented in these EHA (Free EHA Whitepaper) posters," said Claire Harrison, D.M. (Oxon.), Professor of Haematology and a MANIFEST investigator. "In addition, we continue to see signals of disease modification, such as increases in hemoglobin, conversions of transfusion-dependent patients to transfusion independence, and bone marrow fibrosis improvements. If corroborated in further testing, these data suggest that CPI-0610 could potentially change the treatment paradigm in MF."

"We are excited about the emerging profile of CPI-0610," said Jigar Raythatha, Chief Executive Officer of Constellation Pharmaceuticals. "Our goal is to drive CPI-0610 to registration and to transform the standard of care in myelofibrosis and potentially other hematologic diseases."

Data Highlights

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

37 of 51 evaluable patients (73%) achieved a 35% reduction in spleen volume (SVR35) at 12 weeks and had a median spleen volume reduction of 51%
19 of 30 evaluable patients (63%) achieved SVR35 at 24 weeks (the primary endpoint for Arm 3) and had a median spleen volume reduction of 53%
17 of 29 evaluable patients (59%) achieved a 50% improvement in Total Symptom Score (TSS50) at 24 weeks and had a median TSS improvement of 64%
No evidence of correlation between SVR35 response and baseline risk status, platelet count, or spleen volume
Arm 1 (2L) – CPI-0610 monotherapy in JAK-inhibitor-experienced or -ineligible patients

3 of 14 (21%) evaluable transfusion-dependent (TD) patients converted to transfusion independence (TI), the primary endpoint for cohort 1A
5 of 21 (24%) evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 1B) and 9 of 19 (47%) evaluable non-TD patients achieved TSS50 at 24 weeks
11 of 19 (58%) non-TD patients on treatment for at least 12 weeks without any transfusions achieved a ≥1.5 g/dL mean increase in hemoglobin
Arm 2 (2L) – CPI-0610 + ruxolitinib in ruxolitinib-experienced patients

11 of 32 (34%) evaluable TD patients converted to TI, the primary endpoint for cohort 2A
4 of 18 (22%) evaluable non-TD patients achieved SVR35 (the primary endpoint for cohort 2B) and 7 of 19 (37%) 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 (TEAEs) for CPI-0610 monotherapy in 43 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (14.0%), anemia (9.3%), diarrhea (4.7%), and respiratory tract infection (2.3%). Six patients discontinued treatment because of TEAEs. There were no Grade 4 or Grade 5 TEAEs.

Among the most common TEAEs in 70 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (22.9%), anemia (7.1%), fatigue (5.7%), diarrhea (4.3%), respiratory tract infections (4.3%), nausea (2.9%), and abdominal pain (1.4%). Grade 4 TEAEs included thrombocytopenia (1.4%) and anemia (1.4%). Seven patients discontinued treatment due to TEAEs, including four Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), and disease progression.

Among the most common TEAEs in 64 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (15.6%), respiratory tract infections (3.1%), and thrombocytopenia (1.6%). Grade 4 TEAEs included thrombocytopenia (3.1%), anemia (1.6%), and respiratory tract infection (1.6%). Four patients discontinued treatment due to TEAEs, including two Grade 5 TEAEs, each due to multi-organ failure due to sepsis.

For further details, please see the EHA (Free EHA Whitepaper) poster presentations here.

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 (Presentation 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 (Presentation 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 (Presentation 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 analyst/investor event and conference call on June 12 at 8:00 AM EDT to discuss the data from these three posters relating to the MANIFEST clinical trial for CPI-0610 being presented at the European Hematology Association (EHA) (Free EHA Whitepaper) meeting. The agenda of the event will include:

An overview of myelofibrosis (MF) and the potential impact of Constellation’s BET inhibitor CPI-0610 in treating MF
A review of the data from the MANIFEST clinical trial presented in the EHA (Free EHA Whitepaper) posters
A live question-and-answer session
The event will be webcast live and can be accessed on the Investor Relations section of Constellation’s website at View Source To participate in the live question-and-answer session, please dial (877) 473-2077 (domestic) or (661) 378-9662 (international) and refer to conference ID 6275774.

EZH2 Program Prioritization

Constellation reported that it plans to prioritize further clinical development of its next-generation EZH2 inhibitor CPI-0209. The decision is based on a recent data cut and review of ProSTAR, the ongoing Phase 1b/2 clinical study evaluating CPI-1205, a small-molecule inhibitor of EZH2, combined with enzalutamide or abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC). The data did not demonstrate the definitive signal of activity necessary to advance the program into pivotal studies in mCRPC. A full data set from ProSTAR will be presented at a future medical meeting.

"We thank the patients and investigators who participated in ProSTAR," said Jigar Raythatha. "While we are disappointed with the outcome of this study, we remain committed to EZH2 as an important cancer target and will apply the learnings from ProSTAR to our second-generation EZH2 inhibitor, CPI-0209. We believe the deeper and more durable target engagement as well as the improved metabolic properties that CPI-0209 demonstrated in preclinical studies give it the potential to be a best-in-class EZH2 inhibitor for use in a broad range of cancer types. CPI-0209 is progressing through the dose escalation portion of a phase 1/2 clinical trial, and we expect to determine a recommended Phase 2 dose later in the year."

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.

About ProSTAR

ProSTAR is an open-label Phase 1b/2 clinical trial of CPI-1205, a potent and highly selective small-molecule EZH2 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) in the second-line setting. The ProSTAR study is evaluating CPI-1205 in combination with either enzalutamide or abiraterone/prednisone ("abiraterone"), which are androgen receptor signaling (ARS) inhibitors, in mCRPC patients who experienced disease progression while receiving the other ARS inhibitor.