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Precision BioSciences Announces Closing of Initial Public Offering and Full Exercise of the Underwriters’ Option to Purchase Additional Shares

On April 1, 2019 Precision BioSciences (Nasdaq: DTIL) ("Precision"), a genome editing company dedicated to improving life (DTIL) through its proprietary ARCUS genome editing platform, reported the closing of its initial public offering of 9,085,000 shares of common stock, which includes the full exercise of the underwriters’ option to purchase 1,185,000 additional shares of common stock, at a public offering price of $16.00 per share (Press release, Precision Biosciences, APR 1, 2019, View Source [SID1234534879]). The total gross proceeds to Precision were approximately $145.4 million, before deducting underwriting discounts and commissions and expenses payable by Precision. All of the shares were sold by Precision. The shares commenced trading on the Nasdaq Global Select Market under the ticker symbol "DTIL" on Thursday, March 28, 2019.

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J.P. Morgan, Goldman Sachs & Co. LLC, Jefferies and Barclays acted as joint book-running managers for the offering.

A registration statement relating to the securities sold in this offering was declared effective by the Securities and Exchange Commission on March 27, 2019. The offering was made only by means of a prospectus. Copies of the final prospectus relating to this offering may be obtained by contacting: J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, telephone: (866) 803-9204 or email: [email protected]; Goldman Sachs & Co. LLC, Attention: Prospectus Department, 200 West Street, New York, New York 10282, by telephone: (866) 471-2526, facsimile: (212) 902-9316, or email: [email protected]; Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, 2nd Floor, New York, NY 10022, by telephone: (877) 547-6340 or email: [email protected]; or Barclays Capital Inc., c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone: (800) 603-5847.

This press release shall not constitute an offer to sell, or the solicitation of an offer to buy, nor shall there be any sale of, these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

Phase 3 ADMIRAL Trial Data Show XOSPATA® (gilteritinib) Significantly Prolongs Overall Survival in Adult Patients with FLT3 Mutation-Positive Relapsed/Refractory Acute Myeloid Leukemia Compared with Salvage Chemotherapy

On April 1, 2019 Astellas Pharma Inc. (TSE: 4503) (President and CEO: Kenji Yasukawa, Ph.D. "Astellas") reported results from the Phase 3 ADMIRAL clinical trial comparing XOSPATA (gilteritinib) to salvage chemotherapy in adult patients with relapsed or refractory (resistant to treatment) Acute Myeloid Leukemia (AML) with a FLT3 mutation (Press release, Astellas, APR 1, 2019, View Source [SID1234534876]). The results show that patients treated with XOSPATA had significantly longer Overall Survival (OS) than those who received standard salvage chemotherapy. The data were shared today by Alexander Perl, M.D., Abramson Cancer Center, University of Pennsylvania, in a press conference at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting. The data will also be presented during the AACR (Free AACR Whitepaper) Clinical Trials Plenary Session (#CT184), which takes place April 2, 2019, 10:30 a.m. – 12:45 p.m. at the Georgia World Congress Center, Marcus Auditorium, Bldg A-GWCC.

Results from the ADMIRAL trial show the median OS for patients who received XOSPATA was 9.3 months compared to 5.6 months for patients who received salvage chemotherapy (Hazard Ratio = 0.637 (95% CI 0.490, 0.830), P=0.007); one-year survival rates were 37% for patients who received XOSPATA compared to 17% for patients who received salvage chemotherapy.

The most common treatment-emergent adverse events (TEAEs) of any grade occurring in ≥10% of patients during the first 30 days of treatment with gilteritinib were anemia (33%), increased alanine aminotransferase (24%), increased aspartate aminotransferase (24%), febrile neutropenia (21%), thrombocytopenia (19%), constipation (17%), pyrexia (15%), fatigue (15%), decreased neutrophil count (14%), increased blood alkaline phosphatase (13%), nausea (13%), hypokalemia (11%), cough (11%), headache (10%), and diarrhea (10%). The most common TEAEs of any grade occurring in ≥10% of patients during the first 30 days of treatment with salvage chemotherapy were anemia (33%), febrile neutropenia (32%), nausea (30%), diarrhea (28%), hypokalemia (27%), pyrexia (26%), decreased appetite (17%), decreased white blood cell count (17%), thrombocytopenia (16%), constipation (14%), abdominal pain (14%), hyperglycemia (13%), headache (13%), stomatitis (13%), fatigue (11%), decreased neutrophil count (11%), increased aspartate aminotransferase (10%), vomiting (10%), peripheral edema (10%), and hypomagnesemia (10%).

"We are very encouraged by the findings of the ADMIRAL trial," said Alexander Perl, M.D., an associate professor of Hematology-Oncology in Penn’s Perelman School of Medicine. "Patients with relapsed/refractory FLT3 mutation-positive AML generally have a poor prognosis and short survival. Until just recently, they had few treatment options. These findings change the treatment paradigm for this patient population."

XOSPATA was approved by the U.S. Food and Drug Administration (FDA) in November 2018 for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation as detected by an FDA-approved test.[1]

XOSPATA was discovered through a research collaboration with Kotobuki Pharmaceutical Co., Ltd., and Astellas has exclusive global rights to develop, manufacture and commercialize XOSPATA.

XOSPATA was approved by the Japan Ministry of Health, Labor and Welfare (MHLW) for relapsed or refractory AML with FLT3 mutations and launched as XOSPATA 40 mg Tablets in 2018.[2] In February 2019, a marketing authorization application (MAA) for the oral once-daily therapy XOSPATA for the treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation was accepted by the European Medicines Agency for regulatory review.[3]

Astellas is currently investigating gilteritinib in various FLT3 mutation-positive AML patient populations through several Phase 3 trials. Visit View Source to learn more about ongoing gilteritinib clinical trials.

About the ADMIRAL Trial[4]
The Phase 3 ADMIRAL trial (NCT02421939) was an open-label, multicenter, randomized study of gilteritinib versus salvage chemotherapy in adult patients with FLT3 mutations who are refractory to or have relapsed after first-line AML therapy. The primary endpoint of the trial was Overall Survival (OS). The study enrolled 371 patients with relapsed or refractory AML and positive for FLT3 mutations present in bone marrow or whole blood. Subjects were randomized in a 2:1 ratio to receive gilteritinib (120 mg)[5] or salvage chemotherapy.

About XOSPATA (gilteritinib)
XOSPATA is indicated for the treatment of adult patients who have relapsed or refractory Acute Myeloid Leukemia (AML) with a FMS-like tyrosine kinase 3 (FLT3) mutation as detected by an FDA-approved test.1

Important Safety Information

Contraindications
XOSPATA is contraindicated in patients with hypersensitivity to gilteritinib or any of the excipients. Anaphylactic reactions have been observed in clinical trials.

Warnings and Precautions
Posterior Reversible Encephalopathy Syndrome (PRES) There have been rare reports of PRES with symptoms including seizure and altered mental status with XOSPATA. Symptoms have resolved after discontinuation of XOSPATA. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XOSPATA in patients who develop PRES.

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). Of the 292 patients treated with XOSPATA in the clinical trial, 1.4% were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

Pancreatitis There have been rare reports of pancreatitis in patients receiving XOSPATA in clinical studies. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

Adverse Reactions
The most frequent non-hematological serious adverse reactions (≥5%) reported in patients were pneumonia (19%), sepsis (13%), fever (13%), dyspnea (7%) and renal impairment (5%).

Overall, 22 of 292 patients (8%) discontinued XOSPATA treatment permanently due to an adverse reaction. The most common adverse reactions (>1%) leading to discontinuation were pneumonia (2%), sepsis (2%) and dyspnea (1%). The most common adverse reactions (≥20%) were myalgia/arthralgia (42%), transaminase increased (41%), fatigue/malaise (40%), fever (35%), non-infectious diarrhea (34%), dyspnea (34%), edema (34%), rash (30%), pneumonia (30%), nausea (27%), stomatitis (26%), cough (25%), headache (21%), hypotension (21%), dizziness (20%) and vomiting (20%).

Other clinically significant adverse reactions occurring in ≤10% of patients included: electrocardiogram QT prolonged (7%), cardiac failure (grouped terms) (4%), pericardial effusion (3%), pericarditis (2%), differentiation syndrome (1%), anaphylactic reaction (1%) and posterior reversible encephalopathy syndrome (1%).

Lab Abnormalities: The most common lab abnormalities (>20%) that were Grade ≥3 that occurred ≥10% were: hypophosphatemia (12%), alanine aminotransferase increased (12%), hyponatremia (12%), aspartate aminotransferase increased (10%).

Drug Interactions
Combined P-gp and Strong CYP3A Inducers: Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases XOSPATA exposure which may decrease XOSPATA efficacy. Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers.

Strong CYP3A inhibitors: Concomitant use of XOSPATA with a strong CYP3A inhibitor increases XOSPATA exposure. Consider alternative therapies that are not strong CYP3A inhibitors. If the concomitant use of these inhibitors is considered essential for the care of the patient, monitor patient more frequently for XOSPATA adverse reactions. Interrupt and reduce XOSPATA dosage in patients with serious or life-threatening toxicity.

Drugs that Target 5HT2B Receptor or Sigma Nonspecific Receptor: Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (e.g., escitalopram, fluoxetine, sertraline). Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient.

Specific Populations
Lactation: Advise women not to breastfeed during treatment with XOSPATA and for 2 months after the last dose

Atara Biotherapeutics Presents Off-the-Shelf, Allogeneic CAR T Preclinical Results at the American Association of Cancer Research (AACR) Annual Meeting 2019

On April 1, 2019 Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, reported off-the-shelf, allogeneic CAR T platform preclinical proof-of-concept results at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 in Atlanta, Georgia (Press release, Atara Biotherapeutics, APR 1, 2019, View Source [SID1234534875]).

"Atara is building a leading next-generation CAR T pipeline," said Christopher Haqq, M.D., Ph.D., Executive Vice President and Chief Scientific Officer of Atara Biotherapeutics. "Preclinical results presented today demonstrate that our EBV-specific T cell platform has the potential to be efficiently engineered to generate off-the-shelf, allogeneic CAR T immunotherapies with favorable characteristics. We look forward to advancing this technology using novel co-stimulatory domains and intrinsic checkpoint inhibition, leveraging Atara’s research expertise and world-class T cell manufacturing capabilities."

Atara engineered EBV-specific T cells to express second-generation CD19 CARs (EBV.CD19.CAR T), utilizing CD28 or 4-1BB co-stimulatory domains, resulting in high expression of both the CD19 CAR and EBV T cell receptor (TCR). EBV.CD19.CAR T cells exerted potent and specific cytotoxicity against CD19 or EBV-positive cells and had limited activity against CD19-negative cells, while also depleting alloreactive activity. EBV.CD19.CAR T cells also demonstrated a central memory phenotype that balances expansion with effector function and is associated with persistence.

"EBV.CD19.CAR T cells exhibited optimal CAR T characteristics and in vivo function," said Blake T. Aftab, Ph.D., Vice President, Head of Preclinical and Translational Science for Atara Biotherapeutics. "These data also demonstrate that Atara’s off-the-shelf, allogeneic CAR T process effectively eliminated in vitro alloreactivity. Our findings establish feasibility for combining EBV-specific T cells with novel CAR technologies and support our further development of next-generation off-the-shelf, allogeneic CAR T clinical candidates."

EBV.CD19.CAR T anti-tumor activity was evaluated in vivo in a mouse model of aggressive lymphoma. Following a period of tumor establishment, a single injection of EBV.CD19.CAR T cells significantly inhibited tumor growth.

Additionally, yesterday at the AACR (Free AACR Whitepaper) Annual Meeting 2019, Atara’s collaborators at Memorial Sloan Kettering Cancer Center (MSK), Prasad S. Adusumilli, M.D., and Michel Sadelain, M.D., Ph.D., presented Phase 1 clinical results for a mesothelin-target CAR T immunotherapy that included safety data, anti-tumor responses, and combination data with a PD-1 checkpoint inhibitor. The results further support Atara’s planned development of a next-generation, mesothelin-targeted CAR T immunotherapy using MSK’s novel 1XX CAR signaling domain and PD-1 dominant negative receptor (DNR) checkpoint inhibition technologies for patients with mesothelin-associated solid tumors.

Abstract 2310: Functional demonstration of CD19 chimeric antigen receptor (CAR) engineered Epstein-Barr virus (EBV) specific T cells: An off-the-shelf, allogeneic CAR T-cell immunotherapy platform
Session Category: Immunology
Session Title: Adoptive Cell Therapy 2
Poster Presentation Date and Time: Monday, April 1, 2019, from 1:00 p.m. – 5:00 p.m. EDT
Location: Georgia World Congress Center, Exhibit Hall B
Authors: Blake T. Aftab, Rhine R. Shen, Christina D. Pham, Michelle Wu, Daniel J. Munson
Affiliations: Atara Biotherapeutics

Bolt Biotherapeutics Presents Preclinical Proof of Concept Data at American Association for Cancer Research (AACR) Conference

On April 1, 2019 Bolt Biotherapeutics, Inc., a biotechnology company focused on unleashing the power of the immune system to achieve anti-tumor immunity, reported its positive preclinical proof of concept data on its promising Immune-Stimulating Antibody Conjugate (ISAC) platform (Press release, Bolt Biotherapeutics, APR 1, 2019, View Source [SID1234534874]). The data showed the potential of ISACs to eradicate tumors in animal models, which led to immunological memory of tumor-antigen positive and tumor-antigen negative tumors, suggestive of epitope spreading. These data were presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference in Atlanta, Georgia in a poster presentation titled "TLR7/8 immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity."

In contrast to traditional TLR agonists that require intratumoral administration, Bolt presented a series of in vivo studies demonstrating that its novel Boltbody ISACs can be delivered systemically and generate antitumor immunity in several different cancer models. In human tumor models ranging in HER2 expression level, Boltbody ISAC treatment demonstrated significant anti-tumor efficacy against tumors that could not be controlled by the clinically-validated parental antibody, trastuzumab. Furthermore, in a syngeneic tumor model, animals previously cleared of HER2 positive tumors by Boltbody ISAC treatment were challenged with a second tumor lacking expression of the HER2 tumor-antigen and were resistant to tumor growth. In summary, the key preclinical achievements presented are:

 Anti-tumor efficacy in trastuzumab refractory models
 Immunological memory
 Epitope spreading against tumors without HER2 antigen expression

"This is an exciting opportunity for Bolt to be able to share our novel technology for the first time. We believe our Boltbody ISACs offer many unique benefits including the ability to achieve potent localized antitumor activity following systemic administration given the encouraging results observed by others with intratumoral delivery of TLR agonists in patients," stated David Dornan, Ph.D., senior vice president of research at Bolt Biotherapeutics. "We are advancing toward clinical assessment of our lead candidate as rapidly as possible."

"As a physician who has spent decades developing and understanding cancer immunotherapies, I was pleased to see that the Boltbody ISACs not only cleared tumors, but also generated immunological memory. This indicates the potential for a patient’s immune system to keep cancer from returning," stated Ed Engleman, M.D., Bolt founder and co-director of the Immunology and Immunotherapy Research Program at the Stanford Cancer Institute. "Boltbody ISACs demonstrate the potential to treat patients who are refractory to standard of care therapies and have not yet generated a robust anti-tumor immune response."

About Bolt Biotherapeutics’ Immune-Stimulating Antibody Conjugate (ISAC) Platform Technology
The Boltbody platform consists of Immune-Stimulating Antibody Conjugates (ISAC) that harness the ability of TLR agonists to convert cold tumors into immunologically hot tumors (illuminating tumors to the immune system allowing them to be invaded by tumor killing cells). Boltbody ISACs have demonstrated the ability to eliminate tumors following systemic administration in preclinical models and have also led to the development of immunological memory.

Constellation Pharmaceuticals Presents Results from Phase 1b Portion of ProSTAR Clinical Trial of CPI-1205 at AACR Meeting

On April 1, 2019 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported its results from the Phase 1b portion of the ProSTAR clinical trial of CPI-1205 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting in Atlanta (Press release, Constellation Pharmaceuticals, APR 1, 2019, View Source [SID1234534873]). Poster CT094/18, ProSTAR: A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC), was presented at the poster session starting at 1:00 PM EDT today. The Company will present two other posters highlighting its preclinical pipeline later in the AACR (Free AACR Whitepaper) meeting.

"We are pleased to report the ProSTAR Phase 1b results," said Adrian Senderowicz, Chief Medical Officer. "These results show clinical activity in subsets of a heterogeneous population of advanced mCRPC patients in combination with either abiraterone or enzalutamide. Activity was particularly noteworthy in patients taking CPI-1205 in combination with abiraterone, an agent where responses in second-line patients have historically been poor, and in AR-V7-negative patients. Based on the entirety of the results, we initiated the Phase 2 portion of the trial in late 2018 to better define the patient populations most likely to benefit from CPI-1205. We look forward to reporting initial Phase 2 data in the second half of 2019."

The poster presentation included the following highlights from the Phase 1b portion of ProSTAR, using a February 6, 2019, data cutoff:

Baseline Characteristics

The Phase 1b portion of ProSTAR enrolled 36 patients: 20 in the CPI-1205 + abiraterone arm and 16 in the CPI-1205 + enzalutamide arm.

Each arm studied two different dose regimens of CPI-1205 as part of the combination: 800 mg three times daily or 400 mg twice daily + cobicistat (to block CYP3A4).

The Phase 1b portion of ProSTAR was conducted in a heterogeneous patient population who had been treated with a variety of treatment regimens, including chemotherapy. As such, a significant proportion of patients had indicators of poor prognosis at baseline. Of the 36 patients enrolled, 13 (36%) were positive for Androgen Receptor Splice Variant 7, or AR-V7, isoforms (proteins with similar structures); 20 (56%) had unfavorable circulating tumor cell counts; 13 (36%) had previously received chemotherapy; and 18 (50%) had abnormal levels of lactate dehydrogenase (an enzyme in the blood that can indicate tissue damage, cancer, or some noncancerous conditions) at baseline.

Because patients without AR-V7 isoforms have tended to respond better to ARS inhibition than those with AR-V7 isoforms, and given the hypothesis that ARS inhibition acts synergistically with EZH2 inhibition, patients without AR-V7 isoforms may be more likely to benefit from the potential synergistic effect of CPI-1205 with ARS inhibitor therapy.

Clinical Activity

Clinical activity was observed in both the enzalutamide and abiraterone arms, including ³50% PSA reductions and an objective response by RECIST 1.1 criteria.

All PSA responses seen in the trial were ³80%, deeper than the ³50% reduction endpoint in the trial. All PSA responses were found in AR-V7-negative patients. Two out of 18 patients in the abiraterone arm achieved PSA reductions of more than 80%. Patients being treated with abiraterone after enzalutamide historically have been shown to achieve poor PSA responses and rapid time to disease progression. PSA responses are summarized below:

³80% PSA
Reductions in
AR-V7-Positive
Patients ³80% PSA
Reductions in
AR-V7-Negative
Patients
CPI-1205 + abiraterone**

0/8* (0%) 2/10* (20%)
CPI-1205 + enzalutamide**

0/5 (0%) 3/11 (27%)

*
2 patients not evaluable for PSA response

Includes patients treated with CPI-1205 800 mg three times daily and CPI-1205 400mg twice daily + cobicistat

The majority of patients with measurable lesions achieved durable disease control during the study, as follows:

Partial
Response Stable
Disease Disease
Control Rate of
Any Duration Disease
Control Rate
³3 Months
CPI-1205 + abiraterone

0/8 (0%) 6/8 (75%) 6/8 (75%) 4/8 (50%)
CPI-1205 + enzalutamide

1/5 (20%) 2/5 (40%) 3/5 (60%) 3/5 (60%)
Several patients achieved disease control that exceeded or was approaching six months at the data cutoff while continuing therapy.

Safety

CPI-1205 was generally well tolerated in combination with enzalutamide or abiraterone. The most common treatment-related adverse events (³20%) were fatigue, diarrhea, and nausea, which were usually mild to moderate in severity and manageable with supportive care. In combination with enzalutamide, treatment-related adverse events ³ Grade 3 included fatigue, nausea, and increased ALT (n=1; 6.3%, respectively). In combination with abiraterone, treatment-related adverse events ³ Grade 3 included fatigue and increased ALT (n=1; 5%, respectively). For more details, please see the poster here.

Pharmacokinetics/Pharmacodynamics (PK/PD)

Patients in two treatment arms were dosed with 800 mg of CPI-1205 three times daily with enzalutamide or abiraterone. Patients in the other two arms were dosed with 400 mg of CPI-1205 twice daily in combination with cobicistat, a CYP3A4 inhibitor, and enzalutamide or abiraterone. While the Company observed in the trial that cobicistat increased the exposure of CPI-1205, the Company did not observe meaningful differences in pharmacodynamics or efficacy compared to 800 mg of CPI-1205 three times daily without cobicistat. Therefore the recommended Phase 2 dose of CPI-1205 for ProSTAR Phase 2 was determined to be 800 mg three times daily.

Phase 2

The Phase 1b portion of ProSTAR was designed primarily to study the safety, pharmacokinetics, pharmacodynamics, maximum tolerated dose, and a recommended Phase 2 dose of CPI-1205 with abiraterone and enzalutamide. Based on the Phase 1b data, the Company initiated the Phase 2 portion of ProSTAR in late 2018. The Phase 2 portion of the trial is evaluating CPI-1205 in combination with an ARS inhibitor as a second-line treatment for patients with mCRPC. The Company will collect and analyze biomarker and other translational data in Phase 2 to better define which patients may be most likely to respond to treatment with CPI-1205. Two randomized arms of Phase 2 are studying CPI-1205 in combination with enzalutamide versus enzalutamide alone.

In addition, because of the activity seen in the abiraterone arm in the Phase 1b portion of ProSTAR, the Company has also initiated a Phase 2 arm to evaluate CPI-1205 in combination with abiraterone in second-line mCRPC patients. According to a recent study by the laboratory of Dr. Kim Chi of the Vancouver Prostate Centre, few patients responded to treatment with abiraterone after experiencing disease progression on enzalutamide. For this reason, we have not instituted an additional control arm. In the Chi study, out of 101 patients receiving abiraterone after experiencing disease progression on enzalutamide, no patients achieved an 80% reduction in PSA levels and only 4% achieved a 50% PSA reduction.1 The patient population in the Chi study had baseline characteristics that are different from those in the Phase 1b portion of ProSTAR, and more similar to those that are expected to be in ProSTAR Phase 2. For example, unlike ProSTAR Phase 1b, in which patients had been previously treated with a range of therapies – including 36% who had received chemotherapy – ProSTAR Phase 2, like the Chi study, is enrolling only patients receiving second-line therapy with no prior chemotherapy in order to focus on activity in that patient population.

The Company expects to provide an initial update from the Phase 2 portion of ProSTAR in the second half of 2019.

For more information on the Phase 1b portion of ProSTAR, please see the poster here.

1
D Khalaf et al., Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCRPC): results for 2nd-line therapy, poster presented at 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) meeting.

Discovery Pipeline

Constellation is presenting two additional posters at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) meeting that speak to the depth and breadth of the Company’s product pipeline and its expertise in epigenetics. Poster 4351/11, Single-cell RNA sequencing reveals transcriptomic heterogeneity in response to epigenetic inhibitors, will be presented at the 1PM-5PM EDT poster session on April 2. Poster 4722/12, Efficacy of novel EP300/CBP histone acetyltransferase inhibitor in hormone responsive breast cancer, will be presented at the 8AM-12PM EDT poster session on April 3.

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.

About mCRPC

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced form of prostate cancer and is defined by disease progression despite treatment with androgen depletion therapy (ADT). mCRPC may present as one or any combination of the following: a continuous rise in serum levels of PSA, progression of known metastases, or appearance of new metastases. Prognosis is associated with several factors, including the ability to perform certain daily activities and the presence of bone pain. Additional symptoms commonly include anemia (low levels of healthy red blood cells), weight loss,

fatigue, hypercoagulability (abnormal blood coagulation), and increased susceptibility to infection. mCRPC presents as a spectrum of disease, ranging from patients without symptoms but rising PSA levels despite ADT to patients with metastases and significant debilitation.