On June 27, 2018 Pfizer Inc. (NYSE:PFE) reported that the U.S. Food and Drug Administration (FDA) accepted the company’s New Drug Application and granted Priority Review designation for glasdegib, an investigational oral smoothened (SMO) inhibitor, being evaluated for the treatment of adult patients with previously untreated acute myeloid leukemia (AML) in combination with low-dose cytarabine (LDAC), a type of chemotherapy (Press release, Pfizer, JUN 27, 2018, View Source [SID1234527490]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Patients with acute myeloid leukemia who are ineligible for intensive chemotherapy are in critical need of new treatment options to improve their overall survival," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "In an investigational Phase 2 study, glasdegib in combination with low-dose cytarabine showed a significant improvement in overall survival compared to patients who received low-dose cytarabine alone. Glasdegib is the first smoothened inhibitor to potentially offer such a benefit to patients with acute myeloid leukemia, and we are proud that our application was accepted by the FDA for Priority Review."

The FDA grants Priority Review designation to medicines that may offer significant advances in treatment or may provide a treatment where no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in December 2018.

The submission is based on results from the Phase 2 BRIGHT 1003 study, a randomized, open-label, multicenter trial investigating glasdegib combined with LDAC (n=88) versus LDAC alone (n=44) in 132 patients with previously untreated AML or high-risk myelodysplastic syndrome (MDS) who were not eligible for intensive chemotherapy. Results demonstrated a significant improvement in the primary endpoint of overall survival (OS). Median OS was 8.8 months for patients treated with glasdegib plus LDAC compared with 4.9 months for patients treated with LDAC only. This difference represented a 49.9 percent reduction in the risk of death for patients treated with glasdegib plus LDAC (HR: 0.501, 95% CI: 0.334, 0.752, one-sided p-value 0.0003). The BRIGHT 1003 results were presented in 2016 at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

The most frequently (≥30% of patients) reported adverse events (AEs) in patients treated with glasdegib plus LDAC compared to LDAC alone were anemia (45% vs 42%), febrile neutropenia (36% vs 27%), nausea (36% vs 12%), decreased appetite (32% vs 12%), fatigue (31% vs 20%) and thrombocytopenia (30% vs 27%). The most frequently (≥15% of patients) reported serious AEs for patients treated with glasdegib plus LDAC compared to LDAC alone were febrile neutropenia (29% vs 20%) and pneumonia (21% vs 17%).

About Glasdegib

Glasdegib is an investigational, oral, once-daily therapy that is thought to inhibit the SMO receptor, thereby disrupting the Hedgehog pathway. Abnormal Hedgehog pathway activation is thought to play a role in the development of multiple types of cancers, including solid tumors and hematologic malignancies. It has not received regulatory approval in any country.

The Phase 3 BRIGHT AML 1019 trial (NCT03416179), which is evaluating the addition of glasdegib to intensive or non-intensive chemotherapy in patients with newly diagnosed AML, began enrolling earlier this year.

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and accounts for approximately 80 percent of all cases of acute leukemia.1 An estimated 19,520 people are expected to be diagnosed with AML in the U.S. in 2018.1 Despite recent advancements, only approximately one in four patients with AML survive longer than five years, and additional treatment options are needed to reduce incidence of disease progression and relapse.2,3 This is especially true for patients who are unable to receive intensive chemotherapy and are triaged to other treatments associated with poorer outcomes.

On June 27, 2018 Purdue Pharma L.P. reported successful completion of a first-in-human Phase 1 dose escalation study of tinostamustine in patients with relapsed or refractory hematological malignancies for which there are no available therapies (Press release, Purdue Pharma, JUN 27, 2018, View Source [SID1234527497]). The study evaluated the safety and pharmacokinetics, and sought to determine the maximum tolerated dose and inform a Phase 2 dose of tinostamustine. 1

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The multi-acting therapy candidate tinostamustine, previously known as EDO-S101, is a novel and potentially first-in-class alkylating deacetylase inhibitor (AK-DACi) therapy being studied for its potential to improve access to the DNA strands within cancer cells, break them, and counteract the cancer cells’ attempt to repair the DNA damage. It is in development for a range of rare or difficult to treat blood cancers and solid tumors. Based on the results of this Phase I human trial, Purdue will support advancement of tinostamustine into further clinical studies.

"We are pleased with the outcome of this promising early stage oncology program and we believe it has the potential to make meaningful clinical contributions in areas with significant unmet needs," said Craig Landau, MD, president and CEO, Purdue Pharma. "In addition to our established commitments in oncology and neuroscience, we are actively seeking opportunities to collaborate across a number of therapeutic areas as part of our ongoing efforts to diversify our scientific research and bring therapies to market that may improve outcomes for patients."

The reported completion of this study is the first clinical update since Purdue announced in November 2017 significant oncology-related investments to establish a portfolio of drug candidates with the potential to deliver new cancer therapies, in areas of high unmet medical need, to physicians and patients. As part of these investments, Purdue is currently supporting research for four drug candidates across 14 different cancer types. Research on these compounds is being advanced on behalf of Purdue by Mundipharma EDO.

In addition to tinostamustine, Purdue’s clinical stage oncology portfolio includes etoposide toniribate, a novel target-activated topoisomerase inhibitor that delivers the chemotherapy etoposide to tumors in an inactive form where it is ‘switched on’ by enzymes called carboxylesterases. Purdue also has two late pre-clinical stage antibody-drug conjugates, EDO-B776 and EDO-B278, in development. EDO-B776 is being studied for its potential to target the cancer antigen 125 (CA-125) in ovarian cancer. EDO-B278, which targets human tissue factor, is in development for treatment of various solid tumors.

The decision to move tinostamustine into Phase 1 human trials was supported by preclinical studies, which suggest that tinostamustine may deliver both alkylating activity and pan-histone deacetylase (HDAC) inhibition to improve access to the DNA strands within cancer cells, break them, and counteract the cancer cells’ attempt to repair the DNA damage.

Purdue will also continue to selectively seek additional oncology product assets through licensing and acquisition, and the company will maintain a priority interest in candidates with mechanisms complementary to emerging immuno-oncology based treatment paradigms

On June 27, 2018 Forty Seven, Inc. (Nasdaq:FTSV), a clinical stage immuno-oncology company, reported the pricing of its initial public offering of 7,035,000 shares of common stock at a price to the public of $16.00 per share (Press release, Forty Seven, JUN 27, 2018, View Source [SID1234527522]). In addition, Forty Seven has granted the underwriters a 30-day option to purchase up to an additional 1,055,250 shares of common stock solely to cover over-allotments, if any, at the initial public offering price less underwriting discounts and commissions. The shares are expected to begin trading on The Nasdaq Global Select Market under the symbol "FTSV" on June 28, 2018.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Morgan Stanley and Credit Suisse are acting as lead bookrunners, Canaccord Genuity is acting as lead manager, and BTIG and Oppenheimer & Co. Inc. are acting as co-managers for the offering.

The offering is being made only by means of a prospectus. A copy of the final prospectus, when available, may be obtained from Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, Second Floor, New York, New York 10014; or Credit Suisse Securities (USA) LLC, Attention: Prospectus Department, One Madison Avenue, New York, New York, 10010 or by email at [email protected].

A registration statement relating to these securities has been filed with, and declared effective by, the Securities and Exchange Commission. 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.

On June 26, 2018 BerGenBio ASA (OSE:BGBIO) reported that on a top-line, preliminary basis, the first efficacy endpoint has been met in its Phase II clinical trial (BGBC008) evaluating bemcentinib, a first-in-class oral selective AXL inhibitor, in combination with the Merck & Co., Inc., Kenilworth, N.J., USA anti-PD-1 therapy KEYTRUDA (pembrolizumab) as a potential new treatment regimen for advanced non-small cell lung cancer (NSCLC)(Press release, BerGenBio, JUN 26, 2018, View Source [SID1234527463]) . The primary efficacy endpoint requires at least four patients (out of the first 22 treated patients) to achieve clinical responses when treated with the novel drug combination, defined as either complete or partial response, as measured by Response Evaluation Criteria in Solid Tumors (RECIST).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "Immunotherapy has become a major component of the treatment of many cancers – patients who respond to immune checkpoint inhibitors like KEYTRUDA enjoy long-term disease control with excellent quality of life. Unfortunately, only a minority of lung cancer patients receiving KEYTRUDA monotherapy in second-line respond to treatment. The BGBC008 combination trial of bemcentinib with KEYTRUDA evaluates whether the addition of our selective AXL inhibitor will improve the outcome of immunotherapy.

"Clearing the first efficacy threshold in this ongoing Phase II trial is very encouraging and we intend to begin enrolment for Stage 2 of this study in which 24 further patients will be enrolled under the same protocol. Thus far, we are delighted to see activity in a number of patients receiving this novel treatment regimen. A particularly encouraging finding is that we see responses in patients who are negative for the PD-L1 biomarker, for whom KEYTRUDA monotherapy is not indicated. The second stage of the trial is intended to confirm activity and biomarker correlation in a larger group of patients – comprehensive analysis of the Phase II data will continue and will be presented at a future scientific conference.

"Successfully completing this important milestone further supports our belief in the potential of bemcentinib to become a cornerstone of cancer therapy. We look forward to sharing more details from our Phase II clinical programme during major clinical conferences in the coming months."

About the BGBC008 trial combining bemcentinib with KEYTRUDA (pembrolizumab) conducted in collaboration with Merck & Co., Inc.
Design
The BGBC008 trial is a Phase II multi-centre open-label study of bemcentinib in combination with KEYTRUDA (pembrolizumab) in previously treated, immunotherapy naïve, patients with advanced adenocarcinoma of the lung, the most common form of non-small cell lung cancer (NSCLC). The objective of the trial is to determine the anti-tumour activity of this novel drug combination and responses will be correlated with biomarker status (including AXL kinase and PD-L1 expression).

A pre-defined efficacy endpoint was set at four or more responses observed in the first 22 patients based on previously reported response rates to KEYTRUDA monotherapy in the second line setting in NSCLC.

Status June 2018
To date, 4 responses (partial responses as per RECIST v1.1) have been observed in the first 22 patients. A number of patients remain ongoing and are awaiting the confirmation of their best response.

Patients generally tolerated the novel drug combination well – no new safety events were reported from the combination of bemcentinib with KEYTRUDA at full dose.

A preliminary interim analysis of the trial (from 15 patients evaluable for response) was presented at ASCO (Free ASCO Whitepaper) 2018, where tumour shrinkage was observed in about half of the patients analysed to date. Results looked particularly promising in patients who did not express the PD-L1 biomarker, i.e. representing 1/3 of NSCLC patients, a group for whom KEYTRUDA monotherapy as a second line is not indicated.

For more information please access trial NCT03184571 at www.clinicaltrials.gov.

On June 26, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY), reported that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) and granted Priority Review for baloxavir marboxil as a single-dose, oral treatment for acute, uncomplicated influenza in patients 12 years and older (Press release, Hoffmann-La Roche, JUN 26, 2018, View Source [SID1234527464]). The FDA is expected to make a decision on approval by 24 December 2018. A Priority Review designation is granted to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The severity of the recent flu season underscores the need for new options beyond currently available treatments, and if approved, baloxavir marboxil would be the first flu medicine with a novel proposed mechanism of action in nearly 20 years," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Baloxavir marboxil has been shown in clinical trials to decrease the duration of symptoms with one dose, and demonstrated a significant reduction in viral shedding in just one day. We look forward to working with the FDA during the review process."

Baloxavir marboxil is a first-in-class, single-dose investigational oral medicine with a novel proposed mechanism of action designed to target the flu virus, including oseltamivir-resistant strains and avian strains (H7N9, H5N1).7,8,9 Unlike other currently available antiviral treatments, baloxavir marboxil is designed to inhibit the cap-dependent endonuclease protein within the flu virus, which is essential for viral replication.10,11

The NDA is based on results from the phase III CAPSTONE-1 study of a single dose of baloxavir marboxil compared with placebo or oseltamivir 75 mg, twice daily for five days, in otherwise healthy people with flu. Additionally, results from a placebo-controlled phase II study in otherwise healthy people with the flu is included as supporting data in the NDA.

About CAPSTONE-1
CAPSTONE-1 is a phase III multicentre, randomised, double-blind, placebo-controlled study that evaluated the efficacy and safety of baloxavir marboxil in 1,436 people in the United States and Japan. The primary endpoint of the study was time to alleviation of symptoms (TTAS), and important secondary endpoints were time to resolution of fever, time to cessation of viral shedding and the proportion of participants positive for influenza virus titre, or virus levels in the body, by time point. The study found the following results:

Baloxavir marboxil met its primary and secondary endpoints compared to placebo:
Significantly reduced the duration of flu symptoms by more than one day (median time 53.7 hours versus 80.2 hours; p<0.0001);
Significantly reduced the duration of fever by nearly a day (median time 24.5 hours versus 42.0 hours; p<0.0001);
Significantly reduced the length of time viruses continued to be released from the body (median time of viral shedding; 24.0 hours versus 96.0 hours; p<0.0001);
Significantly reduced the levels of virus in the nose and throat from 24 hours through 120 hours.
Similar efficacy results were seen between baloxavir marboxil and oseltamivir in relation to duration of symptoms and fever reduction, but significant differences were observed in time to cessation of viral shedding favouring baloxavir marboxil:
No significant reduction in duration of symptoms (median time 53.5 hours versus 53.8 hours; p=0.7560);
No significant reduction in time to resolution of fever (median time 24.4 hours versus 24.0 hours; p=0.9225);
Significantly reduced the length of time the virus continued to be released from the body (viral shedding; 24.0 hours versus 72.0 hours; p<0.0001);
Significantly reduced the levels of virus in the nose and throat at 24 hours and 72 hours.
Baloxavir marboxil was well-tolerated and had a numerically lower overall incidence of adverse events (20.7%) reported compared with placebo (24.6%) or oseltamivir (24.8%). The most common adverse events reported were diarrhoea (3.0%), bronchitis (2.6%), nausea (1.3%) and sinusitis (1.1%), and all of these adverse events occurred at a lower frequency than placebo.

About baloxavir marboxil
Baloxavir marboxil is a first-in-class, single-dose investigational oral medicine with a novel proposed mechanism of action designed to target the influenza ("flu") A and B viruses, including oseltamivir-resistant strains and avian strains (H7N9, H5N1).7,8,9 Unlike other currently available antiviral treatments, baloxavir marboxil is the first in a new class of antivirals designed to inhibit the cap-dependent endonuclease protein within the flu virus, which is essential for viral replication.

Baloxavir marboxil is being studied in an ongoing phase III development program including paediatric populations with influenza. Data from the global phase III study (CAPSTONE-2) in patients 12 years and older with a high risk of complications from influenza, as defined by the Centers for Disease Control and Prevention (CDC), will be shared at a later date.

Baloxavir marboxil was discovered by Shionogi & Co., Ltd. and is being developed globally by the Roche Group (which includes Genentech in the U.S.) and Shionogi & Co., Ltd. Under the terms of this agreement, Roche holds worldwide rights to baloxavir marboxil excluding Japan and Taiwan, which will be retained exclusively by Shionogi & Co., Ltd. Baloxavir marboxil was approved in February 2018 by the Japanese Ministry of Health, Labour and Welfare for the treatment of influenza types A and B in adult and paediatric patients and is being commercialised in Japan and marketed under the brand name Xofluza.