On March 13, 2020 Eiger BioPharmaceuticals, Inc. (Nasdaq:EIGR), focused on the development and commercialization of targeted therapies for serious rare and ultra-rare diseases, reported financial results for the fourth quarter and full year 2019 and provided a business update (Press release, Eiger Biopharmaceuticals, MAR 13, 2020, View Source [SID1234555557]).

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"We are pleased to announce the submission of the MAA for lonafarnib in Progeria and Progeroid Laminopathies and look forward to completing the NDA submission by end of the month as planned," said David Cory, President and CEO of Eiger. "Site activations, enrollment, and dosing are ongoing in our global Phase 3 HDV study, D-LIVR, and we expect to complete enrollment in 2020. We are closely monitoring the potential impact of COVID-19 on the timing and conduct of D-LIVR. We will remain responsive to any developments and take necessary steps to protect our patients and the integrity of the study."

Recent Highlights and Upcoming Milestones

Lonafarnib in Hepatitis Delta Virus (HDV)

Enrollment of Phase 3 D-LIVR study (N=400) planned to complete in 2020
Lonafarnib in Progeria and Progeroid Laminopathies

Marketing Authorization Application (MAA) to EMA completed
Accelerated Assessment for MAA granted by EMA
New Drug Application (NDA) to FDA on-track for completion by end of March 2020
Peginterferon Lambda (lambda) in HDV

Positive End of Phase 2 meeting with FDA with agreement on single Phase 3 study
Plan to finalize Scientific Advice with EMA
End-of-Treatment data from LIFT (lambda combo with lonafarnib) at EASL 2020
Corporate

Appointed Eldon Mayer as Executive Vice President and Chief Commercial Officer
Fourth Quarter and Full Year 2019 Financial Results

Cash, cash equivalents, and short-term investments as of December 31, 2019 totaled $95.0 million compared to $100.4 million at December 31, 2018, a decrease of $5.4 million.

The Company reported net losses of $16.9 million, or $0.69 per share, and $70.3 million, or $3.08 per share, for the fourth quarter and full year 2019, respectively, as compared to $16.5 million, or $0.93 per share, and $52.4 million, or $3.84 per share, for the same periods in 2018.

Research and Development expenses were $11.9 million and $51.8 million for the fourth quarter and full year 2019, respectively, as compared to $12.0 million and $37.1 million for the same periods in 2018. The increase in full year 2019 expenses was primarily due to costs associated with the Phase 3 D-LIVR HDV study, including drug supply costs, which ramped-up in 2019, employee-related costs from increased headcount and an increase in regulatory related expenses.

General and Administrative expenses were $4.6 million and $17.1 million for the fourth quarter and full year 2019, respectively, as compared to $4.1 million and $14.0 million for the same periods in 2018. The increases in fourth quarter and full year 2018 were primarily due to increases in employee-related costs, including stock-based compensation, from increased headcount and outside services for legal, consulting, advisory and accounting services.

Total operating expenses include total non-cash expenses of $1.6 million and $6.6 million for the fourth quarter and full year 2019, respectively, as compared to $1.6 million and $5.7 million for the same periods in 2018.

As of December 31, 2019, the company had 24.5 million of common shares outstanding

On March 13, 2020 Five Prime Therapeutics, Inc. (NASDAQ: FPRX), a clinical-stage biotechnology company focused on developing immune modulators and precision therapies for solid tumor cancers, reported the publication of results from the phase 1 escalation and expansion study of bemarituzumab in patients with advanced solid tumors and FGFR2b-selected gastroesophageal adenocarcinoma in the digital edition of the Journal of Clinical Oncology (Press release, Five Prime Therapeutics, MAR 13, 2020, View Source [SID1234555555]).

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The purpose of the phase 1 trial was to evaluate the safety, pharmacokinetics, and preliminary activity of single-agent bemarituzumab in patients with FGFR2b-overexpressing GEA. Seventy-nine patients were enrolled in the trial and no dose-limiting toxicities were reported. Bemarituzumab was well tolerated and the most frequent treatment-related adverse events (TRAEs) were fatigue, nausea, and dry eye. The overall response rate observed in this study of advanced-stage patients with high FGFR2b-overexpressing GEA was 17.9% (95% CI 6.1% to 36.9%) with five of 28 patients achieving a confirmed partial response.

"Gastroesophageal adenocarcinoma is the third most common cause of cancer death worldwide and the median overall survival of patients who present with advanced disease remains dismal at only 11 months," said Helen Collins, M.D., Executive Vice President and Chief Medical Officer of Five Prime Therapeutics. "The results of this study underscore the potential of bemarituzumab evaluation as a novel treatment option for patients with advanced gastric and gastroesophageal junction cancer."

"Monotherapy activity of bemarituzumab and its lack of significant overlapping toxicities with standard chemotherapeutic agents suggest that combining bemarituzumab with chemotherapy may potentially benefit patients in the front-line setting whose GEA tumors overexpress FGFR2b," said Daniel Catenacci, M.D. and Associate Professor, the University of Chicago Medical Center and Biological Sciences.

Bemarituzumab is being evaluated in combination with mFOLFOX6 in the Phase 3 FIGHT (FGFR2b Inhibition in Gastric and Gastroesophageal Junction Cancer Treatment) trial in the front-line treatment setting.

On March 13, 2020 Savara Inc. (Nasdaq: SVRA), an orphan lung disease company, reported financial results for the fourth quarter and full year ending December 31, 2019 and provided a business update (Press release, Savara, MAR 13, 2020, View Source [SID1234555554]).

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"Results from the open-label period of IMPALA reaffirm our strong belief that Molgradex could improve outcomes for patients with aPAP, a rare and debilitating lung disease," said Rob Neville, Chief Executive Officer, Savara. "We continue our conversations with the FDA, as our highest priority is to get clarity from the agency regarding the design and endpoints of a second Phase 3 study in aPAP."

PROGRAM UPDATES

Molgradex for aPAP

Announced the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for Molgradex, an inhaled formulation of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), for the treatment of aPAP.
Working in consultation with the FDA to plan a second Phase 3 study.
Completed enrollment in IMPALA-X, an open-label multicenter extension study to determine the long-term safety and use of Molgradex in patients with aPAP. Sixty out of 64 eligible patients enrolled in the study.
The Company reported results from the open-label follow-up period of IMPALA, a Phase 3 study that evaluated Molgradex for the treatment of aPAP. The results, found below, will be discussed on today’s conference call/webcast. Data from the double-blind period of IMPALA were presented at the 2019 European Respiratory Society (ERS) International Congress and can be found on the Articles and Publications page of Savara’s website.

IMPALA Study Design

IMPALA was a randomized, double-blind, placebo-controlled clinical study designed to compare the efficacy and safety of Molgradex with placebo in patients with aPAP. Patients were randomized to receive treatment for 24 weeks in one of three arms: 1) Molgradex 300 µg administered once daily continuously over 24 weeks, 2) Molgradex 300 µg, and matching placebo, each administered once daily every other week, or 3) inhaled placebo administered once daily continuously over 24 weeks. At the end of the 24-week double-blind period, all treatment arms rolled into a 24-week open-label follow-up period and received Molgradex 300 µg administered once daily every other week.

The primary endpoint was change from baseline in alveolar-arterial oxygen gradient, or (A-a)DO2, to week 24. In addition, three key secondary endpoints―St. George’s Respiratory Questionnaire (SGRQ), six-minute walk distance (6MWD), and time to requirement for whole lung lavage (WLL)―along with multiple other secondary and exploratory endpoints were assessed.

IMPALA Open-Label Period

A total of 128 patients completed the open-label period of IMPALA. Sixty-eight patients enrolled in the open-label period through week 48. The other 60 patients were enrolled under an early protocol version of the study through week 72.

During the double-blind period, a dose frequency dependency was observed in most endpoints with continuous administration of Molgradex showing higher efficacy than placebo and continuous administration appearing to result in higher efficacy than once daily dosing every other week. Open-label results presented below focus on the group that had received a once daily continuous dose (OD) of Molgradex during the double-blind period versus those that had received once daily placebo (PBO) during the double-blind period―both of which received once daily dosing every other week during the open-label period.

Improvements in Two Independent Measures of Gas Exchange

In addition to (A-a)DO2, diffusing capacity of the lungs for carbon monoxide (DLCO) is another way to assess gas exchange. As with (A-a)DO2, DLCO is impaired in patients with aPAP and was assessed as an additional secondary endpoint in the study.

Patients who had been in the OD treatment group during the double-blind period:

Improvement from baseline was maintained or progressively increased in these patients during the open-label period of the study. The average (A-a)DO2 improvement in the double-blind period was -12.1 mmHg at week 24, compared to an average improvement from baseline in the open-label period of -12.2 mmHg and -18.8 mmHg at weeks 48 and 72, respectively. (See Figure 1.) The mean absolute improvement in DLCO during the double-blind period was 11.6% predicted at week 24, compared to a mean absolute improvement from baseline in the open-label period of 13.7% and 19.8% predicted at weeks 48 and 72, respectively.

Patients who had been in the PBO group during the double-blind period:

PBO patients that transitioned to active drug in the open-label period showed similar average improvements to those who had been in the double-blind OD group. The average (A-a)DO2 improvement in the double-blind period was -8.8 mmHg at week 24, compared to an average improvement from baseline in the open-label period of -14.6 mmHg and -17.0 mmHg at weeks 48 and 72, respectively. (See Figure 1.) The mean absolute improvement in DLCO during the double-blind period was 3.9% predicted at week 24, compared to a mean absolute improvement from baseline in the open-label period of 14.2% and 18.0% predicted at weeks 48 and 72, respectively.

Improvements in SGRQ

Patients who had been in the OD treatment group during the double-blind period:

Changes from baseline in the SGRQ were maintained and further increased with longer exposure to Molgradex. The average improvement during the double-blind period was -12.3 points at week 24, compared to an average improvement from baseline in the open-label period of -13.1 and -17.4 points at weeks 48 and 72, respectively. (See Figure 2.)

Patients who had been in the PBO group during the double-blind period:

At the end of the open-label period, PBO patients that transitioned to active drug showed similar average improvements in the SGRQ to those who received OD in the double-blind period. The average improvement during the double-blind period was -4.7 points at week 24, compared to an average improvement from baseline in the open-label period of -14.7 and -14.9 points at weeks 48 and 72, respectively. (See Figure 2.)

Improvements in 6MWD

Patients who had been in the OD treatment group during the double-blind period:

The average improvement during the double-blind period was 39.6 meters at week 24, compared to an average improvement from baseline in the open-label period of 48.9 meters and 71.7 meters at weeks 48 and 72, respectively.

Patients who had been in the PBO group during the double-blind period:

The average improvement during the double-blind period was 6.0 meters at week 24, compared to an average improvement from baseline in the open-label period of 40.4 meters and 29.9 meters at weeks 48 and 72, respectively.

Improvements in WLL

During the double-blind period of the study, 33 whole lung lavage procedures were required, including 9 in the continuous group compared to 17 in the placebo group. During the open-label period of the study only 5 whole lung lavage procedures were conducted. The pre-study rate of WLL was 0.8 procedures per patient year, compared to 0.055 procedures per patient year during the open-label period of the study. (See Figure 3.)

The Company intends to present more comprehensive data from the IMPALA study at an upcoming scientific conference and/or submit it for consideration in a peer-reviewed journal.

Molgradex for NTM Lung Infection

The Company reported top line microbiology results from OPTIMA, a Phase 2a, exploratory, open-label, non-controlled clinical study evaluating Molgradex for the treatment of NTM lung infection in patients not affected by cystic fibrosis (CF). The results, found below, will be discussed on today’s conference call/webcast.

OPTIMA Study Design

The OPTIMA study, comprised of a 48-week treatment period and a 12-week follow-up period, enrolled patients with either Mycobacterium avium complex (MAC) infection, or the more difficult-to-treat Mycobacterium abscessus (MABSC) infection. Prior to enrolling, all patients were diagnosed with bronchiectasis, with all except one having radiological evidence of nodular multifocal and/or cavitary bronchiectasis. Two treatment groups of patients were recruited into the study, both of which received Molgradex 300 µg administered once daily. Treatment group one consisted of patients who remained sputum culture positive while currently on a multidrug NTM guideline-based anti-mycobacterial regimen, which had been ongoing for at least six-months prior to the baseline visit. Treatment group two consisted of patients who remained sputum culture positive, but either stopped a multidrug NTM guideline-based anti-mycobacterial regimen at least 28 days prior to screening due to lack of response or intolerance, or never started such treatment.

Summary of Efficacy and Safety Results

Thirty-two patients were treated in the study, of which 24 had MAC infection and 8 had MABSC infection. Of the patients with MAC infection, 11 were in treatment group one and 13 were in treatment group two. Of the patients with MABSC infection, 3 were in treatment group one and 5 were in treatment group two.

Results from the Intention-to-Treat (ITT) population showed that 5 out of 24 patients (21%) with MAC infection achieved a sputum culture conversion, defined as at least three consecutive sputum samples without growth of nontuberculous mycobacteria during the treatment period. Two of these patients, one from each treatment group, remained culture negative through the 12-week follow-up period. Sputum culture conversions were not observed in patients with MABSC infection.

Among the 32 treated patients in the safety population, 14 experienced serious adverse events (SAEs), one of which was considered potentially treatment related. The most common SAE was infective exacerbation of bronchiectasis. Three patients died during the study, with all deaths unlikely related to the study treatment.

The Company will continue to assess data from the OPTIMA study to better understand the clinical outcomes seen in some patients. Next steps for the NTM program will be determined once results from ENCORE, an ongoing Phase 2a, open-label, non-controlled study evaluating Molgradex for the treatment of NTM in patients living with CF, are available.

The Company intends to submit the full data set from OPTIMA for consideration at an upcoming scientific conference.

AeroVanc

Enrollment continues in AVAIL, a pivotal Phase 3 clinical study of AeroVanc for the treatment of persistent methicillin-resistant Staphylococcus aureus (MRSA) lung infection in CF. Total target enrollment is 200 patients. The adult population is fully enrolled, and the Company has enrolled 133 patients out of a target of 150 in the primary analysis population (younger patients between 6-21 years of age). The Company will continue enrollment until Q2 2020 and anticipates enrolling a total of ~140 younger patients. Top line results are expected in early 2021.

Fourth Quarter Financial Results (Unaudited)

Savara’s net loss for the fourth quarter of 2019 was $31.7 million, or $(0.72) per share, compared with a net loss of $10.5 million, or $(0.29) per share, for the fourth quarter of 2018. Research and development expenses were $8.7 million for the fourth quarter of 2019, compared with $9.9 million for the fourth quarter of 2018.

General and administrative expenses for the fourth quarter of 2019 and 2018 were $3.3 million.

As of December 31, 2019, the Company had cash of $49.8 million and short-term investments of $72.0 million. Operating expenses for the fourth quarter of 2019 were approximately $31.5 million which included $19.4 million in noncash goodwill impairment charges. The Company ended the fourth quarter of 2019 with approximately $25.1 million outstanding in short- and long-term debt on its balance sheet, which was used and will continue to be used to bolster operations and advance the development of drug candidates.

Fiscal Year 2019 Financial Results

The Company’s net loss for the year ended December 31, 2019 was $78.2 million, or $(1.95) per share, compared with a net loss of $61.5 million, or $(1.85) per share for the year ended December 31, 2018.

Research and development expenses increased by $1.6 million, or 4.3%, to $38.8 million for the year ended December 31, 2019 from $37.2 million for the year ended December 31, 2018. The increase was primarily due to increased development and regulatory costs associated with the development of Molgradex for the treatment of aPAP, NTM, and NTM in patients with CF as well as development costs associated with the enrollment and other Phase 3 study activities of the AeroVanc program.

General and administrative expenses increased by $2.4 million, or 22.8%, to $13.1 million for the year ended December 31, 2019 from $10.7 million for the year ended December 31, 2018. The increase was primarily due to increased commercial costs related to market research and similar activities for Molgradex, increases in personnel costs, legal, accounting, insurance, business development, and other operating activities.

During the year ended December 31, 2019, the Company recognized $26.9 million in noncash impairment charges to the carrying value of the Company’s goodwill following the results of the IMPALA Phase 3 study of Molgradex for the treatment of aPAP. During the year ended December 31, 2018, the Company recognized a $21.7 million noncash impairment charge against the carrying value of acquired IPR&D related to an ancillary drug candidate, previously assumed by Savara in the 2017 merger, due to unfavorable results from the Phase 2 study. The Company is no longer supporting or pursuing this ancillary drug candidate.

Conference Call/Webcast

Savara management will host a conference call/webcast at 4:30 p.m. Eastern Time (ET) / 1:30 p.m. Pacific Time (PT). Shareholders and other interested parties may access the call by dialing (855) 239-3120 from the U.S., (855) 669-9657 from Canada, and (412) 542-4127 from elsewhere outside the U.S. and requesting the "Savara Inc." call. A live webcast of the call can be accessed on the Investors page of Savara’s website at View Source

Approximately one hour after the call, a telephone replay will be available and will remain available through March 19, 2020 by dialing (877) 344-7529 from the U.S., (855) 669-9658 from Canada and (412) 317-0088 from elsewhere outside the U.S. and entering the replay access code 10139201. A webcast replay will be available on the Investors page of Savara’s website and will remain available for 30 days.

About IMPALA

The IMPALA clinical study was a randomized, double-blind, placebo-controlled, Phase 3 clinical study of Molgradex in 138 patients with aPAP. Patients were randomized to receive treatment for 24 weeks in one of three arms: 1) Molgradex 300 µg administered once daily continuously over 24 weeks, 2) Molgradex 300 µg, and matching placebo, each administered once daily every other week, or 3) inhaled placebo administered once daily continuously over 24 weeks. At the end of the 24-week double-blind period, all treatment arms rolled into a 24-week open-label follow-up period and received Molgradex 300 µg administered once daily every other week. The primary endpoint of the study was change from baseline in alveolar-arterial oxygen gradient, or (A-a)DO2, a commonly used measure of oxygenation impairment, to week 24. In addition, three key secondary endpoints―St. George’s Respiratory Questionnaire (SGRQ), six-minute walk distance (6MWD), and time to requirement for whole lung lavage (WLL)―along with multiple other secondary and exploratory endpoints were assessed to determine improvement in the disease pathology and pathophysiology, clinical symptoms, and function.

About OPTIMA

The OPTIMA clinical study was an exploratory, open-label, non-controlled, multi-center, Phase 2a clinical study of Molgradex in 32 patients with persistent pulmonary NTM lung infection. OPTIMA enrolled patients with chronic Mycobacterium avium complex (MAC) infection or Mycobacterium abscessus (MABSC) infection, with all patients having either antibiotic refractory infection or intolerance to standard NTM antibiotics. Patients with cystic fibrosis were not enrolled. The study comprised a 48-week treatment period and a 12-week follow-up period. Two groups of patients were recruited into the OPTIMA study. Treatment group one consisted of patients who remained sputum culture positive while currently on a multidrug NTM guideline-based anti-mycobacterial regimen, which had been ongoing for at least six months prior to the baseline visit. Treatment group two consisted of patients who remained sputum culture positive, but either stopped a multidrug NTM guideline-based anti-mycobacterial regimen at least 28 days prior to screening due to lack of response or intolerance, or never started such treatment.

The primary endpoint in the study was sputum culture conversion, defined as at least three consecutive sputum samples without growth of nontuberculous mycobacteria. Secondary endpoints included: (i) the number of patients with sputum smear conversion to negative, defined as at least three consecutive negative acid-fast bacilli (AFB) stained sputum smears on microscopy among patients who were smear positive at baseline, (ii) the number of patients with durable sputum culture conversion, defined as sputum culture conversion at or before week 48 and culture still negative for growth of nontuberculous mycobacteria at 12-week follow-up, (iii) the number of patients with durable sputum smear conversion, defined as sputum smear conversion at or before week 48 and AFB stained smear still negative for nontuberculous mycobacteria at 12-week follow-up among patients who were smear positive at baseline, and (iv) other microbiological indicators, exercise capacities, and patient reported outcomes.

About AVAIL

AVAIL is a randomized, double-blind, placebo-controlled, Phase 3 study of vancomycin hydrochloride inhalation powder (AeroVanc) in people living with cystic fibrosis who have methicillin-resistant Staphylococcus aureus (MRSA) lung infection. Target enrollment is 200 patients. During Period 1 of the study, patients are randomly assigned in a blinded 1:1 fashion to receive either AeroVanc (30 mg) twice daily, or placebo, by inhalation for 24 weeks or 3 dosing cycles. A dosing cycle is defined as 28 days of treatment followed by 28 days of observation. During Period 2 of the study, patients receive open-label AeroVanc (30 mg) twice daily for an additional 24 weeks or 3 dosing cycles, to evaluate the long-term safety of AeroVanc.

The primary endpoint is the mean absolute change in FEV1 percent predicted from baseline, which will be analyzed sequentially at week 4 (the end of cycle 1), at week 12 (the end of cycle 2) and at week 20 (the end of cycle 3). Analysis of the primary endpoint will be based on patients between 6-21 years of age. Secondary efficacy endpoints include: (i) time-to-use of another antibiotic medication for pulmonary infection, (ii) the number of successful FEV1-response cycles a patient achieves over Period 1 (weeks 4, 12, and 20), (iii) relative change from baseline in FEV1 percent predicted at weeks 4 and 20, (iv) change from baseline CF Questionnaire-Revised scores at weeks 4 and 20 and (v) change from Baseline in CF Respiratory Symptom Diary-Chronic Respiratory Symptom scores at weeks 4 and 20.

On March 13, 2020 EMD Serono, the biopharmaceutical business of Merck KGaA, Darmstadt, Germany in the US and Canada, and Pfizer Inc. (NYSE: PFE) reported an update from the Phase III JAVELIN Head and Neck 100 study evaluating avelumab in addition to chemoradiotherapy (CRT) versus standard-of-care CRT in patients with untreated locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) (Press release, EMD Serono, MAR 13, 2020, View Source [SID1234555553]). The alliance has accepted the recommendation of the independent Data Monitoring Committee (DMC) to terminate the JAVELIN Head and Neck 100 trial, as the study is unlikely to show a statistically significant improvement in the primary endpoint of progression-free survival (PFS) based on a preplanned interim analysis. A detailed analysis of the Phase III JAVELIN Head and Neck 100 study is being conducted and study findings will be shared with the scientific community.

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EMD Serono and Pfizer Logo (PRNewsfoto/EMD Serono)

There has been limited innovation for patients with locally advanced SCCHN over the past 10 years.1 Despite aggressive standard-of-care treatment with high-dose chemotherapy combined with radiotherapy, LA SCCHN will ultimately recur in a large proportion of patients.2 In recognition of the unmet need for additional treatment options that can prevent recurrence or metastatic disease,3 the alliance initiated the JAVELIN Head and Neck 100 trial, which is the first Phase III study to report topline results for an immune checkpoint inhibitor in combination with CRT in LA SCCHN.

About JAVELIN Head and Neck 100
JAVELIN Head and Neck 100 (NCT02952586) is a Phase III, randomized, double-blind, placebo-controlled, parallel-arm study investigating treatment with avelumab plus standard-of-care CRT followed by avelumab maintenance versus CRT alone in patients with previously untreated LA SCCHN. A total of 697 patients who had not received prior therapy for locally advanced SCCHN and were eligible for CRT with curative intent were randomly assigned to receive avelumab plus CRT or CRT alone. The primary endpoint was PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included overall survival (OS), time to locoregional failure, time to distant metastatic failure, overall response, duration of response and pathologic complete response.

About Head and Neck Cancer
Head and neck cancer is the sixth most common cancer worldwide.4 In 2016, there were nearly 150,000 newly diagnosed cases in the United States, Japan and Europe.4 Approximately 60% of people are diagnosed with head and neck cancer when their disease has already progressed to the locally advanced stage (Stage III-IVB).5 At this stage, the cancer has spread from its site of origin to local lymph nodes, but not another part of the body.6 Standard of care for these patients includes high-dose chemotherapy combined with radiotherapy.7

About BAVENCIO (avelumab)
BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO has been shown in preclinical models to engage both the adaptive and innate immune functions. By blocking the interaction of PD-L1 with PD-1 receptors, BAVENCIO has been shown to release the suppression of the T cell-mediated antitumor immune response in preclinical models.8-10 In November 2014, Merck KGaA, Darmstadt, Germany, and Pfizer announced a strategic alliance to co-develop and co-commercialize BAVENCIO.

BAVENCIO Approved Indications
BAVENCIO (avelumab) in combination with axitinib is indicated in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of (i) adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. These indications are approved under accelerated approval based on tumor response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

Avelumab is currently approved for patients with MCC in 50 countries globally, with the majority of these approvals in a broad indication that is not limited to a specific line of treatment.

BAVENCIO Important Safety Information from the US FDA-Approved Label
BAVENCIO can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis, and evaluate suspected cases with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold BAVENCIO for moderate (Grade 2) and permanently discontinue for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.

BAVENCIO can cause hepatotoxicity and immune-mediated hepatitis, including fatal cases. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater hepatitis. Withhold BAVENCIO for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinue for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis occurred with BAVENCIO as a single agent in 0.9% of patients, including two (0.1%) patients with Grade 5, and 11 (0.6%) with Grade 3.

BAVENCIO in combination with axitinib can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used as monotherapy. Withhold BAVENCIO and axitinib for moderate (Grade 2) hepatotoxicity and permanently discontinue the combination for severe or life-threatening (Grade 3 or 4) hepatotoxicity. Administer corticosteroids as needed. In patients treated with BAVENCIO in combination with axitinib, Grades 3 and 4 increased ALT and AST occurred in 9% and 7% of patients, respectively, and immune-mediated hepatitis occurred in 7% of patients, including 4.9% with Grade 3 or 4.

BAVENCIO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold BAVENCIO until resolution for moderate or severe (Grade 2 or 3) colitis until resolution. Permanently discontinue for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon reinitiation of BAVENCIO. Immune-mediated colitis occurred in 1.5% of patients, including seven (0.4%) with Grade 3.

BAVENCIO can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus.

Monitor patients for signs and symptoms of adrenal insufficiency during and after treatment, and administer corticosteroids as appropriate. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% of patients, including one (0.1%) with Grade 3.

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Manage hypothyroidism with hormone replacement therapy and hyperthyroidism with medical management. Withhold BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) thyroid disorders. Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroiditis, were reported in 6% of patients, including three (0.2%) with Grade 3.

Type 1 diabetes mellitus including diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Withhold BAVENCIO and administer antihyperglycemics or insulin in patients with severe or life-threatening (Grade ≥3) hyperglycemia, and resume treatment when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% of patients, including two cases of Grade 3 hyperglycemia.

BAVENCIO can cause immune-mediated nephritis and renal dysfunction. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater nephritis. Withhold BAVENCIO for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Permanently discontinue BAVENCIO for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% of patients.

BAVENCIO can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation. For suspected immune-mediated adverse reactions, evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue BAVENCIO, administer high-dose corticosteroids, and initiate hormone replacement therapy, if appropriate. Resume BAVENCIO when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue BAVENCIO for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with BAVENCIO as a single agent or in 489 patients who received BAVENCIO in combination with axitinib: myocarditis including fatal cases, pancreatitis including fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.

BAVENCIO can cause severe or life-threatening infusion-related reactions. Premedicate patients with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent infusions based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue BAVENCIO for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.

BAVENCIO in combination with axitinib can cause major adverse cardiovascular events (MACE) including severe and fatal events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue BAVENCIO and axitinib for Grade 3-4 cardiovascular events. MACE occurred in 7% of patients with advanced RCC treated with BAVENCIO in combination with axitinib compared to 3.4% treated with sunitinib. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%).

BAVENCIO can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with BAVENCIO and for at least 1 month after the last dose of BAVENCIO. It is not known whether BAVENCIO is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least 1 month after the last dose of BAVENCIO due to the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥ 20%) in patients with metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, ≥ 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine aminotransferase (20%).

The most common adverse reactions (all grades, ≥ 20%) in patients with locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, ≥ 3%) in patients with locally advanced or metastatic UC were hyponatremia (16%), increased gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%), increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%), hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Fatal adverse reactions occurred in 1.8% of patients with advanced renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib. These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%), and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, ≥20%) in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%), musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%), palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%), decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs 16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%), abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, ≥20%) worsening from baseline in patients with advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%), alanine aminotransferase increased (ALT) (50% vs 46%), aspartate aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs 37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%), platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%), and hemoglobin decreased (21% vs 65%).

On March 13, 2020 Rubius Therapeutics reported that it is minimizing its focus on its rare disease pipeline and taking greater aim at developing treatments for cancer and autoimmune diseases (Press release, Rubius Therapeutics, MAR 13, 2020, View Source [SID1234555552]). Company stock closed down 39% on Thursday to $3.99 per share.

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On Thursday, the company announced a strategic decision to reprioritize its focus on how its RED PLATFORM could be better used for these indications. Cambridge, Mass.-based Rubius’ technology platform is designed to genetically engineer and culture Red Cell Therapeutics that are "selective, potent and off-the-shelf allogeneic cellular therapies for the potential treatment of several diseases across multiple therapeutic areas." In its announcement, Rubius pointed to its lead oncology program, RTX-240, a broad immunostimulatory Red Cell Therapeutic. The company said the U.S. Food and Drug Administration has approved its Investigational New Drug Application and will soon begin dosing patients in a Phase I trial.

RTX-240 is an allogeneic cellular therapy that is engineered to broadly stimulate the adaptive and innate immune systems to generate an antitumor response, according to company data. Rubius said RTX-240 may provide a different approach to treating solid tumors as the asset "expresses 4-1BBL and IL-15TP, a fusion of IL-15 and IL-15 receptor alpha, on the cell surface with the goal of improving antitumor activity and overcoming resistance to immunotherapy" in cancer patients whose disease has become resistant or refractory to immunotherapies, including checkpoint inhibitors.

In addition to RTX-240, Rubius is also eying the filing of an IND for RTX-321, its first artificial antigen-presenting cell for the treatment of HPV-positive cancers. The company anticipates that filing by the end of 2020. Manufacturing for the two oncology assets will be supported at its Rhode Island facility, which Rubius said it now cGMP ready to produce clinical supply for the assets.

In the autoimmune setting, Rubius is focusing on T cell-mediated autoimmune diseases and is pursuing Type 1 diabetes, along with a number of other undisclosed programs. The company expects to provide an update on its preclinical autoimmune pipeline in the future.

Pablo J. Cagnoni, president and chief executive officer of Rubius, said for the past two years, the company has generated exciting oncology preclinical data, which has demonstrated the ability of its Red Cell Therapeutics to "broadly activate the immune system, and induce tumor-specific responses by activating and expanding antigen-specific T cells with our artificial antigen-presenting cells."

"By focusing on the development of our oncology and autoimmune pipeline, we believe we will have the greatest opportunity to bring life-saving therapies to patients, enhance shareholder value and extend our cash runway into 2022," Cagnoni said in a statement. "With our internal cGMP manufacturing established, we are well-positioned to advance this entirely new class of allogeneic cellular medicines."

As a result of its new focus, Rubius is deprioritizing its RTX-134 program for the treatment of phenylketonuria (PKU), as well as its other rare disease programs. The company said there were multiple factors that lead to its decision, including unanticipated delays mostly due to manufacturing challenges with the company’s contract manufacturing organization. Other challenges included the high cost associated with producing chronic, high-dose therapy for enzyme deficiencies and the continued momentum of the company’s oncology pipeline, Rubius said.

The first patient in the Phase Ib PKU trial was dosed in January. The company noted that the patient’s response to the treatment was well-tolerated but any results were "uninterpretable possibly due, in part, to the low dose of cells administered and the sensitivity of the flow cytometry assay used to detect circulating cells." The company has discontinued the trial.

Future capital investments and improvements in manufacturing efficiency, together with enhancements to the RED PLATFORM, may enable Rubius to revisit chronic, high dose-dependent conditions in the future, the company announced.