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Sargramostim - Bayer HealthCare Pharmaceuticals

Drug Profile

Sargramostim - Bayer HealthCare Pharmaceuticals

Alternative Names: BI 61012; GZ 402664; Leukine; Leukine Liquid; Prokine; Recombinant human GM‑CSF; rhuGM-CSF; sargramostim-biosimilar

Latest Information Update: 03 Jun 2020

At a glance

  • Originator Amgen
  • Developer Bayer HealthCare Pharmaceuticals Inc.; Cincinnati Children's Hospital Medical Center; National Cancer Institute (USA); National Institute on Aging; Partner Therapeutics; Sanofi Genzyme; University of California at Irvine; University of California at San Francisco; University of Colorado at Denver; University of Texas M. D. Anderson Cancer Center; Virginia Commonwealth University
  • Class Adjuvants; Chemoprotectants; Granulocyte-macrophage colony-stimulating factors
  • Mechanism of Action Granulocyte stimulants; Haematopoiesis stimulants; Macrophage stimulants; Neutrophil stimulants
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    Yes - Malignant melanoma; Pulmonary alveolar proteinosis
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Acute radiation syndrome; Bone marrow disorders; Neutropenia; Pneumococcal infections; Stem cell mobilisation
  • Phase II Alzheimer's disease; Chronic lymphocytic leukaemia; COVID 2019 infections; Malignant melanoma; Prostate cancer; Pulmonary alveolar proteinosis
  • No development reported Ovarian cancer
  • Discontinued Crohn's disease; Follicular lymphoma; Non-Hodgkin's lymphoma

Most Recent Events

  • 04 Jun 2020 Partner Therapeutics plans a phase II trial for Acute hypoxia (Adjunctive therapy) (Inhalation) (NCT04411680)
  • 28 May 2020 Phase-II clinical trials in COVID-2019 infections (In adults, In the elderly) in Singapore (IV) (NCT04400929)
  • 23 Sep 2019 Safety and efficacy data from a phase II trial in Malignant melanoma released by Partner Therapeutics

Development Overview

Introduction

Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) being developed by Bayer HealthCare Pharmaceuticals Inc. Sargramostim binds to the GM-CSF receptor (GM-CSF-R-alpha or CSF2R) to stimulate proliferation and differentiation of a variety of haematopoietic progenitor cells, with some specificity towards stimulation of leukocyte production. Sargramostim also promotes antigen presentation, upregulates antibody-dependent cellular cytotoxicity (ADCC), and increases interleukin-2-mediated lymphokine-activated killer cell function; it may also augment host antitumoural immunity. Sargramostim is indicated for use following induction chemotherapy in patients 55 years and older with acute myelogenous leukemia (AML). Intravenous or subcutaneous administration is designed to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. The agent is also used in multiple stem cell transplantation settings. Sargramostim has been launched in the US for the treatment of bone marrow disorders, neutropenia, pneumococcal infections, acute radiation sndrome and stem cell mobilisation. Phase II development for Alzheimer's disease, chronic lymphocytic leukaemia, prostate cancer is underway in the US. Development is also underway for the treatment of acute radiation syndrome. The inhaled formulation of sargramostim is being developed by Children's Hospital Medical Center, Cincinnati, in collaboration with Genzyme (now Sanofi Genzyme) and Virginia Commonwealth University, for the treatment of hereditary pulmonary alveolar proteinosis, and is in phase II development in the US. Clinical development for COVID-2019 infections is underway in Singapore.

Bayer discontinued development of the agent in Crohn's disease, Follicular lymphoma, Pneumococcal infections and non-Hodgkin's lymphoma.

In January 2016, Genzyme Corporation was rebranded as Sanofi Genzyme (Sanofi 20-F, March 2016).

As at April 2019, no recent reports of development had been identified for phase-I development in Prostate-cancer in USA (SC, Injection).

Company Agreements

In May 2018, Tanner Pharma Group entered into an agreement with Partner Therapeutics for distribution of Leukine® (sargramostim) in areas outside of the US and Canada where the product had not yet received approval. The distribution will be managed by TannerGAP, a wholly owned subsidiary of Tanner Pharma Group [1]

In February 2018, Partner Therapeutics acquired the global rights to develop, manufacture, and commercialise sargramostim from Sanofi. Additional details were not disclosed. [2]

In October 2016, the Biomedical Advanced Research and Development Authority (BARDA) awarded Sanofi Genzyme a $US37.6 million contract to supply and manage inventory for Leukine®(sargramostim) for the treatment of acute radiation syndrome. The company was also awarded a $US36.5 million BARDA contract, in 2013, for late stage development and procurement of Leukine® [3] .

In April 2007, Bayer HealthCare Pharmaceuticals Inc. was launched in the US. The new company incorporates the former Berlex into Bayer HealthCare Pharmaceuticals as part of Bayer′s acquisition of Schering AG, Germany, Berlex′s former parent company. Bayer HealthCare Pharmaceuticals Inc. (formerly Berlex Laboratories) is responsible for marketing, manufacture and further development of sargramostim [4] .

Schering AG (now Bayer Healthcare Pharmaceuticals) purchased sargramostim from Amgen (formerly Immunex) in July 2002. Immunex was acquired by, and merged into, Amgen a week before sargramostim was purchased by Schering AG. In addition to the purchase price paid by Schering to acquire the product, two additional payments were to be made to Amgen if certain milestones were reached in the development of sargramostim for Crohn's disease [5] . In June 2006, Schering AG was acquired by Bayer and was subsequently renamed as Bayer Schering Pharma AG [6] [7] . Bayer Schering Pharma was renamed Bayer Healthcare Pharmaceuticals in February 2011 [8] .

Bayer and Genzyme Corporation have entered into a strategic alliance whereby Bayer licensed its haematological oncology products to Genzyme. This includes the drug sargramostim. During a transition period, Bayer will provide continuing services to ensure no interruption in product supply [9] .

Genzyme was acquired by sanofi-aventis in April 2011 [10] .

Key Development Milestones

Acute myeloid leukaemia (AML)

Sargramostim is launched for use following induction chemotherapy in patients 55 years and older with acute myelogenous leukaemia (AML).

Sanofi withdrew a phase II trial, prior to enrolment as the company fulfilled its post-marketing requirements(LTS13932; U1111-1148-1183; NCT02520102). This open-label trial to evaluate sargramostim, in patients with AML, following induction or re-induction chemotherapy, and was expected to enrol approximately 165 patients in the US and Czech Republic [11] .

Acute radiation syndrome

In June 2018, the US FDA approved sargramostim for the treatment of adult and paediatric patients acutely exposed to myelosuppressive doses of radiation (haematopoietic syndrome of acute radiation syndrome). The approval was granted based on government-sponsored efficacy studies conducted in animals. Efficacy studies of sargramostim were not conducted in humans with acute radiation syndrome for ethical and feasibility reasons. The sBLA was filed with the FDA in September 2017, and the priority review was granted in December 2017. The PDUFA date of 29 March 2018 was assigned by the FDA [12] [2] .

Alzheimer's Disease (AD)

University of Colorado is conducting a phase II pilot safety and efficacy trial of sargramostim in mild-to-moderate AD patients at 250ug/m2/day subcutaneous for five days per week, for three weeks with follow-up visits at 45 and 90 days. In July 2017, interim results from 20 patients were presented at the Alzheimer's Association International Conference 2017 (AAIC-2017) [13] .

In April 2017, Sanofi in collaboration with National Institute on Aging (NIA) withdrew a phase II study prior to enrolment due to slow recruitment, designed to evaluate the efficacy and activity of innate immune system stimulation with sargramostim to reduce brain amyloid load in patients with mild cognitive impairment due to Alzheimer's disease (ACT14019; U1111-1163-0793; 1UF1AG046143; NCT02667496). The double-blind, parallel, prospective, randomised trial intended to enrol approximately 30 participants in the US [14] .

Results from preclinical studies showed that 20 daily injections of 5µg sargramostim reduced AD pathology more than 50% and completely reversed the cognitive impairment of transgenic AD mice [13] .

Chronic lymphocytic leukaemia (CLL)

In January 2017, Bayer in collaboration with M.D. Anderson Cancer Center completed a phase II trial that assessed the safety and efficacy of sargramostim in combination with rituximab in patients with CLL (2004-0102; NCI-2012-01670; NCT00940342). The open-label trial was initiated in August 2004 and enrolled 119 patients in the US [15] .

Bayer completed a phase II trial using a combination of fludarabine, cyclophosphamide, rituximab, and sargramostim for the treatment of previously untreated CLL. This trial enrolled 60 patients at the M.D. Anderson Cancer Centre in the US (NCT00381004) [16] .

Results from a clinical study showed that bone marrow transplant (BMT) patients treated with sargramostim plus recombinant G-CSF to treat leucopenia showed significantly improved cognition at six months, as compared with BMT patients who received sargramostim alone or no treatment [13] .

Crohn's disease

In June 2007, Bayer Schering Pharma announced that development of sargramostim for Crohn's disease had been discontinued. A worldwide clinical trial programme, called N.O.V.E.L (New Opportunities to Verify Evolving Logic in Crohn's disease), was conducted with sargramostim for this indication and phase III studies were undertaken.

COVID-2019 infections

In May 2020, Partner Therapeutics initiated a phase II investigator initiated trial to investigate immediate versus delayed treatment of intravenously administered sargramostim in improving oxygenation and short- and long-term outcome of COVID-2019 patients with acute hypoxic respiratory failure (SH-Leuk01; NCT04400929). The randomised, double-blind, placebo-controlled trial intends to enrol approximately 30 patients in Singapore [17] .

Follicular lymphoma

A phase II study was initiated in October 2006 in the US and Puerto Rico called the PREMIER (Primary Evaluation Measuring Improved Efficacy of Rituximab; NCT00308087) trial, where sargramostim was added to rituximab therapy in patients with relapsed B-cell follicular lymphoma. However, the trial was terminated due to low accrual [18] [19] .

Haematological disorders

in the US, sargramostim has been launched for myeloid reconstitution after allogeneic or autologous bone marrow transplantation (BMT) in patients with non-Hodgkin's lymphoma, acute lymphoblastic leukaemia and Hodgkin's disease. Sargramostim has also been launched in the US for the treatment of neutropenia in patients with acute myelogenous leukaemia, for mobilisation of haematopoietic progenitor cells into peripheral blood for collection by leukapheresis, myeloid reconstitution following transplantation of autologous peripheral blood progenitor cells and myeloid reconstitution after bone marrow transplantation failure or engraftment delay.

Melanoma

In September 2019, the US FDA granted orphan drug designation to sargramostim for the potential treatment of Stage IIb-IV melanoma [20] .

In November 2019, National Cancer Institute suspended a phase II/III trial designed to study the side effects of nivolumab and ipilimumab when given together with or without sargramostim in patients with stage III-IV melanoma that cannot be removed by surgery (unresectable) (NCT02339571; NCI-2014-02674; EA6141). The trial was initiated in September 2015 and intended to enrol 400 patients in the US.

In December 2010, National Cancer Institute initiated a phase II trial to evaluate the overall survival for the combination of sargramostim (GM-CSF) plus ipilimumab and ipilimumab alone in patients with advanced melanoma. The randomised trial intends to enrol 245 patients in the US. In September 2019, company reported results from the study [20] .

In April 2018, Genzyme withdraws a phase III trial prior to enrolment as no participants enrolled in the trial (11-002177; NCI2013-00645; NCT01826864). The trial was designed to compare the immunodulatory effects of sargramostim with saline, for early-stage melanoma patients undergoing sentinel lymph node dissection. The open label trial intended to enrol patients in the US [21] .

A phase II trial assessing the combination of HD-IL2 and sargramostim for the treatment of advanced melanoma has been completed in the US (NCT00616564). The trial was conducted by the Mt Sinai Medical Center in collaboration with Bayer and Chiron [22] . Sargramostim was also assessed in two other phase II trials (NCT00350597 & NCT00256282) [23] .

Non-Hodgkin's lymphoma

A phase II study evaluating sargramostim in combination with CHOP-R for the treatment of diffuse large B-cell NHL was terminated due to low accrual (NCT00455897) [24] . Another phase II trial was completed in the US (NCT00499343).

Ovarian cancer

As of June 2015, no recent reports of development for sargramostim have been identified for ovarian cancer.

A phase II study assessed the efficacy of sargramostim in 70 patients with ovarian cancer (NCT00157573) [25] . An additional phase II trial evaluated sargramostim as part of chemoimmunotherapy in 59 patients with epithelial ovarian cancer (NCT00501644) [26] . Both trials have been completed in the US.

Pneumococcal infections

In May 2011, Bayer completed a phase II trial that evaluated the immuno-augmentation with sargramostim in patients receiving pneumococcal vaccine while undergoing treatment for advanced CLL (NCT00323557; 2003-0605). The open, parallel, prospective, randomised trial was initiated in June 2004 and enrolled 39 patients in the US [27] .

Prostate cancer

The University of Colorado, in September 2015, initiated a phase I study to evaluate the efficacy of sargramostim, administered after cryotherapy, in patients with prostate cancer (NCT02250014). Approximately 20 subjects are expected to be enrolled in the US [28] .

In May 2014, Bayer and Genzyme, a Sanofi company, completed a phase II randomised, open-label trial that investigated the efficacy of sargramostim in 125 men with hormone-refractory metastatic prostate cancer in the US (NCT00488982) [29] .

In October 2017, Stanford University in collaboration with Bayer terminated a phase II trial due to low accrual, that was designed to assess mitoxantrone + sargramostim in patients with hormone-refractory prostate cancer (NCT00477087; 96817; e-Protocol4738; IRB04738; PROS0017). This trial was initiated in July 2006 and intended to enrol approximately 20 patients in the US [30] .

Two phase II trials were terminated due to primary investigator decision, and another phase II trial was terminated due to low accrual (NCT00447473, NCT00450008 & NCT00313482) [31] [32] [33] .

Pulmonary alveolar proteinosis

In November 2018, the US FDA granted orphan drug designation to sargramostim for the treatment of pulmonary alveolar proteinosis [34] .

Inhaled formulation

A phase II trial evaluated the efficacy of inhaled sargramostim in patients with hereditary pulmonary alveolar proteinosis (NCT01511068). The trial was conducted by the Children's Hospital Medical Center, Cincinnati, in collaboration with Genzyme and Virginia Commonwealth University. Two patients were enrolled in the US [35] .

Liquid formulation

A liquid sargramostim product containing edetate disodium (EDTA) was launched in January 2006 to extend the shelf-life of the original sargramostim lyophilised powder product. However, due to an associated upward trend in spontaneous reports of adverse events, including syncope, Bayer withdrew the liquid formulation in January 2008 and established a special access programme for the lyophilised powder. The special access programme was designed to prioritise the supply of sargramostim for patients with acute myelogenous leukaemia (AML), and those experiencing bone marrow transplantation engraftment failure or delay. The programme was also used to provide continued therapy to patients participating in ongoing clinical studies. A reformulated version of liquid sargramostim without EDTA was subsequently approved by the US FDA and introduced to the market by Bayer in May 2008 [36] [37] .

Drug Properties & Chemical Synopsis

  • Route of administration Inhalation, IV, SC
  • Formulation Infusion, Injection, unspecified
  • Class Adjuvants, Chemoprotectants, Granulocyte-macrophage colony-stimulating factors
  • Target Granulocyte; Haematopoiesis; Macrophage; Neutrophil
  • Mechanism of Action Granulocyte stimulants; Haematopoiesis stimulants; Macrophage stimulants; Neutrophil stimulants
  • WHO ATC code

    A07E (Intestinal Antiinflammatory Agents)

    C05C-X (Other capillary stabilizing agents)

    L03A-A (Colony stimulating factors)

    L03A-A09 (Sargramostim)

    L03A-X (Other immunostimulants)

    N07X (Other Nervous System Drugs)

    R07 (Other Respiratory System Products)

  • EPhMRA code

    A7E (Intestinal Anti-Inflammatory Agents)

    C6A (Other Cardiovascular Products)

    L3A (Immunostimulating Agents Excluding Interferons)

    L3A1 (Colony-stimulating factors)

    N7X (All other CNS drugs)

    R7 (Other Respiratory System Products)

  • Chemical name 23-L-Leucinecolony-stimulating factor 2 (human clone pHG 25 protein moiety)
  • Molecular formula C639 H1002 N168 O196 S8 (for non-glycosylated protein)
  • CAS Registry Number 123774-72-1

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

acute radiation syndrome

Outcome Measure

IFN-gamma

1

adenocarcinoma

Exclusion

GM-CSF

1

adenocarcinoma

Inclusion

PSA

1

adenocarcinoma

Outcome Measure

PSA

1

adult respiratory distress syndrome

Outcome Measure

GM-CSF

1

adult respiratory distress syndrome

Safety

GM-CSF

1

advanced breast cancer

not specified

PGR

HLA-A

HER2

ER alpha

1

1

1

1

Alzheimer's disease

Outcome Measure

IFN-gamma

1

astrocytoma

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

biliary cancer

not specified

PD-L1

1

bone marrow disorders

Outcome Measure

IFN-gamma

1

brain cancer

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

Burkitt's lymphoma

Outcome Measure

GM-CSF

1

chronic lymphocytic leukaemia

not specified

ZAP-70

CD38

1

1

chronic lymphocytic leukaemia

Outcome Measure

IFN-gamma

1

diffuse large B cell lymphoma

Exclusion

GM-CSF

1

diffuse large B cell lymphoma

Outcome Measure

GM-CSF

2

early breast cancer

not specified

PGR

HLA-A

HER2

ER alpha

1

1

1

1

fallopian tube cancer

Inclusion

CA-125

1

fallopian tube cancer

Outcome Measure

CD45

CA-125

1

2

follicular lymphoma

Outcome Measure

GM-CSF

1

glioblastoma

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

glioma

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

malignant melanoma

not specified

IL4

IL2

IL10

IFN-gamma

GM-CSF

1

1

1

1

1

medulloblastoma

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

neuroblastoma

Exclusion

IL2

1

neuroblastoma

Inclusion

IL2

1

neuroectodermal tumours

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

neutropenia

Outcome Measure

IFN-gamma

1

non-Hodgkin's lymphoma

Outcome Measure

GM-CSF

Bcl-2

1

2

non-small cell lung cancer

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

oligodendroglioma

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

ovarian cancer

Inclusion

CA-125

1

ovarian cancer

Outcome Measure

CD45

CA-125

1

2

Parkinson's disease

not specified

Norepinephrine

1

peripheral T-cell lymphoma

Outcome Measure

GM-CSF

1

peritoneal cancer

Inclusion

CA-125

1

peritoneal cancer

Outcome Measure

CD45

CA-125

1

2

pneumococcal infections

Exclusion

GM-CSF

1

pneumococcal infections

Outcome Measure

IFN-gamma

GM-CSF

1

1

prostate cancer

not specified

PSA

1

prostate cancer

Outcome Measure

PSA

IFN-gamma

GM-CSF

4

1

4

prostate cancer

Exclusion

PSA

GM-CSF

2

2

prostate cancer

Inclusion

PSA

GM-CSF

5

1

prostate cancer

Safety

GM-CSF

3

pulmonary alveolar proteinosis

not specified

Surfactant protein D

surfactant protein C

surfactant protein B

MIP-1 alpha

GM-CSF autoantibodies

GM-CSF

colony stimulating factor 2 receptor, beta, low-affinity (granulocyte-macrophage)

colony stimulating factor 2 receptor, alpha, low-affinity (granulocyte-macrophage)

colony stimulating factor 1 (macrophage)

CEA

CA 15-3

ATP-binding cassette, sub-family A (ABC1), member 3

1

1

1

1

1

1

1

1

1

1

1

1

pulmonary alveolar proteinosis

Inclusion

GM-CSF

1

pulmonary alveolar proteinosis

Outcome Measure

IFN-gamma

GM-CSF

1

1

renal cancer

Outcome Measure

VEGF-A

TNF-alpha

1

1

rhabdoid tumour

Outcome Measure

SH3 domain containing GRB2 like 1, endophilin A2

1

stem cell mobilisation

Outcome Measure

IFN-gamma

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Sargramostim - Bayer HealthCare Pharmaceuticals ATP-binding cassette, sub-family A (ABC1), member 3 not specified
B2M not specified
Bcl-2 not specified
BCR Exclusion, Inclusion, Outcome Measure
C-peptide Inclusion, Outcome Measure
CA 15-3 not specified
CA-125 Inclusion, Outcome Measure
CA-19-9 Outcome Measure
CD34 Inclusion, Outcome Measure, Safety
CD38 not specified
CD3d Outcome Measure
CD3e Outcome Measure
CD3g Outcome Measure
CD4 Exclusion, Inclusion, Outcome Measure, Safety
CD8a Outcome Measure
CEA Inclusion, Outcome Measure
colony stimulating factor 1 (macrophage) not specified
colony stimulating factor 2 receptor, alpha, low-affinity (granulocyte-macrophage) not specified
colony stimulating factor 2 receptor, beta, low-affinity (granulocyte-macrophage) not specified
complement component (3b/4b) receptor 1 (Knops blood group) Outcome Measure
complement factor D (adipsin) not specified
CRP Outcome Measure
Dihydroxyacetone phosphate not specified
ER alpha not specified
G-CSF Exclusion, Inclusion, Outcome Measure
Gad65 Auto-antibodies not specified
GM-CSF Exclusion, Inclusion, Outcome Measure, Safety
GM-CSF autoantibodies not specified
gp100 not specified
HER2 Exclusion, Inclusion, Outcome Measure, Safety
HLA-A not specified
HLA-DR Outcome Measure
IA2 Auto-antibodies not specified
ICA Auto-antibodies not specified
IFN-alpha 2 Exclusion, Outcome Measure
IFN-gamma Exclusion, Outcome Measure
IL10 Outcome Measure
IL2 Outcome Measure
IL6 Outcome Measure
Insulin Auto-antibodies not specified
integrin, alpha X (complement component 3 receptor 4 subunit) not specified
interleukin 3 receptor, alpha (low affinity) not specified
ITGA4 not specified
melan-A Exclusion, Inclusion, Outcome Measure
MIP-1 alpha not specified
Norepinephrine not specified
PGR Inclusion, Outcome Measure
Ph chromosome Inclusion, Outcome Measure
Progesterone Exclusion, Inclusion
Prolactin not specified
PSA Exclusion, Inclusion, Outcome Measure
SH3 domain containing GRB2 like 1, endophilin A2 Outcome Measure
surfactant protein B not specified
surfactant protein C not specified
Surfactant protein D not specified
Survivin not specified
Testosterone Inclusion
TGF-beta Outcome Measure
TNF-alpha Outcome Measure
transmembrane protein 37 Outcome Measure
VEGF-A Outcome Measure
WT1 Inclusion, Outcome Measure
ZAP-70 not specified
ZnT8 Auto-antibodies not specified
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
Acute radiation syndrome - In adolescents, In adults, In children, In infants, In neonates Marketed USA SC / Injection Partner Therapeutics 07 Jun 2018
Alzheimer's disease - In adults, In the elderly Phase II USA SC / unspecified National Institute on Aging, Sanofi Genzyme 04 Feb 2016
Bone marrow disorders - - Marketed USA IV / Infusion 02 Jul 1996
COVID 2019 infections associated with acute hypoxic respiratory failure In adults, In the elderly Phase II Singapore IV / Injection Partner Therapeutics 28 May 2020
Chronic lymphocytic leukaemia - Combination therapy, In children Phase II USA SC / Injection Bayer HealthCare Pharmaceuticals Inc., University of Texas M. D. Anderson Cancer Center 01 Sep 2006
Chronic lymphocytic leukaemia - Combination therapy, In adolescents, In adults, In the elderly Phase II USA SC / Injection Bayer HealthCare Pharmaceuticals Inc., University of Texas M. D. Anderson Cancer Center 01 Aug 2004
Crohn's disease - - Discontinued (III) USA SC / Injection 19 Jun 2007
Crohn's disease - - Discontinued (II) Canada SC / Injection 19 Jun 2007
Follicular lymphoma - - Discontinued (II) Puerto Rico, USA SC / Injection Bayer HealthCare Pharmaceuticals Inc. 29 Aug 2009
Malignant melanoma - Combination therapy, Late-stage disease Phase II USA SC / Injection 28 Dec 2010
Malignant melanoma - - Phase II USA SC / Injection Bayer HealthCare Pharmaceuticals Inc., University of California at Irvine 18 Jun 2015
Malignant melanoma - Combination therapy, Inoperable/Unresectable, Second-line therapy or greater Suspended (II/III) USA SC / Injection National Cancer Institute (USA) 08 Nov 2019
Neutropenia - Chemotherapy-induced Marketed USA IV / unspecified 30 Jun 1996
Non-Hodgkin's lymphoma - - Discontinued (II) USA SC / Injection Bayer HealthCare Pharmaceuticals Inc. 19 Jul 2011
Ovarian cancer - - No development reported (II) USA SC / Injection Bayer HealthCare Pharmaceuticals Inc., University of Texas M. D. Anderson Cancer Center 18 Jun 2015
Pneumococcal infections - - Marketed USA SC / Infusion 02 Jul 1996
Pneumococcal infections - Combination therapy, In adolescents, In adults, In children, In the elderly Discontinued (II) USA SC / Infusion Bayer HealthCare Pharmaceuticals Inc., University of Texas M. D. Anderson Cancer Center 01 May 2015
Prostate cancer - Combination therapy, Second-line therapy or greater Phase II USA SC / Injection Bayer HealthCare Pharmaceuticals Inc., University of California at San Francisco, Sanofi Genzyme 17 May 1998
Prostate cancer post cryotherapy - No development reported (I) USA SC / Injection University of Colorado at Denver 28 Apr 2019
Pulmonary alveolar proteinosis - - Phase II USA Inhalation / unspecified Cincinnati Children's Hospital Medical Center, Virginia Commonwealth University, Sanofi Genzyme 01 Aug 2012
Stem cell mobilisation - - Marketed USA IV / unspecified 30 Jun 1996

Orphan Status

Indication Patient Segment Country Organisation Event Date
Malignant melanoma - USA Partner Therapeutics 19 Sep 2019
Pulmonary alveolar proteinosis - USA Partner Therapeutics 06 Nov 2018

Commercial Information

Involved Organisations

Organisation Involvement Countries
Amgen Originator USA
Bayer HealthCare Pharmaceuticals Inc. Owner USA
Sanofi Genzyme Licensee World
Partner Therapeutics Sub-licensee World
Virginia Commonwealth University Collaborator USA
National Cancer Institute (USA) Collaborator USA
University of California at San Francisco Collaborator USA
University of Colorado at Denver Collaborator USA
University of California at Irvine Collaborator USA
Stanford University Collaborator USA
University of Texas M. D. Anderson Cancer Center Collaborator USA
National Institute on Aging Collaborator USA
Tanner Pharma Group Collaborator USA
Cincinnati Children's Hospital Medical Center Collaborator USA

Brand Names

Brand Name Organisations Indications Countries
Leukine Amgen Bone marrow disorders, Neutropenia, Pneumococcal infections, Stem cell mobilisation USA

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Neutropaenia Wrld (25% US) Sanofi Marketed 1991 100 2012 - 02 Apr 2020

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Neutropaenia Wrld (25% US) 36 32 29 0 0 0 0 0 0 20 02 Apr 2020
Total 36 32 29 0 0 0 0 0 0 20

Scientific Summary

  • Adverse Events Frequent: Fever; Flu-like symptoms; Malaise; Skin disorders; Thrombocytopenia
    Occasional: Arrhythmias; Arthralgia; Back pain; Bone disorders; Diarrhoea; Fatigue; Headache; Infections; Injection site reactions; Leucopenia; Vomiting
    Rare: Anorexia; CNS disorders; Confusion; Lethargy; Nausea; Neutropenia; Renal calculi

Pharmacokinetic Measures

Characterstic Measure
T½beta (h) 1 - 2.7 (Adult)

Pharmacokinetics

The mean t½ of sargramostim (either liquid or lyophilised) was approximately 1h when intravenously administered over 2h to normal volunteers and approximately 2.7h when administered subcutaneously.

Intravenous administration

the mean Cmax was 5.0 ng/ml for the liquid formulation and 5.4 ng/ml for the lyophilised formulation. Respectively, the mean clearance rate was approximately 420 and 431 ml·min-1·m-2, while the mean AUC was 640 and 677 ng/ml·min-1.

Subcutaneous administration

the mean Cmax was 1.5 ng/ml for both formulations. The mean clearance was approximately 549 ml·min-1·m-2 for the liquid formulation and 529 ml·min-1·m-2 for the lyophilised formulation. The mean AUC was 549 and 501 ng/ml·min-1, respectively [70] .

The mean t1/2 value in paediatric patients (6-16yrs) with active Crohn's disease in a phase I/II trial ranged from 1.41h to 1.88h. Following 4 µg/kg sargramostim, the mean AUC(0-tlast) was 3.89 and 2.83 ng.h/mL for the 6-11 and 12-16yr groups, respectively. Cmax was 1.62 and 0.799 ng/ml. Sargramostim pharmacokinetics were linear [41] .

Adverse Events

Bone marrow disorders

Treatment with sargramostim (15-240 µg/m2/day) for 14 or 21 days had no adverse effects on long-term graft function or on relapse following autologous bone marrow transplantation in 27 patients affected by lymphoid malignancies [72] .

Colorectal cancer

Interim results from the PROGRESS trial, an open label study of sargramostim in combination with an agressive colon cancer chemotherapeutic regimen, report that grade 3/4 events experienced by patients included diarrhoea (39%), neutropenia (30%), deep vein thrombophlebitis (18%), dehydration (12%), vomiting (12%), syncope (9%), and thromobocytopenia (9%) [52] .

Crohn's disease

Phase II: in an international, multicenter, double-blind, phase II study, 124 patients with moderately to severely active Crohn's disease were randomised to receive Leukine® or placebo for 57 days. In this interim analysis, Leukine® treatment was generally well-tolerated with no serious adverse events; most commonly observed adverse events include mild to moderate injection site reactions, bone pain, headache, fatigue and nausea. The frequency of injection site reactions and bone pain decreased with repeated exposure to Leukine® [51] [48] .

Sargramostim 6 µg/kg/day treatment for up to 6 cycles was generally well tolerated among patients with active Crohn's disease in the N.O.V.E.L. 5 trial (n = 60). The most commonly reported adverse events were injection site reactions, bone pain, nausea, headache, vomiting, arthralgia, back pain and fatigue. The incidence of injection site reactions and bone pain decreased with repeated dosing. There were no reports of drug-related serious events. White cell counts peaked between weeks 2 and 4 of each treatment cycle and returned to normal between cycles [45] .

Phase I: a pilot study, published in the November 9 2002 issue of The Lancet, showed that daily subcutaneous injection of Leukine® was well tolerated [53] .

Hepatitis C

71 patients with chronic hepatitis C virus (HCV) infections were treated with sargramostim (n = 19) or interferon α-2b alone (n = 25) or with sargramostim (n = 27) for 6 months. Sargramostim therapy was associated with a significant increase in total white blood cell and absolute eosinophil counts. This peaked during the first month, but counts declined spontaneously to baseline during the remaining 5 months of therapy [61] [60] .

HIV infections

Treatment with SC sargramostim (125 µg/m2) or placebo twice weekly in combination with zidovudine (300 mg/day) alone or as part of a nucleoside analogue regime. Adverse events lead to withdrawal of 5/53 sargramostim recipients (4 as a result of anaemia and 1 with confusion) and 2/52 patients from the placebo group (1 each as a result of anaemia and thrombocytopenia). Flu-like syndrome and injection site reactions were significantly more common in the sargramostim group, occurring in 8 and 16 patients, respectively, than among placebo recipients (2 and 1 patients, respectively. Fever occurred in similar numbers of patients (25 with sargramostim and 24 with placebo). Most events were grade 1-2 in severity and there was no significant difference between the groups in the incidence of alterations in haematological, hepatic or renal function parameters [76] .

In comparison, apart from mild injection-site reactions, sargramostim was well tolerated in a similar phase III trial in 309 patients which was conducted in the US and Canada [80] .

In a study in 20 patients with HIV treated with SC sargramostim (250µg 3/week) or placebo in addition to antiretroviral regimes containing either indinavir or ritonavir, the most serious adverse event was grade 4 neutropenia; this occurred in 1/10 patients receiving sargramostim. The most common events in sargramostim recipients were injection site reactions (5 patients) and infection (6). Infections occurred in 2/10 patients in the placebo group and there were no injection site reactions. Grade 3 events included nausea and anorexia and nephrolithiasis with obstruction in 1 sargramostim recipient each, and fever (>40°C) in 1 placebo recipient [62] .

Malignant melanoma

The tolerability of sargramostim ± monoclonal antibody (MAb) R-24 was investigated in a phase Ib study in 20 patients with malignant melanoma. Sargramostim (150 mg/m2/day) was administered SC once daily on days 1-21 and MAb R-24 (10 or 50 mg/m2/day) was administered by continuous IV infusion on days 8-15. Six patients received sargramostim only. As a result of previous experience with the development of human antimonoclonal antibody, only 1 course of treatment was administered to each patient. Grade 3-4 adverse events among the 6 patients receiving sargramostim + MAb R-24 10 mg/m2 included hypertension (2 patients), palpitations (1), congestive heart failure (1) and dyspnoea (1). In addition, among 9 patients receiving sargramostim + MAb R-24 50 mg/m2, 1 patient experienced anaphylaxis and 2 patients experienced hypotension (both grade 3-4). Other more frequent, but less severe, adverse events experienced with the combined therapy were diffuse urticaria, nausea, vomiting, diarrhoea, abdominal pain, flu-like symptoms, cough, neurological effects, fever, chest pain and elevated creatinine levels. The most common adverse events experienced with sargramostim therapy alone (before beginning MAb R-24 therapy) were local skin reactions, fever and flu-like symptoms and were of grade 1 or 2 severity. With sargramostim alone, there was 1 case each of grade 3 atrial fibrillation and leucopenia. One allergic reaction with the combination therapy manifested as anaphylaxis. All patients had leucocytosis by day 8 of sargramostim therapy, but a dose reduction was not required [78] .

Multiple sclerosis

Sargramostim was well tolerated in a small phase I trial in patients with relapsing multiple sclerosis. Five patients received IM interferon-β-1a 30µg weekly for 90 days prior to initiation of sargramostim which was titrated up to 250µg three times a week for 6 months. The most commonly reported adverse events were upper respiratory tract infection (80% of patients) and mild vertigo (60%). Mild injection-site pruritus was observed but no significant systemic adverse events were reported [46] .

Prostate cancer

Sargramostim was well tolerated in a phase II trial in 35 patients with prostate cancer. The most common adverse event was grade 1 fever and malaise, which lasted < 6h. Transient grade 2 injection site reactions occurred in 6 patients. Sargramostim (250 µg/m2/day) was administered SC on days 1-14 every 4 weeks (n = 22) or on days 1-14 then 3/week (n = 13) [65] .

Sarcoma

Among the 15 patients with advanced sarcomas receiving yeast-derived recombinant sargramostim monotherapy, adverse events included injection site redness and bone pain, both of which were easily managed with analgesics. One patient was withdrawn from the study because of unilateral leg edema and dyspnea. The treatment cycle consisted of sargramostim 250 µg/m2 administered SC for 14 consecutive days followed by a rest period of 7 days between cycles. 14/15 patients had metastatic disease [59] .

Small cell lung cancer

230 patients with limited-stage small cell lung cancer received chemotherapy and radiotherapy with or without sargramostim, which was administered on days 4-18 of each of 6 cycles. Those who received sargramostim had a significant increase in severe and life-threatening thrombocytopenia and there were significantly more toxic deaths among those patients [67] .

Alzheimer's disease

Interim results from eleven patients treated with sargramostim and nine patients receiving placebo displayed no serious drug-related adverse events, and no evidence of amyloid-related imaging abnormalities (ARIAs), which indicate micro-haemorrhage or vasogenic oedema was observed [13] [74] .

In a phase II trial, the most common Grade 3-5 toxicities in patients treated with sargramostim and ipilimumab were diarrhoea (12.7%) and rash (9.3%) and occurred at similar rate in patients receiving ipilimumab alone. Overall, severe toxicities occurred less frequently in patients treated with sargramostim plus ipilimumab vs ipilimumab alone (44.9% vs 58.3%, Grade 3-5); the most notable reductions were in gastrointestinal and pulmonary toxicities [20] .

Pharmacodynamics

Summary

Eight patients with Mycobacterium avium complex (MAC) bacteraemia were randomised to receive azithromycin or azithromycin + GM-CSF to examine the effect of GM-CSF on clearance of mycobacteraemia and monocyte function. Superoxide anion production was significantly increased ex-vivo in monocytes from patients treated with GM-CSF but not in monocytes from patients treated with azithromycin only. Relative to monocytes obtained from untreated healthy controls, the median differences in viable intracellular MAC at 2, 4 and 6 weeks were -0.76, -0.94 and -0.47 log10 cfu/mL of lysate for cells from GM-CSF treated patients vs -0.15, -0.11 and -0.19 log10 cfu/mL for cells from patients treated with azithromycin alone. No effect on mycobacteraemia was detected. The authors concluded that administration of GM-CSF + azithromycin to AIDS patients with disseminated MAC bacteraemia resulted in the activation of their monocyte as reflected ex vivo in increased oxidative burst and increased mycobactericidal activity. Further investigation of GM-CSF in the treatment of mycobacterial infection in warranted [75] .

In a separate study in 30 AIDS patients randomised into 1 of 3 treatment groups (10 patients/group) receiving azithromycin 1200mg alone, orally on day 1, GM-CSF 250 µg/m2/day alone SC for 5 days or GM-CSF + azithromycin, the M. avium killing capacity of neutrophils and monocytes harvested from each patient before and after therapy was assessed. Post-therapy, neither neutrophils nor monocytes harvested from patients treated with GM-CSF alone or combined with azithromycin demonstrated an improved capacity to kill M. avium. There was also no remarkable change in plasma HIV virus load post-therapy. A larger controlled trial is warranted using a different GM-CSF regimen [82] .

Following a phase II trial in 35 patients with prostate cancer, the possibility that sargramostim suppressed prostate-specific antigen (PSA) production but had no cytotoxic effect was eveluated in a cell proliferation assay in LNCaP human prostate cancer cells. After 120h exposure to sargramostim (0.45-5 ng.ml), the decrease in cel number compared with controls was 10.3-15.2%. PSA secretion was increased by 11.2-73.2% with sargramostim treatment, while a modest (≤ 25%) decrease in intracellular PSA levels was detected by immunoblot analysis. Sargramostim was associated with a < 20% decrease in the transcription of the PSA and androgen receptor genes [65] .

In government-sponsored efficacy studies conducted in animals, sargramostim (7 mcg/kg/day) improved survival by 85% (78% versus 42%; p=0.0018) at day 60, when initiated 48 hours after exposure to myelosuppressive doses of radiation expected to be fatal to 50-60% of in non-human primates at day 60, without requiring supportive whole blood transfusions or individualized antibiotics (36 animals per group). In an exploratory cohort that received higher radiation exposures, myelosuppressive doses to be fatal in 70-80% of non-human primates at day 60, sargramostim was improved survival in 61% animals compared with 17% survival in the control group [12] .

Preclinical studies

sargramostim was shown to directly inhibit the in vitro expression of CCR5 and CXCR4, the co-receptors used by HIV-1 to enter human macrophages. Subsequently, a 70- to 100-fold reduction in viral entry was observed in sargramostim-treated macrophages, accompained by an increased production of β chemokines [69] .

Clinical studies

the safety and efficacy of sargramostim, in combination with antiretroviral therapy including ritonavir or indinavir, was investigated in a phase I study in 20 HIV patients with low CD4+ cell counts (10-590 cells/mm3). Sargramostim or placebo were randomly added to the therapy for a period of 8 weeks and patients observed for a further 4 weeks of follow-up. At the end of this period, in the sargramostim group 8/10 patients showed an increase in CD4+ cell counts of ≥ 30%, compared with 3/10 placebo recipients. Such increases were observed in 6/7 patients who had a CD4+ cell count ≥ 50 at baseline, compared with only 1/8 comparable placebo patients. In addition, 5/7 patients had their viral loads decreased of at least 0.5 log10 or more whereas none of the 8 placebo recipients experienced similar reductions. In 4/7 patients treated with sargramostim, the results were sustained [69] .

Drug Interactions

Summary

Concomitant administration of SC sargramostim (250 µg/dose) did not have a significant effect on the Cmax, t½ or AUC of indinavir in a study in 20 patients with HIV [62] .

Immunogenicity

Summary

The immunological response of sargramostim alone or in combination with monoclonal antibody (MAb) R-24 has been investigated in a phase Ib study in 20 patients with malignant melanoma. Sargramostim 150 mg/m2/day was administered SC od d1-21 and MAb R-24 10 or 50 mg/m2/day was administered by continuous IV infusion d8-15. Six patients received sargramostim only. As a result of previous experience with the development of human antimonoclonal antibody, only 1 course of treatment was administered to each patient. 15/20 patients were evaluable for immunological response. By week 3, there was significant (p ≤ 0.05 vs baseline) enhancement of both granulocyte and monocyte antibody-dependent cellular cytotoxicity (ADCC) at effector/target ratios of 32:1 and 16:1 after treatment with sargramostim. The enhancement of monocyte ADCC at an effector/target ratio of 32:1 was still significant in week 4 (1 week after completing therapy with sargramostim). At effector/target ratios of 32:1 and 16:1, monocyte and macrophage direct cellular cytotoxicity was significantly enhanced by week 3 and 1, respectively. Significant granulocyte direct cellular cytotoxicity was maintained through week 3. Despite elevated levels, neither cell types maintained significant cytotoxicity in week 4 [78] .

A low dose of hepatitis B vaccine (Recombivax®) adjuvanted with sargramostim was as effective as eliciting seroprotective antibody titres in healthy non-responders as a high dose of the vaccine alone [55] [56] .

However, sargramostim was ineffective as an adjuvant to Recombivax® in chronic haemodialysis patients who had previously failed to respond to vaccination [58] .

Vaccinating elderly volunteers with influenza vaccine (FluShield®) adjuvanted with sargramostim elicited more potent antibody responses than vaccination with FluShield® alone [57] .

Therapeutic Trials

Alzheimer's disease

Interim results from eleven patients treated with sargramostim and nine patients receiving placebo showed that the mean changes of the MMSE score, Activities of Daily Living, and Delayed Word Recall score showed improvement in the sargramostim group, as compared with the placebo group by repeated measures mixed model analysis and/or permutation T-tests (p<0.05). These differences became non-significant by the follow-up visits [13] [74] .

A randomised, double-blind, placebo-controlled trial investigated the prophylactic efficacy of sargramostim in reducing the incidence of nosocomial infections in very low birth weight neonates. 264 low birth weight infants were randomly assigned to placebo (n = 130) or recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) 8 µg/kg/day administered IV over 2h daily for 7 days then every other day for 21 days. There was no significant difference in the incidence of confirmed nosocomial infections in the neonates treated with GM-CSF vs placebo (54/134 [40%] vs 51/130 [39%]). In addition, there was no significant difference in the mean number of confirmed infections per infant between the placebo and GM-CSF groups. However, the absolute neutrophil and eosinophil counts were significantly elevated in the treated vs placebo groups on days 7, 21 and 28 post-therapy. The authors concluded that GM-CSFalone did not reduce the incidence of nosocomial infection in very low birth weight infants and that future studies should consider combination therapy such as GM-CSF + polyclonal or monoclonal immunoglobulins [81] .

Acute myelogenous leukaemia

In a double-blind, randomised, placebo-controlled study, sargramostim (250 µg/m2 administered by continuous IV infusion over 4h) was effective and well tolerated in patients with acute myelogenous leukaemia after both induction and consolidation therapy. 60% of patients in the sargramostim group achieved complete remission, compared with 44% in the placebo group. In addition, the median time for neutrophil recovery to 500/µl and 1,000/µl was significantly reduced to 13 days in the sargramostim group, compared with 17 days in the placebo group. Overall, treatment-related toxicity was reduced in the sargramostim group [71] .

When GM-CSF was used during induction chemotherapy in patients with acute myeloid leukaemia, it was shown to prevent infections, and saved costs associated with hospitalisation, laboratory tests, pharmacy services, blood products, diagnostic radiology, supplies, respiratory services and electrocardiograms. This retrospective analysis was based on data from the ECOG trial in which 88 patients were randomised to receive either GM-CSF 250 microg/m2/day given IV over 4h or placebo. The frequency of grade 4-5 infections was significantly lower in patients receiving GM-CSF than in placebo recipients (9.6 vs 36.2%, respectively). Furthermore, GM-CSF recipients had fewer grade 3-5 infections (52 vs 70%) [66] .

Colorectal cancer

Interim results from the PROGRESS trial, an open label study of sargramostim in combination with an agressive colon cancer chemotherapeutic regimen, indicate that sargramostim helped to reduce the toxic effects associated with chemotherapy. Sargramostim was administered to 51 patients with metastatic colorectal cancer in an attempt to improve disease control with the Irinotecan (I), 5-Fluorouracil (F), and Leucovorin (L) regimen by decreasing therapy related toxicities, maintaining the shortened cycle schedule, and improving drug dose delivery. Patients received either a weekly (125 mg/m2 I, 500 mg/m2 F, 20 mg/m2 L) or biweekly combination of chemotherapy followed by sargramostim (250 µg/m2) on days 2-6 or 4-13 respectively. The biweekly chemotherapeutic regimen included: 180 mg/m2 I, 1000 mg/m2 F, 200 mg/m2 L administered on Day 1 and 400 mg/m2 F bolus, followed by 600 mg/m2 F infusion over 22 hours; 200 mg/m2 L on Day 2. Of the 33 evaluable patients, 27 had liver involvement, eight had lung involvement, and 11 had received prior F therapy. No disease progression was observed in 24 patients (73%, p=0.041), nine had progressed (27%), and five had died (15%). Mean dose intensity reached 81% of the planned I and F doses [52] .

Lymphoma

In 39 patients with indolent non-Hodgkin's lymphoma, combination treatment with sargramostin and rituximab resulted in 36% of patients achieving a complete response (CR) and on overall response rate of 79%. In 14 patients antibody dependent cell cytotoxicity (ADCC) was measured post therapy and a greater, median, incremental ADCC activity in patients who had achieved a complete response (16%) than in those who had partial responses (6%) [44] .

Malignant melanoma

Phase II

in a phase II trial involving 45 patients with melanoma who had undergone surgery, disease-free survival, and overall survival at 21 months, was acheived in 60% and 64% of patients, respectively. Each patient received two years of therapy, in the first year patients received cycles of subcutaneous sargramostim followed by interleukin-2, in the second year patients received sargramostim alone unless resected recurrence was experienced [39] . Additional data from this trial showed that the median overall survival was 65 months and median recurrence-free survival was 5.6 months [38] .

In a phase II trial in patients with malignant melanoma, among 245 patients, the addition of sargramostim led to longer survival (median 17.5 vs 12.7 months) [20] .

Phase I

the efficacy of sargramostim alone or in combination with monoclonal antibody (MAb) R-24 was investigated in a phase Ib study in 20 patients with malignant melanoma. Sargramostim (150 mg/m2/day) was administered SC od, on days 1-21 and MAb R-24 (10 or 50 mg/m2/day) was administered by continuous IV infusion on days 8-15. Six patients received sargramostim only. One course of treatment was administered to each patient. There were no partial responders, 2 patients had stable disease and 1 had no response in the sargramostim-only group. Of 14 evaluable patients who received sargramostim + MAb R-24, there were 2 partial responders, 3 patients had stable disease and 3 had no response. Both partial responders received sargramostim + MAb R-24 10 mg/m2/day, 1 of whom had a response duration of 2 months and the other patient was withdrawn from the study on day 14 with grade 4 toxicity [78] .

Sargramostim significantly increased the 1-year survival rate when administered to 30 patients with malignant melanoma following surgery. Patients receiving sargramostim had a median survival of > 20.6 months, compared with 11.2 months in a matched historical control group [79] .

Prostate cancer

In a trial in 35 patients with advanced prostate cancer, sargramostim (250 µg/m2/day) was administered SC on days 1-14 q4w (cohort 1, n = 22) or days 1-14 then 3/week (cohort 2, n = 13). The median overall survival duration was 15.8 months. Ten patients in cohort 1 had oscillating prostate-specific antigen (PSA) levels. The median maximal PSA decrease in this cohort was 37% and 5 patients had a > 50% decline in PSA levels on ≥ 1 occasion. The median response duration was 3.5 months. In cohort 2, only 1 patient did not have a decrease in PSA. Two patients had oscillating PSA levels. The median PSA decrease was 32.4%, but only 1 patient had a decrease of > 50% that was sustained for > 6 weeks. PSA levels in this patient declined from 77 ng/ml at baseline to 0.1 ng/ml and an improvement in a bone scan was evident, a response that was sustained for > 14 months [65] .

Sarcoma

In a phase II trial of yeast-derived recombinant sargramostim as monotherapy in patients with advanced sarcomas, no objective responses were seen and patient accrual was stopped. The treatment cycle consisted of sargramostim 250 µg/m2 administered SC for 14 consecutive days followed by a rest period of 7 days between cycles. 15 patients were enrolled in the trial, of whom 14 had metastatic disease. The best response was 2 patients with stable disease lasting for ≥ 6 cycles [59] .

Small cell lung cancer

230 patients with limited-stage small cell lung cancer received chemotherapy and radiotherapy with or without sargramostim, which was administered on days 4-18 of each of 6 cycles. Those that received sargramostim had a lower complete response rate (36%) compared to those that did not (44%), but the difference was not significant. There was no significant difference in survival between the 2 groups [67] .

Bone marrow disorders

A total of 128 patients undergoing autologous bone marrow transplantation were enrolled in a randomised, double-blind, placebo controlled trial in order to evaluate the effects of sargramostim 250 µg/m2/day intravenously over 2h for 21 days after transplantation. Results from this study demonstrated that sargramostim accelerated the recovery of neutrophilis 7 days earlier than placebo and that in the sargramostim arm fewer infections were observed. A significant reduction in the number of days of administration of intravenous antibiotics was also observed when compared with the placebo group (24 vs 27 days). After 100 days from the transplantation, no difference was noted in the survival rate [73] .

Neutropenia

Sargramostim was as effective as filgrastim in the treatment of chemotherapy-induced neutropenia according to results from a randomised trial. The results indicated that it may be clinically feasible to discontinue these agents when patients attain an absolute neutrophil count (ANC) of ≥ 1500/µl. There was no significant between-group difference in the mean number of days to reach an ANC of 500/µl, while the mean number of days to reach an ANC of 1000 and 1500/µl were slightly, but significantly, lower among filgrastim compared with sargramostim recipients. In about half the patients, ANC values did not change 48h after stopping growth factor therapy. The patients had developed an ANC of < 500/µl within 4 weeks of administration of chemotherapy and were randomised to receive SC sargramostim 250 µg/m2/day (n = 79), or SC filgrastim 5 µg/kg/day (102), until their ANC reached ≥ 1500/µl [68] .

Morbidity and mortality after chemotherapy is frequently caused by pancytopenia. Withdrawal of granulocyte-macrophage colony-stimulating factor (priming) induces haematopoietic stem-cell arrest. Therefore, administration of granulocyte-macrophage colony-stimulating factor prior to chemotherapy may decrease the severity and duration of pancytopenia by protecting haematopoietic stem cells from chemotherapy-induced cytotoxicity. In keeping with this hypothesis, sargramostim appeared to protect haematopoietic progenitor cells from cytotoxicity associated with chemotherapy in women with early-stage breast cancer. In this double-blind cross-over study, patients (n = 20) receiving 4 courses of cyclophosphamide and doxorubicin were randomised to receive priming with sargramostim or placebo on days 5 to 1 before each course. On day 16, patients had a higher mean neutrophil count and a lower proportion exhibited severe neutropenia (< 500/µl). The times to neutrophil and platelet nadirs were significantly shorter after priming compared with before [64] .

Phase III

the phase III N.O.V.E.L 4 study, evaluating sargramostim in patients with moderate-to-severly active Crohn's disease, failed to meet its primary endpoints. in this double-blind study, 286 patients were randomised to receive, via subcutaneous injection, sargramostim 6µg/kg/day, or placebo, for eight weeks. Response was defined as a Crohn's Disease Activity Index (CDAI) decrease of ≥ 100 points, and remission as a CDAI score of ≤ 150 points. No significant differences were seen between treatment with sargramostim and placebo, with respect to the primary enpoints of response and/or remission at eight weeks; remission rates for sargramostim- and placebo-treated patients were 22.3% and 22.6%, respectively. Response rates were 41.1% and 33.3%, respectively. However, a trend towards treatment benefit was demonstrated in the trial and a secondary composite remission/response analysis showed sargramostim to be numerically better than placebo [42] [40] .

Phase II

results from the phase II, double-blind, N.O.V.E.L 2 study, investigating sargramostim in patients with active corticosteroid-dependent Crohn's disease, demonstrated that the drug was signifacntly more effective than placebo for induction of steroid-free clinical remission. Patients (n = 129) requiring 10-40mg of prednisone or equivalent, were randomised to receive, via subcutaneous injection, sargramostim 6µg/kg/day, or placebo, for 12-22 weeks depending on baseline corticosteroid dose. The primary endpoint was achieved, with sargramostim treatment being significantly more effective at inducing corticosteroid-free clinical remission (CDAI ≤ 150) four weeks after steroid withdrawl [42] .

A 20-22% improvement in total IBDQ (inflammatory bowel disease questionnaire) from baseline was reported for patients receiving sargramostim, versus 7-13% for placebo. In concurrence with this, 12- 20% improvements in the Physical Component Summary score were also reported for patients receiving treatment [43] .

In the multicentre, double-blind, phase II, N.O.V.E.L. 1 (New Opportunities to Verify Evolving Logic in Crohn's disease) study, 124 patients with moderately to severely active Crohn′s disease were randomised to receive sargramostim or placebo for 57 days. 48% of patients treated with sargramostim had a decrease of the Crohn's disease activity index (CDAI) of more than 100 points, and 40% of patients achieved clinical remission by the end of the study (CDAI less than or equal to 150), versus 26% and 19% of the placebo-treated patients, respectively (p=0.013 and p=0.014, respectively). 54% of patients treated with sargramostim achieved a CDAI decrease of more than 70 points, versus 44% of placebo-treated patients (p=0.275). These results were achieved without the use of steroids and/or immunosuppressants. The proportion of patients achieving CDAI response (70 and 100 points) and remission were significantly different from placebo at day 29. Significant differences between the sargramostim and placebo groups were observed in the time to 100 point response (30 days vs. not reached, p=0.003) and remission (56 days vs. not reached, p=0.004) [51] [77] .

In the above phase II study, patients who responded at the end of treatment (57 days) were followed for up to six months. In the 30-day follow-up period, 42% of patients treated with sargramostim showed a significantly sustained improvement in clinical response compared to placebo recipients (21%). While, 33% of patients treated with sargramostim achieved significant clinical remission compared to placebo recipients (14%). In sargramostim treated patients, the Median time to loss of ≥70 points in the CDAI and ≥100 points was 10 weeks and 8 weeks, respectively. The median time to loss of remission (CDAI score > 150) was 8 weeks, while the median time to disease relapse (CDAI > 220) after remission induction was 10 weeks. Response was maintained beyond six-month follow-up in 15% of patients [49] [50] .

Interim data from the N.O.V.E.L. 5 trial (n = 60) demonstrated that sargramostim 6 µg/kg/day treatment for up to 6 cycles induced response and remission among patients with moderately-to-severely active Crohn's disease. Median reduction in CDAI score after one cycle was 172 with 53% of patients achieving a 100 point response and 40% of patients achieving remission (CDAI ≤ 150). Response and remission rates were similar to those established in previous studies [45] .

Results from a phase I/II trial in paediatric patients (6-16yrs) with active Crohn's disease showed a remission/response rate of 83% (15/18 patients) [41] .

Phase I

in a dose-escalating, pilot study, 15 patients with moderate-to-severe idiopathic Crohn's disease treated withsargramostim (4, 6 or 8 µg/kg/day) showed a significant decrease in disease symptoms over the eight-week course of therapy, as measured by the Crohn's disease activity index (CDAI). At 8-weeks, the mean CDAI significantly decreased by 190 points from baseline. A total of 75%, 85% and 75% of patients in the GM-CSF 4, 6 and 8 µg/kg/day treatment groups, respectively, responded to therapy. In total, 12 patients achieved a clinical response to therapy and 8 achieved clinical remission [53] .

Sargramostim had therapeutic benefit as adjunctive treatment of refractory oropharyngeal candidiasis in patients with AIDS. In 3 case reports, patients who had failed therapy with azoles (fluconazole or itraconazole) or amphotericin B were treated daily with sargramostim and either fluconazole or amphotericin B for 14 days. Clinical resolution of candidiasis had occurred in all 3 patients by day 14; however, despite continuation of the anti-fungal therapy, relapse of disease occurred in all 3 patients within 2 weeks of discontinuation of sargramostim therapy [54] .

In a prospective, open-label phase II trial, sargramostim therapy caused improvement in > 50% of patients with pulmonary alveolar proteinosis. Twenty-five patients with pulmonary alveolar proteinosis and circulating antibody to granulocyte macrophage colony stimulating factor (GM-CSF) received a starting dose of sargramostim 250 mg/day that was rapidly increased to a maximum of 18 µg/kg/day. Treatment duration was 12 weeks (n = 5) and ≥ 24 weeks (n = 18); 21 patients completed the trial. The mean duration of follow-up (post-therapy) was 39 months. There was radiographic and A-a (alveolar to arterial) gradient improvement in 13 patients. In patients responding to sargramostim therapy, the A-a gradient decreased from 36.2mm Hg (baseline) to 17.9mm Hg at follow-up; in non-responders, it increased from 40.1mm Hg (baseline) to 49.3mm Hg at follow-up. Prior to the trial, 21/25 patients had received whole lung lavage; during the trial, 14 patients remained free of whole lung lavage, but 11 required it for an average of two sessions [47] .

Hepatitis C

71 patients with chronic hepatitis C virus (HCV) infections were treated with sargramostim (n = 19) or interferon α-2b alone (n = 25) or with sargramostim (n = 27) for 6 months. Treatment with interferon α-2b alone and with sargramostim resulted in biochemical responses in 54.2% and 31.8% of patients, respectively, with sustained biochemical responses reported in 1 patient each from these 2 groups. 13 patients receiving interferon α-2b monotherapy and 18 who also received sargramostim were viraemic at 3 months. Mean HCV RNA titre was significantly reduced, relative to baseline, with decreases of 10% for patients receiving interferon α-2b alone and 14% of those also receiving sargramostim [61] .

No biochemical or virological responses occurred in patients given sargramostim (65, 125 or 250 µg/m2) monotherapy, and mean HCV RNA levels were not significantly reduced, relative to baseline, by any sargramostim dose used [60] .

HIV infections

In a phase III study conducted in Brazil, 105 AIDS patients (CD4 cell count < 300 cells/mm3) received either sargramostim (125 µg/m2) or placebo, SC twice weekly, in combination with zidovudine monotherapy or combination nucleoside analogue therapy including zidovudine. At the end of 6 months, median viral load was reduced -0.60 log10 in the sargramostim group compared with -0.07 log10 in the placebo group. Decreases of ≥ 1 log10 copies/ml occurred in 20/53 (38%) sargramostim recipients vs 9/51 (17%) patients in the placebo group. Viral load was reduced to < 500 copies/ml at ≥ 2 evaluations in 11% of the sargramostim group, compared with 2% of the placebo group. Mean increases in CD4+ cell count for sargramostim recipients after 1, 3 and 6 months were 57, 64 and 35 cells/µl, respectively. In the placebo group, CD4+ cell count increased by 22 and 12 cells/µl after 1 and 6 months, respectively, but decreased by 2 cells/µl at month 3. The difference between the placebo and sargramostim goups was only statistically significant at 3 months. 80% of sargramostim recipients and 59% of the placebo group had increases in CD4+ cell count of ≥ 30%; this difference was statistically significant. Significantly fewer sargramostim recipients had new mutations at 6 months (50% vs 80% for placebo) [76] .

Sargramostim demonstrated beneficial effects in patients with advanced HIV infection according to the results of a phase III study conducted in Canada and the USA. In this multicentre study, 309 such patients were randomised to receive SC sargramostim 250µg (n = 155) or placebo, 3 times weekly for 24 weeks. After 1 month, sargramostim recipients had increases from baseline in total lymphocyte and CD4 cell counts. A significantly greater proportion of sargramostim, compared with placebo, recipients maintained undetectable viral loads. Compared with placebo recipients, sargramostim recipients had a significantly lower incidence of infections or death; the median time to first infection or death was also significantly longer. At week 24, increases in CD4+ cell counts, relative to baseline, had occurred in 31% of sargramostim recipients, but none of the placebo group. Among patients with baseline CD4+ counts of 50-100 cells/µl, increases occurred in 52% given sargramostim, compared with 6% of those given placebo. HIV RNA level was < 400 copies/ml at baseline and at week 24 in significantly more patients in the sargramostim group (83% vs 54%) [63] [80] .

Results from a study in 20 patients with HIV indicated that treatment with SC sargramostim (250µg 3/week) in addition to indinavir- or ritonavir-containing antiretroviral therapy was significantly more effective than treatment with the antiretroviral regimens + placebo. Median maximum decreases in HIV RNA levels, relative to baseline, were 0.40 log10copies/ml for the sargramostim group, compared with 0.33 log10copies/ml for placebo recipients; decreases of ≥ 0.5 log10copies/ml occurred at ≥ 2 time points in the study in 5/10 and 1/10 patients in the sargramostim and placebo groups, respectively. Mean maximal increase in CD4 cell count was 129.6 cells/µl with sargramostim, compared with 57 cells/µl with placebo, and increases of ≥ 30% over baseline occurred in 7 and 3 patients in the sargramostim and placebo groups, respectively [62] .

Future Events

Expected Date Event Type Description Updated
30 Jun 2020 Trial Update Partner Therapeutics plans a phase II trial for Acute hypoxia (Adjunctive therapy) (Inhalation) (NCT04411680) (700322554) 04 Jun 2020

Development History

Event Date Update Type Comment
04 Jun 2020 Trial Update Partner Therapeutics plans a phase II trial for Acute hypoxia (Adjunctive therapy) (Inhalation) (NCT04411680) Updated 04 Jun 2020
28 May 2020 Phase Change - II Phase-II clinical trials in COVID-2019 infections (In adults, In the elderly) in Singapore (IV) (NCT04400929) Updated 03 Jun 2020
02 Apr 2020 Financial Update Credit Suisse financial data update Updated 11 Apr 2020
12 Nov 2019 Phase Change - Suspended(II/III) Suspended - Phase-II/III for Malignant melanoma (Combination therapy, Inoperable/Unresectable, Second-line therapy or greater) in USA (SC) Updated 12 Nov 2019
23 Sep 2019 Scientific Update Safety and efficacy data from a phase II trial in Malignant melanoma released by Partner Therapeutics [20] Updated 23 Sep 2019
19 Sep 2019 Regulatory Status Sargramostim receives Orphan Drug status for Malignant melanoma in USA [20] Updated 23 Sep 2019
28 Apr 2019 Phase Change - No development reported No recent reports of development identified for phase-I development in Prostate-cancer in USA (SC, Injection) Updated 28 Apr 2019
06 Nov 2018 Regulatory Status Sargramostim - Bayer HealthCare Pharmaceuticals receives Orphan Drug status for Pulmonary alveolar proteinosis in USA [34] Updated 12 Nov 2018
11 Jun 2018 Regulatory Status Planned Prescription Drug User Fee Act (PDUFA) date for Acute radiation syndrome (In neonates, In infants, In children, In adolescents, and In adults) in USA (SC) is 2018-03-29 [2] Updated 11 Jun 2018
07 Jun 2018 Phase Change - Marketed Launched for Acute radiation syndrome (In neonates, In infants, In children, In adolescents, and In adults) in USA (SC) Updated 11 Jun 2018
06 Jun 2018 Phase Change - Registered Registered for Acute radiation syndrome (In neonates, In infants, In children, In adolescents, and In adults) in USA (SC) [12] Updated 11 Jun 2018
30 May 2018 Licensing Status Tanner Pharma Group agrees to distribute sargramostim in countries outside USA and Canada [1] Updated 30 May 2018
30 Apr 2018 Trial Update Genzyme withdraws a phase III trial in Malignant-melanoma in USA prior to enrolment as no patients enrolled (NCT01826864) Updated 10 May 2018
01 Feb 2018 Licensing Status Sargramostim sub-licensed to Partner Therapeutics worldwide [2] Updated 05 Feb 2018
31 Dec 2017 Regulatory Status Sargramostim receives priority review status for Acute radiation syndrome in USA [2] Updated 11 Jun 2018
23 Oct 2017 Trial Update Stanford University and Bayer terminates a phase II trial in Prostate cancer (Second-line therapy or greater, Combination therapy) in USA due to low accrual (SC) (NCT00477087) Updated 04 Dec 2017
29 Sep 2017 Phase Change - Preregistration Preregistration for Acute radiation syndrome (In neonates, In infants, In children, In adolescents, and In adults) in USA (SC) [2] Updated 11 Jun 2018
16 Jul 2017 Scientific Update Interim efficacy and adverse events data from a phase II safety and efficacy trial in Alzheimer's disease presented at the Alzheimer's Association International Conference 2017 (AAIC-2017) [13] Updated 28 Aug 2017
16 Jul 2017 Trial Update Alzheimer’s Association plans a clinical trial for Alzheimer’s disease [13] Updated 28 Aug 2017
16 Jul 2017 Trial Update University of Colorado initiates enrolment in a phase II pilot safety and efficacy trial for Alzheimer's disease in USA before July 2017 [13] Updated 28 Aug 2017
05 Apr 2017 Trial Update Sanofi withdrew a phase II trial prior to enrolment due to slow recruitment in Alzheimer's disease (In adults, In the elderly) in USA (SC) (NCT02667496) Updated 19 Apr 2017
28 Feb 2017 Active Status Review Sanofi withdraws a phase II trial in Acute myeloid leukaemia in Czech Republic and USA prior to enrolment, since the company has fulfilled post-marketing requirements (NCT02520102) Updated 04 Apr 2017
01 Jan 2017 Trial Update Bayer completes a phase II trial in Chronic lymphocytic leukaemia (Combination therapy, In adolescents, In adults, In elderly) in USA (SC) (NCT00940342) Updated 01 Mar 2017
06 Oct 2016 Phase Change - Clinical Clinical trials in Acute radiation syndrome in USA (Parenteral) [3] Updated 12 Oct 2016
06 Oct 2016 Regulatory Status Sanofi Genzyme intends to file an sBLA for the treatment of patients with Acute radiation syndrome in USA [3] Updated 12 Oct 2016
04 Feb 2016 Phase Change - II Phase-II clinical trials in Alzheimer's disease (In adults, In the elderly) in USA (SC) (NCT02667496) Updated 08 Mar 2016
01 Jan 2016 Company Involvement Genzyme is now called Sanofi Genzyme Updated 14 Dec 2016
10 Sep 2015 Phase Change - II/III Phase-II/III clinical trials in Malignant melanoma (Combination therapy, Inoperable/Unresectable, Second-line therapy or greater) in USA (SC) (NCT02339571) Updated 12 Nov 2019
01 Sep 2015 Phase Change - I Phase-I clinical trials in Prostate cancer in USA (SC) Updated 17 Nov 2015
13 Aug 2015 Trial Update Genzyme plans a phase II trial for Acute myeloid leukaemia in Czech Republic and USA (SC) (NCT02520102) Updated 13 Aug 2015
18 Jun 2015 Phase Change - No development reported(II) No recent reports on development identified - Phase-II for Malignant melanoma and Ovarian cancer in USA (SC) Updated 18 Jun 2015
01 May 2015 Phase Change - Discontinued(II) Discontinued - Phase-II for Pneumococcal infections (Combination therapy, In adolescents, In children, In the elderly, In adults) in USA (SC) Updated 01 Mar 2017
27 Jan 2015 Active Status Review Sargramostim is still in phase II trials for Chronic lymphocytic leukaemia in USA Updated 18 Jun 2015
20 Jan 2015 Trial Update Bayer completes a phase II trial in Chronic lymphocytic leukaemia (Combination therapy, In children, In adolescents, In adults, In the elderly) in USA (NCT00381004), sometime before January 2015 Updated 20 Jan 2015
01 May 2014 Trial Update Bayer and Genzyme complete a phase II trial of sargramostim in men with hormone-refractory metastatic prostate cancer in the US (NCT00488982) Updated 20 Jan 2015
01 Feb 2014 Trial Update Cincinnati's Children's Hospital Medical Center, Virginia Commonwealth University and Genzyme complete a phase II trial in Pulmonary alveolar proteinosis in USA (NCT01511068) Updated 29 Feb 2016
19 Jul 2013 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
01 May 2013 Phase Change - No development reported(II) No development reported - Phase-II for Pneumococcal infections (Combination therapy, In adolescents, In children, In the elderly, In adults) in USA (SC) Updated 01 Mar 2017
01 Aug 2012 Phase Change - II Phase-II clinical trials in Pulmonary alveolar proteinosis in USA (Inhalation) Updated 29 Feb 2016
27 Apr 2012 Trial Update Massachusetts General Hospital and Bayer completes a phase II trial in Ovarian cancer in the US (NCT00157573). Updated 26 May 2012
19 Jul 2011 Phase Change - Discontinued(II) Discontinued - Phase-II for Non-Hodgkin's lymphoma in USA (SC) Updated 18 Jun 2015
01 May 2011 Trial Update Bayer completes a phase II trial in Pneumococcal infections (Combination therapy, In children, In adults, In adolescents, In the elderly) in USA (SC) (NCT00323557) Updated 01 Mar 2017
08 Apr 2011 Company Involvement Genzyme Corporation has been acquired by sanofi-aventis Updated 11 Apr 2011
03 Apr 2011 Company Involvement Bayer Schering Pharma is now Bayer Healthcare Pharmaceuticals Updated 03 Apr 2011
28 Dec 2010 Phase Change - II Phase-II clinical trials in Malignant melanoma (Combination therapy, Late-stage disease) in USA (SC) (NCT01134614) Updated 23 Sep 2019
31 Jul 2010 Trial Update Stanford University and Bayer complete a phase II trial in Prostate cancer (Second-line therapy or greater, Combination therapy) in USA (NCT00477087) Updated 05 Oct 2010
20 Apr 2010 Trial Update Genzyme Corporation terminates phase II trial [NCT00308087; PREMIER] in Non-Hodgkin's lymphoma in USA Updated 20 Apr 2010
29 Aug 2009 Phase Change - Discontinued(II) Discontinued - Phase-II for Follicular lymphoma in USA and Puerto Rico (SC) Updated 18 Jun 2015
02 Jun 2009 Licensing Status Bayer HealthCare and Genzyme finalise strategic alliance agreement, with Bayer's haematological oncology products now licensed to Genzyme [9] Updated 08 Jun 2009
30 Jun 2008 Scientific Update Final efficacy data from a phase II trial in Malignant melanoma released by Bayer [38] Updated 03 Jul 2008
03 Jun 2008 Scientific Update Efficacy data from a phase II trial in Melanoma presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO-2008) [39] Updated 09 Jun 2008
19 May 2008 Regulatory Status Re-formulated liquid sargramostim is approved by the US FDA and introduced to the US market Updated 22 May 2008
23 Jan 2008 Regulatory Status Bayer withdraws the liquid formulation of sargramostim and establishes a special access programme Updated 15 May 2008
19 Jun 2007 Phase Change - Discontinued(II) Discontinued - Phase-II for Crohn's disease in Canada (SC) Updated 21 Jun 2007
19 Jun 2007 Phase Change - Discontinued(III) Discontinued - Phase-III for Crohn's disease in USA (SC) Updated 21 Jun 2007
30 May 2007 Scientific Update Data presented at the Digestive Disease Week-2007 (DDW-2007) added to the pharmacokinetics and Inflammatory Bowel Disorders therapeutic trials sections [40] , [41] Updated 30 May 2007
04 Apr 2007 Company Involvement Berlex Inc has been acquired by Bayer HealthCare (MR 9074204) Updated 05 Apr 2007
29 Dec 2006 Company Involvement Schering AG is now called Bayer Schering Pharma AG Updated 11 Jan 2007
03 Nov 2006 Phase Change - II Phase-II clinical trials in Malignant melanoma in USA (SC) Updated 09 Jan 2009
03 Nov 2006 Phase Change - II Phase-II clinical trials in Ovarian cancer in USA (SC) Updated 09 Jan 2009
03 Nov 2006 Phase Change - II Phase-II clinical trials in Non-Hodgkin's lymphoma in USA (SC) Updated 03 Nov 2006
01 Sep 2006 Phase Change - II Phase-II clinical trials in Chronic lymphocytic leukaemia (In children, In adolescents, In adults, In the elderly, Combination therapy) in USA (SC) (NCT00381004) Updated 01 Mar 2017
03 Aug 2006 Scientific Update Interim results from the phase III clinical trial N.O.V.E.L. 4 in patients with moderately-to-severly active Crohn's disease have been added to the Inflammatory Bowel Disorders therapeutic trials section [42] Updated 03 Aug 2006
03 Aug 2006 Scientific Update Interim results from the phase II clinical trial N.O.V.E.L. 2 in patients with steroid-dependent Crohn's disease have been added to the Inflammatory Bowel Disorders therapeutic trials section [42] Updated 03 Aug 2006
01 Jul 2006 Trial Update Stanford University and Bayer initiates enrolment in a phase II trial in Prostate cancer (Second-line therapy or greater, Combination therapy) in USA (SC) (NCT00477087) Updated 04 Dec 2017
20 Jun 2006 Company Involvement Schering AG has been acquired by Bayer Updated 30 Oct 2006
31 Jan 2006 Phase Change Berlex re-launches a reformulated version of sargramostim in USA Updated 12 Mar 2007
07 Nov 2005 Scientific Update Data from a media release have been added to the Inflammatory bowel disorder therapeutic trials section [43] Updated 07 Nov 2005
25 Oct 2005 Trial Update Schering has initiated a phase III trial for Crohn's disease Updated 25 Oct 2005
16 Jun 2005 Scientific Update Data from a media release have been added to the Cancer therapeutic trials section [44] Updated 16 Jun 2005
01 Jun 2005 Scientific Update Data presented at the Digestive Disease Week-2005 (DDW-2005) have been added to the adverse events and Inflammatory bowel disorders therapeutic trials sections [45] Updated 01 Jun 2005
09 May 2005 Trial Update Berlex has completed enrolment in the N.O.V.E.L .2 trial for Crohn's Disease in the US and Canada Updated 09 May 2005
26 Apr 2005 Scientific Update Data presented at the 57th Annual Meeting of the American Academy of Neurology (AAN-2005) have been added to the adverse events section [46] Updated 06 May 2005
25 Apr 2005 Phase Change - I Phase-I clinical trials in Multiple sclerosis in USA (unspecified route) Updated 06 May 2005
22 Mar 2005 Phase Change - No development reported(III) No development reported - Phase-III for Mucositis in USA (unspecified route) Updated 22 Mar 2005
26 Nov 2004 Phase Change - II Phase-II clinical trials in Pulmonary alveolar proteinosis in USA (SC) Updated 26 Nov 2004
26 Nov 2004 Scientific Update Data presented at the 70th Annual Meeting of the American College of Chest Physicians (CHEST-2004) have been added to the Respiratory tract disorders therapeutic trials section [47] Updated 26 Nov 2004
01 Aug 2004 Phase Change - II Phase-II clinical trials in Chronic lymphocytic leukaemia (Combination therapy, In adolescents, In adults, In elderly) in USA (SC) (NCT00940342) Updated 09 Jan 2009
30 Jun 2004 Phase Change - II Phase-II clinical trials in Crohn's disease in Canada (SC) Updated 05 Jul 2004
30 Jun 2004 Trial Update Berlex has initiated enrolment in the N.O.V.E.L. 3 and N.O.V.E.L. 4 trials for crohns disease in the US and 10 countries outside the US Updated 05 Jul 2004
01 Jun 2004 Phase Change - II Phase-II clinical trials in Pneumococcal infections (Combination therapy, In children, In adults, In adolescents, In the elderly) in USA (SC) (NCT00323557) Updated 01 Mar 2017
25 May 2004 Scientific Update Data presented at the Digestive Disease Week-2004 (DDW-2004) have been added to the adverse events and Inflammatory bowel disorders therapeutic trials sections [48] , [49] , [50] Updated 25 May 2004
01 Apr 2004 Company Involvement Aventis Behring LLC has merged with ZLB Bioplasma to form ZLB Behring Updated 01 Apr 2004
29 Mar 2004 Phase Change - III Phase-III clinical trials in Crohn's disease in USA (SC) Updated 09 Jun 2004
16 Oct 2003 Scientific Update Data from a media release have been added to the adverse events and Inflammatory Bowel Disorders therapeutic trials sections [51] Updated 16 Oct 2003
15 Jul 2003 Scientific Update Data from a media release have been added to the adverse events and Haematological disorders therapeutic trials sections [52] Updated 15 Jul 2003
12 Nov 2002 Scientific Update A study has been added to the adverse events and Inflammatory Bowel disorders therapeutic trials sections [53] Updated 12 Nov 2002
25 Jul 2002 Licensing Status Sargramostim has been purchased by Schering AG worldwide Updated 25 Jul 2002
24 Jul 2002 Company Involvement Immunex has been acquired by, and merged into, Amgen Updated 24 Jul 2002
10 May 2002 Licensing Status Schering AG has agreed to acquire sargramostim Updated 10 May 2002
30 Jan 2002 Licensing Status Sargramostim is available for licensing Updated 30 Jan 2002
31 Oct 2001 Phase Change - II Phase-II clinical trials in Crohn's disease in USA (SC) Updated 14 May 2002
31 Jan 2001 Scientific Update Clinical studies have been added to the Mycoses [54] and Vaccines [55] , [56] , [57] , [58] therapeutic trials sections Updated 31 Jan 2001
30 Jan 2001 Scientific Update A phase II study has been added the Cancer therapeutic trials and adverse events sections [59] Updated 30 Jan 2001
26 Jan 2001 Phase Change - No development reported No-Development-Reported for Hepatitis C in USA (SC) Updated 26 Jan 2001
26 Jan 2001 Scientific Update A case report has been added to the adverse events section Updated 26 Jan 2001
26 Jan 2001 Scientific Update A study in patients with hepatitis C has been added to the Viral Infections therapeutic trials and adverse events sections [60] , [61] Updated 26 Jan 2001
26 Jan 2001 Scientific Update A study in patients with HIV has been added to the Viral infections therapeutic trials, adverse events and drug interactions sections [62] Updated 26 Jan 2001
26 Jan 2001 Scientific Update Two studies in patients with HIV have been added to the Viral Infections therapeutic trials and adverse events sections (849570 and 812616) Updated 26 Jan 2001
17 Jul 2000 Phase Change - II Phase-II clinical trials for Varicose ulcer in USA (Unknown route) Updated 17 Jul 2000
17 Jul 2000 Phase Change - III Phase-III clinical trials for Mucositis in USA (Unknown route) Updated 17 Jul 2000
22 Jun 2000 Phase Change - III Phase-III clinical trials for HIV infections treatment in Latin America (SC) Updated 22 Jun 2000
12 May 2000 Scientific Update A study has been added to the Viral infections therapeutic trials section [63] Updated 12 May 2000
03 Feb 2000 Scientific Update A study in patients with breast cancer has been added to the Haematological Disorders therapeutic trials section [64] Updated 03 Feb 2000
08 Oct 1999 Regulatory Status FDA says Immunex's AIDS claims are misleading Updated 08 Oct 1999
17 Aug 1999 Scientific Update A study has been added to the adverse events and Cancer therapeutic trials and pharmacodynamics sections [65] Updated 17 Aug 1999
04 May 1999 Scientific Update A study has been added to the Cancer therapeutic trials section [66] Updated 04 May 1999
26 Jan 1999 Phase Change Investigation in Neonatal infections in USA (IV-infusion) Updated 26 Jan 1999
14 Oct 1998 Scientific Update A study has been added to the Cancer therapeutic trials and adverse events sections [67] Updated 14 Oct 1998
02 Sep 1998 Scientific Update A study has been added to the Haematological disorders therapeutic trials section [68] Updated 02 Sep 1998
17 May 1998 Phase Change - II Phase-II clinical trials for Prostate cancer (second-line, combination therapy) in USA (SC) Updated 17 May 1998
26 Mar 1998 Phase Change Investigation in Mycobacterium avium complex infections in USA (SC) Updated 26 Mar 1998
05 Mar 1998 Scientific Update A study has been added to the Viral infections therapeutic trials and pharmacodynamics sections [69] Updated 05 Mar 1998
08 Jul 1997 Scientific Update Studies have been added to the pharmacokinetics, adverse events and therapeutic trials sections [70] , [71] , [72] , [73] Updated 08 Jul 1997
05 May 1997 Phase Change - III Phase-III clinical trials for HIV infections treatment in USA (SC) Updated 05 May 1997
05 May 1997 Phase Change - III Phase-III clinical trials for Mycoses in USA (IV) Updated 05 May 1997
02 Jul 1996 Phase Change - Marketed Launched for Acute myeloid leukaemia in USA (IV-infusion) Updated 02 Jul 1996
02 Jul 1996 Phase Change - Marketed Launched for Bone marrow disorders in USA (IV-infusion) Updated 02 Jul 1996
30 Jun 1996 Phase Change - Marketed Launched for Neutropenia in USA (IV) Updated 30 Jun 1996
30 Jun 1996 Phase Change - Marketed Launched for Stem cell mobilisation in USA (IV) Updated 30 Jun 1996
01 Feb 1996 Phase Change - II Phase-II clinical trials for HIV infections treatment (IV) Updated 01 Feb 1996
26 Jan 1996 Phase Change - Registered Registered for Bone marrow disorders in USA (IV) Updated 26 Jan 1996
26 Jan 1996 Phase Change - Registered Registered for Neutropenia in USA (IV) Updated 26 Jan 1996
22 Jan 1996 Phase Change - Registered Registered for Stem cell mobilisation in USA (IV) Updated 22 Jan 1996
12 Oct 1995 Phase Change - Registered Registered for acute myeloid leukaemia in USA (IV) Updated 12 Oct 1995
28 Apr 1995 Phase Change - Preregistration Preregistration for Chemoprotection in USA (IV) Updated 28 Apr 1995
28 Nov 1994 Phase Change - Preregistration Preregistration for Chemoprotection in European Union (IV) Updated 28 Nov 1994
28 Nov 1994 Phase Change - Suspended Suspended-Unspecified Phase in Chemoprotection in Japan (IV) Updated 28 Nov 1994

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