Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder in which a materialcalled surfactant builds up in the lungs and makes it hard to breathe. In addition toshortness of breath, people with aPAP can experience persistent cough, overwhelmingfatigue, unintentional changes in weight, chest or back pain, suddenly feeling out ofshape, and general discomfort.Currently, there are no approved medications for aPAP in the United States, but thesymptoms of aPAP can be treated with whole lung lavage (WLL). WLL is an invasiveprocedure that temporarily removes surfactant, and it can result in serious consequenceslike trauma to the lung, a collapsed lung, and prolonged requirement for artificialventilation.Savara is studying an investigational drug called molgramostim nebulizer solution to seeif it activates the cells that help clear surfactant from the lungs, which improvesoxygen transfer from the lungs to the bloodstream. Molgramostim nebulizer solution isadministered by inhalation using a hand-held nebulizer. In clinical trials, molgramostimnebulizer solution has shown improvements in gas exchange and patient reported outcomes.This expanded access program will make molgramostim nebulizer solution available to adultpatients with diagnosed aPAP. Access must be obtained through the treating physician.Patients will dose molgramostim nebulizer solution 300 micrograms (mcg) once daily and befollowed by their physician every 3 months to assess their clinical status and report anyadverse events.
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease mediated by
autoantibodies targeting granulocyte macrophage colony-stimulating factor (GM-CSF),
resulting in malfunctioning macrophages with impaired surfactant catabolism. The latter
causes accumulation of surfactant in the alveoli, which has a negative impact on gas
exchange between lung and blood. The clinical course of autoimmune PAP varies among
patients with continuously slowly progressive disease in most patients, spontaneous
improvement in a small percentage (5-7%), and rapid progression and/or pulmonary
fibrosis, respiratory failure, and death in others. The most common cause of death is
respiratory failure followed by secondary pulmonary bacterial infections. Estimated
5-year mortality rates vary between 10-30%, with overall disease-specific survival rates
at 5 years exceeding 80%.
There are currently no approved pharmacological treatments for aPAP in most of the world.
Whole lung lavage (WLL) is the primary treatment option currently available for most aPAP
patients. However, its invasive nature, limited access, and the variable effect of WLLs
due to lack of standardization emphasize that there is an unmet need for a non-invasive,
safe and well-tolerated, easily accessible and effective treatment for aPAP patients.
The rationale for treating aPAP patients with molgramostim nebulizer solution is based on
the capacity of GM-CSF to promote differentiation and mobilization of different myeloid
leukocyte subsets including neutrophils, tissue macrophages/dendritic cells or their
circulating precursors. It is crucially involved in anti-microbial pulmonary host defense
and ameliorates lung injury by increasing the size and activation of the alveolar
macrophage pool. GM-CSF also contributes to the proliferation of megakaryocytic and
erythroid progenitors and plays a key role in surfactant homeostasis, by maturation of
alveolar macrophages.
Molgramostim is a non-glycosylated recombinant human granulocyte macrophage colony
stimulating factor (rhGM-CSF) produced by using recombinant DNA technology via a
bacterial (E. coli) expression system. Molgramostim is formulated in a sterile nebulizer
solution (molgramostim nebulizer solution) which is supplied in vials containing 300 µg
of molgramostim in 1.2 mL solution and is administered by inhalation via an
investigational eFlow Nebulizer System (PARI Pharma GmbH).
Results of a completed randomized, placebo-controlled clinical trial support the safety,
tolerability, and efficacy of inhaled molgramostim nebulizer solution as a treatment for
autoimmune PAP patients.
Drug: Molgramostim nebulizer solution
Solution for inhalation
Other Name: Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF)
Inclusion Criteria:
Eligible patients must:
1. Be ≥18 years of age at the time of signing the informed consent.
2. Agree to use a highly effective form of contraception (see Section 3.5).
3. Have a positive serum anti-granulocyte macrophage colony-stimulating factor (GM CSF)
autoantibody test result confirming aPAP.
4. Have a history of pulmonary alveolar proteinosis (PAP), based on examination of a
lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed
tomogram (HRCT) of the chest.
5. Have at least one symptom of aPAP, including but not limited to dyspnea (at rest or
with exertion), cough, or fatigue.
6. Be capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol.
7. Be willing and able to comply with the visit schedule and treatment plan specified
in the protocol, as judged by the physician.
Exclusion Criteria:
Eligible patients must not:
1. Have a diagnosis of hereditary or secondary PAP, or a metabolic disorder of
surfactant production.
2. Require a whole lung lavage (WLL) at the time of screening (patient may be eligible
1 week post WLL).
3. Have received GM-CSF treatment within 1 month prior to the screening visit.
4. Have been treated with any investigational product within 5 half-lives or 3 months
(whichever is longer) prior to the screening visit.
5. Have a history of allergic reactions to GM-CSF or any of the excipients in the
nebulizer solution.
6. Be using significant (e.g., more than 10 mg/day systemic prednisolone)
immunosuppression.
7. Have a history of severe and unexplained side effects during aerosol delivery of any
medicinal product.
8. Have a history or current diagnosis of a myeloproliferative disease or leukemia.
9. Have any other medical condition which in the opinion of the physician would make
the patient unsuitable for treatment with molgramostim nebulizer solution.
10. Be pregnant or breastfeeding, or planning to become pregnant during treatment with
molgramostim nebulizer solution.
University of California
Los Angeles, California, United States
University Florida Health
Gainesville, Florida, United States
University of Maryland School of Medicine
Baltimore, Maryland, United States
Washington University School of Medicine
St Louis, Missouri, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
UT Southwestern Medical Center
Dallas, Texas, United States
Yasmine Wasfi, MD., Ph.D.
512-851-1364
yasmine.wasfi@savarapharma.com
Michele Rhee, MBA, MPH
617-807-0488
michele.rhee@savarapharma.com
Not Provided