Disease Background
-aPAP (autoimmune pulmonary alveolar proteinosis) caused by autoantibodies against GM-CSF (granulocyte-macrophage colony-stimulating factor), lowers ability of macrophages to clear aveolar surfactants
-GM-CSF replacement therapy, basically trying to overcome auto-antibodies to clear surfactant in lungs; normal auto-antibody is 3 ug/mL, some patients show >100 ug/mL

Current SoC: Whole Lung Lavage (WLL)
–RR ~70-80%, P(A-a)O2 ~12-18 mmHg, 25 mmHg in severe
– Lung infused with up to 50L (median 25L) of saline with percussion to physically remove surfactant
-Relapse up to 57% (Gay 2017)
-Occasionally rituximab to eliminate B cells too
-Beccaria 2014 showed 70% remained free from recurrence during 7 year observation
-Many patients need multiple WLL, fairly invasive procedure

IMPALA Ph 3 – 24 week trial
–Primary endpoint: Change from baseline in P(A-a)DO2, powered to show 10 mmHg difference
–Secondary endpoints: St. George’s questionnaire (QoL, 1-100, 100 with most limitations), and 6 minute walk test (6MWT), time to WLL

-SVRA 300 ug daily (higher end of dose ranges tested), or daily every other week; more potent nebulizer (?) Lamira Nebulizer System, same as INSM, INSM showed 43% delivery (Shirley 2019)
-600 ug didn’t seem to show AEs in Ph1
-No major side effects seen, SVRA saying dose is about 3x of previous trials, nonglyc 10x more potent than fully glyc protein, lower in vitro bio activity for glyc, nonglyc faster clearance
-Some responses after dose-escalation in other trials
-AEs possible on daily arm though not likely
-45 patients each, 25/26 eligible went to open-label extension IMPALA-X, most recruited in Japan, not eligible
-Baseline P(A-a)O2 ~40 mmHg; moderate-severe population
-Primary endpoint 10 mmHg P(A-a)O2 difference, possible, but need to show ~12-18 comparable to WLL to be truly successful
-Crtieria: No WLL 1 month prior to trial; don’t know % of patients who had WLL (?), efficacy probably increases with more WLL

Past inhaled GM-CSF trials

Wylam 2006
-250 ug bid every other week, 32 weeks, dose escalate up to 500 ug, 12 patients; 11 responders; 5 relapse, 2 WLL, 1 needed 500 ug bid; Leukine
-Best responses seen at 34.5 weeks, best gas exchange values at 24.1 weeks, baseline 31.3 -> 12.9 mmHg -P(A-a)O2; 5 relapse within 1 year, 18.4 mmHg decrease, RR 91.67%

Tazawa 2010
-250 ug days 1-8, 9-14 none for 12 weeks, then 125 ug days 1-4, 5-14 none for 12 weeks; 39 patients, 24 responders, 24 total weeks, RR 61.5%
-High dose 12 week phase, -8.3 mmHg
-1 relapse, 29 remained stable without further therapy for 1 year
-9/55 improved in pre-observation period, baseline 42.6 mmHg
–6MWT 393 -> 444m; P(A-a)O2 decrease 12.3 mmHg, 18.2 mmHg in responders
-No increase in GM-CSF autoantibodies
-Leukine (sargramostim)

Papiris 2014
-6 patients, 250 ug days 1-4, 5-8 none as long as necessary, dose escalate if needed, 14-65 months; 6 responders, 5 WLL, 2 relapse
-25.6 month remission, 2 relapsed on down dosing, Leukine
-WLL average 4.4 months before
-Baseline 49.48 mmHg -> 32.1 mmHg at 6 months, 32.5 months at 12 months, 17.4 mmHg decrease at 6 months, RR 100% GM-CSF works as long as there is ample time

Ohkouchi 2017
-5 case studies, 125 ug bid days 1-8, 9-14 none for 12 weeks, maintenance 125 ug qd days 1-4, none 9-14 for 12 weeks, 5 responders, no relapse, Leukine, 24 total weeks
-All patients failed when taking GM-CSF before WLL
-Case 1: First GM-CSF did nothing over 2 years, WLL slight improvement but relapse after few months, second GM-CSF successful after 4 weeks
-Median time after WLL was 3 months
-Baseline 40.78 mmHg, decrease around 20 mmHg (no hard data, graph only), RR 100%

Gajewska 2018
-Case study, adolescent, inhaled molgramostim (Molgradex), Savara compound
-300 ug daily, every other week, then after 7 months to 300 ug daily
-17 months later, stable and inhalations discontinued
-Improvements in FEV1 2.33 L (62%) -> 2.58 (79%); FVC 2.64 L (70%) -> 3.05 (79%), total lung capacity 72% -> 77%, CO diffusing capacity 54% -> 74%
-Disease severity score was 2 of possible 5

Tazawa 2014 (2010 follow up paper)
-125 ug bid every other week, 24 weeks, 3 patients, 1 WLL, 3 responders, 1 relapse
-30 month observation, 23/35 did not require additional therapy
-5/12 requiring additional therapy had WLL earlier, 18/23 not requiring did NOT have WLL
-Mean time to additional treatment was 50.5 weeks

Caveats
-Other studies: all open label, some dose-escalated, some did not see effect until after 24 weeks, alternate dosing schedules, some needed higher doses
-GM-CSF after WLL shows better efficacy, makes sense due to physical clearing first of lungs
-Most used Leukine, a glycosylated, recombinant GM-CSF
-Ohkouchi did NOT see any improvement in GM-CSF before WLL
-No correlation with auto-antibody level and efficacy, threshold effect would mechanistically make sense
-Uses molgramostim vs Leukine (sargramostim), chem structure different, non-glycosylated, company says more potent
-“fully glycosylated GM-CSF is biologically more active in vivo compared to its non-glycosylated counterpart”
-Chronic GM-CSF may lead to asthma as it prolongs survival of eosinophils
-Not all studies excluded spontaneous improvers, about 8% usually lower PaO2 levels at baseline
-Own case study took 17 months to resolve, DSS was only 2
-Other trials used sargramostim vs molgramostim
-Lag of 4-12 weeks seen in inhaled, 6-12 weeks in subQ to benefit
-SVRA hopes to be 1L treatment, doubtful especially in severe patients, and given GM-CSF appears to work better after WLL

Positives
-Nebulizer shows 12-20% output in Wylam 2006, 5 current nebulizers including PARI show 23-25% output
-SubQ shows 6/11 responses and 6/14 responses, ~10 mmHg decrease (Seymour 2001, Venkateshiah 2006)
-Spontaneous resolution occurs in 3-25% of patients after WLL
-SubQ has some AEs (injection site, and some first dose effect, fever chills nausea) in 29-85%, most subQ pts needed therapy within 39 months
-Inhaled seems to show 12-18 mmHg decrease vs subQ 10 mmHg
-No bone marrow effects of subQ with inhaled
-WLL extremely invasive, requires anesthesia