Bridging the gap in copd treatment

1. LABA/LAMA FDC:
Bridging the gaps in
precision management
of COPD
Version 2.0 30-06-2021

2. Outline
COPD burden
Role of LABA/LAMA FDC in COPD management
Clinical evidence of Glyco-formo FDC
Optimal Dose selection for GF combination (DPI & MDI)
Comparison with Tio-formo Combination
Summary
Version 2.0 30-06-2021

3. COPD Burden
India contributes to 22% of Global COPD Burden, but 35% of global COPD DALYs
Measure Global India
Percentage of
Global
India’s Global
Ranking
COPD
Prevalence 251.6 million 55.3 million 21.98% 1st
Deaths 2.9 million 848,165 28.90% 2nd
DALYs 63.4 million 22.4 million 35.27% 1st
India State-Level Disease Burden Initiative CRD Collaborators. Lancet Glob Health. 2018;6(12):e1363–e1374.
COPD is the most common chronic medical condition leading to hospitalization in adults
Version 2.0 30-06-2021

4. Goals for treating Stable COPD
Version 2.0 30-06-2021

5. Suboptimal treatment
Suboptimal pharmacotherapy
o Monotherapy vs LABA/LAMA
o Inadequate control of Circadian variability in symptoms
o Quick onset of action
o Unavailability of Selective drugs (M3 selectivity)
o Tolerability, Cardiovascular safety
Suboptimal inhaler device
o Errors DPI
o Low PIFR – inadequate inspiratory Flow
o DPI vs MDI
Version 2.0 30-06-2021

6. Inhaler management in
about 50% of patients
with COPD is not
aligned with GOLD
recommendations, with
half of these being
under-treated
Labaki WW et a. BRN Rev. 2019;5(4):233-48
Symptomatic COPD pts often undertreated –
SPIROMIC study
Version 2.0 30-06-2021

7. COPD: high symptom burden persists in most patients when
using a mono-bronchodilator
Version 2.0 30-06-2021

8. A range of outcome measures need to be considered in
COPD
Version 2.0 30-06-2021

9. Role of LABA/LAMA FDC in COPD management
Synergistic
Bronchodilation
• Symptom improvement
• Increases FEV1
Control of Circadian
variability in COPD
symptoms
• Better symptom control
Better lung function
improvement than
monotherapy
• Improves exercise
tolerance
• Reduces exacerbation
Improves quality of life
Version 2.0 30-06-2021

10. Version 2.0 30-06-2021

11. LABA/LAMA: Synergistic bronchodilation
1. Combination acts on different sites of action
LAMA
more effective in proximal/central/larger
airways – predominant M3 receptors
LABA
More effective on distal/ peripheral/
smaller airways
Version 2.0 30-06-2021

12. LABA/LAMA: Synergistic bronchodilation:
2. Combination Inhibits release of Ach
Combination decreases release of
parasympathetic ACh at prejunctional level
Combination inhibits release of non-
neurogenic ACh from bronchial epithelium
Tashkin et al. International Journal of COPD 2018:13 1873–1888
Calzetta L et al. Expert Review Of Respiratory Medicine. 2018;12(4):261–64
Version 2.0 30-06-2021

13. LABA/LAMA: BID dosing: Control of Circadian Variability in Symptoms
• Prevalence of nocturnal symptoms & sleep disturbance may be seen in> 75% COPD pts.
• Potential long-term consequences can include lung function changes, increased exacerbation frequency,
emergence or worsening of CVD, cognitive effects, depression, impaired QOL, increased mortality
International Journal of Chronic Obstructive Pulmonary Disease 2020:15 1269–1285
Version 2.0 30-06-2021

14. LABA/LAMA: Better Lung function improvement than ICS/LABA
Version 2.0 30-06-2021

15. Version 2.0 30-06-2021

16. Version 2.0 30-06-2021

17. Early LABA/LAMA initiation – A consensus statement
Level of consensus on different treatments in
patients younger and older
with moderate obstruction
Level of confidence in different approaches used in
early management of COPD to reduce
the functional decline
Di Macro F et al. Int J Chron Obstruct Pulmon Dis. 2019;14:353–360.
Version 2.0 30-06-2021

18. GOLD 2021: Combination Bronchodilator Rx
• Combining bronchodilators with different mechanisms and durations of action
 better bronchodilation
• LABA/LAMA in one inhaler  greater lung function improvement than
monotherapy
• Greater impact on PROs or QoL compared to monotherapies
• Twice daily regimen for LABA/LAMA has shown to improve symptoms and
health status
• More effective than monotherapy in preventing exacerbations
• LABA/LAMA was better than ICS/LABA in decreasing exacerbations
PROs – patient reported outcomes
GOLD 2021 Guidelines
Version 2.0 30-06-2021

19. GOLD 2021:
LABA + LAMA
plays a central
role
Version 2.0 30-06-2021

20. Clinical Evidence of
GLYCO- FORMO FDC (GFF)
Version 2.0 30-06-2021

21. PINNACLE 1 & 2 – Study design
• Efficacy and safety of (GFF) 18/9.6-mg
MDI in moderate to very severe COPD
• Sample size - PINNACLE 1 – 2103 pts,
PINNACLE 2 – 1615 pts
• Study duration- 24 weeks
• Study participants- Patients aged 40 to
80 years, had a clinical history of
moderate-to-very severe COPD, were
current/ex-smokers (>10 pack-years).
Martinez F et al. Chest. 2017;151(2):340–357.
Version 2.0 30-06-2021

22. PINNACLE 1 & 2 - Efficacy
Trough FEV1: PINNACLE-1/2, GFF MDI showed significant differences of 59/54 mL and
64/56 mL vs GP MDI and FF MDI, respectively (P < .05)
Version 2.0 30-06-2021

23. PINNACLE 1 & 2 - Efficacy
Hanania NA et al. Respir Med. 2017;126:105–115.
LSM treatment differences over 52 weeks in ITT of PINNACLE 1 & 2
GFF MDI showed Significantly better improvement in dyspnea Score, QOL and rescue
medication use compared to monotherapy & TIO
Version 2.0 30-06-2021

24. PINNACLE 1 & 2 – Response to dual BD depends on symptom
burden
Version 2.0 30-06-2021

25. PINNACLE 3: : Long term safety and efficacy of GFF MDI
(52 weeks)
Hanania NA et al. Respiratory Medicine 2017;126:105-115.
GFF MDI: Improvement in lung function is maintained over a long period of time.
Version 2.0 30-06-2021

26. PINNACLE 3: Results
Hanania NA et al. Respiratory Medicine 2017;126:105-115.
GFF MDI showed Significantly better improvement in QOL and rescue medication use
compared to monotherapy & TIO
Version 2.0 30-06-2021

27. PINNACLE 4: Results (Asian and European countries)
Lipworth BJ et al. Int J Chron Obstruct Pulmon Dis. 2018 Sep 26;13:2969-2984.
Version 2.0 30-06-2021

28. Network metaanalysis reveals comparable efficacy and safety of
GFF to other LABA-LAMAs
Trough FEV1 Peak FEV1
FEV1 AUC0–4
Siddique M et al. Ther Adv Respir Dis 2019, Vol. 13: 1–23
SGRQ in symptomatic COPD
GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs
Version 2.0 30-06-2021

29. Conclusions: NMT patients achieved better lung function with GFF
versus monotherapy, without increased safety risk.
NMT- no Maintenance therapy Zheng et al. Respiratory Research (2020) 21:69
Version 2.0 30-06-2021

30. International Journal of Chronic Obstructive Pulmonary Disease 2020:15 99–106
Conclusion: GFF MDI significantly improved lung function versus in GOLD
category A patients with moderate-to-very severe COPD, with no
unexpected safety findings
Version 2.0 30-06-2021

31. Optimal dose Selection for
GFF DPI
Version 2.0 30-06-2021

32. GLYCO 2 study: Which BID dose is the optimal dose?
GB 12.5, 25 or 50 μg BID versus placebo, versus open label extension of tio 18 μg OD
Adjusted mean 12 h trough FEV1 on Day 7
∆ 115 ml
∆ 142 ml
∆ 136 ml
∆ 71 ml vs TIO
∆ 47 ml vs TIO
Adjusted mean pre-dose morning FEV1 on Day 8
Singh D et al. Int J Chron Obstruct Pulmon Dis. 2017;12:2001–2014.
These results suggest that GB 12.5 μg & 25 μg BID are the
optimal doses in patients with COPD
Version 2.0 30-06-2021

33. GFF 25/12 – Indian Evidence
Non-Inferiority study GFF (25/12 mcg) BID vs Gly (50 mcg) OD
356 pts to receive either GF (n=178) or G (n=178) over 12-week
o Mean FEV1% predicted 52.42%
At week 12
o Mean change in trough FEV1 from baseline was 120 ml in GF group and 60 ml G group (both
p<0.0001)
o Mean change from baseline in mMRC was -0.85 with GF vs G (p<0.0001)
o Mean change from baseline in CAT score was -7.94 with GF vs -6.21 with G and mean
between group difference was -1.73 (p<0.05)
Both treatments were well tolerated
Salvi et al. 2019. ERS. PA2476
Conclusion: GFF 25/12 mcg found to be safe and efficacious in Indian patients
Version 2.0 30-06-2021

34. GFF 12.5/12- Indian Phase 3 Clinical Trial
Phase 3, Randomized, Double-Blind, Parallel-Group, Active-controlled Study
Sample size- 331, Sites- 27, Study Duration- 12 weeks
GFF 12.5/12 DPI Vs GLYCO 50 OD DPI
At 12 weeks
mean increase in peak FEV1 from baseline to Day 85 was higher in GFF group
(0.318 L [± 0.025]) in comparison to glyco 50 OD group (0.203 L), favouring the
FDC. Difference between the 2 treatment groups was statistically significant.
(p<0.0001)
mean change from baseline in trough FEV1 on Day 86 was 0.1931 L in the GFF
group and 0.1184 L in the Glyco 50 OD group. Difference between the 2
treatments was 0.078 L (p=0.0153)
Ref- Data on File
Version 2.0 30-06-2021

35. GFF 12.5/12- Indian Phase 3 Clinical Trial
reduction in the symptom scores, improvement in FVC, increase in FEV1 AUC0-2h
was greater in GFF group.
Overall, the incidence of AEs, TEAEs in the safety population was low and
comparable across the 2 treatment groups.
Conclusion-
GFF 12.5/12 DPI showed superior improvement from baseline in peak FEV1 at Day
85 and was well tolerable for use in subjects with COPD.
Ref- Data on File
Version 2.0 30-06-2021

36. Why GF 25/6 is not Enough?
24 mcg/ day is the
most studied dose of
Formoterol Globally
(Mono/ dual/TT
combinations)
Much higher
broonchodilation with
24 mcg/day dose
compared to 12
mcg/day
24mcg/day – similar
adverse events as
12mcg/day dose
International Journal of Chronic Obstructive Pulmonary Disease 2020:15 3105–3122
Version 2.0 30-06-2021

37. International Journal of Chronic Obstructive Pulmonary Disease 2020:15 3105–3122
Dose of Formoterol Available globally
Version 2.0 30-06-2021

38. International Journal of Chronic Obstructive Pulmonary Disease 2020:15 3105–3122
Dose of Formoterol Available globally
Version 2.0 30-06-2021

39. Most of the global clinical trials for TT or Dual therapy (GF) have
evaluated and established 12 mcg bid dosing of Formoterol
Version 2.0 30-06-2021

40. Version 2.0 30-06-2021

41. Optimal dose Selection for
GFF MDI
Version 2.0 30-06-2021

42. Respiratory Medicine 120 (2016) 16-24
Dose Ranging studies:
18/9.6 mcg bid (i.e 9/4.8 two puffs bid) Is the optimum dose
of GFF MDI
Version 2.0 30-06-2021

43. Fabbri et al. Respiratory Research (2016) 17:109
Version 2.0 30-06-2021

44. Version 2.0 30-06-2021

45. Several Global Clinical Trials have proved efficacy and
safety of GFF MDI 18/9.6mcg
PINNACLE
1
PINNACLE
2
PINNACLE
3
PINNACLE
4
ETHOS KRONOS
Martinez F et al. Chest. 2017;151(2):340–357
Hanania NA et al. Respiratory Medicine 2017;126:105-115
Lipworth BJ et al. Int J Chron Obstruct Pulmon Dis. 2018 Sep 26;13:2969-2984
http://dx.doi.org/10.1016/S2213-2600(18)30327-8.
N Engl J Med 2020; 383:35-48
Version 2.0 30-06-2021

46. Comparison of GFF MDI
with TIO-FORMO Combination
Version 2.0 30-06-2021

47. Glyco is more selective than Tio
• Glycopyrrolate is kinetically more
selective (10.7-fold) for M3 receptors
over M2 receptors
• Tiotropium is only 4.3-fold selective for
M3 over M2 receptors
• Tiotropium would take 4 - 5 times
longer than glycopyrrolate to
equilibrate with the M3 receptor
(at equi-effective concentrations)
Sykes D et al. J Pharmacol Exp Ther. 2012;343(2):520–528.
Version 2.0 30-06-2021

48. Glyco is faster acting LAMA than Tio
The onset of action (3.4 min) of glycopyrrolate was like that obtained with
ipratropium bromide and faster than tio (8.4 min), aclidinium (6.4 min)
Haddad EB et al. Br J Pharmacol. 1999;127(2):413–420.
Tashkin DP, et al. Int J Chron Obstruct Pulmon Dis. 2018.
• Immediate relief of dyspnea- Suitable for emergencies
• helpful when adherence to treatment is suboptimal, since compliance increases
when the patient perceives rapid improvement of symptoms
• convenient in patients with a large variability of symptoms
• Such observations suggest that in the symptomatic patient, glycopyrronium is
preferred over tiotropium or umeclidinium
Why rapid onset bronchodilator is useful?
Version 2.0 30-06-2021

49. Irrationality of combining OD, BID drugs together :
Tio-Formo
The actives in a combination should have similar
pharmacokinetics
All of the actives in a combination should have a
similar duration of action
https://main.mohfw.gov.in/sites/default/files/6404452866Kokate%20Report.pdf
Version 2.0 30-06-2021

50. GFF MDI: Approved by all leading global agencies
GFF MDI TIO-FORMO
• USFDA
• EMA
• India
• Japan
• Canada
• China
• Australia etc
• Lebanon
• India
Version 2.0 30-06-2021

51. Gly offers similar protection against CID as by Tio
• Post-hoc analysis of GLOW1, GLOW2, GLOW5 and
SHINE studies to compare the efficacy of
glycopyrronium and tiotropium
In terms of Clinically important deterioration (CID) delay
and/or reduction
D’Urzo et al. NPJ Prim Care Respir Med. 2018;28(1):18.
Gly is as effective in delaying time to CIDs as Tio
Version 2.0 30-06-2021

52. Mastrodicasa MA et al. Expert Opin Investig Drugs. 2017;26(2):161–174.
Version 2.0 30-06-2021

53. TIOTROPIUM: Increased Risk of Stroke, MI, Angina
especially in high risk patients
Lancet Respir Med 2016 http://dx.doi.org/10.1016/ S2213-2600(15)00518-4
Version 2.0 30-06-2021

54. Glycopyrronium: Better overall safety Profile than TIO
Lancet Respir Med 2016 http://dx.doi.org/10.1016/ S2213-2600(15)00518-4
International Journal of COPD 2018:13 1873–1888
Version 2.0 30-06-2021

55. Gly is Safer than Tio in high CV risk patients
Randomized, open-label, active-
controlled study
1050 Mod to Very Severe COPD with
Cardiac comorbidities
o High-risk Cardiac COPD: Pts with ≥2 risk
factors for CVD (IHD, MI ± Heart failure)
o Low-risk Cardiac COPD: Pts with <2 risk
factors for CVD (Hypertension)
Results
o GLY was safer in ‘High risk Cardiac COPD’
o TIO rate of CV events and MACE were higher
among patients not receiving background
LABAs
Ferguson GT. Chronic Obstr Pulm Dis 2019;6(1):86-99.
Less Cardiac side effects with even the double dose of Glyco compared to Tio

56. Summary
• Initial treatment of COPD must be optimal.
• Early treatment with Bronchodilators improves FEV1, symptoms and probably Disease
progression.
• Dual bronchodilators improves outcomes compared to single bronchodilators particularly
in more symptomatic pts.
• Selection of Proper patient profile is of paramount importance
Version 2.0 30-06-2021

57. Version 2.0 30-06-2021