Causes of attrition for inhaled pharmaceuticals

Transcription

1 Causes of attrition for inhaled pharmaceuticals APSGB-HESI Workshop on Inhaled Drug Induced Alveolar Macrophage Responses, Stevenage (30 th -31 st October 2012) Ian Robinson, AstraZeneca R&D

2 Introduction Inhaled therapy has delivered a number of significant therapeutic advances over the years and continues to offer the potential for interesting opportunities in the future Perceived Advantages: Local treatment for lung disease Minimise (unnecessary) systemic exposure to avoid side effects/toxicity Therefore less risk of attrition Disadvantages: Requires specialist expertise and large investment But..Maybe attrition has not been so different just for different reasons! (and can we do something about that!) 2

3 Survey of attrition in the AZ inhaled portfolio Looked back at AZ portfolio over last 7 years Identified compounds where we generated, as a minimum: Repeat dose in vivo inhalation tox data Of at least 7-days In at least 1 species With a range of doses Including a reasonable number of animals All small molecules All targeted at local activity in the lung Identified compounds: 33 3

4 Results! Reasons for Attrition: Systemic Toxicity : 0 Physicochemical properties : 2 Target/efficacy failure : 5 Safety : 10 Portfolio : 16 4

5 Safety: Adverse histopathological observations in the Respiratory tract Upper respiratory tract/major airways Most common = inflammatory, hyperplastic and metaplastic changes in respiratory epithelia, particularly in larynx (rodents) and nose Lung Severe toxicity/tissue damage is rare But minor changes such as small increases in inflammatory cells and alveolar macrophages, are common 5

6 Sometimes its rather obvious : 405 6

7 Cyno onths inhaled study lung effects at high dose (4.g/kg) Lung - Aggregates of Alveolar Macrophages, moderate (red arrow) - Alveolar Inflammatory Cells, slight (green arrow) 7

8 Cyno onths inhaled study lung effects following recovery (high dose, 4.g/kg) Lung - Aggregates of Alveolar Macrophages, slight NOTE. 5 lung lobes were examined from animal 463. In only one lobe were two focal macrophage aggregates found. No inflammatory or granulomatous reaction associated with the macrophages. 8

9 Lung findings in 3m cyno study 25 g/kg main study Alveolar foamy macrophages, epithelial hyperplasia x100 Perivascular and Alveolar inflammation x40 9

10 Recent AZ experience: Alveolar macrophage aggregates / accumulation Incidence in Monkey inhalation studies Doses Neb 1 m Neb 1 m Control 0 / 1 0/0 0 / 0 1/0 1 / 1 0/0 0 / 0 1 / 0 0/0 Low 2 / 2 0 / 0 0 / 0 3 / 0 0 / 1 Mid 3 / 3 0 / 0 1 / 0 2 / 2 0 / 1 High 3 / 3 0/3 0 / 0 1/1 2 / 2 1/0 3 / 2 1 / 0 1/0 10

11 Recent AZ experience: Alveolar macrophage aggregates / accumulation Incidence in Rat inhalation studies Doses 6 m n=15 6 m n=16 6 m n=16 6 m n=16 pmdi n=10 n=10 Control 4 / 5 8 / 4 1 / 0 0 / 0 0 / 0 3 / 3 Low 1 / 0 5 / 6 0 / 0 0 / 0 0 / 0 3 / 1 Mid 2 / 3 3 / 9 1 / 0 0 / 0 0 / 0 7 / 1 High 2 / 6 14 / 8 3 / 0 0 / 0 0 / 0 3 / 5 11

12 Recent AZ experience: Alveolar macrophage aggregates / accumulation Incidence in Dog inhalation studies Doses pmdi Control 3 / 2 2 / 1 1 / 0 0 / 0 0 / 0 0 / 0 Low 3 / 3 2 / 0 2 / 0 0 / 0 0 / 0 0 / 0 Mid 3 / 3 1 / 3 0 / 1 0 / 0 0 / 1 0 / 0 High 3 / 3 3 / 3 1 / 1 0 / 0 0 / 0 0 / 0 12

13 Recent AZ experience: Alveolar macrophage aggregates / accumulation Incidence in Mouse inhalation studies Doses n=10 n=10 n=10 Control 0 / 0 0 / 0 0 / 0 Low 0 / 0 0 / 0 0 / 0 Mid 0 / 0 0 / 0 0 / 0 High 0 / 0 0 / 0 0 / 0 13

14 Information on spontaneous findings in the literature Chamanza, R et al (2010) 14 Author 00 Month Year Set area descriptor Sub level 1

15 Chamanza, R et al (2010) 15 Set area descriptor Sub level 1

16 Resolution of Inflammation terminates the inflammatory response Pathologic Inflammation - Failed Resolution Chronic Inflammation Physiologic Inflammation Spontaneous Resolution v Lipoxins Resolvins LTS PGs Cell Influx Neutrophil Apoptosis MØ Clearance Resolution 16

17 Interpreting the Significance of Increased Alveolar Macrophages in Rodents following Inhalation of Pharmaceutical Materials Kristen J. Nikula (Chair), 1 Jeffrey E. McCartney, 2 Timothy McGovern, 3 Glen K. Miller, 4 Natasha Neef, 5 Marielle Odin, 6 Michael V. Pino, 7 and Matthew D. Reed 8 Introduction Pulmonary alveolar DRAFT macrophages, which are normal resident cells, respond to changes in the local micro-environment. Responses by alveolar macrophages may represent normal tissue adaptations that maintain normal lung function, or may contribute to pathophysiological processes with potentially adverse sequelae. Currently, there are no generally accepted criteria by which to distinguish non-adverse versus adverse findings that include increases in alveolar macrophages when observed in inhalation studies of pharmaceutical materials. The absence of established or standardized morphological nomenclature, or inconsistent application of nomenclature, further contribute to lack of clarity in interpreting alveolar macrophage responses for human risk assessment. For these reasons, regulatory agencies may adopt conservative approaches to observations of increased alveolar marcophages in inhalation studies. An overly conservative approach to identifying the no-adverse-effect-level (NOAEL) with regard to macrophage increases can have an undue impact on the ability to dose escalate to efficacious levels in the clinic, thereby affecting overall inhalation drug development success or timelines. Therefore, it is imperative to establish which findings represent normal adaptive responses, and to distinguish adaptive responses from those having potentially adverse consequences. A working group was established to review currently available data regarding alveolar macrophage responses to inhaled pharmaceuticals in toxicity studies and to evaluate parameters used for risk assessment. 17

18 Conclusion Observation of small increases in inflammatory cells and macrophages in the lung is a significant cause of concern and attrition for inhaled pharmaceuticals Which raises questions: Are we able to make appropriate risk assessments? How well do we understand these observations? Can we distinguish treatment related changes from background? Can we determine if the effects are progressive or resolving? Can we define if the effects are adverse or non-adverse? 18

19 APSGB/HESI Joint International Workshop CHALLENGES FOR INHALED DRUG DISCOVERY AND DEVELOPMENT: INDUCED ALVEOLAR MACROPHAGE RESPONSES DATE: Tuesday 30 th October Wednesday 31 st October 2012 LOCATION: GlaxoSmithKline R & D Stevenage United Kingdom 19