Olorofim: Discovery and development of a novel IV and oral orotomide - - PowerPoint PPT Presentation

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Olorofim: Discovery and development of a novel IV and oral orotomide - - PowerPoint PPT Presentation

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Olorofim: Discovery and development of a novel IV and oral orotomide class candidate for systemic mould infections Dr Emma Harvey Global Head of Medical Affairs F2G Ltd Olorofim_RICAI_December 2019 1 Disclaimer Olorofim is not currently

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Olorofim: Discovery and development of a novel IV and oral orotomide class candidate for systemic mould infections

Dr Emma Harvey Global Head of Medical Affairs F2G Ltd

1 Olorofim_RICAI_December 2019

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Disclaimer

Olorofim is not currently approved for use in any market

Olorofim_RICAI_December 2019 2

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Agenda

Olorofim … ▪Is the first orotomide antifungal ▪Stops growth quickly; Cell rupture follows ▪Is active in vivo: PK-PD driven by Cmin ▪Target levels readily achieved in man both PO and IV ▪Phase 2 Open-Label study has recruited > 40 patients

Olorofim_RICAI_December 2019 3

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Olorofim structure

Previously known as F901318 MW = 499 Formula = C28H27FN6O2 > 99% protein bound in all species

4 Olorofim_RICAI_December 2019

F2G, Ltd., data on file

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Orotomide Mechanism of Action

▪Olorofim is a potent selective inhibitor of fungal dihydroorotate dehydrogenase (DHODH)

▪ DHODH is a key enzyme involved in pyrimidine biosynthesis

▪Humans also have this enzyme

▪ But, > 2000-fold difference in IC50 between human and fungal enzymes

▪Pyrimidine inhibition has profound effects as it interferes with

▪ DNA synthesis and cell cycle regulation ▪ RNA synthesis and protein production ▪ Cell wall synthesis ▪ Phospholipid synthesis

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Oliver et al. PNAS 113:12809-14, 2016.

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(PEZIZOMYCOTA)

(BACTERIAL)

OLOROFIM SENSITIVE

OLOROFIM INTRINSIC RESISTANCE

DHODH Protein Homology Taxonomy

6 Olorofim_RICAI_December 2019

Work in collaboration with Paul Boyer, Univ Manchester

Note the clustering of activity within the Pezizomycota: DHODH structurally conserved across these species

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Aspergillus: In vitro

▪Olorofim MICs are tightly clustered

▪MIC90s are 0.03-0.06 mg/L (CLSI and EUCAST) ▪MICs are of the same order for all Aspergillus spp. tested ▪>2900 isolates from 35 species including: ▪>2300 isolates of 4 most common species1 ▪220 isolates of 16 cryptic species2

▪No induction of resistance with serial passage ▪Spontaneous resistance seen at low frequency ▪Cross-resistance is not seen

▪MICs of the same order in azole-resistant isolates ▪MICs of the same order in amphotericin-resistant species

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7

1.

  • A. fumigatus, flavus, niger, and terreus

2.

  • A. alliaceus, aureoterreus, calidoustus, carneus, citrinoterreus, fumigatiaffinis, hiratsukae, hortai, insuetus, keveii,

lentulus, ochraceus, pseudofischerii, sclerotiorum, tubingensis, and udagawae

Beckmann et al. ICAAC 2015; Fothergill et al. ICAAC 2015; Buil et al.JAC 2017; Rivero- Menéndez et al ECCMID 2017; Oliver et al PNAS 2016; Jorgensen et al. TIMM 2017

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In vitro activity against other fungi

▪Scedosporium spp., L. prolificans and numerous other moulds* and endemic dimorphic fungi

▪MICs similar to Aspergillus

▪Fusarium spp

▪Mixed and method-dependent results ▪Further investigative work underway

▪Mucorales, Candida spp., Cryptococcus neoformans

▪Not active (structurally different DHODH enzyme)

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*Tested to date: Acremonium persicinum, Acrophialophora fusispora, Rasamsonia spp., Phaeoacremonium spp., Sarocladium kilienses, Scopulariopsis brevicaulis, Microascus spp., Sporothrix schenkii, Trichoderma spp., Ramichloridium (Myrmecridium) schulzeri, Paecilomyces spp., Pleurostomophora richardsiae, Verruconis gallopava, Chaetomium spp., and Penicillium spp. (including P. marneffiii).

Wiederhold et al. JAC 2107, Biswas et al. Med Mycol 2018; Alastruey et al. TIMM 2017; Oliver et al. PNAS 2016; F2G Ltd, data on file

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Across the related fungi, the MICs are tightly clustered

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F2G Ltd, data on file

>2900 Aspergillus isolates >300 Scedosporium isolates >100 Lo Pro isolates

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Agenda

Olorofim … ▪Is the first orotomide antifungal ▪Stops growth quickly; Cell rupture follows ▪Is active in vivo: PK-PD driven by Cmin ▪Target levels readily achieved in man both PO and IV ▪Phase 2 Open-Label study has recruited > 40 patients

Olorofim_RICAI_December 2019 10

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Fungicidal: Growth inhibition begins at ~30 minutes and leads to killing

▪ 16-hour-old A. fumigatus hypha ▪ Actively growing ▪ Treated with 0.1 mg/L olorofim ▪ Growth inhibition at ≈ 30 mins ▪ Cell rupture at ≈ 24 hours

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Untreated hyphae 0.1 mg/L olorofim (24h)

Olorofim_RICAI_December 2019

Time-lapse video (48h compressed to ~ 15 seconds)

Shown here are TEM views of the effect of olorofim at 24h

Note normal nucleus, cytoplasmic content, and continuous cell wall Note absence of cytoplasmic content, broken/thin cell wall

du Pre S et al. Antimicrob Agents Chemother 62:e00231-18, 2018.

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Cell rupture is then seen

▪Cell viability marker (Green = Dead)

▪DiBac: Bis-(1,3-Dibutyl barbituric Acid) Trimethine Oxonol

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25 50 75 100

24h 48h 72h 96h 120h

% lysed

du Pre S et al. Antimicrob Agents Chemother 62:e00231-18, 2018.

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Effects on conidia as well

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Untreated Conidia treated for 24h with olorofim (0.1 µg/mL). Note breaks in cell wall.

  • A. fumigatus conidia were incubated at 37C in Vogel’s minimal medium.

du Pre S et al. Antimicrob Agents Chemother 62:e00231-18, 2018.

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Agenda

Olorofim … ▪Is the first orotomide antifungal ▪Stops growth quickly; Cell rupture follows ▪Is active in vivo: PK-PD driven by Cmin ▪Target levels readily achieved in man both PO and IV ▪Phase 2 Open-Label study has recruited > 40 patients

Olorofim_RICAI_December 2019 14

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In vivo activity

▪In vivo activity (mostly murine, some rabbit) shown for

▪ A. fumigatus, A. flavus, A. terreus, A. nidulans, A. tanneri ▪ Scedosporium apiospermum ▪ Lomentospora prolificans ▪ Scedosporium (Pseudallescheria) boydii ▪ Coccidioides immitis

▪In vivo activity has been shown PO & IV

▪ Endpoints: Survival, tissue burden, and GM

▪Works equally well on azole-and amphotericin B-resistant Aspergillus isolates:

▪ Azole-resistant (A. fumigatus, A. tanneri, L. prolificans) ▪ Amphotericin B-resistant (A. terreus, A. tanneri)

Olorofim_RICAI_December 2019 15 Hope et al. mBio 8:1-17, 2017; Seyedmousavi et al. Antimicrob Ag Chemother 63:e00129-19, 2019; J Lackner et al. J Antimicrob Chemo 73:3068-73, 2018; Seyedmousavi et al. Trends in Medical Mycology (abstract), 2019; Wiederhold et al. AAC 2018;62(9):e00999-18.

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R

Olorofim activity against A. fumigatus

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20 40 60 80 100 2 4 6 8 10

% survival Study Day

  • A. fumigatus (NIH 4215, azole wild-type)

Susceptible to OLO, POSA, and VORI

Drug

Control POSA OLO

Reminder: It’s tricky to study voriconazole in the mouse due its rapid metabolism. This model used IV dosing using posaconazole not voriconazole.

Neutropenic mouse model, inhalation IA, drug given IV starting 6h after infection through Day 3; Olorofim MIC 0.03 mg/L for both isolates; Posaconazole (POSA) MIC 0.125 mg/L (NIH 4215) and 0.5 mg/L (11628); VORI MIC 0.5 (NIH 4215) and 16 mg/L (11628). Hope et al. mBio 8:1-17, 2017; Jeans et al. J Infect Dis, 206:442-52, 2012; Simitsopoulou et al. Antimicrob Ag Chemother 52:3301-6, 2008.

Control study, wild- type strain: OLO and POSA are both active.

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Olorofim is effective in vivo

  • vs. azole-resistant A. fumigatus

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20 40 60 80 100 2 4 6 8 10

Study Day

  • A. fumigatus (11628, G138C mutant)

Susceptible to OLO, Resistant to POSA and VORI

Drug

Control POSA OLO

Neutropenic mouse model, inhalation IA, drug given IV starting 6h after infection through Day 3; Olorofim MIC 0.03 mg/L for both isolates; Posaconazole (POSA) MIC 0.125 mg/L (NIH 4215) and 0.5 mg/L (11628); VORI MIC 0.5 (NIH 4215) and 16 mg/L (11628). Hope et al. mBio 8:1-17, 2017; Jeans et al. J Infect Dis, 206:442-52, 2012; Simitsopoulou et al. Antimicrob Ag Chemother 52:3301-6, 2008.

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Olorofim activity vs

  • A. tanneri in CGD mouse model

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20 40 60 80 100 2 4 6 8 10

Study Day

  • A. tanneri (NIH 1004). Susceptible to OLO,

Resistant to VORI, POSA, and AmB Control Control VORI OLO

Survival curves for mice with oxidative-deficient (CGD) neutrophils. Infection by tail vein injection, drug IP starting 6h after infection through Day

  • 9. MICs for B5213 and NIH 1004 were 0.01 and 0.06 mg/L (OLO), 0.5 and 4 mg/L (VORI), 0.125 and 0.5 mg/L (POSA), and 0.5 and > 16 mg/L

(AmB). Seyedmousavi et al. Antimicrob Ag Chemother 63:e00129-19, 2019.

When tested against AmB-resistant A. tanneri, OLO remains active but the azole fails

Drug

CGD= chronic granulomatous disease

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Drug

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Olorofim activity in vivo

  • vs. amphotericin-resistant A. terreus

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% survival Study Day

Similar results for olorofim dosed IV and PO Control Ampho OLO, po

Neutropenic mouse model, intravenous IA, drug dosed from Day 1 to Day 9; A. terreus with OLO MIC of 0.01 mg/L, amphotericin B MIC of 2 mg/L; Lackner et al. J Antimicrob Chemo 73:3068-73, 2018.

OLO, iv

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Olorofim activity against Scedosporium

  • spp. and Lomentospora prolificans

25 50 75 100 5 10 15

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25 50 75 100 5 10 15 25 50 75 100 5 10 15

% survival Day

  • S. apiospermum
  • S. boydii

Control OLO

  • L. prolificans

OLO VORI AMB S S R S S R S R R

Neutropenic mouse model, intravenous infection, drug dosed from Day 1 to Day 10. Actual MICs were OLO (0.02, 0.01, 0.03 mg/L), VORI (0.5, 0.5, 8 mg/L), AMB (8, 8, 8 mg/L); Seyedmousavi et al. Trends in Medical Mycology (abstract), 2019. Drug

O C O C S = sensitive R = Resistant

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Drug

20 40 60 80 100 3 6 9 12 15 18 21 24 27 30

Olorofim activity in a murine model of coccidioidomycosis

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% survival Study Day

Control FLU OLO low

Intracranial C. immitis infection on Day 0; Therapy Day 2-14; FLU 25 mg/kg BID, OLO 6.67 mg/kg TID (low), or OLO 13.3 mg/kg TID; 10 mice/group. Wiederhold et al. AAC 2018;62(9):e00999-18.

OLO high

Survival curves:

  • Drug given on

days 2-14

  • Good initial effect

in all 3 arms

  • But, higher

mortality in last week with FLU and low dose

  • lorofim (OLO-

Low) Why?

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Olorofim activity in a murine model of CNS coccidioidomycosis

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Intracranial C. immitis infection on Day 0; Therapy Day 2-14; FLU 25 mg/kg BID, OLO 6.67 mg/kg TID (low), or OLO 13.3 mg/kg TID; 10 mice/group. Wiederhold et al. AAC 2018;62(9):e00999-18.

Day 9

20 40 60 80 100 3 6 9 12 15 18 21 24 27 30

% survival

Study Day

C Flu O-lo O-hi

C Flu O-lo O-hi

Consistent with early benefit, CFU/g in brain is reduced in all 3 groups at Day 9 But…

Brain CFU/g

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Olorofim is effective in a murine CNS coccidioidomycosis model

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Intracranial C. immitis infection on Day 0; Therapy Day 2-14; FLU 25 mg/kg BID, OLO 6.67 mg/kg TID (low), or OLO 13.3 mg/kg TID; 10 mice/group. Wiederhold et al. AAC 2018;62(9):e00999-18.

Day 30 Day 9

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% survival

Study Day

C Flu O-lo O-hi

C Flu O-lo O-hi

Day 30 (2 weeks off drug):

  • FLU: CFU rebound
  • OLO-low: CFU rebound
  • OLO-hi: CFU cleared

Olorofim is fungicidal to Cocci

Brain CFU/g

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Formal PK-PD

▪Murine & rabbit pulmonary aspergillosis model

▪A. fumigatus & A. flavus, including azole-R isolates ▪Outcome measures: survival, GM, pathology

▪Summary:

▪Time-dependent efficacy – inhibition of growth within an hour; fungicidal within 24 hours ▪Consistent with observed MICs as well as data from other in vivo studies, identical results obtained for azole-resistant and azole-susceptible strains ▪A total drug trough (Cmin) of >0.3 mg/L is our target in man

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Hope et al. mBio 8(4):1-17, 2017

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Agenda

Olorofim … ▪Is the first orotomide antifungal ▪Stops growth quickly; Cell rupture follows ▪Is active in vivo: PK-PD driven by Cmin ▪Target levels readily achieved in man both PO and IV ▪Phase 2 Open-Label study has recruited > 40 patients

Olorofim_RICAI_December 2019 25

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PO and IV

▪Linear PK, widely distributed to tissues including lung, liver and brain ▪Total daily doses of 120-180 mg yield plasma Cmin exposures exceeding the PK-PD target ▪Oral bioavailability approaches 100%

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F2G, Ltd., data on file

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Metabolism

▪Cleared by multiple CYPs ▪Doesn’t induce CYPs ▪Weak 3A4 inhibition (less than fluconazole) ▪DDI’s:

▪Can be given in combination with tacrolimus ▪Can be given in combination with novel immunotherapies (ibrutinib, venetoclax)

Olorofim_RICAI_December 2019 27

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Agenda

Olorofim … ▪Is the first orotomide antifungal ▪Stops growth quickly; Cell rupture follows ▪Is active in vivo: PK-PD driven by Cmin ▪Target levels readily achieved in man both PO and IV ▪Phase 2 Open-Label study has recruited > 40 patients

Olorofim_RICAI_December 2019 28

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Phase 2 Open-Label Study (1)

▪Now enrolling

▪ClinicalTrials.gov Identifier: NCT03583164

▪Key entry criteria

▪Proven IFI or probable IA (EORTC-MSG 2008 criteria) ▪Limited treatment options

▪Example reasons to enroll

▪Lomentospora prolificans or other multi-drug resistant/cross-resistant fungus ▪Lack of response/intolerance with current agents

▪Design

▪Open-Label olorofim for up to 90 days (extensions are possible if longer therapy is deemed useful) ▪Data-Review Committee to adjudicate at 6 and 12 weeks

Olorofim_RICAI_December 2019 29

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Phase 2 Open-Label Study (2)

As of 1st December 2019, 48 patients enrolled ▪M:F 31:17 (64%:36%); Age range (mean) of 19-84 (50) years ▪Heme Malignancy: 19 (40%) and HSCT: 10 (21%) ▪Lung Transplant: 8 (18%) ▪Solid Tumor: 1 (2%), AIDS: 1 (2%), and other conditions: 9 (19%). Site ▪Lung: 29 (60%) and Sinus: 3 (6%) ▪Bone: 2 (4%), Joint: 3 (6%), and Chest wall: 2 (4%) ▪CNS: 4 (8%) and Disseminated: 5 (10%).

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F2G, Ltd., data on file

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Enrolment by species

Species

Aspergillus (S) Aspergillus (R) Lomentospora prolificans Scedosporium spp Coccidioides spp Scopulariopsis Fusarium

  • ther

22 6 9 3 4

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1 1

2

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Phase 2 Open-Label Study (3)

▪Experience to date

▪All patients dosed with oral olorofim to date – including gut GVHD ▪Olorofim has been well tolerated; median therapy duration of 12 weeks, maximum 15 months ▪DDIs have been limited and as predicted: dosed with ibrutinib, tacrolimus, and other challenging agents ▪Complex and slowly resolving infections such as cerebral aspergillosis and osteomyelitis due to L. prolificans have been readily managed with extended dosing

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F2G, Ltd., data on file

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Breakthrough Therapy Designation

▪Olorofim was granted Breakthrough Therapy Designation by FDA in November 2019 ▪Decision made on the basis of preliminary clinical data presented to FDA ▪This potentially provides a pathway to earlier regulatory approval than conventional pathways ▪Further discussions with FDA on-going

Olorofim_RICAI_December 2019 33

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Next phase of studies

▪Phase 3 study has been designed and agreed with FDA ▪Planned commencement in late 2020 ▪Study 32 to continue

Olorofim_RICAI_December 2019 34

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Summary

▪Olorofim is an antifungal agent with a novel mechanism of action: Selective inhibition of fungal DHODH ▪Lethal to Aspergillus and other filamentous fungi ▪Active against azole- and amphotericin B-resistant Aspergillus ▪Effective in animal models of aspergillosis, scedosporiosis, and coccidioidomycosis ▪PK/PD studies have identified a target for successful therapy using a total plasma Cmin as a PD target ▪Dose proportional PK; Predictable and manageable DDIs ▪Open-label study is enrolling; Extended dosing well tolerated ▪Phase 3 study design agreed

35 Olorofim_RICAI_December 2019

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Thank you for your attention

Any questions?

Olorofim_RICAI_December 2019 36