Doravirine (DOR)From Discovery to Development

Nov. 2018

Daria Hazuda

Merck and Co

1

2

Approval Timeline

❖ US: Pifeltro and Delstrigo (Aug. 30, 2018)

❖ Canada: Pifeltro (Oct 12, 2018); Delstrigo (Nov. 9, 2018)

❖ EU: Positive opinion for Pifeltro and Delstrigo (Sept 20, 2019); Pifeltro (Nov. 23, 2018)

Doravirine: A Novel NNRTI

Approved HIV NNRTIs

3

Nevirapine (NVP)

(1996)

Efavirenz (EFV)

(1998)

Delavirdine (DLV)

(1997)

Etravirine (ETR)

(2008)

Rilpivirine (RPV)

(2011)

Cl CN

ON

O

F3CN NH

NO

Doravirine (MK-1439)

Rarely use

Presentation Outline

4

Preclinical studies

− Structure guided discovery

− Resistance

− Safety

Clinical Studies:

− Efficacy

− Safety

− Resistance

− Future opportunities?

Brief History of the HIV NNRTI Class

5

*Anticipate discontinuation in October 2018. DOR=doravirine; DVL=delavirdine; EFV=efavirenz; ETR=etravirine; NNRTI=nonnucleoside reverse transcriptase inhibitor; NVP=nevirapine; RPV=rilpivirine.

Early/mid 1990s: discovery of first NNRTIs; 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and tetrahydroimidazo[4,5,1-jkj][1,4]benzodiazepin-2(1H)-one and -thione (TIBO)

Late 1990s: approval of the 1st NNRTI; NVP in 1996, DLV in 1997 & EFV in 1998,2nd generation NNRTIs ETV and RPV approved in 2008 & 2011 respectively

Efavirenz (EFV), was most widely used NNRTI for over a decade but removed from the preferred list in the US guidelines due to CNS tolerability issues

NNRTI Dosing Comments

Nevirapine (NVP)(1998)

BID/QD Resistance (K103N, Y181C)

Efavirenz (EFV)(1998)

QD Resistance (K103N)

DDI

CNS toxicity

Etravirine (ETR)*(2009)

BID DDI

Resistance (Y181C)

Rilpivirine (RPV)(2011)

QD Decreased efficacy in patients with viral load >100k copies and CD4 < 200 cells at baseline.

Resistance (E138K, Y181C)

DDI

Some Key Considerations For the Discovery of Next Generation NNRTIs

6

1. Montaner JS et al. JAMA. 1998;279(12):930-937. 2. Sustiva Prescribing Information. BMS Princeton, NJ. Revised January 2017. 3. Squires K. Week 48 results of the Phase 3 DRIVE-AHEAD study. Presented at IAS 2017. Abstract TUAB0104LB. 4. Katlama C et al. AIDS. 2009;23(17):2289-2300. 5. Molina JM et al. Lancet. 2011;378(9787):238-246. 6. Cohen C et al. Lancet. 2011;378:229-37.

*Not approved for ARV treatment-naïve.

Challenges for HIV NNRTI Drug Discovery

7

Structural Diversity− >20 year history of NNRTI drug discovery efforts

“Improving” on the resistance profile of approved NNRTIs:- Allosteric pocket w/high degree of flexibility

Improving the safety profile vs approved NNRTIs − Derisking CNS toxicity

Improving the drug interaction profile− Derisking induction potential

Dose/physical properties to enable STR/FDCs

Virology and Structural Biology Approaches to Derisk Resistance

0

20

40

60

80

100

MK-1439

0

20

40

60

80

100

Efavirenz

EFV

MK-1439

Select

K103N; L100I

Select

V106A; L234I

Day 96

Day 48

Crystallography

Resistance Profiling

Resistance Selection

L100

K103

MK-1107, A Structurally Novel NNRTI, Provided the Basis for DOR

9aTested in 50% FBS; bTested in 10% FBS. EC50=half maximal effective concentration; FBS=fasting blood sugar1. Lai M, Feng M, Falgueyret, J, et al. Antimicrob Agents Chemother. 2014;58(3):1652-1663.

The observation that preorganized structures of MK-1107 and related analogs bound to mutant and WT RTs provided potent compounds with markedly improved antiviral activity against WT and NNRTI-resistant viruses that were superior to more flexible analogs was key to the design of DOR

1

1 1

10

0

50

100

150

200

250

300

IC5

0 (

nM

)

0

50

100

150

200

250

300

IC5

0 (

nM

)

0

50

100

150

200

250

300

IC5

0 (

nm

)

Doravirine EFV

RPV ETR

0

50

100

150

200

250

300

IC5

0 (

nM

)

DOR Potency is Improved vs EFV, RPV and ETR Against Viruses with Common NNRTI Resistance Mutations

Resistance Selection with NNRTI Resistance Viruses at Clinically Relevant Drug Concentrations Predicts Clinical Efficacy

• No viral breakthrough was observed for DOR in the selection with K103N, Y181C, G190A, and K103N/Y181C mutants

• Viral breakthrough was detected for RPV and EFV in the selection with K103N, Y181C, and K103N/Y181C mutants (except EFV with Y181C mutant)

11

G190A and K103N/Y181C

P4 P6 P8

DOR

RPV

EFV

K103N and Y181C

P4 P6 P8

DOR

RPV

EFV

*P indicates the passage number.

Feng M et al. Antimicrob Agents Chemother. 2016;60(4):2241-2247.

Data are Consistent with Clinical Profile of EFV and RPV

The X-ray Structure of DOR With HIV Reverse Transcriptase (RT) is Consistent the Observed Resistance Profile

12

Reprinted with permission from Feng M, et al. Antimicrob Agents Chemother. 2015;59(1):590-598. Copyright (2015) American Society for Microbiology1. Côté B, Burch JD, Asante-Appiah E, et al. Bioorg Med Chem Lett. 2014;24(3):917-922 2. Feng M, Wang D, Grobler JA, et al. Antimicrob Agents Chemother. 2015;59(1):590-598.

Doravirine interacts with backbone of K103 (not side chain)No interaction with Y181, L100, E138, K1012

NNRTI Mutation Pathway

DOR1 V106A V106A/F227L

2 V106A → V106A/L234I → V106A/L234I/F227L or V108I

EFV

1 L100I L100I/K103N

2 L100I → L100I/V179D → L100I/V179D/P225H or M230L

3 K103N L100I/K103N

1 E138K → E138K/L100I → E138K/L100I/V179I

RPV 2 E138K E138K/V106A

3 K101P K101P/V179I

*Experiments were performed under low multiplicity conditions in MT4GFP cells.

Compound concentration

Feng M et al. Antimicrob. Agents Chemother. 2015;59(1):590-598.

DOR Resistance Develops via a Distinct Mutation Pathway in In Vitro Resistance Selection Studies

13

Preclinical Data Suggests Improved CNS Profile of Novel NNRTIs

Neuro Target In Vitro Activities (IC50 < 10μM)EFV RPV MK-1439 MK-8507

Norepinephrine transporter Norepinephrine transporter Serotonin 5-HT2B None

Dopamine transporter Dopamine transporter

Progesterone PR-B Progesterone PR-B

Serotonin 5-HT2A PDE3

Serotonin 5-HT2B Serotonin 5-HT2B

Serotonin 5-HT2C (< 1μM) Monoamine Oxidase MAO-A

Serotonin 5-HT6 (< 1μM) 4 S/T Kinases

Androgen AR Androgen AR

Cannabinoid CB1

8 others

Efavirenz (50mpk) vs. pbo

MK-8507 (100mpk) vs. pbo

Rat EEGMK-8507: No effect @ 100mpkAUC0-24h = 136.7 µM·hCmax = 12.2 µM

Effect on qEEG Translates from Rats to Rhesus Monkeys to Humans

Human non-REM sleep

Efavirenz (50mpk BID, 7 days) qEEG spectral ratio (veh:drug) during NREM sleep

PN048, healthy males receiving efavirenz(600mg QD, 7 days); qEEG during NREM Sleep

Rhesus non-REM sleep

Tannenbaum, P. et. al., CROI, 2015, Seattle, Washington, Abstract # 449.

Simen, A., et. al, J. Sleep Res. ,24, 66-73

Clinical Studies

16

17

Phase 2 and 3 Clinical Program for DOR and DOR/3TC/TDF

PN Comparator / Population

Ph

ase

2 030DRIVE-BEYONDNCT02629822

DOR/3TC/TDF in TN participants with transmitted resistance to NNRTIs

Ph

ase

3

018DRIVE-FORWARD

NCT02275780

DOR vs. boosted-darunavir (with FTC/TDF or ABC/3TC) in TN adults

021DRIVE-AHEADNCT02403674

DOR/3TC/TDF vs. EFV/FTC/TDF in TN adults

024DRIVE-SHIFT

NCT02397096

DOR/3TC/TDF in participants switching from other regimens

DOR Ph3 Trials Efficacy at 96 Weeks: DRIVE-FORWARD (DOR vs DRV) and DRIVE-AHEAD (DOR vs EFV)

†FDA Snapshot Approach

Proportion with HIV-1 RNA <50 c/mL

22,8

48,9

76,9

87,4 88,784,3

8178,6 80,5 77,5

19,5

45,9

73,481

84,980,8 79,9

76,475 73,6

0

20

40

60

80

100

0 8 16 24 32 40 48 56 64 72 80 88 96

DOR/3TC/T…EFV/FTC/TDF

Per

cen

tage

of

Par

tici

pan

ts (

95

% C

I)

Treatment Week

DOR/3TC/TDF is non-inferior to EFV/FTC/TDF at Week 96

Per

cen

tage

of

Par

tici

pan

ts (

95

% C

I)

Treatment Week

DOR shows greater efficacy than DRV at Week 96

18

Summary of DOR Clinical Adverse Events at Week 96

DOR/3TC/TDF(N=364)

n (%)

EFV/FTC/TDF(N=364)

n (%)

Difference in % estimate (95% CI)

≥1 AEs 321 (88%) 339 (93%) -4.9(-9.3, -0.7)

Drug-related AEs 116 (32%) 236 (65%) -33.0 (-39.6, -26.0)

Serious AEs 21 (6%) 30 (8%) -2.5 (-6.3, 1.3)

Drug-related 1 (<1%) 4 (1%) -0.8 (-2.5, 0.5)

Discontinued due to AE

11 (3%) 27 (7%)-4.4 (-7.9, -1.2)

Drug-related 8 (2%) 24 (7%) -4.4 (-7.7, -1.5)

Serious 2 (1%) 4 (1%) -0.5 (-2.3, 1.0)

Serious drug-related

1 (<1%) 3 (1%)-0.5 (-2.2, 0.8)

Deaths 0 (0%) 2 (1%) -0.5 (-2.0, 0.5)

19

Neuropsychiatric Adverse Events (Predefined) at Week 96

10,2

14

4,9 5,2

0,5

38,2

27,5

8,57,4

1,4

0

10

20

30

40

Dizziness Sleepdisorders anddisturbances

Alteredsensorium

Depressionand suicide/

self-injury

Psychosis andpsychoticdisorders

DOR/3TC/TDF EFV/FTC/TDF

Pe

rce

nta

ge o

f p

arti

cip

ants

-28.0 (-33.9, -22.1) -13.5 (-19.3, -7.6) -3.6 (-7.4, 0.1) -2.2 (-5.9, 1.4) -0.8 (-2.7, 0.8) Difference (95% CI)

20

Fasting Lipids, Change from Baseline at Week 96

-0,4 -0,5

4,1

-1,1

4,5

14,0

17,7

21,9 22,5

4,2

-5

0

5

10

15

20

25

mg

/dL

DOR DRV+r

At Week 96, DOR Exhibits a More Favorable Lipid Profile

-0,6 -2,1-0,1

-9,6

2,1

10,815,0

23,418,8

8,4

-15-10

-505

1015202530

LDL-C Cholesterol HDL-C

DOR/3TC/TDF EFV/FTC/TDF

mg

/dL

DRIVE-FORWARD (DOR vs DRV)

DRIVE-AHEADDOR/3TC/TDF vs EFV/FTC/TDF

21

Summary of Genotypic and Phenotypic Resistance from Doravirine Phase 3 Clinical Trials (WK 48): DRIVE FORWARD and DRIVE-AHEAD

NNRTI+NRTI mutations from DOR armsa : 7/747 (0.9%)

NNRTI mutation

mutation DOR EFVA98G/F227C >93 9.0

A98G/V106I/H221Y/F227C >110 19

V106A/P225H/Y318F >210 4.8

V106I/F227C >105 2.5 (Sc)

V106I/H221Y/F227Cb >96 1.7 (S)

V106M/F227C >98 11

Y188L >181 >120

NNRTI mutation

mutation DOR EFVK103N Sb 6.4

K103N S 32

K103N S 20

K103N S 5.3

K103N S 11

K103N S 6.8

K103N/V108I S 22

K103N/E138G S 11

K103N/M230L 36 292

K103N/P225H S 24

G190E 18 112

G190E Fc F

a DRIVE-FORWARD (DOR+NRTIs) (n=383) and DRIVE-AHEAD (DOR/3TC/TDF); bFrom DRIVE-FORWARD, the rest of mutations were from DRIVE-AHEAD; csusceptible

aDRIVE-AHEAD (EFV/FTC/TDF); bThe fold-change cut-off employed here is 2.5. The actual fold-change cut-off for DOR has not been established; cFailed

NNRTI+NRTI mutations from EFV arma : 12/363 (3.3%)

22

Summary from DRIVE-BEYOND Week 48 • Enrollment stopped early due to assessment of lack

of feasibility to enroll in a reasonable period of time

• 10 participants randomized• 8 participants with K103N, 2 participants with G190A

• All participants suppressed to HIV-1 RNA <50 copies/mL• 2 participants discontinued prior to Week 48

– 1 participant was discontinued at Week 36 for non-compliance (G190A)• HIV-1 RNA 5393 copies/mL at Week 24, but 70 copies/mL at viral failure confirmation

– 1 participant was lost to follow-up at Week 16 (K103N)

• 8 participants completed Week 48 and all had HIV-1 RNA <50 copies/mL

23

DRIVE-SHIFT Efficacy Analysis

90,8

1,67,6

94,6

1,8 3,6

0

10

20

30

40

50

60

70

80

90

100

HIV-1 RNA <50 copies/mL HIV-1 RNA ≥50 copies mL No Virologic Data in Window

% o

f Pa

rtic

ipan

ts

DOR/3TC/TDF Week 48

Baseline Regimen Week 24

• No participants who received DOR/3TC/TDF developed viral drug resistance • 24 participants had evidence of prior NNRTI mutations (K103N, Y181C, G190A). All

24 participants remained suppressed on DOR

24

Conclusions:

1. DOR displays better potency compared with RPV, EFV, and ETR against the top 11 prevalent NNRTI-associated mutants.

2. DOR exhibits unique mutation development pathways

3. DRIVE-FORWARD shows DOR has greater efficacy than DRV at week 96

4. DRIVE-AHEAD shows DOR has non-inferior efficacy to EFV at week 96

5. DRIVE-BEYOND demonstrates DOR is efficacious against common NNRTI-associated mutants (K013N, G190A)

6. DRIVE-SHIFT shows non-inferior efficacy at Week 24, compared to continuation of the baseline regime. DOR is shown to be efficacious against common NNRTI-associated mutants (K103N , Y181C, and G190A)

7. DOR demonstrates superior neuropsychiatric profile compared to EFV

8. DOR displays superior lipid profile to PI or EFV

9. DOR demonstrates good safety profile and is well tolerated by HIV patients

25

MK-8591 (EFdA): A Nucleoside with a Novel Mechanism(s) of Action

Licensed from Yamasa Corp (Japan)

Unique profile and mechanisms of action†

• Non-obligate chain terminator

• Inhibits HIV reverse transcriptase by preventing translocation

• Potent antiviral activity

• MK-8591-TP exhibits persistence (t1/2 = 103 hr) in human PBMCs allowing for extended-duration dosing (in vitro and in vivo)

† Michailidis, E., et al. J. Biol. Chem., 2009, 284:35681-91; Michailidis, E., et al. J. Biol. Chem., 2014, 289:24533-48Kirby, K. A., et al. Cell Mol. Biol., 2011, 57:40-6; Nakata, H., et al. Antimicrob. Agents Chemother., 2007: 51:2701-8

26

27

The DOR-associated mutation at F227 hyper-sensitizes HIV to MK-8591

Mutation Antiviral Potency (nM) Fold-change (EC50Mut/WT EC50WT)

3TC MK-8591 3TC MK-8591

WT 601 ± 142 (n=9) 0.81 ± 0.029 (n=5) 1.0 1.0

A98G 683 ± 99 (n=4) 0.85 ± 0.089 (n=4) 0.88 1.0

V106I 643 ± 129 (n=4) 0.83 ± 0.065 (n=4) 0.93 1.0

F227C 1360 ± 94 (n=4) 0.15 ± 0.026 (n=11) 2.26 0.18

A98G/F227C 809 ± 146 (n=4) 0.15 ± 0.026 (n=7) 1.25 0.18

A98G/V106I/H221Y/F227C 1160 ± 314 (n=4) 0.81 ± 0.124 (n=8) 1.93 1.00

V106A/P225H/Y318F 550 ± 109 (n=4) 0.67 ± 0.076 (n=7) 0.92 0.84

V106I/F227C 692 ± 212 (n=4) 0.35 ± 0.048 (n=7) 1.15 0.44

V106I/F227C/H221Y 758 ± 244 (n=4) 0.40 ± 0.075 (n=4) 1.26 0.49

V106M/F227C 771 ± 62 (n=4) 0.30 ± 0.048 (n=5) 1.28 0.37

Y188L 826 ± 140 (n=4) 1.22 ± 0.159 (n=2) 1.37 1.51

• F227C substitutions in reverse transcriptase (RT) are the major mutations seen in HIV that develop resistance to DOR

• Viruses with F227C alone or in combination with other substitutions (A98G/F227C, V106I/F227C, V106M/F227C, &

V106I/H221Y/F227C) were more susceptible to MK-8591, but these mutants exhibited no change in susceptibility to 3TC

• No F227C mutations was identified in selection experiments with the combination of DOR/MK-8591, but was selected

with the combination of DOR/3TC, thereby supporting that F227C mutant is hyper-susceptible to MK-8591

• As shown on prior slide, in vitro two-drug combination resistance selection studies suggest DOR/MK-8591 exhibits a

higher barrier to resistance development compared to the combination of DOR/3TC, dolutegravir/3TC, & bictegravir/3TC

• Phase 2 study of DOR + MK-8591 is currently underway

28

In vitro resistance selection studies comparing two-drug combinations: DOR + MK-8591 vs InSTI + 3TC

Column 1 2 3 4 5 6 7 8 9 10 11 12

Concentration (xEC50)

8x 4x 4x 2x 2x 1x 1x 0.5x 0.5x 0.25x 0.25x 0.0x

Dolutegravir/3TC Bictegravir/3TCDOR/MK-8591 DOR/3TC

Plate Layout

➢ In vitro resistance selection was performed with WT virus (NL4-3) in MT4-GFP cells

➢ Viral breakthrough was monitored via the detection of green fluorescence; the results above are from passage 13

Note: The clinical trough concentrations of MK-8591 (1 mg) and DOR (100 mg) are >20-fold and >70-fold higher than the EC50, respectively.

At clinically relevant drug concentrations, the combination of DOR/MK-8591 exhibited higher barrier

for resistance development compared with 2 drug combinations containing integrase inhibitors

Acknowledgements

Merck Virology, Chemistry & Preclinical Development

Merck Virology Clinical Development

Merck Clinical Pharmacology

Collaborators, investigators and patients