Combination therapy:

Navigating the minefield of

safety vs efficacyJordan J Feld MD MPH

Toronto Centre for Liver Disease

Sandra Rotman Centre for Global Health

University of Toronto

Disclosures

• Consulting: Abbvie, Gilead, Janssen, Merck

• Research: Abbvie, Gilead, Janssen, Merck,

Regulus

Outline

• What combinations are possible?

• Rational choices

• Approach to evaluation – lessons from other

diseases

– Efficacy

– Safety

Approaches to therapyViral Targets - DAA

• Viral entry

• cccDNA

formation/transcription/de

gradation

• RNA intermediates

• Encapsidation

• DNA replication

• Assembly

• Release

Immune Targets

• Innate immune response

– IFN

– TLR agonists

– RIG-I agonists

• Adaptive immune

response

– Anti-antagonists

(checkpoint inhibitors)

– Vaccination

Combination Approaches

Viral target

A+ Viral target

A NA + NA

Viral target

A+ Viral target

B NA + RNAi

Immune

Target A + TLR7 + VaccineImmune

Target B

Viral target

A+

NA + TLR7

Immune

Target A

Attractive combinations

Nuc

HBV DNAsuppression

+ +Immunoe

Target

RNAi

Nucleic Acid Polymers

cccDNAi

+/- cccDNAi

+/- entry inhibitor

+/- RNAi

+/- CpAM

TLR/RIG-I agonist

αPD1/PDL1

Therapeutic

vaccine

May not need all 3 ‘classes’…mix and match

Viral ProteinDepletion(s, x, core)

Key Questions

• Efficacy

– How much proof do we need for each agent in a

combination approach?

– Do we need clear ‘value’ for each agent?

– Do we need different endpoints for different targets?

• Safety

– Safety for each agent vs each combination?

‘Easy’ scenario – combine approved

drugs

Drug A

Proven activity

Proven safety

Drug B

Proven activity

Proven safety

Trial of A + B vs A vs B

(Nuc + PegIFN)

Even here…some challenges

- Population

- Duration

- Endpoints

- Big trial (2 control arms)

More difficult if new agents…Assume the 3-target paradigm is correct…

Drug A

Dose 1

Dose 2

Dose 3

Measurement

of activity & safety

Drug B

Dose 1

Dose 2

Dose 3

Measurement

of activity & safety

Drug C

Dose 1

Dose 2

Dose 3

Measurement

of activity & safety

Drug A + B

Drug A + C

Drug B + C

Drug A + B + C

Markedly more complicated if interactions, preferred

dose/duration/pop’n not clear or different endpoints by

MOA

What does combination mean?1. Sequential therapies (in either direction)

2. Concomitant from the start

3. Sequential + concomitant

• Allows assessment of each drug ‘alone’ and in combination

(and see effect on HBV DNA)

– Efficacy

– Safety

• More complicated if a third drug or 2 novel drugs

Drug A

Dose 1

Dose 2

Dose 3

12 weeks 12 weeks

Drug A + NA

A few lessons/cautions from HCV

Good examples

1.Rapid assessment of efficacy – ideal scenario

2.Better than expected (Peg/RBV)

Bad examples

1.Value of each agent in a combo (Merck)

2.Insisting on your own pipeline (BMS)

3.Unexpected toxicity (BMS)

Day0 2 4 6 8 10 12 14

-7

-6

-5

-3

-2

-1

0

1

Mean

lo

g10

HC

V R

NA

ch

an

ge f

rom

baselin

e

(IU

/mL

)

-4

Placebo

Polymerase then protease

Protease then polymerase

Combo

Gane Lancet 2010

Good Example 1 - DAAs

• Brief monotherapy followed by combo therapy

• Should be more effective in HBV – higher barrier to resistance

• But non-DNA endpoints take a long time to see an effect!

• Requires a permissive regulatory agency (thx NZ) – monotherapy…

Do you need all parts of your combo?

Prior Treatment Experience Treatment-experienced Cirrhosis

Grazoprevir (PI)/Ruzasvir (NS5A)/3682 (Nuc) x 8-16w G3 HCV

PP

SV

R1

2

• Highly effective…should have led to a Phase 3 study

• But FDA said…before you go to 3, are you sure 2 would not be

adequate?

• Back to the drawing board with NS5A + Nuc…may have killed their

HCV program Lesson: Make sure you need all of the combo

Lawitz AASLD 2016 – Abstract 110

Recognize your weaknesses…BMS HCV therapies

1.Daclatasvir – excellent pan-genotypic well tolerated NS5A

2.Asunaprevir – a weak protease inhibitor with toxicity issues

3.Beclabuvir – weak non-nuc polymerase inhibitor with toxicity

issues

Great portfolio or 1 great drug?

Lesson: Insistence on going alone can kill good drugs

Good Example 2 – Better than expected

IFN RBV

The IFN/RBV example

• Challenging precedent

• Very modestly effective therapy combined with a therapy with no activity as monotherapy

• Why was it ever tried? How would we know to do this again?

• Argues against the ‘must prove each component works’ approach

• Makes the case for ‘rational combinations’ for which each component is safe, whether effective alone or not

But endpoints and populations

may be the biggest issue

Endpoints

• With HCV or HIV simple…viral load

• Easy to measure– Changes rapidly

– Goal is undetectability in the body serum is pretty good surrogate for liver (HCV), less so for HIV

• HBV – not so simple– HBV DNA

– HBsAg

– HBeAg/anti-Hbe

– cccDNA

– HBV RNA or HBcrAg

– ALT, fibrosis…and the list goes on

Is there consensus?

Sterilizing cure(cccDNA loss)

Too hard to achieve

Sustained Virological Response(sAg +ve, DNA negative, off therapy)An advance but not enough of one

Functional Cure(sAg loss with undetectable DNA

& Normal ALT)Challenging but achievable goal

88% of attendees at EASL/ASSLD HBV Endpoints conference chose Functional Cure as the preferred goal

for future therapies

HBsAg• Preferred endpoint…but some issues

• 1. May mean different things with different targets• Natural clearance = cccDNA loss/silencing…ie what we want

• cccDNA target – probably same as above

• siRNA – blocks translation…probably no effect on cccDNA transcription unless it induces immune control

• Other antiviral – probably what we want but may depend

• Immune target – immune control - probably what we want

• False negative integrated DNA could produce sAg even in people who have cleared/silenced all cccDNA

2. Decline is SLOW! • Need long-term therapy to see an effect – probably more true with optimal

response above – major issue to avoid excluding a good drug

• If surrogate, what decrease in quant HBsAg matters? 0.5 log, 1 log, more?

3. Similar challenges likely with HBV RNA, crAg etc• Potentially other issues given uncertainty of ‘what they mean’ and whether that

differs by MOA of therapy

Different target…different

endpoint• May be a major challenge with different mechanisms of

action

– Virological target - multiple

– Immunological target – multiple

• May need ‘proof of concept’ early endpoints…possibly

including liver biopsy…for each target (Phase 1, 2a/2b)

eg. RIG-I activator works (ISG induction, even if

limited sAg decline)

• Clinically relevant endpoint for approvals (e.g. HBsAg)

(Phase 3)

Populations

• HCV/HIV – pretty easy

– Genotype

– Cirrhosis vs non-cirrhotic (start non-cirrhotic)

• HBV

– Which phase of disease for which approach?

– Certain strategies may not work in all phases

• e.g. Immunotherapy may not work in IT patients

Nuc suppressed or not nuc

suppressed – a key question

Nuc SuppressionPros

• Safety – intuitively ‘makes sense’… less likely to flare

• Clinical need – patients on therapy need therapy (?)

• Additive/synergistic effect –DNA suppression may help whatever other mechanism is being evaluated

• Easiest patients to find!!

Cons

• Safety – flares may still occur but significance less clear

• May miss an effect…if a therapy requires ‘active disease’ with inflammation…

• Lose assessment of HBV DNA as an endpoint

• Additional DDIs to consider

DNA can be useful…

DNA levels sAg levels

• Much greater effect seen on DNA than sAg

• If treat nuc suppressed patients…may miss this activity

Korolowicz PLoS One 2017

SB-9000 (RIG-I agonist) given to infected woodchucks

Bottom line on efficacy

• Not simple to measure

– Different agents with different mechanisms very

challenging

– Cannot always predict outcome of combinations

– The combination should not just be what you have in

house (a fatal mistake in HCV!!)

• Endpoints and populations remain a challenge

Safety

Step 1: Drug Interactions

• Relatively straightforward (but studies not cheap!)

• Most DDIs can be predicted once metabolism and

elimination of agents are known

• Initial healthy volunteer studies with standard PK

measurements

• Do we need to do DDI studies in patients with liver

disease? Can be done…but not easy, may not

always be necessary

• Do they need to be done for all agents & NAs?

Step 2: Toxicity

1. Flares

– Complicated!

2. Everything else

– Similar to non-HBV therapies

– Challenge is sorting out the culprit

Non-hepatic AEDrug A + Drug B + Drug C

Non-hepatic AE not seen with monotherapy studies

What’s the conclusion?

1.Type of AE may help – e.g. immune mediated more likely to

be PD1 than CpAM (but not certain!)

2.Is it an idiosyncratic reaction from A, B or C missed in BRIEF

monotherapy studies or from the combination?

3.Is it a class effect or a drug-specific effect?

BMS HCV Nuc – cardiac toxicity 1 death – killed the program

Lesson: Chronic animal tox studies critical before combo

ALT flares…a special problem

Same issues of attribution apply as with non-hepatic AE with

combo therapy

Immune-mediated flare

(“good flare”)

Autoimmune Hepatitis

(“bad flare”)

DILI

(“bad flare”)

- Viral control

- Suppression of HBV

DNA (if not on NA)

- May lead to HBeAg

and/or HBsAg loss

- Usually self-limited but

can be severe/fatal

- ‘What we want’ as long

as not too severe

- NA rescue may help

- Idiosyncratic or dose

dependent

- Most mechanisms

unknown

- Hy’s Law hard to

apply with elevated

ALT at baseline

- Can be severe/fatal

- No specific therapy

- Likely only with

immunotherapy

(anti-PD1/PDL1)

- Rapid onset

- Can be severe/fatal

- Steroid responsive

The flares we ‘want to see’

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

0

1 0 0

2 0 0

3 0 0

1 4 8 12 16 20 242 3B L

HB

sA

g, IU

/mL A

LT

, U/L

IFN

-γ S

po

ts/ 1

06

Cells

Week

Nivolumab (anti-PD1) + TDF

ALT flare leading to HBsAg clearance

Gane EASL 2017

Sorting out DILI in HBV

• Workshop to develop stopping rules for HBV

flares…no consensus reached!

• Suggested approach

Baseline ALT On-treatment change

1-2 x ULN >5 x baseline & >10 x ULN

2-5 x ULN >3 x baseline

≥ 5 x ULN >2 x baseline

This may be one argument for NA-suppressed patients

Kullak-Ublick Drug Safety 2014

Would biopsy help

• Unknown

• FDA feels likely of ‘limited value’

– Invasive

– Too non-specific to distinguish

• Not totally sure I agree…

– May be valuable as we learn more

– May give evidence of activity or lack thereof

HBV Forum EASL 2017

ALT flares during combo therapyHBRN IT Trial: Entecavir lead-in x 8w + PegIFN x 40 in IT adults

• ALT flares occurred in 68%, none icteric

• Associated with sAg decline in some but not all

• Are they good or bad? What do they mean?

Feld AASLD 2017

ALT flares can be helpful

Suresh PLoS One 2017

• ALT flare suggests ‘activity’

• Only occur during SB 9200…resolve with Nuc

• Determined approach in trials…SB9200 followed by ETV

RIG-I agonist before or after ETV sequential therapy in woodchucks

Some guidance from the FDA

FDA plans to have a ‘HBV Drug Development

Guidance Document’ - 2018

N Brown & T Block Summary of FDA/HBF/HBV Forum meeting

Key points

• Populations to study– Naïve ideal but NA-suppressed easier to find both

• DDI studies– Not required for all add-ons to NAs if no DDI expected

– Required for all other types of novel therapies

• Duration– Allow longer than standard 4w Ph 1b trials eg. 12w (if

pre-clinical/animal data supportive)

• Combos– Combo tox studies in animals first if >1 new agent

N Brown & T Block Summary of FDA/HBF/HBV Forum meeting

Summary

• Both efficacy and safety are a major challenge

with multiple new agents developed at once

• Added complexity with various endpoints and

populations to study

• Choosing the right combo, in the right patients,

for the right duration will be challenging

• Even if the science is perfect…innovative

approaches to trial design will be needed…

• Dr Chan how are we going to get there?