CCR5 Antagonist CCR5 Antagonist Drug Development Issues Drug - - PowerPoint PPT Presentation

CCR5 Antagonist CCR5 Antagonist Drug Development Issues Drug Development Issues

FDA Perspective FDA Perspective

Presentation Outline Presentation Outline

• Summarize recommendations for development of:

Summarize recommendations for development of:

• Antiretrovirals in general

Antiretrovirals in general

• CCR5 antagonists, specifically

CCR5 antagonists, specifically

• Summarize unanswered questions

Summarize unanswered questions

• safety

safety

• efficacy

efficacy

• tropism changes and resistance

tropism changes and resistance

Development of New Classes of Development of New Classes of Antiretroviral Agents Antiretroviral Agents

• General HIV drug development principles

General HIV drug development principles apply apply

• HIV RNA and CD4 data through Week 24

HIV RNA and CD4 data through Week 24 for accelerated approval for accelerated approval

• HIV RNA and CD4 data through Week 48

HIV RNA and CD4 data through Week 48 (minimum) for traditional approval (minimum) for traditional approval

• Two adequate and well-controlled studies

Two adequate and well-controlled studies

• Evaluation of class and drug-specific

Evaluation of class and drug-specific concerns concerns

• May require additional data and longer

May require additional data and longer follow-up follow-up

Indications Indications

• Antiretroviral-experienced patients

Antiretroviral-experienced patients

• minimum of 24 weeks of data

minimum of 24 weeks of data

• Antiretroviral-naïve patients

Antiretroviral-naïve patients

• minimum of 48 weeks of data (all ARVs) with

minimum of 48 weeks of data (all ARVs) with commitment for 96 weeks of follow-up (CCR5 commitment for 96 weeks of follow-up (CCR5 antagonists) antagonists)

After Proof-of-Concept: Timing of After Proof-of-Concept: Timing of Naïve and Experienced Studies Naïve and Experienced Studies

• Risk/Benefit:

Risk/Benefit:

• Depends on safety: preclinical (including

Depends on safety: preclinical (including resistance) and clinical data resistance) and clinical data

• If safety concern present - begin with treatment

If safety concern present - begin with treatment experienced studies then naïve studies, if appropriate experienced studies then naïve studies, if appropriate

• If safety concern absent/minimal - naïve and

If safety concern absent/minimal - naïve and treatment experienced studies at the same time treatment experienced studies at the same time

• Drug-drug interactions

Drug-drug interactions

• necessary to support coadministration of multiple

necessary to support coadministration of multiple ARVs for background regimens ARVs for background regimens

CCR5 Drug Development CCR5 Drug Development

DAVDP Goal DAVDP Goal: :

• Provide consistent advice on amount and

Provide consistent advice on amount and type of information needed for approval type of information needed for approval BUT BUT allow for flexibility in overall allow for flexibility in overall development plans development plans

CCR5-Specific Evaluations CCR5-Specific Evaluations

• Safety and activity data in mixed/dual (R5/X4) patients

Safety and activity data in mixed/dual (R5/X4) patients

• For all populations (R5 and R5/X4):

For all populations (R5 and R5/X4):

• Stringent adjudication of new AIDS-defining events

Stringent adjudication of new AIDS-defining events by independent review committee by independent review committee

• Class-specific AEs for CCR5 antagonists

Class-specific AEs for CCR5 antagonists

• changes to immune system by blocking

changes to immune system by blocking endogenous CCR5 receptors endogenous CCR5 receptors

• Tropism changes

Tropism changes

• impact on disease progression

impact on disease progression

• monthly tropism reports to monitor changes, viral

monthly tropism reports to monitor changes, viral load and CD4 load and CD4

• Stored baseline samples for future analyses

Stored baseline samples for future analyses

Tropism and Resistance Evaluations Tropism and Resistance Evaluations

• Loss of virologic response (increased

Loss of virologic response (increased HIV RNA) and have a change in tropism HIV RNA) and have a change in tropism

• Main considerations - determine if:

Main considerations - determine if:

• Coreceptor change occurred

Coreceptor change occurred

• Outgrowth of a minor population of virus not

Outgrowth of a minor population of virus not detected at screening occurred detected at screening occurred

• Resistance to the CCR5 inhibitor occurred

Resistance to the CCR5 inhibitor occurred (through a mechanism other than a coreceptor (through a mechanism other than a coreceptor change) change)

• PI/RTI resistance emerged

PI/RTI resistance emerged

Analyses for Tropism Changes Analyses for Tropism Changes R5 to R5/X4 or X4 R5 to R5/X4 or X4

• In vitro susceptibility to coreceptor inhibitor (phenotype)

In vitro susceptibility to coreceptor inhibitor (phenotype)

• Nucleotide sequence analysis (genotype):

Nucleotide sequence analysis (genotype):

• gp120 region to identify AA changes that may

gp120 region to identify AA changes that may contribute to tropism change or resistance (potential contribute to tropism change or resistance (potential AA changes verified via site-directed mutagenesis) AA changes verified via site-directed mutagenesis)

• PR and RT

PR and RT

• Clonal evaluation of virus at screening or baseline and

Clonal evaluation of virus at screening or baseline and subsequent timepoints to determine if outgrowth of subsequent timepoints to determine if outgrowth of minor population occurred minor population occurred

• Phylogenetic analysis to determine relationship of

Phylogenetic analysis to determine relationship of emerging CXCR4 virus to emerging CXCR4 virus to “ “original

• riginal”

” CCR5 virus CCR5 virus

Virologic Failure Follow-up Virologic Failure Follow-up

• At least five year follow-up to obtain long-

At least five year follow-up to obtain long- term data on: term data on:

• HIV RNA

HIV RNA

• CD4

CD4

• tropism

tropism

• Progression to AIDS (number of AIDS-

Progression to AIDS (number of AIDS- defining events and death) defining events and death)

• Evaluations at least 2-3 times per year

Evaluations at least 2-3 times per year

Unanswered Questions Unanswered Questions

• 1. What is the impact of tropism changes on
• 1. What is the impact of tropism changes on
• safety parameters?

safety parameters?

• virologic success or failure?

virologic success or failure? 2.

• 2. Is the amount, type, and duration of data sufficient to

Is the amount, type, and duration of data sufficient to address safety concerns for tropism changes? address safety concerns for tropism changes?

• What are the feasibility concerns for the five-year

What are the feasibility concerns for the five-year follow-up commitment and what mechanisms can follow-up commitment and what mechanisms can be used to ensure sufficient data collection and be used to ensure sufficient data collection and minimize lost-to-follow-up minimize lost-to-follow-up

• 3. What is the role of CCR5 antagonists in treatment
• 3. What is the role of CCR5 antagonists in treatment

regimens? regimens?

• Are CCR5

Are CCR5’ ’s a substitute for PI/NNRTIs; one s a substitute for PI/NNRTIs; one nRTI nRTI vs dual nRTIs? vs dual nRTIs?

Tropism and Resistance Questions Tropism and Resistance Questions

• 4. What resistance/tropism information is needed at the
• 4. What resistance/tropism information is needed at the

time of approval of new CCR5 antagonists, and time of approval of new CCR5 antagonists, and how much? how much?

• Is data from a subset of study subjects acceptable, and if

Is data from a subset of study subjects acceptable, and if so, from what proportion? so, from what proportion?

5. 5. In clinical practice will tropism testing be done at In clinical practice will tropism testing be done at screening, post-failure, or routinely? screening, post-failure, or routinely?