Novel Drug Delivery Systems

Marta Boffito

HIV Clinical Forum for Nurses and PharmacistsLondon, UK

October 2018

Novel DDS

• What are they

• Novel versus conventional

• Why do they matter in HIV Medicine

DDS

• Drug delivery is the method of administering a pharmaceutical compound to achieve a therapeutic effect

• HIV: oral method of delivery

Other conventional DDS

• Buccal/sublingual delivery

• Rectal delivery

• Intravenous delivery

• Subcutaneous delivery

• Intramuscular delivery

Other conventional DDS

• Buccal/sublingual delivery

• Rectal delivery

• Intravenous delivery

• Subcutaneous delivery

• Intramuscular delivery

Other conventional DDS

• Buccal/sublingual delivery

• Rectal delivery

• Intravenous delivery

• Subcutaneous delivery

• Intramuscular delivery

Intramuscular drug delivery

• Advantages– Drug is absorbed slowly, prolonged effect– Sustained exposure over time– Larger volume than SC– By-pass first pass metabolism

• Disadvantages– Invasive – patient discomfort– Irritation– Inflammation– My require training

LESS DRUG INTERACTIONS

Long-acting CAB IM + RPV IM was non-inferior to oral CAB + ABC/3TC

CAB IM + RPV IM Q4W or Q8W maintains virologic suppression through to Week 96

Margolis et al. Lancet 2017

ABC, abacavir; CAB, cabotegravir; IM, intramuscular injection; QD, once-daily; Q4W, once every 4 weeks; Q8W, once every 8 weeks; RPV, rilpivirine; VL, viral load; 3TC, lamivudine.

Oral CAB + ABC/3TC QD induction

CAB IM + RPV IM Q8W

CAB IM + RPV IM Q4W

Oral CAB + ABC/3TC QD

% subjects VL <50 c/mL

Week 32 Week 96

Q8W 95% 94%

Q4W 94% 87%

Oral CAB 91% 84%

Patient acceptability for long-acting formulations

1. Margolis et al. Lancet 2017; 2. Eron et al. IAS 2017

*Based on observed case data set of subjects who completed HIV Treatment Satisfaction Questionnaire status version at Week 96.CAB, cabotegravir; IM, intramuscular injection; LA, long acting; Q4W, once every 4 weeks; Q8W, once every 8 weeks; RPV, rilpivirine.

Patient-reported outcomes at Week 96 maintenance treatment*1,2

How satisfied are you with your current treatment? How satisfied would you be to continue with your present form of treatment?

Very satisfied Very dissatisfied

6 5 4 3 2 1 0

Injectable ARVs

• Phase III development underway for monthly injectable containing 2 ARVs (CAB/RPV)

• Maintenance regimen (VL<20)

• CAB alone in late-stage development as an every-other-monthly injection

• CAB highly effective in preventing HIV acquisition in animal models

TREATMENT

PrEP

Barnhart, Global Health: Science and Practice 2017

Exploratory advantages I

SSAT040: [RPV] in tissue

0

1

10

100

1000

0 10 20 30 40 50 60 70 80

Ril

piv

irin

e (

ng

/ml)

Time (days)

300 mg (n=20) 600 mg (n=20) 1200 mg (n=20) assay LLQ

Vaginal Rectal

Jackson et al. CPT 2014

[RPV] = rilpivirine concentrations, LLQ = lower limit quantification

Exploratory advantages II

Drawbacks of injectable cabotegravirand rilpivirine

1. High dosing volumes (≥3mL), IM in the buttocks

1. Extended PK tail, risk of resistance if lost to follow-up

2. Deliverability of injections is resource-intensive

3. Oral lead-in period complicates implementation

4. DDI with rifampicin

5. Low genetic barrier

What’ s next?

New NRTI or NtRTI

PIPELINE

Novel class of HIV capsid inhibitors• GS-CA1 PK in rats• Extended release formulation

• Single SC injection maintains plasma concentrations well above the paEC50 for > 10 weeks• Potential for monthly or longer intervals

PIPELINE

Tse et al. CROI 2017

TAF Thin Film PolycaprolactoneDevice Prototypes:

(A) 2.5mm diameter, 40mm long prototypes loaded with 230mg 1:1 TAF:PEG300 (w/w)

(B) 0.6mm diameter, 20mm long prototype loaded with 26mg 1:1 TAF:PEG300 (w/w)

Summary of pipeline

Barnhart, Global Health: Science and Practice 2017

Broadly neutralizing antibodies (bnAbs)

• Particularly for prevention

• Can block HIV viruses in macaques

• Two large trials underway with VRC01 IV to prevent infections in people

• New formulations with concentrations 100-fol) lower than VRC01 and given SC every 6 months

• Feasibility of manufacturing antibodies at high scale and reasonable cost?

• Refrigeration

Pegu et al. Immunol Rev 2017

Conclusions

• Several highly potent agents in the pipeline

• Promising technologies for long-acting delivery

• Bright prospects for very long-acting ARVs for treatment and prevention

• Ideally products fit for implementation not only in high income but also in low-income countries

• Keystone in finally controlling HIV epidemic