Novel Drug Delivery Systems Marta Boffito HIV Clinical Forum for Nurses and Pharmacists London, UK October 2018
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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
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