The paediatric antiretroviral pipeline

19 July 2014. Related: Pipeline report, Antiretrovirals, Paediatric care.

By Polly Clayden

Since last year’s Pipeline Report dolutegravir (DTG) was approved for children aged 12 years and older in the United States and Europe. [1, 2] The approvals for this age group were granted at the same time as that for adults—a good precedent for older children.

At the other end of the age band spectrum, in the United States, raltegravir (RAL) was approved for infants aged four weeks and older [3] and atazanavir (ATV) for three months and older. [4]

The World Health Organization (WHO) 2014 Supplement to the 2013 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection includes a useful pediatric chapter, ‘Optimizing Antiretroviral Drugs for Children: Medium- and Long-Term Priorities’. [5] The chapter considers both priority formulations needed to treat children according to the guidelines and research priorities for pipeline drugs at advanced stages of development.

The list of pediatric formulations recommended by WHO and currently available was updated, and shows that what we have on offer now is still far from optimal. [6]

UNITAID, Drugs for Neglected Diseases Initiative (DNDi) and the Medicines Patent Pool (MPP) launched the Paediatric HIV Treatment Initiative (PHTI) that should help to move along the development and delivery of specific formulations and regimens appropriate to children. Despite considerable strides in the last few years, innovation and access in antiretrovirals for children still lags behind that for adults. [7]

WHO Recommendations

One of the goals of treatment optimization is to align pediatric antiretroviral regimens with recommendations for adults. With current options, the youngest children need to be considered differently, and there is some room for interpretation in the guidelines as to what age this harmonization should begin.

In order to implement the revised guidelines, child-sized solid dosing forms of recommended antiretrovirals, in appropriate strengths, are needed to facilitate dosages according to WHO simplified dosing tables.

Where possible these should be fixed-dose combination (FDC) dispersible tablets. For compounds that cannot be formulated in this way (large and/or insoluble molecules) granules are preferable to liquids. Liquid formulations are expensive, have short shelf lives, and often require a cold chain, making them hard to store and transport.

WHO recommendations for children are shown in table 1.

ABC: abacavir
AZT: zidovudine
EFV: efavirenz
FTC: emtricitabine
LPV/r: lopinavir/ritonavir
NVP: nevirapine
TDF: tenofovir disoproxil fumarate
3TC: lamivudine
NNRTI: non-nucleoside reverse transcriptase inhibitor
NRTI: nucleos(t)ide reverse transcriptase inhibitor
TB: tuberculosis

Missing Formulations

In contrast to adults—who have two preferred first line regimens and a couple of alternatives—WHO recommendations for children are not very simple and somewhat aspirational. Only one regimen, zidovudine (AZT) plus lamivudine (3TC) plus nevirapine (NVP) is currently available as an FDC. Many gaps remain in available products for children

According to recommendations from the Paediatric Antiretroviral Drug Optimization (PADO) conference—that informed the WHO 2014 supplement—and the Paediatric Antiretroviral Working Group (PAWG) of the WHO, the following formulations must be given priority in the medium term (five years):

• Zidovudine (AZT) or abacavir (ABC) plus 3TC plus lopinavir/ritonavir (LPV/r)
  These formulations are in development and urgently needed to make it possible to give FDCs to children younger than three. Solid forms could overcome palatability issues with the currently available LPV/r liquid formulation that tastes dreadful (although taste making is a lot harder than it sounds). Many barriers with supply chain—transport, storage and distribution—would also be addressed.
• ABC plus 3TC plus efavirenz (EFV)
  Currently this regimen can only be given by using ABC/3TC co-formulated tablets with EFV tablets. A one-pill once-daily regimen for children aged three to 10 years would be useful. There is some discussion as to what dosing ratios for the FDC best facilitate recommendations for the individual agents across weight bands. Optimal doses need to avoid under and overdosing of children at either end of each weight band, as far as possible, and be most suitable from a regulatory standpoint.
• Darunavir/ritonavir (DRV/r)
  This boosted protease inhibitor could offer an alternative to LPV/r second-line. Children who fail on LPV/r-based first-line regimens particularly need a robust option second-line. Dosing recommendations (approved by regulators in the United States and Europe) for DRV/r for children in low- and middle-income countries need to be simplified to reduce the number of different formulations and minimize pill burden. A 240/40 mg DRV/r tablet for twice-daily dosing is a priority for children in weight bands 10 kg and above. There is a waiver for children less than three years old.
• Ritonavir (RTV) granules
  An alternative to the liquid formulation is needed to make double boosting—adding extra RTV to overcome pharmacokinetic interactions with tuberculosis (TB) drugs during cotreatment—easier with LPV/r.

Beyond five years, the participants of the PADO conference recommended that an FDC containing raltegravir (RAL) with 3TC and ABC or AZT should be encouraged. This regimen would provide a second line option, particularly to the children who fail on LPV/r first-line before they are three years old.

Three of the new drugs, currently under investigation or in phase III for adults or children, were recommended to be given priority:

• Dolutegravir
  This integrase inhibitor has recently been approved for adults and children aged 12 years and above. It is currently under study for use in all age groups from birth. DTG has shown good safety, efficacy and tolerability so far, does not require boosting and has a low milligram dose. There is a lot of interest in this drug as an option for adults and children for first- and second-line regimens.
• Tenofovir alafenamide fumarate (TAF)
  A potentially safer alternative to tenofovir disoproxil fumarate (TDF)—which is associated with renal and bone toxicity—is a priority for children. Early data in adults suggests that TAF might have a better safety profile than TDF but this has yet to be confirmed in children. It also has a low milligram dose. It might also be an alternative to ABC, and contribute to harmonizing children’s regimens with adults, particularly if it could be coformulated with DTG and 3TC.
• Cobicistat (COBI)
  COBI might be a useful booster for children. RTV-boosted pediatric versions of atazanavir (ATV) and DRV are unavailable and COBI-boosted pediatric formulations are under investigation.

The Pipeline

This list is not exhaustive—pediatric investigation plans will be in place or under discussion for the agents in early phases of development described in the adult antiretroviral chapter—but includes those where studies have started in children.

For approval by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) antiretrovirals are studied in children in deescalated age bands: 12 to 18 years; six to 12 years; two to six years; six months to two years and less than six months. Data are required in the youngest age groups—down to newborns—unless a regulatory waiver is obtained.

The majority of formulations currently in development are solid rather than liquid ones—a vast improvement on earlier pediatric antiretrovirals.

Nucleotide Reverse Transcriptase Inhibitor

Tenofovir alafenamide fumarate

TAF is not being developed as a single agent for adults or children but it is considered to be of high priority for future optimized generic FDCs.

The originator company, Gilead is investigating a coformulation with FTC, which hopefully will provide data to inform the dose of TAF as a component of future unboosted generic regimens.

Development of a TAF-containing FDC (see below) is priority for the company.

Non-Nucleoside Reverse Transcriptase Inhibitors

Etravirine

A scored 25 mg etravirine (ETR) tablet, and dosing recommendations for treatment-experienced children and adolescents ages six to less than18 years of age and weighing at least 16 kg, are currently approved. [8] The recommended dose is based on 5.2 mg/kg twice daily.

IMPAACT P1090 is evaluating the drug in treatment-naive and -experienced children ages two months to six years. [9] Phase I/II studies in the younger age groups are currently enrolling treatment-experienced children. There is a waiver for infants less than two months.

Rilpivirine

Rilpivirine (RPV) is approved for adults with viral load less than 100,000 copies/mL. PAINT (Pediatric study in Adolescents Investigating a New NNRTI TMC278), is an ongoing, open label, 48-week phase II trial looking at RPV pharmacokinetics, safety and efficacy in treatment naive adolescents aged 12 to 18 years, weighing more than 32 kg. [10]

RPV steady-state pharmacokinetics plus preliminary four-week safety and efficacy data from PAINT (with a 25 mg once daily dose) showed comparable RPV pharmacokinetic parameters between adults and adolescents. [11]

Participants (n=23) of a median age of 15 years were enrolled from sites in India, Thailand, Uganda and South Africa. All were treated with RPV in combination with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), taken with a meal.

There was no apparent relationship between pharmacokinetic parameters and weight, age or between sexes. PAINT is ongoing.

IMPAACT P1111 is planned in children from neonates (two weeks) to less than 12 years. [12]

A granule formulation is in development.

Protease Inhibitors

Atazanavir

FDA recently approved ATV oral powder for use in treatment naive or experienced infants over three months of age who weigh more than 10 kg or less than 25 kg. [13]

The oral powder must be mixed with food or drink for administration and RTV must be given immediately afterwards. It comes in packets containing 50 mg ATV.

Table 3 shows the recommended dosage of ATV oral powder and RTV.

The safety, pharmacokinetic profile, and virologic response of ATV in infants were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451 (PRINCE 2), and AI424-397 (PRINCE 1). [14, 15, 16, 17, 18]

This approval for the youngest age group has taken its time—adult ATV approval was in 2003 and for older children in 2008.

Lopinavir/ritonavir

There is currently an 80/20 mg/mL liquid formulation of LPV/r, but it is unsuitable for most settings. It tastes appalling. There are also scaled down 100/25 mg heat stable tablets available for children, but these are only suitable for those weighing 10 kg or more. The tablets are formulated with the active ingredient embedded in a matrix of insoluble substances, so cannot be split or crushed as they lose bioavailability.

Cipla has developed a more acceptable solid formulation of LPV/r, which has been submitted to the FDA for approval.

This formulation (40/10 mg LPV/r) consists of a finite number of pellets in a capsule, which is opened and sprinkled on soft food. The development of this formulation of LPV/r has involved complex nomenclature: first called sprinkles, then briefly mini-tabs these are now referred to as pellets.

Data from a randomized crossover pharmacokinetic study in HIV-negative adults comparing a single dose of pellets from 10 capsules of LPV/r with a single dose of 5 mL Kaletra oral solution found most pharmacokinetic parameters fell within the conventional bioequivalence range of 80% to125 %. Where they fell outside, the differences were not large. [19] Both formulations were administered with about 150 g porridge and 240 mL water.

Initial data from CHAPAS-2 [20]—which compared twice-daily pellets to tablets in children ages four to 13 years, and pellets with syrup in infants ages three to 12 months in a randomized cross-over pharmacokinetics study—found high variability in the younger cohort with both pellets and syrup, with no significant differences in sub-therapeutic concentrations between formulations. In the older children, LPV/r concentrations were lower in children receiving the pellets than in those who got the tablets.

The caregivers found the pellets were more acceptable for infants but not for older children, mainly due to the taste. Storage, transport, and conspicuousness of treatment were less problematic for pellets compared with syrups, but for older children, several caregivers commented about the number of capsules needing to be used.

At week eight, when they could chose which formulation to continue with, the majority of caregivers chose to continue pellets rather than syrups for the infants, but only a quarter of the older children chose pellets over tablets, and taste was particularly to blame.

When the investigators performed the same comparison in one to four year olds, LPV exposure with pellets was higher than with syrup and historical data for children aged six months to 12 years. [21] There was moderately high variability in with both formulations but neither gave subtherapeutic levels.

Poor taste was reported most frequently as a problem with both formulations, followed by swallowing difficulty. Although the majority of caregivers rated both formulations unpleasant, they reported easier storage and transportation with pellets compared to syrup.

The LPV/r pellets have been submitted to the FDA for approval.

DNDi and Cipla are now developing a more palatable version of LPV/r for infants and young children: combined 4-in-1 granule formulation (finer than the 0.8mm pellets and more sand-like in texture) FDCs with two NRTIs, ABC or AZT, plus 3TC.

In recognition of the urgency of suitable options for the youngest age group DNDi was awarded a substantial grant by UNITAID to expedite the development and delivery of the 4-in-1 formulations. [22] The partnership is now working on further PK and acceptability investigations of improved granules with better taste masking.

The plan is to have the optimized 4-in-1 formulations by 2015.

Integrase Inhibitors

Dolutegravir

The FDA and EMA recently approved DTG for children and adolescents aged 12 and above. Since FDA approval DTG has also been approved in a further nine countries.

It is being evaluated for children in IMPAACT P1093 – an ongoing, phase I/II, open label pharmacokinetic, safety and efficacy study in children and adolescents. [23] Preliminary 24-week data from the 12 to 18 years cohort of the study were included with the adult regulatory submissions and led to the recent approvals.

Twenty-four week data have been shown for children aged six to 12 years and 48-week data for children and adolescents aged 12 to 18 years. [24]

Treatment experienced but integrase inhibitor naive children (n=11) with viral load > 1000 copies/mL were enrolled in an intensive PK evaluation. Participants received DTG tablets (10, 25, 50mg) dosed at 1 mg/kg once daily (based on weight bands) added to a stable, failing regimen, with optimized background therapy added after the pharmacokinetic evaluation, which was performed between days five and 10.

Children were a median age of 10 years and had received prior antiretroviral treatment for a median duration of about nine years and just over half were triple class experienced. The dose of 1 mg/kg once a day achieved adequate DTG exposure. Adolescents, aged 12 to 18, had also previously achieved pharmacokinetic parameters comparable to those in adults with the pediatric weight band dose. [25] Both age groups showed good short-term safety and tolerability.

And in a safety and efficacy evaluation of the older age group, at 48 weeks, 74% of adolescents (n=23), a median of 15 years achieved virologic suppression <400 copies/mL and 61% <50 copies/mL. There were no serious adverse events. [26]

Two reduced-strength 10 mg and 25 mg tablets have been developed for children.

A granule formulation is in development, and results from a phase I pharmacokinetic study in HIV-negative adults has been shown. [27] The granules were given with and without 30 mL of various liquids and compared to the current tablet formulation given with 240 mL of tap water.

Participants received a single dose of DTG as a 50 mg tablet (adult formulation) and as 10 g of granules given: with no liquid; with purified water; mineral water; or infant-formula milk.

DTG exposures of the granule formulation were all moderately higher than those of the tablet formulation, with or without liquids. Exposure was highest when the granule formulation was given with formula milk.

The granule formulation is currently being evaluated in the six to 12 age group of IMPAACT P1093.

A possible treatment strategy trial ODYSSEY (PENTA 20) of DTG in all age groups of children is also under discussion.

Development of a pediatric formulation of the FDC of DTG plus ABC plus 3TC, (572-Trii)—currently under investigation for adults—is also planned. Following the results from the ARROW trial, [28] which found once-daily dosing of ABC and 3TC non-inferior to twice-daily in children, ViiV is submitting data for this indication, which will inform the development of the once-daily pediatric formulation. The development of this formulation will depend on the DTG dosages across the age groups and the dosing ratios of the regimen components.

Further along the adult pipeline, the follow-up integrase inhibitor S/GSK-1265744, under investigation as a long-acting formulation, has provoked interest as a potential treatment of adolescents (as has the long-acting formulation of RPV).

The company is working in partnership with Clinton Health Access Initiative (CHAI) and Mylan on a dispersible tablet FDC of ABC plus 3TC. They will transfer the technology and resources to the generic company for production, registration, and distribution of this at the lowest possible cost for low-income countries. [29] Any lessons learned with the collaboration should be used to ensure that DTG—assuming it fulfills its early promise—is available, including in appropriate FDCs, for children in poor countries without delay.

Raltegravir

In December 2013 the FDA approved a new oral suspension formulation of RAL for use in infants aged four weeks and older, weighing at least 3 kg to less than 20 kg. [30]

Each single-use packet for oral suspension contains 100 mg of RAL, which is suspended in 5 mL of water giving a final concentration of 20 mg/mL.

The updated label now includes detailed information about dosing of both this suspension and the pediatric chewable formulation. Because the formulations are not bioequivalent, chewable tablets and the oral suspension are not interchangeable and have specific guidance.

The oral suspension is expected to be commercially available by the third quarter of 2014.

The adult 400 mg film-coated RAL tablet is approved in the United States for use in children ages six to less than 18 years, weighing above 10 kg, and 100 mg and 25 mg chewable tablets are approved for children above two to less than 12 years at a maximum dose of 300 mg. [31] The 100 mg tablet is scored so it can be divided in half.

The pediatric program is ongoing in IMPAACT P1066. [32]

RAL also has the potential for use as prophylaxis to prevent vertical transmission to infants, and for treatment of HIV-infected infants. IMPAACT P1097 is an ongoing phase IV washout (passive) pharmacokinetic and safety study of infants, born to women who received at least two weeks of RAL (400 mg twice daily) in pregnancy and through labor. [33, 34, 35]

This is the first clinical trial of an investigational antiretroviral to look at neonatal pharmacokinetics. RAL crosses the placenta well. It is metabolized primarily by a liver enzyme (UGT-1A1), which is immature in neonates. UGT pathways increase in activity hugely in the first weeks of life, reaching adult levels within three to six months.

Early results from this study show good placental transfer with cord blood to maternal plasma concentration ratio of approximately 1.5. Transplacental half- life is long—24 to 36 hours—in neonates. Neonatal RAL elimination is highly variable.

IMPAACT P1110 is an open label pharmacokinetic and safety single and multiple dose study of RAL granules in high-risk HIV-exposed neonates. [36] Multiple dosing will be from birth to six weeks and HIV-infected infants will continue after six weeks.

Elvitegravir

Elvitegravir (EVG) is an integrase inhibitor, given with a booster and mostly used for adults in the FDC containing EVG/COBI/FTC/TDF (E/C/F/TDF).

A phase Ib open-label non-randomized trial, conducted in treatment-experienced adolescents 12 to 18 years receiving 150 mg once daily EVG plus a RTV-boosted protease inhibitor-optimized background regimen, showed comparable exposures to that seen in adults. [37]

Two pediatric formulations are in development—a 50 mg tablet and a 5 mg/mL suspension. Single dose pharmacokinetics evaluations compared two formulations to the 150 mg adult formulation (all boosted by RTV) in a crossover study in HIV-negative adults. [38]

All formulations of EVG were given with 100 mg RTV within five minutes of a standard meal.

In this study, both pediatric formulations were bioequivalent to the adult formulation.

These RTV-boosted formulations will be evaluated in children in an ongoing phase II/III study in children aged 4 weeks to less than 18 years of age. [39]

EVG is also being studied in treatment naive adolescents aged 12 to 18 years as a component of the adult FDC, E/C/F/TDF containing EVG 150 mg, COBI150 mg, FTC 200 mg and TDF 300 mg. [40, 41] Early data has shown similar exposures of all the individual agents to adults and good virologic suppression. Study of E/C/F/TDF in adolescents and children continues.

PENTA 17 will evaluate EVG with DRV/r in stable, virologically suppressed children.

An adolescent study of the FDC containing EVG/COBI/FTC/ TAF (E/C/F/TAF) in treatment naive adolescents is also ongoing. [42] Gilead plan to submit regulatory applications that include approval requests for adolescents ages 12 to less than18 years for this FDC.

Pharmacokinetic Booster

Cobicistat

COBI is a CYP3A inhibitor with no antiretroviral activity that is approved for adults as a booster of ATV 300 mg or DRV 800 mg. It is also under investigation for children and adolescents six years and above as a component of the FDCs E/C/F/TDF and E/C/F/TAF.

A 50 mg pediatric immediate release tablet and a 20 mg pediatric dispersible tablet are in development. Both were compared to the 150 mg adult tablet formulation in a crossover study in HIV negative adults. [43] Both formulations were bioequivalent to the adult one.

COBI is being studied in treatment experienced children ages three months to 18 years, who are suppressed and on a RTV boosted ATV- or DRV-containing regimen. [44] The study will switch children from the RTV to COBI booster and look at steady state pharmacokinetics and confirm the dose. It will also evaluate the safety, tolerability, and efficacy of ATV/COBI or DRV/COBI.

There is a lot of interest in the potential role for COBI, not least because the RTV patent has not allowed coformulation with protease inhibitors other than the originator company Abbvie’s LPV.

CCR5 Receptor Antagonist

Maraviroc

The A4001031 maraviroc (MVC) study is ongoing in children aged two to less than18 years old who are infected with the CCR5-tropic virus (virus variants that use the CCR5 receptor for entry). This drug will not work for people with the CXCR4-tropic virus or in dual- or mixed-virus (CCR5/CXCR4) populations. [45]

Preliminary data in 29 children showed body surface area (BSA)–based doses of MVC provided adequate exposures when administered with a protease inhibitor as part of their background regimen. Children who were not receiving a boosting agent in their background regimen required at least doubling of the initial dose. [46]

A BSA–scaled twice-daily tablet dose of MVC in treatment-experienced children six years and above concomitantly receiving boosted protease inhibitors (DRV/r and LPV/r) achieved concentrations similar to those in adults receiving 150 mg MVC twice daily with a boosted protease inhibitor. [47]

Data from 94 participants in the A4001031 study continued to show that dosing is complex and determined by BSA and concomitant medications. [48]

BSA-based dosing with boosters scaled from the 300 mg adult dose provides MVC exposures achieving the target Cavg >100 ng/mL in all cohorts. [49]

Non-boosted regimens are still under evaluation and pharmacokinetic data suggests that doses are likely to be higher than the initial adult BSA scaled dose.

Enrollment in A4001031 will continue out to five years.

What Needs to Be Done?

Despite progress scaling up antiretrovirals, the gap in coverage between adults and children is growing. The latest estimates suggest that only 34% of children less than 15 years old, eligible by WHO 2013 guidelines, were receiving treatment compared with 61% coverage for adults.

Partly due to the lack of suitable formulations, children’s treatment remains much more centralized than adults. Task shifting and integration of services have not been adopted so widely for children compared to adults. We know how important it is to bring care and treatment closer to the people: every extra kilometer means loss to follow up.

The solid forms of LPV/r in the pipeline—the first awaiting approval any time soon—will do away with the need for a cold chain and other aspects of storage, transport, distribution and administration.

Their arrival will be good news: new formulations will not only enable countries to adopt WHO 2013 guidelines but will make task shifting and decentralization more possible.

Other good news is that there have been concerted efforts in the last year or so to define actions needed to increase access to drugs and formulations for children. It is encouraging that the recommendations from the PADO Conference, published in the WHO 2014, supplement as well as the roundtable, organized by DNDi that followed it, [50] differ little from those made in the Pipeline Report in this and previous years.

1. Implement WHO Recommendations
   As simpler formulations identified to implement the guidelines become available, countries must ensure that they are swiftly approved and distributed, with appropriate training for health workers.
2. Support New Models of Research and Development
   More innovative models of research and development, as well as agreements between originator companies and generic ones to produce child-adapted formulations in a timely fashion must be made.UNITAID, DNDi and the MPP recently announced the PHTI to expedite development and delivery of new antiretroviral formulations. [51] The initiative will work on the priority formulations with a focus on research and development, intellectual property, and market shaping. DNDi will coordinate the research and development component of the PHTI, working with pharmaceutical companies, academic institutions, WHO expert groups, and other stakeholders.
3. Ensure that Patents are Not an Obstacle
   The MPP is putting a lot of emphasis on pediatric antiretrovirals and for the PHTI it will build on patent sharing agreements that have already been negotiated.ViiV Healthcare (DTG, ABC), Gilead Sciences (TDF, FTC), and Bristol-Myers Squibb (ATV), have licensed to the MPP. Merck/MSD and Abbvie are in negotiations to license pediatric formulations of RAL and LPV/r.Licenses for the drugs in development need to make it easy to transfer patent agreements from one age group to another as approval is gained.
4. Speed Up Approval
   The gap needs to be narrowed between approval of new drugs for adults, children and neonates.Harmonization of regulatory requirements (including age categories and weight bands) between stringent authorities, WHO prequalification, and national authorities is urgently needed to help speed up approval.
5. Coordinate Procurement
   Guidance on optimal formulations needs to be easily available to countries and updated as better ones become available.Companies need to be informed of the priority formulations.Donors need to ensure the availability of low volume products in a diminishing market.

References

All links last accessed June 4 2014.

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