TB: ‘child-friendly, first-line combination drugs will be available in 2016’

He was instrumental in forging key organisational partnerships and building the pipeline of TB drug candidates when he was the Director of Research & Development at TB Alliance. In an email to R. Prasad, he explained the various facets of paediatric TB drug development. Excerpts:

Is there a greater involvement by drug companies in producing paediatric TB formulations after UNITAID provided a grant of $16.7 million and USAID also contributed funds?

The goal of the grant is to develop first-line TB treatments designed for children, in the proper doses and formulations, but also to help catalyse paediatric TB drug development among pharmaceutical companies through a variety of incentives. More accurately defining the market, clarifying the regulatory pathways for new products, and addressing barriers to entry for manufacturers are all within the scope of our work, and will help bring new partners into the field.

We’ve already engaged and entered into collaborations with interested generic manufacturers, including Svizera, which will help improve access to treatments. It’s also important to note that TB Alliance’s work under this grant will aim to reduce the lag time between adult and paediatric formulations of new drugs, accelerating the availability of new TB drugs in paediatric form. For example, we are working with Janssen to speed up the availability of the paediatric formulation of bedaquiline, which was approved for the treatment of MDR-TB in adults last year.

Has any Indian pharmaceutical company shown interest in developing fixed-dose combination drugs for children?

The current paediatric TB fixed-dosed products sold through the WHO’s Global Drug Facility are produced by Indian pharma companies (Lupin and Macleods). TB Alliance has already entered into an agreement with Svizera to produce new first-line treatments in the doses now recommended by WHO and we are in discussion with other Indian pharmaceutical companies.

Because of their experience, Indian manufacturers are among those for whom we see a likely role in producing new TB drug products for children.

How long will it take to come up with fixed-dose combination drugs for first-line TB drugs? How long will a trial take and how many subjects are needed to test bioavailability?

One of the significant challenges to the development of new paediatric TB treatments is the need for additional clarity on what is needed for such a product to receive approval by the various regulatory authorities around the world. These studies can take 6 to 18 months to complete. The quantity and scope of these studies required for regulatory approval can vary by country. We are working to collect that information and disseminate it widely, so that those with the capacity to work in this space have a clear understanding of what needs to be done, how to do it, and what regulators need to see to make approval decisions.

That said, we expect that the first wave of new, simpler, fixed-dose combinations for children will be available in 2016, fulfilling a significant need.

Since we need several dosages to cater to different weight bands, will the cost of drug development increase?

Fixed-dose combinations of current first-line TB treatments are weight-banded for both adults and children. The improved first-line TB treatments for children that will be made available as a result of this grant will be weight-banded as well. Dose-ranging studies are underway for the small group of newborns for whom this information is not already available. Dispersible tablets allow the same tablet to be dissolved in water or other liquid; different amounts are then given for each of the different weight groups, which is a cost-effective means of delivery.

When will the first-line, fixed-dose combination drugs become available?

Our goal is to have optimised formulations of existing first-line treatment for children available to be sold through a global procurement agency by 2016, with a phased market rollout to follow.

Are there attempts to produce child-friendly second-line drugs? Can combination drugs be produced for such drugs?

There are a number of obstacles to developing fixed-dose combinations of the current second-line drugs for children, including the fact that not all the second-line TB drugs are administered the same way. Kanamycin and capreomycin are delivered via injection, for example. While many groups advocate for drug developers to develop child-friendly formulations of the current second-line drugs, in the long run, we need new drugs to treat MDR-TB. Only then can we shorten the long treatment time (up to two years) and avoid the many toxicities that are associated with today’s MDR-TB treatments. Compared with adults, children respond better to second-line treatment. With the development of new regimens for the treatment of drug-resistant TB with hopefully new drugs to which there is no pre-existent resistance, combination products will become readily available for treatment of what is now considered drug-resistant TB.

How long would it take and how many children are needed to undertake bioavailability of fixed-dose combination drug trials?

The number of children to be enrolled and the timeline for either a bioavailability or bioequivalence study are agreed upon between the manufacturer and the regulatory authority reviewing the product for market authorisation/approval.

The child-friendly combination drugs are for <5 five years. But do we know the disease burden in this age group?

For clarification, child-friendly TB products are limited to children under 30 kg which limits the use of the drugs by weight and not by age. Depending on the region of the world, median weights for different age groups can vary. Children five years and under are a critical group, since they are most susceptible to becoming sick and dying from TB; however, all children need improved TB treatment.

Determining the actual number of paediatric patients, including those who are younger than five years, is a challenge, given the overall challenges in diagnosing paediatric TB.

However, as part of this grant and in conjunction with other groups such as WHO, we are working to develop a better estimate of this cohort than has previously been available.

Source: The Hindu