Drugs for Neglected Diseases Initiative, North America Inc.

Visceral Leishmaniasis
DNDi’s short-term approach for visceral leishmaniasis was to develop new treatments by combining existing drugs and/or shortening treatment duration in order to increase tolerability, reduce burden on health systems, and offer greater affordability, whilst also preventing or delaying emergence of resistance. Another objective is the geographical extension of existing drugs in other countries and regions. In 2010, DNDi and LEAP partners delivered the SSG&PM combination therapy for East Africa, now recommended as first-line treatment for VL in the region. SSG&PM has been included in the national guidelines of Sudan, South Sudan, Ethiopia, and Kenya. PM is registered in Uganda (2011) and Kenya (2013), and is in the process of registration in Sudan and Ethiopia. In India, a Phase III trial demonstrated the efficacy of combination therapies of already registered drugs. In 2014, the government of India recommended use of single-dose AmBisome® as a first option and paromomycin/miltefosine combination as the second option for treatment instead of using miltefosine as monotherapy. DNDi has collaborated with the National Control Programmes of India and Bangladesh, MSF, the Bihar State Health Society, and the Indian Council for Medical Research to assess the effectiveness and safety of these new treatments at the primary healthcare level and facilitate their introduction. In Latin America, DNDi is participating in a study sponsored by the Brazilian Innovation Agency (FINEP) to evaluate the safety and efficacy of Glucantime®, AmBisome®, and amphotericin B as monotherapies, and of AmBisome®/Glucantime® combination to treat VL patients. The national control programme has extended the use of AmBisome® as second-line treatment based on the interim safety data from this trial.

Leishmania and HIV co-infection is a growing problem, difficult to manage clinically due to poor response to treatment with frequent relapses of disease, and is eventually fatal. DNDi is working with partners towards better treatment for HIV/VL co-infected patients in Africa using existing drugs at different dose/regimen and in combination, and is collaborating with ITM-Antwerp in a secondary prophylaxis study.

In the medium term, DNDi is assessing the combination of fexinidazole and miltefosine for the treatment of visceral leishmaniasis patients in terms of efficacy and safety. This could be the first oral-only combination therapy for visceral leishmaniasis.

DNDi’s long-term strategy for visceral leishmaniasis is to bring new oral drug candidates into clinical development through its lead optimization programme with the ultimate goal of improving the safety profile and efficacy of the existing tools with a second oral-only combination treatment.

In addition, DNDi supports the Leishmaniasis East Africa Platform (LEAP). A new visceral leishmaniasis treatment for adults and children based on a new chemical entity would ideally be efficacious against all species of Leishmania in all regions as well as against resistant strains, have at least 95% efficacy, be short course (once a day for 10 days oral; or 3 shots over 10 days), easy to use, compatible for combination therapy, safe in pregnant and breastfeeding women and for immunocompetent/immunosuppressed patients, affordable, and adapted to tropical climates.

By 2020, DNDi aims to deliver from its VL-specific portfolio:
- Potentially a safe, effective, low-cost, and short-course oral combination treatment
- A new treatment for PKDL that is shorter course and better tolerated than current options
- Treatment options for HIV/VL co-infected patients
- A new first-line treatment regimen for visceral leishmaniasis in Latin America

Cutaneous Leishmaniasis
For cutaneous leishmaniasis, DNDi’s objective is to develop short, safe, efficacious, affordable, and field-adapted treatments, at least for lesions caused by L. tropica and L. braziliensis. As a short-term strategy, DNDi is developing a topical treatment based on amphotericin B, and aims to improve treatment strategies using currently available treatment modalities in combination.

In the medium to long term, DNDi aims to develop an oral drug and an immunemodulator for use in combination with chemotherapy. This novel approach aims to initially eliminate parasites with chemotherapy, followed by enhancement of the patient’s immune response with an immune-stimulating agent.

A new topical or oral treatment for cutaneous leishmaniasis would ideally be efficacious against all species, show at least 95% efficacy, be easy to use, short course (14-28 days), compatible for combination therapy, produce minimal scarring, be safe in pregnant and breastfeeding women, affordable and adapted to tropical climates.

By 2020, DNDi aims to deliver from its CL-specific portfolio:
- A safe, effective, and shorter-course treatment for cutaneous leishmaniasis

DNDi’s short-term goal was to make better use of existing treatments, for example through the development of a paediatric dosage form of benznidazole – a goal which was achieved in 2011. The treatment is registered in Brazil (2011), and was included on the WHO Essential Medicines List for children in 2013. An agreement signed in 2013 with the Mundo Sano Foundation will ensure a second source of the treatment previously solely manufactured by LAFEPE. Collaborative activities will continue to support country registration and adoption, and greater treatment availability to patients.

As a medium-term strategy, DNDi has been assessing known families of compounds such as the new azole antifungal drug, E1224, for activity against T. cruzi in adult chronic patients. Results from a proof-of-concept trial showed E1224 monotherapy to have some short-term effect on parasite clearance but with insufficient long-term efficacy, and the current regimen of benznidazole to be efficacious in the long term, but with side effects. Alternative benznidazole regimens, including reduced dosing and duration of treatment in monotherapy and combination treatment with E1224 are being explored. Fexinidazole, also in development for HAT and VL, is also being evaluated. Additionally, DNDi continues to search for potential biomarkers of treatment response to enhance clinical trial capabilities for evaluation of new compounds.

As part of its long-term strategy, DNDi continues to identify and engage partners from private and public sectors in order to identify, characterize, and advance the development of promising compounds as well as to pursue discovery efforts for innovative therapies.

In addition, DNDi supports clinical research capabilities and access through the Chagas Clinical Research Platform, which was launched in 2009.

Ideally, a new treatment would be for both acute and chronic phases of the disease, useful against most parasite species in all regions, with a better safety profile than existing drugs, non-inferior efficacy to benznidazole, easy-to-use (oral, once-a-day for less than 30 days, requiring no hospitalization and little or no monitoring), affordable, and adapted to tropical climates.

By 2020, DNDi aims to deliver from its Chagas-specific portfolio:
- An effective and safe new oral treatment regimen of chronic indeterminate Chagas disease, ideally also effective against the acute form of the disease
- Biomarkers to gain understanding of disease progression and ease the development of tools for evaluation of treatment response to support drug development

DNDi’s strategy is to develop a new compound with macrofilaricide activity for use as a safe and field-adapted macrofilaricidal drug for patient case management and possibly later MDA if needed.

As a medium-term strategy, DNDi is assessing emodepside, a potent antihelminthic drug used in combination with praziquantel to treat parasitic worms in cats and dogs, as a clinical candidate to treat humans.

As a long-term strategy, DNDi is assessing additional opportunities through an active screening programme of drug compounds emanating from animal health/ pharmaceutical companies and academic institutions, with the goal of selecting one or two candidates to move into clinical development.

Ideally a new treatment for adults and children will be a macrofilaricide (efficacious
against the adult form of worms), oral, short-course treatment, well tolerated, affordable, and adapted to tropical climates.

In 2010, DNDi was called on by various organizations, including Médecins Sans Frontières, WHO, and UNITAID, to apply its expertise to the development of paediatric HIV treatments. DNDi’s position, notably that paediatric HIV is a neglected disease, was published as a ‘Perspective’ in the New England Journal of Medicine in August 2011.

DNDi is pursuing two objectives to address the needs of HIV-infected children:
Develop and register two solid first-line 4-in-1 LPV/r-based fixed-dose combinations (FDCs) with two NRTIs. All components of the combination will be developed in the form of tastemasked granules, stable with no need for refrigeration, presented in a single unit with appropriate strengths to accommodate weight band dosing.
Develop and register a heat stable stand-alone ritonavir booster formulation that is well taste-masked and can be added to any PI-based paediatric ARV regimen and can be used to counteract the negative drug-drug interactions between PIs and rifampicin-containing TB treatments.

Before these formulations are made available however, as a short-term strategy, DNDi will start testing the use of PI-based treatment with existing LPV/r-based solid formulations before the availability of the 4-in-1 FDC, in order to provide better treatment for infants today and promote in-country adoption. The heat-stable pellets are already a great improvement, however the bitter taste remains and is a barrier to use in treating this chronic disease. DNDi participated in the CHAPAS-2 trial that compared LPV/r sprinkles (hereafter referred to as pellets) to the LPV/r liquid formulation. These pellets will be used in combination with NRTI dispersible tablets in implementation studies (LIVING Study).

In the longer-term, DNDi is working with its industrial partner, Cipla Ltd., on combining taste-masked LPV/r granules with two NRTIs into a single unit dose. This modular concept is flexible, so that any of the components can eventually be substituted to provide new fixed-dose combinations.

In addition, in order to address the needs of HIV/TB co-infected children, DNDi is developing a formulation of ritonavir for superboosting LPV/r at a 1:1 ratio. As a short-term strategy, DNDi is conducting a study to establish the pharmacokinetics, efficacy and safety of superboosted LPV/r in children in South Africa with the existing ritonavir solution.

The ideal first-line treatment for paediatric HIV would be a protease inhibitor-based all-in-one antiretroviral regimen for HIV-infected children which is a safe and efficacious, is an adapted formulation suitable for infants and children, is an easy-to-use fixed-dose combination, is palatable, addresses drug-drug interaction with medicines for tuberculosis, and is adapted to tropical climates (no refrigeration needed).

By 2019, DNDi aims to deliver from its paediatric HIV portfolio:
- Two new four-in-one paediatric formulations containing a PI (LPV/r) and two NRTIs (ABC or AZT and 3TC)
- One stand-alone paediatric booster RTV for HIV-TB co-infected children

Fosravucoazole (E1224) is a potent orally-available triazole which is under development for Chagas’ disease. Recent evidence suggests that it could be an effective treatment for fungal Mycetoma which would also be affordable. The efficacy of E1224 will be compared to the current treatment (itraconazole) in a randomized controlled clinical trial, examining its effect on moderate mycetoma lesions.

1. Regional R&D:
Short term (2 years) - Prove alternative regimens:
DNDi and partners aim to conduct Phase III clinical trials
proving the efficacy of sofosbuvir (SOF) + daclatasvir
(DCV) as a public health tool in Malaysia and Thailand.
Medium-term (5 years) - Developing a pipeline: License
most promising compounds from patent holders to
combine with other drugs to develop a novel regimen
for HCV to be used as a public health tool.

2. Support affordable access:
Create an actively engaged project Hep C Advisory
Group that can advise the project on the rapidlychanging
HCV treatment access landscape. The
group will be comprised of both Access and
Scientific experts. The project will be both informed
by and inform the project Hep C Advisory Group.
DNDi believes there are many avenues for access
including but not limited to: developing alternative
treatments with favorable licensing / access terms,
patent oppositions, compulsory licensing and
voluntary licensing.

The mission of the Global Antibiotic Research and Development Partnership (GARDP) is to develop new antibiotic treatments addressing antimicrobial resistance and to promote their responsible use for optimal conservation, while ensuring equitable access for all in need. GARDP is being incubated by the Drugs for Neglected Diseases initiative (DNDi) in collaboration with the World Health Organization (WHO) and in support of the Global Action Plan for Antimicrobial Resistance.

A partnership model for product development based on the experience gained from the field of neglected diseases can provide an important element of the overall strategy for R&D in the field of antibiotics. Such a partnership can test new incentives that also contribute to conservation of and access to new antibiotic treatments. By doing so, it can provide an important alternative to the traditional market-driven pharmaceutical approach, by focusing on products that the pharmaceutical industry will likely not develop for lack of profitability.

Launched in May 2016, GARDP is now in its incubation, or start-up phase, hosted by DNDi. This means that until the end of 2017, GARDP will build up its team, establish a legal entity, and set out its long-term strategy and roadmap. In addition, GARDP aims to have at least two projects that address urgent global health needs ready for implementation by the end of 2016, and two more by the end of 2017.