Zika virus: A neglected disease with no specifically designed drugs


I was shocked to see in recent weeks how a potential connection between a virus infection and  pregnant women have led to a global concern for the association with a high number of babies being born with microencephaly, initially in Brazil but with other cases shown worldwide, and it has even been associated to the rare Guillain-Barré Syndrome (1). Children with these syndromes are likely to have shorter life expectancies. A recent opinion article (2) with extensive research on this particular virus is analised in this blog.

After the epidemic outbreak of the Ebola virus in 2014-2015 which killed thousands of people in Africa and risked to generate a pandemic crisis, mobilising the World Health Organisation (WHO) and Governments, we have been exposed to another case of unprepared health concern with serious global implications.

Zika virus (ZIKV) is a virus from the Flaviviridae family with genetically similarities with the ones responsible for the Dengue Fever and the Yellow Fever. ZIKV was isolated and reported over 60 years ago and since then the small number of publications, the lack of a crystal structure, the abscence of reports of molecules having been screened either in vitro or in vivo in animal models, and the lack of patents covering drugs targeting ZIK virus (although there are some focused in compounds addressing the Dengue Fever), has left it as an undoubtedly case of a “Neglected Disease”.

So, despite of having some knowledge of the virus, little if not nothing seems to have been done in order to understand its risks, exposing under this circumstances, right now, its danger after the outbreak. The WHO has had to move faster than 2 years ago with the Ebola epidemic, and has  issued a Public Health Emergency of International Concern (PHEIC).

Ekins and co-workers(2), after extensive research on related viruses and taking into consideration antivirals and non-related drugs, suggest to create a fast-track plan of action in order to tackle the problem with more urgency, leadership and preparation. This could be applicable to other future outbreaks and put us in a better situation to fight future epidemics.

With the information we have on other closely related virus like the Dengue, the immediately plan of action against this outbreak should have to start with the use of already FDA-approved antivirals profiled against related viruses (with a safety and efficacy profile proved) as a starting point in fighting the ZIKV, and test other drugs, non antivirals and compounds from commercial sources (eg. Libraries) in a descendent order of priority as shown in Fig 1.

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Figure 1. Compounds and chemical libraries suggested to be tested against Zika virus

Without much further do, the authors propose the following Drug Discovery plan:

  1. To develop a cell or ZIKV-target based in vitro assay, which might have to be done in special protective environments, limiting the number of companies or organisations capable of such as assays.
  2. The immediate test of all kind of available drugs (up to 48 FDA approved known antivirals) into the previously generated and validated assay, capable to produce some results against the absence of any other treatment, as reflected in Table 1.
  3. To study and understand the genome of the ZIKV and how a chemotherapy approach could lead to effectively target the virus.
  4. To develop and use “homology models” showing the suggested protein sequence based in similar/ related viruses with known molecule action-modes using target prediction software, such as SWISS-MODEL.
  5. To establish a pharmacological profile with a suitable/ ethical animal model

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Table 1. List of potential compounds to tes.t

Equally important and without leaving it off the schedule, the scientific community should undertake efforts to reveal the virus structure, its function and physiology and establish the relationship between the infection and the human neurological abnormalities.

Despite of getting even better co-ordinating resources through management organisations like WHO, more should be addressed in an emergency outbreak from National Governments and Health Institutions through funding (eg. from the FDA repurposing approved drugs, from big pharmaceutical companies through the donation of chemicals to be tested, from biotechs investing in the development of ZIKV-based in vitro assays, from ground-field-experienced organisations like Medecins Sans Frontieres, etc…)

We need to retain alert against highly likely-to happen diseases lurking upon us at any time and learn from past actions to make us better prepared to fight them.

Blog written by: Jose Gascon

References

  1. Oehler E, Watrin L, Larre P, Leparc-Foffart I, Lastere S, Valour F, Baudouin L, Mallet HP, Musso D, Ghawche; Zika virus infection complicated by GuillainBarre syndrome–case report, French Polynesia, December 2013. Euro Surveill. 2014; 19(9): 20720
  2. Ekins S, Mietchen D, Coffee M, Stratton TP, Freundlich JS, Freitas-Junior L, Muratov E, Siqueira-neto J, Williams AJ, Andrade C; Open drug discovery for the Zika virus. F1000Research 2016, 5:150

 

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Multidrug Co-Crystals Leading to Improved and Effective Therapeutics in Drug Development


In the last ten years, research has been focused on alternative therapeutic strategies for drug development and one of them is co-crystals. A review of the development, production and future of co-crystals has recenlty been published by Thipparaboina R. and co-workers .

The definition of co-crystals given by the FDA is “solids that are crystalline materials composed of two or more molecules in the same crystal lattice”, usually the interactions between molecules are weak, having non-colavent interactions. The discovery of the first co-crystal structure was quinhydrone complex synthesise by Friedrich Wohler in 1844, he found that this co-crystal was composed of a 1:1 ratio of quinone and hydroquinone. In drug development a co-crystal or multidrug co-crystal (MDC) is an active pharmaceutical ingredient (API) with a neutral compound in the same crystal lattice with non-ionic interactions between the two.

The interest in co-crystals for the pharmaceutical industry has increased in the last ten years, thanks to the development of multidrug co-crystals, for example the recent success of the phase II clinical trial of Celecoxib and Tramadol drugs by ESTEVE and Muldipharma Laboratories GmbH for the treatment of acute pain. There is a large list of existing multidrug co-crystals, their interactions improve solubility and bioavailability in therapeutic treatments. Some examples are, Ethenzamide and Gentisic acid which increase the solubility and dissolution rate (Srinivasulu et al., 2009); Meloxicam and Aspirin that significantly increase bioavailability (Cheney et al., 2011).  Co-crystals give the opportunity to treat a specific group of patients with one drug. The multidrug co-crystal Sildenafil and Aspirin presented dual therapeutic effects, treating erectile dysfunctions in cardiovascular complication patients (Zegarac et al., 2014). The following table lists the multidrug co-crystals developed so far.

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The production of multidrug co-crystals is similar to normal crystallography procedures, however, the success depends on several factors and a deep understanding of both components to co-crystalize. Important factors to consider in the production of MDC are temperature, presence of impurities, rates of evaporation, differential solubility, solvent properties, supersaturation, cooling, etc. Scaling up the production of MDC is feasible and successful, several techniques such as spherical co-crystallization, spray-drying technologies, solvent crystallization, sonic crystallization and others have been used for the production of co-crystals (Fig1).

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In 2013 the Food and Drug Administration (FDA) released a regulatory guideline for the classification of pharmaceutical co-crystals and soon after, in 2014, the European Medicines Agency (EMA) released a paper on the use of co-crystals in pharmaceutical research, however there are no many regulatory guides for the pharmaceutical market. At the moment there are few marketed co-crystal products, such as Entresto (Sacubitril-Valsartan), approved by the FDA in 2015, for the treatment of heart failure, and Lexapro (Escitalopram Oxalate), approved in 2009, for the treatment of major depressive and anxiety disorders. For the pharmaceutical industry it could be quite challenging to patent MDC and their method of production. In addition, every patent office requires different criteria for co-crystals registration. Every year the number of patents granted to multidrug co-crystals by the European Patent Office (EPO) and the United States Patent Office (USPTO) has increased. The patents available currently in MDC are listed in table 2.

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It is a challenge for pharmaceutical research and industry to find appropriate drug co-crystals combinations for the therapeutic and pharmaceutical market. However, several factors need to be considered for the production of MDC, such as incompatibility between compounds, impurities, differential solubility and dose variability. The latter is an important factor to be considered for optimal success of MDC. For example, the common stoichiometry of co-crystals is a 1:1 ratio, however some dose range between drugs are variable and the slight increase of dose of one can modify or cause undesirable side effects to the patient. The development of validated predicted models for MDC is required to avoid pitfalls.

On the other hand, novel treatments for psychiatric disorders and neuropathic pain can be approached with the used of lithium and magnesium salts to form multidrug co-crystals. Also nanotechnology can be used for the production of nano-crystals for drug delivery or clinical applications.

The pharmaceutical industry needs be aware of the different considerations in terms of multidrug co-crystals such as, predicted models, FDA regulations, patents, safety and bioavailability. Although challenging multidrug co-crystals could be a novel approach for developing an effective therapeutic, however the commercial success hasn’t emerged rapidly. There needs to be further investment in research for the development of multidrug co-crystals.

Blog written by Thalia Carreno Velazquez

 

 

References

Cheney, M.L. et al. (2011) Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J. Pharm. Sci. 100, 2172–2181

Srinivasulu, A. et al. (2009) Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. CrystEngComm 11, 1823–1827.

Thipparaboina, R. et al. (2016) Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today 21, 481-490.

Zegarac, M. et al. (2014) A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate. CrystEngComm 16, 32–35

What’s new in the market: the 2015 FDA drugs approval


Another year has gone and forty-five new drugs have been approved by FDA. A nice analysis has been published by Asher Mullard in Nat Rev Drug Disc 2016, 15, 73-76, providing the statistic related to these new drugs (for the complete list see Table 1 in the paper).

2015 was a very prolific year with double approval rate with respect to the period 2005-2009 and with rejections at an all-time low, with only two drugs not been approved.

Twenty-five drugs were filed with a priority review (FDA will take action within six months from the filing compared to ten months for the standard filing), ten with a breakthrough status (status given to speed up the development and approval of drugs with significant advances over approved therapy), six with an accelerated approval (status given to drugs used to treat unmet medical need disease).

Figure 1 reports the percentage of approvals for each therapeutic area. Oncology played a big role with 1/3 of the approved drugs indicated for this therapeutic area.

Figure 1

Figure 1. Pie chart indicating the newly approved drugs divided by therapeutic area.

Of particular interest is Palbociclib, a first-in-class CDK4/CDK6 inhibitor developed by Pfizer for the treatment of hormone-receptor-positive advanced breast cancer, which has received accelerated and breakthrough designation status; forecast sales are predicted to be in the region of $5 billion per year by 2020; other predicted blockbusters are indicated in Figure 2, including two monoclonal antibodies: Alirocumab and Evolocumab, first-in-class inhibitors of PCSK9, a protein involved in the regulation of blood cholesterol level. Forecast sales for these two drugs are expected to be over $2 billion per year. In total over a third of the approved drugs are expected to be blockbusters.

Figure 2

Figure 2. Forecast blockbusters.

Twenty-one of the approved drugs have an indication for orphan diseases, of which about 50% are anticancer drugs, indicating the success in developing new and more selective anticancer agents, including four drugs to treat multiple myeloma.

Looking at 2016 potential new approval, forty New Molecular Entity and Biologics Licence Application were filed in 2015. A selection of these potential new drugs is reported in Figure 3.

Figure 3

Figure 3. New drugs seeking approval in 2016

This includes Eteplirsen, a first exon-skipping oligonucleotide for the treatment of Duchenne muscular dystrophy and Venetoclax, a first-in-class BCL-2 inhibitor for the treatment of chronic lymphocytic leukaemia.

We will find out their destiny during this year; keep a eye on our blog!

Blog written by Marco Derudas

 

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Bexarotene in Alzheimer’s Disease: A case of lack of replication, lack of replication, lack of replication


In a previous blog (see here) we briefly discussed drug repositioning as an alternative approach to identifying novel therapies for Alzheimer’s disease. This strategy follows in the wake of the recent failures last year of the large Phase 3 trials with Bapineuzumab and Solineuzumab. At the forefront of drug repositioning has been Baxter International’s Gammagard which is one of a number of IVIG (intravenous immunoglobulin; obtained from the pooled plasma of healthy volunteers) treatments approved for boosting the immune system. Based on an initial small, 18-month, 24-patient study in which Alzheimer’s patients appeared to respond to the therapy (see here), Phase 3 studies were initiated. However, hopes were never especially high given that the proposed mechanism – infused antibodies would help clear amyloid peptide and/or tau protein – was vague at best and was not based upon preclinical mechanistic studies. Unfortunately these doubts proved warranted when in early May, a press release from Baxter (see here) disclosed that Gammagard had failed it’s primary endpoints and as a result it became yet another casualty in the Alzheimer drug development mine field.

In contrast to Gammagard, for which there is a marked absence of preclinical data to support its use in Alzheimer’s disease, a paper from Cramer and colleagues made quite a splash when it was published in Science in early 2012 (see here). They described how the Eisai skin cancer drug Bexarotene (marketed as Targretin) enhanced the clearance of amyloid and improved cognitive performance in preclinical animal models. Bexarotene was approved by the FDA in December of 1999 for the treatment of refractory cutaneous T-cell lymphoma and in the aftermath of the Science publication, doctors were inundated with requests for “off-label” prescriptions of Bexarotene for the treatment of Alzheimer’s patients (see here, for example). Although perfectly legal, the off-label prescribing of Bexarotene raises separate issues of patient safety and ethics (as discussed in the New England Journal of Medicine), especially since the clamour for Bexarotene was based on preliminary evidence from a single study. Indeed, recent studies have failed to replicate important aspects of the initial report (see here, here, here and here, with the authors response here). Most notably, although some inconsistent effects on amyloid peptide concentrations and cognitive improvements were observed, there was a failure to replicate the reduction in amyloid plaques reported in the initial study. These studies highlight the difficulty in reproducing preclinical data, a topic illustrated very well by the Bayer group (see here). Obviously, the publication of a single article, albeit in an august journal such as Science, should be treated with caution until it is replicated. Nevertheless, clinical studies have commenced and the effects of Bexarotene are being studied in the clinic in a Phase Ib biomarker study in healthy young adults as well as in Alzheimer’s disease patients in a Phase 2 [18F]AV-45 amyloid imaging trial. It is a sobering reflection on the large unmet need in Alzheimer’s disease that despite all the caveats and with the limitations highlighted even within the popular press (e.g. “A huge caveat here is that many promising drugs seem to work in mice but fail when used in humans”, Forbes magazine, 10th of February, 2012), a single publication can create a demand for the off-label use of a drug that is has significant side-effects but for which there is, as yet, no evidence of clinical efficacy in Alzheimer’s disease.