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Successfully Predict Neuropathic Pain Conditions

Posted by MD Biosciences on Jun 29, 2015 11:21:00 AM

The rodent has historically been used as the dominant model for the study of pain mechanisms and new therapeutics. There are good reasons for this such as the practicalities and ease of use with small animals as well as the scientific value of having a large database of prior research for predictive validity. The rodent models will continue to be the workhorse driving research and drug discovery, however there is a large failure rate of drugs moving into clinical stages, which failure of rodent models to predict the biology of the clinical condition certainly plays a role. The most well known example of this is the NK1 antagonist that exhibited efficacy-related translational failure in the clinic.

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Topics: Neuro/CNS

Novel Biomarkers| Detecting early-stage Acute Kidney Injury (AKI)

Posted by MD Biosciences on May 7, 2015 10:47:16 AM

Acute kidney injury is a disease that is characterized by a rapid loss of kidney function, including the rapid fall in glomerular filtration rate (GFR) and the retention of nitrogenous waste over the course of hours and days. AKI is a complex, multifactorial disease with inflammatory, ischemic, necrotic and apoptotic events that occur simultaneously, leading to damage and functional kidney failure. The process of kidney injury occurs in stages starting with increased risk, followed by damage as a result of ischemic injury or toxicity, followed by a decrease in glomerular filtration rate (GFR), which further progresses to kidney failure.

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Topics: Acute Kidney Injury (AKI)

Drug Discovery Success Rates | Role of Preclinical Study Design.

Posted by MD Biosciences on Apr 22, 2015 12:16:55 AM

In 2014, an article was published in Nature analyzing the clinical development success rates for investigational drugs. It's no surprise that the success rates are still somewhat dismal with 1 in 10 drugs that enter clinical phases pushing through to FDA approval. The article breaks down the success rate in each phase for differing classes of drugs as well as various therapeutic indications. NMEs were found to have the lowest success rates in every phase of development (7.5%) whereas biologics had nearly two times the success rate (14.6%).

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Topics: Preclinical Discovery

Translating Preclinical Data to the Clinic

Posted by MD Biosciences on Mar 24, 2015 1:07:37 PM

It's a question that comes up regularly, from scientists who contact us to publications to conference lectures. One of the challenges in preclinical drug discovery is how translatable is the preclinical data from animal studies to the human situation?

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Topics: in vivo pain models, Preclinical Discovery

The Value of Phenotypic Screening

Posted by MD Biosciences on Mar 24, 2015 11:21:23 AM

Preclinical strategies used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. In the earlier days of drug de- velopment, phenotypic screening was largely employed and identified molecules that modify a disease phe- noytpe by acting on a previously unidentified target or simultaneously on more than one target. In the 1980s, advances in molecular biology and genomics led to a shift in developing compounds against defined targets that were implicated in disease. The success rate of clinical stage candidates, however has not improved and phenotypic screens are coming back into light. 

In a recent publication, analysis of different discovery strategies for 259 approved new molecular entities (NMEs) and new biologics between 1999 and 2008 showed that the contribution of phenotypic screening to the drug discovery of first-in-class small molecule drugs exceeded that of target-based approaches in an era when the major focus was on target-based approaches (Swiney, D and Anthony, J. Nature Rev. Drug Disc. (2011) 10:507-519). 

 

Phenotypic Screening gets another look?

While phenotypic screening is getting a second look and making its way back into some biopharma's discovery toolbox, many phenotypic screens are established on the basis of cellular systems or systems that are set to ‘mimic’ the in vivo environment. These systems range from a simple single cell types to more complex cell or tissue systems. What can occur with in vitro phenotypic screens that aim to mimic the in vivo environment is:

  • The screen is most often selectively look at single pathways and therefore miss inter-pathway interactions

  • The screens, while aiming to mimic the in vivo environment, don’t predict the in in vivo effect and unexpected biology, interactions or potential toxicity effects that are often observed in vivo.

  • Can miss pharmaceutical candidates whose pharmocology isn't evident until it is in a complex biological system.

This has led us to develop a more comprehensive, in vivo phenotypic screening platform, Senerga®. The Senerga® Phenotypic Screening platform consists of a series of matrices designed to cover maximum biological pathways to identify pharmaceutically relevant candidates that also show no predictive toxicity effects early on in the discovery process. This enables researchers to move beyond well-defined targets from the literature or their existing programs and discover new disease biology and potential targets.  

The benefit to using this powerful screening program:

  • Enables researchers to see effects on disease phenotypes in a complex biological setting with multiple pathways involved.
  • Obtain predictive toxicology data at the same time.
  • Expands therapeutic potential of libraries as it covers maximum biological pathways with biomarkers to support potential mechanisms
  • Identify hits relatively quickly that can be put through further target validation or efficacy proof of concept studies. 

With the need to move quickly and fill drug discovery pipelines with new candidates, this phenotypic screening platform is designed to efficiently screen compound libraries rapidly (within 3 - 9 months dependent on the size of the library). The resulting data is mined for hits that are identified from modified disease phenotypes and biological pathways. If you'd like to speak with a scientist about utilizing the Senerga® Phenotypic screening platform, please fill out the following details and a scientist will be in contact with you. 

 

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Assessing Subjective Pain | Preclinical Pain Studies

Posted by MD Biosciences on Feb 19, 2015 10:57:04 AM

Rodent models of pain such as nerve injury models are important to understand the mechanisms that may contribute to human neuropathic pain. Imaging studies in human have identified cortical regions specifically involved in the subjective, conscious perception of pain. Although laboratory animals process painful stimuli using similar mechanisms and thresholds of awareness as humans, it is much harder to assess the subjective pain experienced by animals as they can not self-report. This has led researchers to rely on objective measures of pain-related behaviors such as evoked responses to noxious stimuli. Humans, however, are able to voice discomfort, which provides rapid and direct access to the subjective experience. 

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Topics: in vivo pain models

Increase Validity of Preclinical Pain Research

Posted by MD Biosciences on Jan 20, 2015 11:12:09 AM

If you work in drug discovery and development, you are well aware of the failure rate at clinical trials. Industry estimates are that clinical candidates have a 85-90% chance of failure during clinical trials, the most costly stage of evaluation. A report in Nature Biotechnology 32, 40–51  breaks this success/failure rate down between phases as well as the likelihood of approval from the start of clinical trials. For candidates that are suspended during clinical stages, 83% of these reported efficacy or safety as the reason for suspension. 

This is costly and time consuming for drug developers. So is there a way to increase the predictability from preclinical phases to clinical phases?  We have been evaluating this question for a number of years in our Research Group at MD Biosciences. Animal models used in preclinical development phases are pivotal for understanding mechanisms that contribute to human disease conditions and effective therapies. Rodent models are commonly employed due to their reproducibility and simplicity, however the predictability to the clinic is often times lacking.

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Topics: Pain, Neuro/CNS, in vivo pain models

Preclinical Pig Models for Therapeutic Studies

Posted by MD Biosciences on Nov 7, 2013 11:08:00 AM

Historically, rodent models have been used for the discovery of various biological mechanisms within disease states as well as preclinical development of therapeutics. Unfortunately there are many ways that the biology of rodents fails to accurately predict the clinical conditions of humans - this is particularly the case in pain therapeutics. This can be evidenced by the estimates that as many as 80% of all drug candidates across therapeutic areas fail in the most expensive stages of development - clinical trials. While the failures can be attributed to various reasons such as insufficient efficacy, unacceptable safety profiles or PK properties. With the high cost of developing new therapeutics, there is certainly the need to validate biological and pharmacological findings in models using larger species, which can also address some of the known differences between rodents and human. The pig is one species which may provide more translatable data to the human condition, particularly in therapeutic areas such as cardiovascular, skin or wound healing conditions, metabolic and pain.

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Topics: Pain, CRO/outsourcing, Cardiovascular, Dermal, metabolic

Preclinical Models for Diabetic Neuropathy

Posted by MD Biosciences on Sep 5, 2013 9:12:00 AM

Diabetic neuropathies include a range of dysfunctions of the peripheral nerves that can be broadly categorized into generalized symmetric polyneuropathies and focal/multifocal neuropathies. Diabetic neuropathy (DN) is the most common long-term complication suffered by individuals afflicted with either type 1 diabetes (T1D) or type 2 diabetes (T2D). It is the leading cause of non-traumatic amputations and results in significant morbidity, mortality, and economic burden. Of patients suffering from DN, approximately 30% experience pain that is severe, debilitating, largely unresponsive to current pharmacotherapies, and persistent for several years. DN pain is often localized to the feet, described as “burning” or “sharp,” and worsens at night or during periods of fatigue or stress. DN pain can be spontaneous and/or can be in the form of either allodynia (pain caused by a normally benign stimulus) or hyperalgesia (exaggerated pain caused by a normally mildly painful stimulus) or both. [1-3] 

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Topics: metabolic

Cell Types Involved in ischemic Neuroinflammation

Posted by MD Biosciences on Sep 4, 2013 11:10:00 AM

Post-stroke neuroinflammation is a very complex phenomenon involving multiple resident and invading cell types at varying degrees of differentiation or activation each expressing specific subsets of diffusible factors, receptors, cellular adhesion molecules, and other markers, all of which is changing as time passes to create an initially neurotoxic and then finally neuroprotective environment. This inflammatory process in the penumbra offers a broad array of potential cellular and molecular targets with much wider therapeutic windows. At the cellular level, neurons, microglia, astrocytes, and cerebrovascular endothelial cells are the first affected by the ischemic conditions and their responses to massive cell death in neighboring tissue initiates the precisely timed arrival of successive subsets of leukocytes – first neutrophils, followed by monocytes and macrophages, and finally T cells. Targeting these cells via manipulation of their phenotypes or activation states or their movements into lesion sites or their release of harmful mediators represents a major investigative pathway toward potential therapeutics for ischemic stroke sufferers. [1-4]

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Topics: Neuro/CNS