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Posts Tagged ‘Investigational New Drug’


Humacyte, Inc., a pioneer in regenerative medicine, presented the results of foundational U.S. preclinical studies of its investigational bioengineered blood vessel at the American Society of Nephrology’s ‘Kidney Week 2013’ Annual Meeting in Atlanta, GA.

Reporter: Aviva Lev-Ari, PhD, RN

HUMACYTE

Media Contacts:

Gail Thornton

West Mill Consulting

908-392-3420

Gail@westmillconsulting.com

Jim Modica

West Mill Consulting

908-872-4919

Jim@westmillconsulting.com

Humacyte Highlights Preclinical Data

Of Its Investigational Bioengineered Blood Vessel

 

  • Humacyte investigational bioengineered blood vessel technology represents a research and development milestone in the field of vascular tissue engineering.
  • Preclinical data on the investigational bioengineered blood vessel were presented at the American Society for Nephrology ‘Kidney Week’ meeting.
  • The pre-clinical data suggest that the Humacyte technology may have the potential to be associated with lowered vessel clotting and incorporation with animal model tissues.

RESEARCH TRIANGLE PARK, N.C., November 13, 2013Humacyte, Inc., a pioneer in regenerative medicine, presented the results of foundational U.S. preclinical studies of its investigational bioengineered blood vessel at the American Society of Nephrology’s ‘Kidney Week 2013’ Annual Meeting in Atlanta, GA.

The scientific presentation – by Shannon L. M. Dahl, Ph.D., co-founder and vice president, Technology and Pipeline Development, Humacyte – summarized U.S. preclinical data of the company’s investigational bioengineered vessel technology, which is being developed for use as the first off-the-shelf, human-derived, artificial blood vessel. The presentation’s title was ‘Preclinical Dataset Supports Initiation of Clinical Studies for Bioengineered Vascular Access Grafts.’ Co-authors were: Jeffrey H. Lawson, M.D., Ph.D.; Heather L. Prichard, Ph.D.; Roberto J. Manson, M.D.; William E.Tente, M.S.; Alan P. Kypson, M.D.; Juliana L. Blum, Ph.D.; and Laura E. Niklason, M.D., Ph.D.

Potential Of Investigational Bioengineered Vessels Explored In Pre-Clinical Studies

These U.S. preclinical data suggest that the investigational bioengineered vessel may be associated with lowered vessel clotting and incorporation with animal model tissues. This investigational technology is being developed with the goal of pursuing approval for use in patients with chronic kidney disease, a major global health problem affecting 26 million Americans[i] and around 40 million people in the European Union (EU).[ii] Individuals who progress to end-stage renal disease (ESRD) require renal replacement therapy (hemodialysis or kidney transplant); more than 380,000 patients currently require hemodialysis in the U.S.,[iii] and some 250,000 patients require hemodialysis or have had kidney transplants in the EU.[iv]

In ESRD patients, synthetic vascular grafts are prone to wall thickening, which results in graft clotting. Such clotting is the major cause of graft failures. As a result, ESRD patients experience frequent hospitalization and re-operation. The investigational bioengineered vessels, if successfully developed and approved by regulatory authorities, could offer the potential for significant cost savings to the healthcare system if approved for use in patients who require vascular access for ESRD. These investigational bioengineered vessels represent a research and development milestone in the field of vascular tissue engineering, as this technology could have the potential to help reduce or avoid surgical interventions and hospitalizations for patients with ESRD.

First Off-the-Shelf Investigational Bioengineered Vessel In Clinical Studies

“In the preclinical studies described, our investigational bioengineered vessels were repopulated with cells and remodeled like living tissue in the animal model,” said Dr. Dahl. “These investigational bioengineered vessels are produced using donated human vascular cells and then go through a process that is intended to decellularize the investigational vessels to remove the donor identity from the newly created vessels. This process is designed to produce investigational human grafts with the potential to be implanted into any patient at the time of medical need, enabling our investigational product to become the first truly off-the-shelf engineered graft to have moved into clinical evaluation. Demonstrating safety and performance in patients with end-stage renal disease could set the stage for follow-on development of our technology in other vascular procedures, such as replacement or bypass of diseased vessels, of vessels damaged by trauma, or for other vascular procedures.”

In 2012, Humacyte submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration to conduct a multi-center U.S. clinical trial, involving up to 20 patients across three sites. In this trial, which will assess safety and performance of the investigational bioengineered vessels to provide vascular access for hemodialysis in ESRD patients, the first investigational bioengineered vessel was implanted in the arm of a kidney dialysis patient at Duke University Hospital in June, 2013.

European studies are already underway; as part of a multi-center study in Poland, the first patients were implanted with the investigational vessels in December 2012 and the vessels were first used for hemodialysis in February 2013. The primary endpoints of the study in Poland are safety, tolerability, and patency, to be examined at each visit within the first six months after graft implantation (see clinicaltrials.gov).

Studies Planned in Additional Patient Populations

Humacyte also will carry out a study in Poland to test safety and performance of the investigational bioengineered vessel as an above-knee bypass graft in patients with peripheral arterial disease (PAD). The study began in October of this year.

First-in-human interim study results for the investigational bioengineered vessel technology from Humacyte will be presented on Wednesday, November 20, 2013, at the American Heart Association Scientific Sessions (abstract) in Dallas, TX.

About Investigational Bioengineered Blood Vessels

The Humacyte investigational bioengineered blood vessels are manufactured in a novel bioreactor system. The investigational bioengineered vessels go through a process of decellularization, which is designed to render vessels potentially non-immunogenic and implantable into any patient. These investigational bioengineered vessels are designed to be stored for up to 12 months under standard refrigerated conditions, including, if successfully developed and approved, on-site in hospitals. Subject to receipt of regulatory approval, these properties could make the investigational bioengineered vessels readily available to surgeons and patients, and could eliminate the wait for vessel production or shipping. Data from studies of the investigational bioengineered vessels in large animal models reflect resistance to thickening for up to one year, and the early human studies that are now underway will provide safety and performance  data in patients to support a future application for regulatory approval.

About Humacyte

Humacyte, Inc., a privately held company founded in 2005, is a medical research, discovery and development company with clinical and pre-clinical stage investigational products. Humacyte is primarily focused on developing and commercializing a proprietary novel technology based on human tissue-based products for key applications in regenerative medicine and vascular surgery.  The company uses its innovative and proprietary platform technology to engineer human, extracellular matrix-based tissues that are designed be shaped into tubes, sheets, or particulate conformations, with properties similar to native tissues. These are being developed for potential use in many specific applications, with the goal to significantly improve treatment outcomes for a variety of patients, including those with vascular disease and those requiring hemodialysis. The company’s proprietary technologies are designed to result in off-the-shelf products that, once approved, can be utilized in any patient. The company web site is www.humacyte.com.

Forward-Looking Statement

Information in this news release contains “forward-looking statements” about Humacyte. These statements, including statements regarding management’s projections relating to future results and operations, are based on, among other things, management’s views, assumptions and estimates, developed in good faith, all of which are subject to known and unknown factors that may cause actual results, performance or achievements, or industry results, to differ materially from those expressed or implied by such forward-looking statements.

# # #


[iv]http://www.ekha.eu/usr_img/info/factsheet.pdf

SOURCE

From: Gail Thornton <gail@westmillconsulting.com>
Reply-To: Gail Thornton <gail@westmillconsulting.com>
Date: Wed, 13 Nov 2013 16:47:00 -0800 (PST)
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Subject: American Society of Nephrology Kidney Week – Humacyte Press Release

 

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Reporter: Aviva Lev-Ari, PhD, RN

AstraZeneca PLC (AZN) Signs $200 Million Deal With BIND Therapeutics for Cancer Drug

4/22/2013 7:19:42 AM

CAMBRIDGE, Mass. & WILMINGTON, Del.–(BUSINESS WIRE)– BIND Therapeutics and AstraZeneca announced today that they have entered into a strategic collaboration to develop and commercialize an AccurinTM, a targeted and programmable cancer nanomedicine from BIND’s Medicinal Nanoengineering platform, based on a molecularly targeted kinase inhibitor developed and owned by AstraZeneca.The collaboration is based on emerging data suggesting that nanomedicines like Accurins selectively accumulate in diseased tissues and cells, leading to higher drug concentrations at the site of the tumor and reduced exposure to healthy tissues.

Under the terms of the agreement, the companies will work together to complete Investigational New Drug (IND)-enabling studies of the lead Accurin identified from a previously-completed feasibility program. AstraZeneca will then have the exclusive right to lead development and commercialization and BIND will lead manufacturing during the development phase. BIND could receive upfront and pre-approval milestone payments totaling $69 million, and more than $130 million in regulatory and sales milestones and other payments as well as tiered single to double-digit royalties on future sales.

“We are excited to grow this collaboration with AstraZeneca, a leading global biopharmaceutical company committed to developing innovative medicines for patients,” said Scott Minick, President and CEO of BIND. “One year ago, BIND started several feasibility projects with major pharmaceutical companies. Our collaboration with AstraZeneca is the first one completed and had very successful results. Due to the advanced nature of this program, we now plan to move an Accurin with optimized therapeutic properties quickly into product development.”

“AstraZeneca believes that targeted therapies which specifically address the underlying mechanisms of disease are the future of personalized cancer treatment,” said Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit. “Our oncology teams are actively exploring a range of platforms to deliver targeted therapies, with a strategic focus on unlocking the significant potential of nanoparticles as an approach to cancer treatment. We view BIND’s targeted nanomedicines as a leading technology in this field.”

About Accurins™

BIND Therapeutics is discovering and developing Accurins, proprietary new best-in-class therapeutics with superior target selectivity and the potential to improve patient outcomes in the areas of oncology, inflammatory diseases and cardiovascular disorders. Leveraging its proprietary Medicinal Nanoengineering® platform, BIND develops Accurins that outperform conventional drugs by selectively accumulating in diseased tissues and cells. The result is higher drug concentrations at the site of action with minimal off-target exposure, leading to markedly better efficacy and safety.

About BIND Therapeutics

BIND Therapeutics is a clinical-stage biopharmaceutical company developing a new class of highly selective targeted and programmable therapeutics called Accurins. BIND’s Medicinal Nanoengineering® platform enables the design, engineering and manufacturing of Accurins with unprecedented control over drug properties to maximize trafficking to disease sites, dramatically enhancing efficacy while minimizing toxicities.

BIND is developing a pipeline of novel Accurins that hold extraordinary potential to become best-in-class drugs and improve patient outcomes in the areas of oncology, inflammatory diseases and cardiovascular disorders. BIND’s lead product candidate, BIND-014, is currently entering Phase 2 clinical testing in cancer patients and is designed to selectively target PSMA, a surface protein upregulated in a broad range of solid tumors. BIND also develops Accurins in collaboration with pharmaceutical and biotechnology partners to enable promising pipeline candidates to achieve their full potential and to utilize selective targeting to transform the performance of important existing drug products.

BIND is backed by leading investors Polaris Venture Partners, Flagship Ventures, ARCH Venture PartnersNanoDimension, DHK Investments, EndeavourVision and Rusnano. BIND was founded on proprietary technology from the laboratories of two leaders in the field of nanomedicine, Professors Robert Langer, David H. Koch Institute Professor of the Massachusetts Institute of Technology (MIT) and Omid Farokhzad, Associate Professor of Harvard Medical School.

For more information, please visit the company’s web site at http://www.bindtherapeutics.com.

Contact:

Media:

The Yates Network

Kathryn Morris, 845-635-9828

Kathryn@theyatesnetwork.com

SOURCE:

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Predicting Drug Toxicity for Acute Cardiac Events

Reporter: Larry H Bernstein, MD, FACP

https://pharmaceuticalintelligence.com/?p=10679/Predicting Drug Toxicity for Acute Cardiac Events

Pharmaceuticals Dilemma

The pharmaceutical industry has, as the clinical diagnostics industry, consolidated, and seen new entries that are at some time merged into an established giant, needing resources to grow.  In the past, it was considered essential for a scientific commercial entity to invest at least 8 percent of budget to R&D.   However, the cost of manufacturing has gone down, but a large part of the budget outside of manufacture has to be taken up with, maybe a few exceptions, development, validation in clinical trials, and marketing.  This leaves the situation precarious without a basic research base, and has lead to consortia between academic centers, the federal governmant, and the industries.  I can’t venture into the role of Wall Street Investment and Venture Capital in the process of innovation, proprietary rights to discoveries, and viability.  A large problem they encounter really comes down to complexity of the biomedical reality, that keeps peeling off layers like an onion, exposing new problems to deal with.  As a result, we have seen repeated recalls of drugs that were blockbusters, over the last 2 decades.  To date, every “miracle” drug to manage sepsis and the several cardiac related drugs have  resulted in unexpected toxicities.
One of the leading causes of drug attrition during development is cardiac toxicity, which has a serious impact on cost and can impact getting new drugs to patients. Detecting cardiovascular safety issues earlier in the drug development program

  • would produce significant benefits for pharmaceutical companies and, ultimately, public health, but
    • the reduction of therapeutic toxicities will not be easy and depends on the
    • emergence of genomic-based personalized medicine.

Comprehensive cardiovascular and electrophysiology assessments are routinely conducted in vivo and in vitro early in the preclinical or lead optimization phases of drug development. For example,

  • the isolated perfused guinea pig heart preparation (classically called the Langendorff preparation)
  • can be used to screen a series of related new chemical entities (NCE)

in the lead optimization phase for preliminary information on the relative effects on contractility and rhythm.
Additionally, intact animal non-GLP studies—generally conducted in anesthetized, non-recovery models—are designed to assess

  • effects of NCEs on a range of acute hemodynamic and cardiac parameters such as
    • heart rate,
    • blood pressure,
    • electrocardiogram (ECG),
    • ventricular contractility,
    • vascular resistance,
    • cardiac output, etc.

These studies employ small numbers of animals, but may allow termination of research into NCEs with obvious cardiovascular side effects. These preparations also provide information on the involvement of the

  • autonomic nervous system in the cardiovascular responses of the NCE.

Such effects can be important determinants in the total cardiovascular response to an NCE, and this information cannot be obtained with any known in vitro method.
But what if there are dangers that are not predictable in the short term because of the time span under which the effects can be viewed? The effects themselves are a result of interactions between

  • the drug,
  • endothelial cell receptors,
  • and/or imbalance in oxidative stress promoters and suppressors,
  • and involve signaling pathways.

That is a difficult challenge that may only be realized

  • by rapidly advancing knowledge at the molecular cell level.

The ICH S7A and ICH S7B guidelines provide

  • guidance on important physiological systems and
  • assessment of pharmaceuticals on
    • ventricular repolarization and
    • proarrhythmic risk.

The guidelines were designed to protect patients from potential adverse effects of pharmaceuticals. Since these guidelines were issued in 2000 and 2005, respectively,

  • cardiac safety study designs have been realigned
  • to identify potential concerns prior to administering the first dose to humans.

It is now routine for all NCEs to be evaluated using an

  • in vitro Ikr assay such as the hERG voltage patch clamp assay to assess for
    • the potential for QT interval prolongation.

Systems have evolved to screen large numbers of compounds

  • using automated high-throughput patch clamp systems early in the lead
  • optimization/drug discovery phase.

This is a cost effective method for determining an initial go/no-go gate. Once a compound has progressed to

  • the development phase, it can once again be assessed with the hERG assay
  • utilizing the gold standard manual patch clamp assay.

If the NCE under investigation is a cardiovascular therapy, then

  • pharmacological characterization should occur
  • early in the lead development process.

In addition to the techniques just discussed,

  • a variety of “disease models” are available to help determine
    • whether the NCE will be efficacious in a clinical setting.

However sound the in vitro data used in screening and selection process (e.g., receptor-binding studies),

  • NCEs that have been shown to be active in at least one in vivo model (e.g,. salt-sensitive Dahl rat model)
  • have a higher likelihood of clinical success.

Once a lead is identified, it should still go through the generalized safety characterization discussed earlier.
The in vivo study designs for NCEs reaching the development phase to support the Investigational New Drug (IND) application (just prior to the first human dose) require acquisition of

  1. heart rate,
  2. blood pressure, and
  3. ECG data
    • using an appropriate species
    • at and above clinically relevant doses.

The trend in the industry for these regulatory-driven studies has been to

  • utilize animals surgically instrumented with telemetry devices that
  • can acquire the required parameters.

The advantage of using instrumented animals over anesthetized animals is that

  • data can be acquired from freely moving animals over greater periods of time
  • without anesthetic in the test system,
    • which has the potential to confound and perturb results interpretation.

Appropriate dose selection relative to those used in the clinic provides valuable information about

  • potential acute cardiac events and
  • how they may impact trial participants.

The obvious limitation here is that the method of observation is essentially

  • the same or less than that which is used in clinical practice,
  • relying mainly on classical physiology to detect
    • inherently deep seated processes.

But it is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events,

the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on

  • clinical history,
  • physical examination,
  • effective use of the laboratory, and
  • increasingly helpful imaging technology.

and age, sex, diet, and ability to carry out the activities of daily living before treatment and 6 months to a year after discharge are relevant.

The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. There will be more to say about this.
Animal studies
Telemetry-instrumented animals can be used as screening tools earlier in the drug selection phase. Colonies of animals that can be reused, following a suitable wash-out period,
provide an excellent resource for screening compounds to detect unwanted side effects. The use of these animals

  • coupled with
  • recent advances in software-analysis systems allow for rapid data turnaround,
    • enables scientists to quickly determine if there are any potentially unwanted signals.

If any effects are detected on, for example, blood pressure or QT interval, then the decision to

  • either shelve the drug or
  • conduct additional studies

can be made before advancing any further in the developmental phase.   While this is very good for observing large effects, is it really sufficient for avoidance of late phase failure?

Interestingly, the experience that has been acquired since the approval of the ICH guidelines

  • has allowed pharmaceutical companies to temper their response to finding a potentially unwanted signal.
  • Rather than permanently shelve libraries of compounds that, for example, were
  • found to be positive in the hERG assay—common practice when the 2005 guidelines came into being—
    • companies can now determine a risk potential based on knowledge gained with the intact animal studies.

Similarly, if changes in hemodynamic parameters are detected, there are follow-up experiments employing anesthetized or telemetry models that include additional measurements like

left ventricular pressure.
These experiments can be utilized to further assess their potential clinical impact
by examining effects on
myocardial contractility,
relaxation, and
conduction velocity.
These techniques primarily address acute effects: those following a single exposure.
Chronic effects—those seen with long-term administration of the NCE to an intact organism—are difficult to obtain in early development, but are routinely monitored during safety studies,
are conducted non-clinically during Phase 1 and 2 of the development process.

  • ECGs typically are collected to evaluate the chronic cardiac effects in non-rodent species during these studies. It is recommended that
    • JET (jacketed external telemetry) techniques, which permit the recording of ECG’s—
    • but not blood pressure—

be applied in freely moving animals. If chronic effects are discovered,

  • follow-up experiments can be conducted with any of the techniques mentioned in this article.

As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to establish an approach

  • to determine best practices for conducting key preclinical cardiovascular assessments in drug development.
  •  to provide sensitive preclinical assays that can detect high-probability safety concerns.

Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into

  • clinical outcomes and
  • to encourage collaborations
    • between preclinical and clinical scientists involved in cardiac safety assessment.

This has been conducted under the umbrella of the International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium, which has bought together

  • industrial,
  • academic, and
  • government scientists
    • to discuss and determine what steps are necessary
    • to establish an integrated cardiovascular safety assessment program.

The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.
http://www.dddmag.com/articles/2012/08/predicting-potential-cardiac-events?et_cid=2816494&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2farticles%2f2012%2f08%2fpredicting-potential-cardiac-events.

A recent poster presentation I think makes a good statement of advances that should move us forward:

http://www.biotechniques.com/multimedia/archive/00178/BTN_0311-March_Post_178205a.pdf

Another possibility is genetic testing to determine the likelihood of stroke, for example Corus CAD is

  • a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes.
  •  it creates an algorrhytm-based score that determines the likelihood that a patient has obstructive coronary artery disease.

https://pharmaceuticalintelligence.com/2012/08/14/obstructive-coronary-artery-disease-diagnosed-by-rna-levels-of-23-genes-cardiodx-heart-disease-test-wins-medicare-coverage/
“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.
This discussion will be followed with a discussion of the evaluation of the patient acutely presenting with symptoms and signs that are suggestive of either acute pulmonary or cardiac disease, or both, that may be suggestive of a non ST elevation AMI. It becomes more difficult if ST depression or T-wave inversion is not detected.
Related articles
Obstructive Coronary Artery Disease diagnosed by RNA levels of 23 genes – CardioDx, a Pioneer in the Field of Cardiovascular Genomic Diagnostics
https://pharmaceuticalintelligence.com/2012/08/14/obstructive-coronary-artery-disease-diagnosed-by-rna-levels-of-23-genes-cardiodx-heart-disease-test-wins-medicare-coverage/

English: QT interval corrected by heart rate.

English: QT interval corrected by heart rate. (Photo credit: Wikipedia)

Schematic diagram of normal sinus rhythm for a...

Schematic diagram of normal sinus rhythm for a human heart as seen on ECG (with English labels). (Photo credit: Wikipedia)

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Overview of New Strategy for Treatment of T2DM: SGLT2 Inhibiting Oral Antidiabetic Agents

 

Author and Curator: Aviral Vatsa, PhD, MBBS

Type 2 diabetes mellitus (T2DM) is a chronic disease, which is affecting widespread populations in epidemic proportions across the globe 1. It is characterised by hyperglycemia, which if not controlled adequately, eventually leads to microvascular and metabolic complications (Fig 1). Traditionally, T2DM management includes alteration in lifestyle, oral hypoglycemic agents and/or insulin. The present pharmacological approaches predominantly target glucose metabolism by compensating for reduction in insulin secretion and/or insulin action. However, these approaches are often limited by inadequate glucose control and the the possibility of severe adverse effects such as hypoglycemia, weight gain, nausea, and sometimes lactic acidosis 2–4 (Fig 1). Hence the search for new drugs with different mechanism of action and with little side affects is key in providing better glycemic control in T2DM patients and hence offering better prognosis with reduced morbidity and mortality.

Figure 1 (credit: aviral vatsa): Short overview of Type 2 diabetes mellitus (T2DM): complications, present therapeutic approaches and their limitations.

Along with pancreas, our kidneys play a vital role in regulating glucose levels in the plasma. Under physiological conditions, kidneys absorb 99% of the plasma glucose filtered through the renal glomeruli tubules. Majority i.e. 80-90% of this renal glucose resorbtion is mediated via the sodium glucose co-transporter 2 (SGLT2) 5,6. SGLT2 is a high-capacity low-affinity transporter that is mainly located in the proximal segment S1 of the proximal convoluted tubule 6. Inhibition of SGLT2 activity can thus induce glucosuria which inturn can lower blood glucose levels without targeting insulin resistance and insulin secretion pathways of glucose modulation (Fig 2).

Figure 2 (credit: aviral vatsa): Schematic overview of regulation of plasma glucose by sodium glucose co-transporter (SGLT).

Thus inhibition of SGLT2 provides a novel way to modulate blood glucose levels and consequently limit long term complications of hyperglycemia 7,8. Moreover, SGLT2 inhibitors will selectively target the renal glucose transportation and spare the counter regulatory hormones involved in glucose metabolism because SGLT2 is almost exclusively located in the kidneys. This novel way of glucose modulation will likely avoid severe side affects, e.g. hypoglycemia and weight gain, that are seen with present antidiabetic pharmacological agents.

Agents currently under development

Table below gives an overview of the SGLT2 inhibotors in development.

(Credit: Chao et al 2010)

 

In summary, increasing urinary glucose excretion represents a new approach to addressing the challenge of hyperglycaemia. SGLT2 inhibitors may have indications both in the prevention and treatment of T2DM, and perhaps T1DM, with a possible application in obesity. Further studies in large numbers of human subjects are necessary to delineate efficacy, safety and how to most effectively use these agents in the treatment of diabetes.

Bibliography

  1. Diabetes Atlas. International Diabetes Federation, (2009) at <www.diabetesatlas.org>
  2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).
  3. Buse, J. B. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628–2635 (2004).
  4. Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287, 360–372 (2002).
  5. Brown, G. K. Glucose transporters: Structure, function and consequences of deficiency. Journal of Inherited Metabolic Disease 23, 237–246 (2000).
  6. Wright, E. M. Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 280, F10–F18 (2001).
  7. Chao, E. C. & Henry, R. R. SGLT2 inhibition — a novel strategy for diabetes treatment. Nature Reviews Drug Discovery 9, 551–559 (2010).
  8. Ferrannini, E. & Solini, A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nature Reviews Endocrinology 8, 495–502 (2012).

 

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Reported & Curated by: Dr. Venkat S. Karra, Ph.D.

Predicting Potential Cardiac Events

One of the leading causes of drug attrition during development is cardiac toxicity, which has a serious impact on cost and can impact getting new drugs to patients. Detecting cardiovascular safety issues earlier in the drug development program would produce significant benefits for pharmaceutical companies and, ultimately, public health.

Comprehensive cardiovascular and electrophysiology assessments are routinely conducted in vivo and in vitro early in the preclinical or lead optimization phases of drug development. For example, the isolated perfused guinea pig heart preparation (classically called the Langendorff preparation) can be used to screen a series of related new chemical entities (NCE) in the lead optimization phase for preliminary information on the relative effects on contractility and rhythm. Additionally, intact animal non-GLP studies—generally conducted in anesthetized, non-recovery models—are designed to assess effects of NCEs on a range of acute hemodynamic and cardiac parameters such as heart rate, blood pressure, electrocardiogram (ECG), ventricular contractility, vascular resistance, cardiac output, etc. These studies employ small numbers of animals, but by allowing scientists to terminate research into NCEs with obvious cardiovascular side effects, they can eliminate the need for larger animal studies later in the development process. These preparations also provide information on the involvement of the autonomic nervous system in the cardiovascular responses of the NCE. Such effects can be important determinants in the total cardiovascular response to an NCE, and this information cannot be obtained with any known in vitro method.

The ICH S7A and ICH S7B guidelines provide guidance on important physiological systems and assessment of pharmaceuticals on ventricular repolarization and proarrhythmic risk. The guidelines were designed to protect patients from potential adverse effects of pharmaceuticals. Since these guidelines were issued in 2000 and 2005, respectively, cardiac safety study designs have been realigned to identify potential concerns prior to administering the first dose to humans. It is now routine for all NCEs to be evaluated using an in vitro Ikr assay such as the hERG voltage patch clamp assay to assess for the potential for QT interval prolongation. Systems have evolved to screen large numbers of compounds using automated high-throughput patch clamp systems early in the lead optimization/drug discovery phase. This is a cost effective method for determining an initial go/no-go gate. Once a compound has progressed to the development phase, it can once again be assessed with the hERG assay utilizing the gold standard manual patch clamp assay.

If the NCE under investigation is a cardiovascular therapy, then pharmacological characterization should also occur early in the lead development process. In addition to some of the techniques already discussed, a variety of disease models are available to help determine if the NCE will be efficacious in a clinical setting. However sound the in vitro data used in screening and selection process (e.g., receptor-binding studies), NCEs that have been shown to be active in at least one in vivo model (e.g,. salt-sensitive Dahl rat model) have a higher likelihood of clinical success. Once a lead is identified, it should still go through the generalized safety characterization discussed earlier.

The in vivo study designs for NCEs reaching the development phase to support the Investigational New Drug (IND) application (just prior to the first human dose) require acquisition of heart rate, blood pressure, and ECG data using an appropriate species at and above clinically relevant doses.

The trend in the industry for these regulatory-driven studies has been to utilize animals surgically instrumented with telemetry devices that can acquire the required parameters. The advantage of using instrumented animals over anesthetized animals is that data can be acquired from freely moving animals over greater periods of time without anesthetic in the test system, which has the potential to confound and perturb results interpretation. Appropriate dose selection relative to those used in the clinic provides valuable information about potential acute cardiac events and how they may impact trial participants.

Animal studies
Telemetry-instrumented animals can be used as screening tools earlier in the drug selection phase. Colonies of animals that can be reused, following a suitable wash-out period, provide an excellent resource for screening compounds to detect unwanted side effects. The use of these animals coupled with recent advances in software-analysis systems allow for rapid data turnaround, which enables scientists to quickly determine if there are any potentially unwanted signals. If any effects are detected on, for example, blood pressure or QT interval, then the decision to either shelve the drug or conduct additional studies can be made before advancing any further in the developmental phase.

Interestingly, the experience that has been acquired since the approval of the ICH guidelines has allowed pharmaceutical companies to temper their response to finding a potentially unwanted signal. Rather than permanently shelve libraries of compounds that, for example, were found to be positive in the hERG assay—common practice when the 2005 guidelines came into being—companies can now determine a risk potential based on knowledge gained with the intact animal studies.

Similarly, if changes in hemodynamic parameters are detected, there are follow-up experiments employing anesthetized or telemetry models that include additional measurements like left ventricular pressure. These experiments can be utilized to further assess their potential clinical impact by examining effects on myocardial contractility, relaxation, and conduction velocity.

These techniques primarily address acute effects: those following a single exposure. Chronic effects—those seen with long-term administration of the NCE to an intact organism—are difficult to obtain in early development, but are routinely monitored during safety studies, which are conducted non-clinically during Phase 1 and 2 of the development process. ECGs typically are collected to evaluate the chronic cardiac effects in non-rodent species during these studies. While traditional ECGs can be taken, it is recommended that JET (jacketed external telemetry) techniques, which permit the recording of ECG’s—but not blood pressure—in freely moving animals, be applied. If chronic effects are discovered, follow-up experiments can be conducted with any of the techniques mentioned in this article.

As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to establish an approach to determine best practices for conducting key preclinical cardiovascular assessments in drug development. From this, the hope is to provide sensitive preclinical assays that can detect high-probability safety concerns. Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into clinical outcomes and to encourage collaborations between preclinical and clinical scientists involved in cardiac safety assessment.

This has been conducted under the umbrella of the International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium, which has bought together industrial, academic, and government scientists to discuss and determine what steps are necessary to establish an integrated cardiovascular safety assessment program. The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.

http://www.dddmag.com/articles/2012/08/predicting-potential-cardiac-events?et_cid=2816494&et_rid=45527476&linkid=http%3a%2f%2fwww.dddmag.com%2farticles%2f2012%2f08%2fpredicting-potential-cardiac-events.

Another possibility is genetic testing to determine the likelihood of stroke, for example Corus CAD is a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes. Using an algorithm, it then creates a score that determines the likelihood that a patient has obstructive coronary artery disease.

“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.

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