Posts Tagged ‘Drug Discovery’
Posted by CorDynamics on September 09th, 2014
The recent heart failure announcement of the PARADIGM-HF lit up the news sites, and for good reason.
PARADIGM-HF is a clinical trial designed to assess the composite outcome of death or hospitalization in >8000 AHA Class II-IV heart failure patients assigned to receive either enalapril or a novel combined angiotensin receptor antagonist–neprilysin inhibitor. The trial, detailed in The New England Journal of Medicine, was stopped early due to an “overwhelming” benefit from receiving the angiotensin receptor antagonist–neprilysin inhibitor.
Angiotensin receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors have been used in the treatment of heart failure for many years. So what was special about this new method of attacking the disease? The neprilysin inhibitor aspect appears to be critical for the superior efficacy.
Neprilysin inhibition causes an increase in circulating levels of natriuretic peptides. Natriuretic peptides are a family of moieties that cause increased levels of sodium to be excreted by the kidneys. In addition they are vasodilators, inhibit renin-angiotensin-aldosterone axis function and have anti-hypertrophic properties among other effects. One can see why this approach may be beneficial to the failing heart.
Going beyond simply relieving hemodynamic load, increasing our understanding of the complex pathophysiology involving cardiac dysfunction and failure will lead to improved treatments for the > 20 million patients with this condition.
Filed under: Drug Discovery Services, Heart Failure, Hemodynamics |
Posted by CorDynamics on June 20th, 2014
Developing weight-loss drugs to help the estimated 35% of Americans struggling with obesity should be an easy gain for the biotech and pharmaceutical industry. As of late, it seems to be a losing proposition—for a variety of reasons.
FDA Extra Cautious with Safety and Marketing Regulations
Cardiovascular side effects are at the heart of the FDAs concern. The simple fact is that many biological pathways involved in appetite control are also shared with the cardiovascular system.
A generation ago, doctors were prescribing amphetamine-like stimulants, which were appetite suppressants, but also had very unfavorable cardiovascular side effects. In the 1990s the combination of fenfluramine and phentermine (fen-phen) resulted in appetite suppression as well but caused a pathological change in both cardiac valves and pulmonary arterial function.
This tumultuous history has made worldwide regulators particularly sensitive to cardiovascular safety in this therapeutic area. Case in point and as reported in FierceBiotech last week, Orexigen (OREX) had to wait three long years to take a second shot at an approval for its weight drug NB32, earlier called Contrave. Now the company has to wait another three months for an FDA marketing decision as they talk through a regulatory requirement on tracking cardiovascular outcomes among people taking the therapy.
Prescriptions Thin from Physicians
Doctors have not been prescribing weight-loss medications as often as was expected. Previous safety concerns combined with marginal reported benefits from patients has made physicians think twice before suggesting the medications.
According to Bloomberg, the average weight loss was only 4 percent to 8 percent above what patients taking placebos demonstrated. While this is medically important, it may not be enough to offset side effects as headaches or upset stomach. Also some insurers are reluctant to cover co-pays for drugs.
It’s an interesting caveat. As drug developers we focus so much on FDA approvals, we have to remember the approval of doctors and patients is important as well.
Filed under: Drug Safety Services |
Posted by CorDynamics on March 11th, 2014
Here’s a familiar dilemma. Your research team detects unanticipated cardiovascular activity in your lead candidate but there is limited test article for follow-up discovery and safety studies.
In these cases, we often suggest either conscious telemetry or an anesthetized preparation in the guinea pig as an effective model for cardiovascular testing, when appropriate. Since they are smaller in size, guinea pigs can serve as a viable species when compound supply is limited.
In some cases, the guinea pig can use five times less compound to conduct studies than amounts needed for their larger counterparts, such as rabbits.
The Conscious Model
Using telemetry to deliver quasi beat-to-beat data, this guinea pig model generates ultra high fidelity QT interval correction. View Conscious Validation Data
The Anesthetized Model
In this preparation, we employ a well-characterized anesthetized method to screen for cardiovascular effects early. Cardiovascular parameters such as blood pressure, heart rate, as well as ECG are measured and cardiac functional assessments can also be provided. View Anesthetized Validation Data
While a plus in terms of compound conservation, the guinea pig’s small size and inherent anatomical obstacles do pose potential roadblocks. This is especially true in the hands of less experienced technical personnel. Guinea pigs have rather obscure vascular access due to the lack of a tail and their orogastric structure can make orally dosing somewhat challenging.
Although the guinea pig is not appropriate for every situation, with careful planning and expert execution, this species does indeed play a valuable role in the successful de-risking funnels employed by a number of our biopharmaceutical clients.
Filed under: Drug Discovery Services, Drug Safety Services, Telemetry |
Posted by CorDynamics on December 11th, 2013
Over the past 10 years, we’ve worked with clients to investigate potential anti-thrombotic treatments along with those interfering with the coagulation cascade.
Frankly, up until recently the requests for these types of experiments have been relatively infrequent. It was thought we had reached a new age of discovery in coagulation therapy, with the introduction of recent antiplatelet agents.
Recent challenges have arisen with these new modalities; most notably complications from excess bleeding. Some researchers have even suggested these compounds may not replace warfarin as first line therapy.
During 2013 our laboratories have experienced a notable uptick in the requests for thrombosis models.
Recently we released data demonstrating the ‘re-introduction’ of a well-characterized mouse model of arterial thrombosis. In these mice, we produce a carotid arterial thrombus using a process that can be interrupted by efficacious test articles.
Briefly, we dose mice with either vehicle or active test article prior to administration of FeCl3 to the external surface of the carotid artery. Following this exposure to FeCl3, thrombotic occlusion of the carotid artery occurs in a matter of minutes in the untreated animal. Test article efficacy can be quantitated as alterations in coronary artery blood flow along with time to occlusion.
Models like this provide a better understanding of the biological pathways associated with thrombosis. With this knowledge in hand, a number of our clients are taking a renewed look at the compounds in their arsenals in an effort to continue addressing this critical therapeutic area.
Filed under: Drug Discovery Services, Thrombosis |
Posted by CorDynamics on February 28th, 2013
We covered the complexities surrounding heart failure drug development in a blog we published last summer. In it, we pointed out:
Once developers clear the hurdle of finding a compound with promise, the bar is set high for proving their efficacy and superiority over existing drugs to gain regulatory approval.
Most heart failure medicines have to go through a variety of different measures for efficacy. One of which is “quality of life” as measured by the American Heart Association ratings for heart failure.
For example: Can bedridden patients begin to get out of bed and move around more?
Unfortunately for researchers working on spironolactone, recent reports illustrate this case in point.
In patients experiencing heart failure with preserved ejection fraction, spironolactone did in fact demonstrate improved left ventricular diastolic function but did not have any effect on heart failure symptoms, quality of life, depressive symptoms or hospitalizations.
Although the trial did show improvements in diastolic abnormalities of the left ventricle, the lack of clinical improvements means researchers will most likely conduct further studies, perhaps with patients in more advanced stages of heart failure.
We work in the area of heart failure discovery with some clients who are taking a more non-traditional approach to treating this condition. An example of this would be using dual pharmacology involving both increasing heart function while simultaneously reducing the extrinsic burdens.
Filed under: Drug Discovery Services, Heart Failure |
Posted by CorDynamics on February 13th, 2013
Finding Treatments for an Orphan Drug
We have added a powerful capability to our most requested small animal pulmonary arterial hypertension model – measuring pulmonary artery pressure via single or dual channel telemetry.
The hypoxia-semaxanib rat assessment has rapidly become the most requested assay among our Pulmonary Arterial Hypertension offerings. PAH — an orphan disease, with unmet medical treatment—is characterized by increased blood pressure in the arteries of lungs, causing dizziness, shortness of breath and can lead to heart failure.
CorDynamics was the first laboratory to report the protective effects of bosentan and sildenafil in this model.
In an effort to refine the data, we have now added the option to include daily readings of pulmonary artery pressures.
Why is this important in the discovery of new therapeutics for PAH?
While a terminal assessment of pulmonary pressure provides end-stage confirmation of efficacy, interim measurements of the PAH temporal course can be critical when timing the initiation of reversal therapy.
Our daily data demonstrate that the variability associated with the model is small, even over six weeks of hypoxia. Animals progressed through development of PAH in a similar linear fashion. After six weeks in hypoxia, systolic pulmonary pressure increased greater than 400% versus baseline. In addition, right ventricular hypertrophy was robust. The low variability helps in the assessment of test article efficacy – and allows for better distribution of dose levels without having to add inordinate experimental numbers.
As we approach another celebration of World Rare Disease Day on February 28th it’s gratifying to have something new to report in the campaign to develop an orphan drug for PAH.
Filed under: Drug Discovery Services, Pulmonary Arterial Hypertension, Telemetry |
Posted by CorDynamics on January 22nd, 2013
Over the years, we’ve worked with clients to investigate potential treatments for myocardial ischemia/reperfusion injury. The challenge: biological processes associated with infarction and reperfusion injury are complicated and historically it’s been difficult to develop drugs that successfully salvage tissue damaged during a heart attack.
Our laboratory has released data demonstrating the reduction of myocardial infarct size in rats using one of our “gold-standard” small-animal preclinical models. In these rats, we produce cardiac ischemic damage to help clients study therapies that may reduce the amount of injured tissue resulting from a heart attack.
Briefly, we dosed rats with either vehicle or 100 mg/kg nor-NOHA (a selective arginase inhibitor) at 15 minutes prior to ligation of the left coronary artery. Following 30 minutes of myocardial ischemia, reperfusion was initiated and monitored for 2 hours. After 2 hours, infarct size was measured.
Models like this provide a better understanding of the biological pathways associated with reperfusion injury. In this case, the pathway of interest involves nitric oxide. With this knowledge in hand, a number of our clients are taking another look at the compounds in their arsenals in an effort to continue to refine them to address this critical therapeutic area.
Off the Beaten Path…
Our learnings from reperfusion injury are also being applied to other acute and chronic inflammatory conditions. Because reperfusion injury involves the inflammatory response, many types of compounds can be studied in this model to learn more about their effectiveness in a variety of conditions.
Filed under: Drug Discovery Services, Ischemia Reperfusion Models |
Posted by Theresa Gralinski, Marketing Director at CorDynamics on December 19th, 2012
The CorDynamics team is saying goodbye to a great 2012 and looking forward to more research and collaboration with colleagues in 2013. Closing one calendar and turning to a new one, some of the first dates to fill in are our trade show exhibitions.
As we continue to grow the early-stage drug discovery side of our business, we will again be visiting the Experimental Biology meeting in Boston, April 20-24. I look forward to attending this event and meeting with colleagues focused on linking drug discovery to development.
In addition to EB, we’ll also be exhibiting at SOT, SPS and ACT.
- Society of Toxicology 52nd Annual Meeting
San Antonio, Texas March 10-14
- 2013 Safety Pharmacology Society Annual Meeting
Rotterdam, The Netherlands September 16-19
- American College of Toxicology 34th Annual Meeting
San Antonio, Texas November 3-6
If you’re going to be at any of these meetings, please put us on your calendar.
Wishing you a very Healthy and Happy New Year.
Theresa Gralinski, Marketing Director
Filed under: Drug Safety Services |
Posted by Theresa Gralinski, Marketing Director at CorDynamics on November 14th, 2012
I spent most of last week at the American College of Toxicology meeting in Orlando taking the industry’s proverbial temperature.
Over the last four years this meeting’s attendees seemed concerned about feverishly downsizing, feverishly cutting budgets or feverishly outsourcing. People just didn’t feel well. This year attendees seemed to be “feeling” healthy and more optimistic.
I saw five clear signs that industry outsourcing is officially IN.
1. Back to Business—With mass waves of downsizing behind a number of our colleagues, clients and competitors, the focus of discussions turned to current programs and upcoming projects.
2. Changing Roles—Longtime friends were embracing new positions, translating their pharma drug safety and drug discovery experience into success at virtual biotechs or contract research organizations.
3. New CROs and Consultants Join the Ranks—We welcomed new CROs to the “club” and I met with quite a few toxicologists who have decided to work as consultants to share their expertise to meet the anticipated demand.
4. Buzzwords—Collaboration. Customized. Experience. Responsive. Did I say collaboration?
5. Social Media…Really?—Admittedly the industry is still skeptical of the idea in a regulated industry. However with more drug developers looking for external services, vendors and CROs want to be easily found. (Shameless examples: cardiovascular CRO, prolonged QT interval, cardiovascular pharmacology.) Social media is a good way to get the message out.
I polled attendees on their comfort levels with the top social media platforms. Results: LinkedIn=Great; Blogging=Good; Twitter=So-So; Facebook=No Thanks.
Did you get a different temperature reading from the meeting? Or, did you sense a healthier optimism as well? Feel free to comment here or you can find me on Linkedin.
Filed under: Drug Discovery Services, Drug Safety Services, Preclinical Consulting Services |
Posted by Michael Gralinski, Chief Executive Officer at CorDynamics on October 05th, 2012
Safety Pharmacology Society 2012 Meeting Reveals the “New Normal”
I’m on my way back from a trade show exhibit at the Safety Pharmacology Society meeting in Phoenix. Four days in the desert were filled with sessions, events as well as many friends and colleagues stopping by the CorDynamics booth to say hello.
It didn’t hurt that my business partner Peter Senese once again claimed the prime booth space—as greeter to all—right inside the exhibit hall entrance. We opened up with a vendor show where we were airing Monday Night Football live. A consistent group enjoyed the game over a beer or two, and shared insight into the current state of their organizations.
Attendance was down a bit from previous meetings. The continuing consolidations, mergers, and belt-tightening by nature reduced the size of representation from more than a few companies. Nevertheless, the topic seemed to pass as the ‘new normal’ instead of being the focus as years before.
Positive Signs, Rational Approach to Forward Progress
Clients stopped by to discuss their unique drug development projects. Overall, their questions came down to two general categories.
- Timelines—When can our new project be initiated? When can we expect results?
- New Technology—Are CorDynamics’ new technologies generating solid data? How can we incorporate small animal dual pressure telemetry into our studies? Can we screen for cardiovascular liability in guinea pigs?
Leaving the plus 100-degree weather for the tempered fall of Chicago, we’re coming back with good feelings for the remainder of 2012. Happily, new projects continued to flow into the labs during our absence.
We look forward to next years’ SPS meeting in Rotterdam, Netherlands. Word is that Peter already claimed our lead-in booth space. Hope to see you there.
Filed under: Drug Discovery Services, Drug Safety Services, Langendorff Heart, Telemetry |