The CorDynamics team has a vast level of expertise in this area. Our laboratories feature dedicated telemetry suites where we conduct studies in six small- and large-animal species. Over the last few years we have expanded the integration of our unique telemetry expertise into drug discovery studies. For cardiovascular efficacy interrogations in particular, telemetry studies provide a wealth of data and insight.

Taking atrial fibrillation as an example, we have used telemetry to facilitate the development of a chronic disease model. More specifically, we combine the measurement of atrial electrophysiological parameters with more traditional telemetry variables to optimize the interrogation of new chemical entities in the model.

Leveraging telemetry studies during the discovery phase also allows for the consecutive testing of multiple compounds to help clients determine the best molecules to move forward. The broad scope of data generated by these studies is indeed impressive, yet resource sparing.

Please feel free to contact me directly to discuss how radiotelemetry can facilitate efficacy assessments in addition to interrogating the safety profile of lead candidates.

Regards,
Dr. Michael Gralinski, CorDynamics CEO

At CorDynamics, we address pulmonary hypertension as a complex disorder involving consideration of several physiological systems for its study, diagnosis and treatment. Though no single animal model of PH fully mimics its clinical course, together, the variety of models available has certainly increased our understanding of the disease.

Changes in the cellular structure and function of the pulmonary vasculature occur during the development of PH. Chronic PH creates pressure on the right side of the heart, leading to right ventricular hypertrophy and ultimately, heart failure. Clinically, PH is defined by a mean pulmonary artery pressure of 25 mmHg at rest or 30 mmHg during exercise. There are several classifications of PH based on its origin, however most PH cases can be categorized as either idiopathic, or secondary to an existing pathologic condition such as chronic obstructive pulmonary disease, left-sided heart failure, blood clots, and other various diseases. Currently, there is no cure for PH, and it is often associated with a poor prognosis.

Treatments to alleviate the symptoms of PH remain less than ideal, often requiring constant infusion, or resulting in side effects such as systemic hypotension or liver toxicity. Due to the variety of etiologies leading to PH and the difficulties of exclusively targeting the pulmonary vasculature, PH research remains a challenging endeavor. Several animal models involving both chemical and surgical methods have been developed to study the pathology of PH and investigate potential therapies. In this article we will focus on two of the most common techniques to induce pulmonary hypertension – injection with monocrotaline and exposure to hypoxia.

Monocrotaline-induced PH Models

Monocrotaline is a toxic alkaloid that is activated by the liver and selectively affects the pulmonary vasculature without producing systemic hypertension. Though monocrotaline-induced PH has been most commonly studied in rats, this technique has also been used in dogs and non-human primates. In rats, a single subcutaneous injection of monocrotaline results in the development of PH, with an approximate doubling of pulmonary artery pressure generally occurring within three to four weeks. Accompanying right ventricular hypertrophy and pulmonary edema are apparent by six weeks.

Histologic analysis of lungs from monocrotaline-treated animals exhibit an increase in pulmonary vessel wall medial thickness that correlates with an increase in pulmonary arterial pressure. Using this model, responses to compounds can be evaluated in vivo, as well as on isolated pulmonary arteries.

Hypoxia-induced PH Models

Unlike the systemic arteries, pulmonary arteries constrict in response to hypoxia in order to shunt blood to more ventilated areas of the lungs. This physiologic phenomenon has been exploited in models of PH using exposure to chronic and acute hypoxia. In these models, animals are subjected to either low oxygen conditions (i.e. 10% O2) or reduced atmospheric pressure. Chronic hypoxia leads to remodeling of pulmonary vasculature. Manifestations of PH can revert to pre-hypoxia levels once animals are exposed to normal room air. Studies utilizing hypoxia-induced pulmonary hypertension have been performed in a variety of species ranging from mice to non-human primates, with some species more sensitive to the pulmonary effects of hypoxia (i.e. rats, guinea pigs) than others.

As PH continues to afflict millions around the world, these models will remain valuable instruments in the search for improved PH treatments.

Regards,

Dr. Elaine Tanhehco, CorDynamics Chief Scientific Officer

Overall, we’ve seen a promising uptick in the number and scope of typical IND-enabling CV safety studies along with their associated screening endeavors and mechanistic follow-ups. The supply of capital is loosening up for a number of biotechs, and larger Pharma companies continue to hone their pipelines via acquisition and the revisiting of projects previously placed on hold.

The demand for our discovery services has swelled noticeably since the start of 4Q’09 as well. You may recall a recent writing detailing our experimental offerings in pulmonary arterial hypertension. What started as a methods development expedition for one client more than two years ago has now blossomed into critical outsourcing relationships with multiple biopharmaceutical companies using several well-established paradigms in this therapeutic area.

But we’ve not been content with only PAH Discovery work; as of this writing, our laboratories are also actively conducting efficacy experiments in ischemia/reperfusion injury, thrombosis, congestive heart failure, and atrial fibrillation  — with the latter two areas strongly leveraging our expertise in advanced conscious instrumented models.

I had the pleasure of attending the 2009 American Heart Association Scientific Sessions in Orlando during November. While sitting down with a current small biotech client – they also noted the window of progress opening again. For them, this meant the ability to finally start vetting promising compounds across therapeutic platforms rather than just focusing on a single area that’s been successful. For the industry as a whole, the ability to have multiple backup strategies in the case of primary failure will be critical as we navigate toward recovery.

I look forward to the 2010 Western Pharmacology Society meeting in San Diego during February. We exhibited at this meeting when it was held in Honolulu a few years ago, and the organizers use a brilliant tactic to break up the agenda and maximize the attendance. There are sessions during the morning and evening, with free time during the day to enjoy the locale. I hope to see you there.

Regards,

Dr. Michael Gralinski, CorDynamics CEO

My team and I are returning from the 2009 Safety Pharmacology Society meeting in Strasbourg, France. With us was our lead veterinary technician, Ms. Melissa Fisher, who was awarded a Junior Investigator Travel Award for her work with her colleagues developing a model of hypoxic pulmonary vasoconstriction / pulmonary arterial hypertension (PAH) in the cynomolgus monkey.

After conducting more than 18 experiments interrogating the intertwining roles of anesthesia, arterial oxygen tension, and surgical plane in the stability of the model, our labs are now providing clients with a paradigm that defines a compound’s ability to selectively reduce pulmonary artery pressure in the presence of existing PAH using non-human primates. Building on our previous work in the dog and rat, Melissa rose to the challenge and coordinated the experiments to bolster the disheartening lack of scientific literature in this arena. There are no reliable publications describing PAH in the monkey; only a few aged papers detail measurement of arterial oxygen tension or other tangential parameters having a relationship to pulmonary function in this species.

Looking at the graphs below, we’ve defined the selectivity for prostacyclin (a well-characterized vasodilator) in this model. The experiments could not have gone any better. We previously demonstrated that 10% inhaled oxygen is sufficient to induce a greater than 30% increase in pulmonary artery pressure. At the lowest studied dose of prostacyclin (1.5 μg/kg/min), there was no appreciable reduction in either pulmonary artery pressure or systemic arterial pressure during the hypoxic vasoconstriction.

However, at 15 μg/kg/min, our labs uncovered the differential vasoactivity of prostacyclin on the pulmonary architecture.

As a result of these data, we are highly confident that we can uncover similar properties in proprietary molecules; improvements would likely involve either an augmented differential response or via longer pharmacodynamic action than prostacyclin.

Melissa was excited to accept the award and present the team’s research in France. We believe these paradigms can be of tremendous value as the industry looks toward meeting patient needs in the area of pulmonary hypertension.

Regards,

Dr. Michael R. Gralinski, CorDynamics CEO

The following data suggests against relying solely on pure in vitro assays, including stem cell based paradigms and focused ion channel studies, for early decision making and compound selection. This is especially true in the prediction of cardiovascular safety.

In 2008, our laboratories interrogated over 120 discrete compounds in the isolated perfused heart for their potential to interact with cardiac function. A majority of these studies were conducted in response to direct evidence of ion channel blockade (for example, I_Kr [hERG] antagonism) or as part of a standard testing funnel within the individual Sponsor’s safety assessment function.

Although we had extensive anecdotal experience that would ultimately validate the outcome, upon analysis of the data we are able to state that pure in vitro assays will not accurately predict the full integrative cardiac effects of many late Discovery compounds or preclinical development candidates. In fact, these assays often introduce uncertainty into the testing funnel due to their lack of complexity.

 For example, in the data set below note that approximately 50% of test articles had appreciable effect on PR interval (atrial to ventricular conduction) – a parameter not even capable of interrogation in these cellular-based assays.

These ‘non-QT related’ findings can be as looming of a roadblock as lengthening of repolarization. The pharmacists’ shelf carries a number of compounds that are known for PR prolongation, most notably the recent anti-virals such as rotinavir and more seasoned medicines like the tricyclic antidepressants. An August 2009 Journal of the American Medical Association study has demonstrated that even slight PR interval prolongation is associated with an increase in atrial fibrillation and all-cause mortality.

Of additional interest, only 20% of the compounds showed potential liability for QT interval prolongation. Given the impetus for conducting these assays, this suggests a high propensity for false positivity with interrogation of I_Kr anatagonism alone.

This scenario has been played out in project team meetings countless times. “We have a ‘hit’ in the ion channel assay, why does the isolated heart [or in vivo assay] not translate?”

This reasoning is folly; we’ve lost our way in the quest for faster, cheaper methods to get a clinical candidate. Far fewer of our colleagues ask the related, more appropriate question; “We have a clean signal in the whole heart [or in vivo] approach, why is there a signal in the ion channel assay?” The answer is, of course, identical in both scenarios. However, the latter approach demonstrates a more reasonable grasp on the science behind the conduct of the assays.

The integrative approach is infinitely more complicated than a single ion channel or cell type. The more reasonable paradigm limits the sometimes misleading influence of relying entirely on these simple assays. They have a role in the testing funnel. However, without complementary interrogation, compounds not likely to have a clinical effect risk being unnecessarily de-prioritized.

Regards,

Dr. Michael  Gralinski, CorDynamics CEO

We’ve recently returned from the 2009 Society of Toxicology meeting in Baltimore. As usual, it was refreshing to catch up with friends, reconnect with previous co-workers, and get the current pulse of our clients.

Other than the scientific topics at hand, the buzz of the convention hall was focused on the current global economic state and the ramifications of continuing job losses and shrinking budgets throughout R&D. Not exactly the catalyst of uplifting discussion. Although difficult to quantify, I did feel some improvement in the attitude and outlook of the people who stopped by compared to our last major trade show in November 2008.

One of our Southern California clients, who attended both meetings, captured it perfectly during a discussion at the CorDynamics booth. She noted, “The end of last year (2008) felt dour and somber.” We both agreed that things seemed to have calmed since then, but the universal feeling was that the current year will be a volatile one.

In addition to this uncertainty, we heard of 2009 R&D budgets that are either flat or have been cut versus previous years. At past meetings attendees’ inquiries were focused on timelines and deliverables, while this year the talk was on maximizing their outsourcing budgets.

At CorDynamics, our inherently affordable cardiovascular models – from the isolated heart to anesthetized and conscious telemetry in a variety of paradigms — provide unparalleled value at precisely the right time. Now, perhaps more than ever, it’s vital to select the right compounds to move forward.

Over the last six months, we’ve seen an increase in our earlier de-risking studies, namely isolated heart and screening telemetry assessments. While meeting deadlines is a critical part of our business (for example, in March we started multiple monkey telemetry studies with just three weeks lead time), getting feedback from our clients such as ‘your pricing was by far the best I’ve gotten’ [Outsourcing Manager, Mid-US client] remains just as important, especially in 2009.

The meeting ended on a high note for the CorDynamics team. We look forward to our upcoming exhibitions in September at Strasbourg, France (2009 Safety Pharmacology Society) and in November at Palm Springs, USA (2009 American College of Toxicology).

Regards,

Dr. Michael Gralinski, CorDynamics CEO