Just an fyi, Aryx is working on a potentially clean amiodarone for atrial fibrilliation. Some good background on the market is in here.
ATI-2042 for Atrial Fibrillation. ATI-2042 is an oral anti-arrhythmic agent in Phase 2 clinical development for the treatment of patients with atrial fibrillation. ATI-2042 was designed to have the efficacy of amiodarone, a drug that has been used for many years, despite its adverse side effects, because physicians consider it to be the most effective drug for treating patients with atrial fibrillation. Amiodarone accumulates in many different organs and can only be metabolized by CYP450, potentially leading to serious side effects that are not immediately reversible upon withdrawal of the drug. Since ATI-2042 is predominantly metabolized through the esterase pathway, accumulation in the organs and drug-drug interactions are expected to be reduced. We have completed a Phase 2 clinical trial with ATI-2042 involving six atrial fibrillation patients with implanted recordable pacemakers who failed previous drug therapy. ATI-2042 quickly reduced the amount of time these patients were in atrial fibrillation by up to 87%. We are conducting an additional Phase 2 clinical trial to further characterize the dose-response effect of ATI-2042 in patients with atrial fibrillation.
ATI-2042—Anti-Arrhythmic Agent for the Treatment of Atrial Fibrillation
Our third product candidate, ATI-2042, is currently in development for the treatment of atrial fibrillation. We engineered ATI-2042 with the goal of developing a therapy equally effective as, but safer than, amiodarone. We hold a composition of matter patent on ATI-2042 and have filed for other use and manufacturing patent applications in the United States and other jurisdictions. ATI-2042 is currently in Phase 2 clinical development.
Amiodarone Background
Atrial fibrillation is the most common form of cardiac arrhythmia, or abnormal heart rhythm, affecting greater than 6.4 million people in the United States, Europe and Japan. Atrial fibrillation is caused when the atria quiver instead of beat. During atrial fibrillation, the atria contract and relax erratically between 350 and 600 times per minute versus normal heart rhythm of 60 to 80 beats per minute. Patients with atrial fibrillation experience debilitating symptoms and suffer a compromised quality of life. Because the pumping function of the atria does not work properly in atrial fibrillation patients, blood is not completely emptied from the heart's chambers, causing it to pool and sometimes clot. In patients with atrial fibrillation, clotted blood can dislodge from the atria and flow to the brain, causing stroke. Atrial fibrillation also compromises the pumping function of the heart often leading often to intolerable symptoms that need therapy.
Atrial fibrillation treatments focus on a reduction of symptoms and returning the heart to normal rhythm. Concerns surrounding available atrial fibrillation treatments include both safety and efficacy issues. The most common treatment for atrial fibrillation is drug therapy. Current pharmacological treatments for atrial fibrillation are limited in their use due to safety and efficacy issues, while non-pharmacological approaches such as implantable devices and surgery are currently less favored because of their costs and invasive nature.
Amiodarone is the current "gold standard" for the pharmacological treatment of atrial fibrillation. Amiodarone possesses a unique, balanced pharmacological effect on sodium, potassium and calcium channel inhibition as well as certain receptors in the heart that are responsible for its effectiveness. Clinical studies have shown that amiodarone is uniquely superior to other anti-arrhythmic drug treatments. While amiodarone is not approved by the FDA for the treatment of atrial fibrillation, it is a commonly prescribed off-label treatment due to the lack of equally efficacious treatments. However, amiodarone has a slow onset of action and its use has been severely limited by life-threatening and toxic side effects that result from the accumulation of the drug in the liver, lungs, nerves, thyroid and other tissues.
Many of the adverse effects of amiodarone are believed to derive from its very slow elimination from the body due to its dependence on the CYP450 system for metabolism. In patients taking daily oral doses of amiodarone, the drug slowly accumulates in the body where it remains, avoiding metabolism by liver enzymes. This leads to the gradual development of organ specific toxicities. Similarly, when amiodarone is discontinued many weeks or months are required for the drug to be totally eliminated from the body. Due to this slow elimination, toxicity and side effects due to accumulation usually take months or weeks to reverse, if ever. Since these side effects can be progressive, they can be fatal before all the drug is eliminated from the body.
Our Anti-Arrhythmic Agent
We are developing ATI-2042 for the reduction of atrial fibrillation burden in patients who suffer from repeated episodes of atrial fibrillation, or paroxysmal atrial fibrillation, and prevention of recurrence of symptomatic atrial fibrillation in patients with or without structural heart disease who experience on-going, or persistent, atrial fibrillation. Paroxysmal atrial fibrillation is generally defined as episodes of atrial fibrillation that can terminate spontaneously and last no longer than one week and generally no less than 24 hours.
ATI-2042 is designed using our RetroMetabolic Drug Design technology with the goal of retaining the efficacy of amiodarone but with better safety. ATI-2042's affinity for the major calcium, potassium and sodium ion channels, as well as certain receptors in the heart, very closely matches that of amiodarone. ATI-2042, like amiodarone, contains iodine which we intentionally retained since we believe it contributes to amiodarone's efficacy. We have engineered ATI-2042 not to be primarily dependent on CYP450 for its metabolism while matching amiodarone's balanced receptor profile. A variety of preclinical studies with ATI-2042 provide evidence that the drug preserves the efficacy of amiodarone but with more rapid metabolism and no tendency towards accumulation.
Potential Market and Commercialization Strategy
Approximately 2.4 million people in the United States have been diagnosed with atrial fibrillation. It is estimated that atrial fibrillation is responsible for more than 75,000 strokes per year in the United States alone. It is estimated that approximately two million patients in the United States were treated for their atrial fibrillation with a prescription drug in 2006. It is estimated that 45% of atrial fibrillation patients in the United States receive a therapeutic which is considered primarily to be arrhythmic therapy while the remainder is treated with a therapeutic primarily considered to be "rate therapy". Based on our own market research, we believe an estimated one-third, or approximately 600,000, of atrial fibrillation patients treated in the United States for their arrhythmia receive amiodarone. In addition, although a generic drug, and in spite of its serious safety issues, amiodarone achieved annual sales in the six largest global markets, outside the United States, of approximately $147 million.
Based on our own market research, we believe amiodarone is considered to be the "gold standard" antiarrhythmia medication for the prevention of atrial fibrillation recurrence. ATI-2042 was designed to retain the efficacy of amiodarone, but a better side effect profile. Amiodarone is believed to provide both rhythm and rate therapy, and ATI-2042 is intended to retain this effect.
Clinical Development Status
We have completed one pilot Phase 2 clinical trial in patients who suffer from repeated episodes of atrial fibrillation, or paroxysmal atrial fibrillation. This is a patient population that is particularly difficult to treat.
We have a larger ongoing Phase 2 trial in patients who suffer from paroxysmal atrial fibrillation designed to characterize the safety, tolerability and efficacy of ATI-2042. Based upon these data, if positive, we intend to seek a large pharmaceutical company partner to continue to develop the product candidate through Phase 3 clinical trials and commercialization. We anticipate that the partner will be responsible for these late-stage development and commercialization costs. We believe that the Phase 2 trial underway will provide the safety and efficacy data necessary to establish the proof-of-concept for ATI-2042.
Phase 2 Trial in Paroxysmal Atrial Fibrillation (CLN-208). We successfully completed this open-label dose-escalation design Phase 2 trial testing the safety and efficacy of ATI-2042 in the treatment of paroxysmal atrial fibrillation in six patients for an eight week period. This type of atrial fibrillation occurs intermittently with the frequency and duration of the paroxysmal atrial fibrillation episodes defining its severity. The endpoint was to establish that the percent of time the patient spent in atrial fibrillation, called their atrial fibrillation burden, would be significantly reduced compared to baseline. Atrial fibrillation burden is an accepted method by which cardiologists and electrophysiologists monitor the effectiveness of treatment in patients with paroxysmal atrial fibrillation. The patients in this trial had an implanted pacemaker with the capability of monitoring the duration and severity of the episodes of atrial fibrillation and logging the results. The patients' atrial fibrillation burden was measured at weekly intervals. The first two weeks served as the untreated baseline period. Following the baseline period, ATI-2042 was then administered twice a day (bid) in ascending doses over the next eight weeks; 200 mg bid for two weeks, 400 mg bid for two weeks, 600 mg bid for two weeks, and 800 mg bid for two weeks. Treatment with ATI-2042 was then stopped and the final two weeks served as a washout period to measure the level of atrial fibrillation burden.
The results provide evidence of the efficacy of ATI-2042 in reducing the atrial fibrillation burden in all six patients, with a statistically significant reduction in atrial fibrillation burden apparent even at the lowest dose of 200 mg bid. The results are illustrated in the following table. At baseline, the patients had a mean atrial fibrillation burden of 20%. This was reduced to a mean of 1.5% of time spent in atrial fibrillation over a two-week period at the highest dose of 800 mg bid. As dosing increased, average atrial fibrillation burden was reduced by 71% at 200 mg bid compared to baseline (p=0.03), by 72% at 400 mg bid compared to baseline (p=0.03), by 80% at 600 mg bid compared to baseline (p=0.06) and by 87% at 800 mg bid compared to baseline (p=0.06). At the two highest doses, one patient decided to not complete the study due to gastrointestinal discomfort and statistical significance was not achieved. After the cessation of treatment, the atrial fibrillation burden gradually increased to pretreatment values by the second week.
The rapid onset and offset of antiarrhythmic activity of ATI-2042 are mirrored by the blood levels of the candidate drug that were measured at intervals throughout the trial. Plasma levels of ATI-2042 increased in proportion to the increase in dose, and after cessation of dosing, the concentration of ATI-2042 and its metabolites all decreased to almost zero within one week. This is an important advantage for ATI-2042 compared to amiodarone, which can take months to be completely eliminated from the body, giving rise to the serious side effects that ATI-2042 is designed to address. ATI-2042 was generally well tolerated, with transient and expected changes in measures of thyroid function, as well as gastrointestinal complaints such as dyspepsia, lower abdominal pain, loose stools and nausea being reported, especially at the highest dose. The more prevalent side effects coupled with considerations for the incremental improvement in response at the highest dose led us to not include the 800 mg bid dose in further clinical
trials. These mild side effects are similar to those seen with amiodarone. There were no drug related serious adverse events.
Phase 2 Trial in Paroxysmal Atrial Fibrillation (CLN-205). This Phase 2 trial is currently enrolling patients in North America and Europe. Targeted to test the safety and efficacy of ATI-2042 in paroxysmal atrial fibrillation patients who have an implanted dual-chamber pacemaker with recording capabilities, this randomized, double-blind, placebo-controlled study builds off of the results of CLN-208. Doses of 200 mg bid, 400 mg bid and 600 mg bid, or placebo, are being administered for a twelve week treatment period. Administration of ATI-2042 or placebo follows a four week baseline period during which each patient's untreated atrial fibrillation burden is established so that only appropriately highly burdened patients are enrolled and the drug's effect can be properly established. The safety of the drug will also be assessed. Results from this trial are expected in the third quarter of 2008. If the results of CLN-205 mirror the results of the completed CLN-208, we believe we will have established the proof-of-concept on this product candidate and determined the appropriate dosing regimen to be used in Phase 3.
Phase 1 Clinical Trials. We have successfully completed three Phase 1 clinical trials testing ATI-2042 in 83 healthy volunteers. The results of these Phase 1 clinical trials in healthy volunteers indicated that single doses up to 800 mg and repeat oral dose safety studies at doses up to 1600 mg/day in healthy volunteers did not show any clinically significant adverse events. Moreover, pharmacokinetic analysis in these subjects showed that ATI-2042 had a shorter half-life than amiodarone and did not display the tendency towards the accumulation associated with amiodarone. The results of a drug-drug interaction study indicated that at doses expected to be used in Phase 3 trials ATI-2042 was well tolerated when administered with the anticoagulant warfarin. Also at expected therapeutic doses, no cardiovascular adverse events were noted, and there was no effect on the surface electrocardiogram. An additional Phase 1 clinical trial was discontinued due to the inability to identify suitable subjects.
<<ATI-2042's preclinical studies contain results that are currently being monitored in the clinic. Inhibition of testicular function was observed in one animal species as part of these studies. No such effect has been observed to date in the clinic and monitoring continues. In published studies, a similar effect is thought to be correlated with the accumulation of amiodarone in tissues. A possible renal effect was also observed at high doses in our rat and dog toxicology studies for ATI-2042 . While we will continue to monitor patients for these effects, there is no assurance these effects will not occur in patients as part of our ongoing and planned clinical trials for ATI-2042, and have a resulting adverse effect on our ability to obtain requisite regulatory approval to market and sell ATI-2042.>> |
