GLG News by Bosentan Prescribers for PAH (US)

Robert ArisProfessor of MedicineUniversity of North Carolina at Chapel Hill School of Medicine - CC

Oral Treprostinil: An effective medicine hiding in a study with a challenging design?

November 18, 2008

Analysis of:Freedom-C Trial of Oral Treprostinil in Pulmonary Arterial Hypertension Fails to Meet Primary Endpoint | ir.unither.com

This phase III study was done without the benefit of conventional drug development with Phase I and Phase II studies (which would have provided more information about the effective dose) preceding it because pharmacokinetic date from IV and SC dosing studies were used to extrapolate for the oral dosing. While in hindsight, this may have not been ideal, the trial holds a lot of promise that treprostinil will be effective since there was a nice dose-response curve and the higher doses clearly appeared to be effective. Oral Treprostinil is probably very similar to subcutaneous and intravenous prostanoids (remodulin and flolan) that require a slow uptitration of dose to allow the patient to become tolerant to the side effects. Thus having smaller doses for titration, which were available later in the trial, probably would have allowed for greater success had these doses been available earlier in the study.

Robert ArisProfessor of MedicineUniversity of North Carolina at Chapel Hill School of Medicine - CC

Mild PAH improved by early treatment with bosentan

July 18, 2008

Analysis of:Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. | www.sciencedirect.com

While functional class II (FC II) PAH patients have been included in previous clinical trials, the EARLY trial is the first study to concentrate (ie recruit exclusively) FC II PAH patients.  This is important because the definition of functional class II is that a patient has a sight limitation in physical activity. Understanding "slight" is not so easy in clinical practice and there has been some reservation in treating "slightly" ill patients with very expensive drugs without better outcome studies in this target group. Thus the results of the EARLY study (Lancet June 2008) are welcome news to the PAH community.  Analyses were done with 168 patients and showed significant improvements in pulmonary vascular resistance and a strong trend (p = 0.075) toward improvement in 6 minute walk distance in bosentan-treated patients.  These results will certainly compell clinicians to treat patients with "slight" PAH more aggressively.

Robert ArisProfessor of MedicineUniversity of North Carolina at Chapel Hill School of Medicine - CC

Peer reviewed literature on Ambrisentan, a selective ETRA for PAH

June 10, 2008

Analysis of:Ambrisentan for the Treatment of Pulmonary Arterial Hypertension | circ.ahajournals.org

This Circulation paper is the first peer reviewed data on the 2 pivotal Phase III trials on ambrisentan that lead the FDA to approving it for the treatment of PAH in July 2007. This paper is critically important since all new research needs to withstand the rigor of peer-review for physcians to fully embrace the findings.  And the journal Circulation is a top notch publication with "rigorous" reviewers.  Thus this publication will be well received by the PAH community and can be assimilated into the overall database of knowledge on PAH.

Warren BotnickPresidentPSS Clinical Research

Exciting Prospect for Alternative Treatment of COPD and asthma

September 19, 2007

Analysis of:Newly Discovered Fatty Acids May Lead To Novel Treatments For COPD And Asthma | www.medicalnewstoday.com

Eicosanoids appear promising in the treatment of such airways diseases as COPD and asthma, which affect millions worldwide.  Any alternative to current anti-inflammatory therapy, which consists almost entirely of forms of corticosteroids, would almost certainly be welcomed and adopted in widespread fashion.

Warren BotnickPresidentPSS Clinical Research

Ceftobiprole for Community-Acquired Pneumonia is Breakthrough in Therapy

September 19, 2007

Analysis of:Basilea Announces Positive Top-line Data from Phase III Study of Ceftobiprole in Community-acquired Pneumonia Requiring Hospitalization | www.pipelinereview.com

Cephalosporins have been standard therapy for pneumonia for many years, but to date this class of drug has been ineffective against MRSA.  Ceftobiprole appears to represent a breakthrough in this regard.  I would expect the drug to be well tolerated and, for the most part, to cause few major adverse effects.  However, the use of ceftriaxone as a comparator is odd, as this would not be used as monotherapy by most physicians in the USA for patients with CAP who are sick enough to warrant hospital admission.

Warren BotnickPresidentPSS Clinical Research

Worldwide Market for Lunivia (eszopiclone) Uncertain

September 19, 2007

Analysis of:GlaxoSmithKline and Sepracor Inc. announce international alliance for commercilisation of Lunivia | www.pipelinereview.com

Though the potential international market for eszopiclone is large, interest in the product among sleep specialists in the US has leveled off.  Its success internationally may well depend more on distancing the product from other agents such as the Ambien "family," a decidedly difficult task, and on continuing to downplay the major side effect of bad taste, and less on the size of the potential patient population.  For many prescribers, it has become apparent that Lunesta is new but not necessarily improved.

Warren BotnickPresidentPSS Clinical Research

Emergence of Dabigatran for Prevention and Treatment of Blood Clots

September 17, 2007

Analysis of:Dabigatran Etexilate As Effective As Enoxaparin In Lowering Blood Clot Risk After Hip Replacement | www.medicalnewstoday.com

These data help strengthen the growing perception that oral agents in general, direct thrombin inhibitors in particular, and perhaps specifically dabigatran, represent the future of anticoagulation therapy.  Safety data are of paramount importance, given the prior failure of ximelagatran in this respect, and thus far dabigatran indeed has avoided causing similar liver toxicity.  Ongoing studies of dabigatran, and of other oral agents such as the factor Xa inhibitors, in treatment of venous thrombosis and pulmonary embolism will add critical information in this area.

Warren BotnickPresidentPSS Clinical Research

Anticoagulant TB-402 Data Raise Hopes but Raise Safety Concerns

September 12, 2007

Analysis of:ThromboGenics and BioInvent Announce Successful Completion of Phase I Clinical Trial of the Anticoagulant TB-402 | www.pipelinereview.com

Phase I data are promising for prevention on VTE, a major worldwide health problem.  However, inhibition of factor VIII raises grave safey concerns, despite safety profile in this study.  Long duration of action and cost also will be important considerations (current drug costs for this indication can be very low).

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