Pulmonary Artery Hypertension (PAH)
There are several drugs in development for PAH and one expects that as each new one is approved it is quite likely to be prescribed for patients with COPD. Before considering these mostly novel agents, let's consider how often a pulmonary vasodilator other than oxygen might be an appropriate agent to use in COPD. An excellent review of PAH in COPD was published in this Journal last year to which I refer as background (Burger CD, COPD 2009; 6:137-44). PAH is relatively uncommon in COPD; estimates vary but rarely exceed a few percent of all COPD patients, and when present, is usually mild, mean pulmonary artery pressures rarely being above 34 mmHg (a mean pressure of 25 mmHg is considered the upper limit of normal by NIH).
PAH in COPD is understood to result from general pulmonary vasoconstriction due to persistent hypoxemia. In the more severe cases, if not treated, it can lead to pulmonary artery remodeling, right ventricular hypertrophy, cor pulmonale, etc. This is what used to be called the “blue bloater” in the Burrows/Fletcher classification of COPD, and is now group III in the World Health Organization (WHO) clinical classification of PAH. Oxygen supplementation is the physiologically appropriate primary treatment, and, if used for 18 or more hours per day, has good results including prolongation of life. In theory, a pulmonary vasodilator other than oxygen might worsen arterial desaturation by over-riding the reflex pulmonary vasoconstriction that reduces regional perfusion to under-ventilated lung regions, increasing V/Q inequality and the R-to-L shunt-like effect. This has been the anecdotal experience and has very recently been verified in the only publication I could find of a controlled trial of a PDE5i in PAH specifically due to COPD (Blanco I, et al. AJRCCM 2010;181: 270-78). In that study, sildenafil administration lowered mean PA pressure by about 6 mmHg at rest, but PaO2 decreased by 6 mmHg and the A-a O2 gradient rose by 7 mmHg, all changes being statistically significant. If confirmed, this would suggest that pharmacologic pulmonary vasodilators should be used with caution in PAH due solely to COPD, as the authors recommended.
However, about 1–4% of patients with PAH secondary to COPD have mean pulmonary artery pressures out of proportion to the severity of their COPD—mean pressures above 35 mmHg and sometimes much higher. An associated vasculopathy has been suggested in these rather uncommon cases. In them, the clinical course tends to be worse, acute exacerbations of COPD are said to be more common and more severe, as are complications due to right heart failure, which tends to dominate the clinical picture. Oxygen supplementation alone does not normalize their hemodynamics, so the addition of pulmonary vasodilators may be appropriate in order to decrease right heart afterload, diminish congestive failure and the consequent limitation of physical activity. Nevertheless, the clinical utility of pulmonary vasodilators in COPD has yet to be experimentally verified. In fact, the above citation is the only prospective clinical trial of vasodilators in COPD-associated PAH to have been published, and all but one of the subjects in that study had mean PA pressures between 20 and 34 mmHg—the mildest category. Moreover, other studies of pulmonary vasodilators in PAH that have been done include patients with a variety of different etiologies, making it difficult to know in what forms of PAH a vasodilator would be appropriate. With that in mind, here are some drugs that were recently approved for PAH and some that are in the pipeline seeking an indication for PAH.
Three principal classes of pulmonary artery vasodilators are being investigated, PDE5i's, prostacyclin analogs, and endothelin-1 antagonists. In the PDE5i group, Tadalafil, otherwise known as Cialis (Eli Lily), was FDA-approved for WHO group 1 PAH (Idiopathic Familial PAH Associated with other conditions, e.g., collagen vascular disease) in May 2009. For the PAH indication the dose is a little higher than that for its ED indication; the brand name of the PAH formulation is Adcirca. There have been several reports of Sildenafil, otherwise known as Viagra (Pfizer) for PAH since the first in 2002. Four sildenafil PAH studies are listed in clinicaltrials.gov, one of which was initiated in February this year (see below), and another of which had not yet been initiated in March this year, but which is limited to PAH due to COPD (NCT00730067).
Of the prostacyclin analogs, Iloprost was approved as an inhaled solution for WHO group 1 PAH in 2004 under the brand name Ventavis (Actelion Pharms Ltd.). The inhalation route was necessary because of systemic side-effects from use by other routes. However, its half-life in the circulation when inhaled is very short, about 30 minutes, so treatment with the initially approved product had to be repeated 6–9 times daily. The July 2009 approval was for a new nebulizer dose formulation at double concentration. United Therapeutics Corporation has 2 orally bioavailable, chemically stable, prostacyclin analogues, beraprost and treprostinil. Beraprost-MR (modified release) has been approved for PAH in Japan and has been given orphan drug status in Europe. No studies of that agent are listed in clinicaltrials.gov, and its future in USA is doubtful at best. Treprostinil, United Therapeutics's other prostacyclin analog, was approved for parenteral treatment of WHO group 1 PAH a few years ago as Remodulin, and as a q.i.d. nebulizer formulation, Tyvaso, in 2009. United Therapeutics has also been working on an oral formulation. They are trying to overcome the problem that all prostacyclin analogs seem to share—the need for frequent treatments because of the short half-life. Increasing the dose is not practical because of the drug's narrow therapeutic margin. The solution they will be testing is a novel slow-release technology of tablet formulation in which “treprostinil…will be released through an extremely small hole that is laser-drilled into the coating of each tablet”.
In the endothelin-1 (ET) antagonist category, we already have bosentan and ambrisentan. The most advanced new ET-1 antagonist appears to be Sitaxsentan (Pfizer) which is in several PAH studies either as monotherapy or in combination with sildenafil. It is relatively specific for ETA inhibition, which is desirable, and has negligible inhibition of the beneficial effects of ETB such as stimulation of nitric oxide production. Clinical trials, however, have not shown it to be much more effective than bosentan (suggesting the reason why a combination with sildenafil is being studied). It might have an advantage as a once-daily treatment as opposed to bosentan's twice-daily regimen. However, there are drug-drug interactions with warfarin and cyclosporine requiring a dose reduction of these agents, and liver enzymes need to be monitored. Ambrisentan is approved in both USA (Letairis) and Europe (Volibris®), and is also relatively specific for ETA. Incidentally, bosentan is itself in trials in combination with sildenafil.
There are other classes of drugs for PAH that do not fall into any of the 3 treatment groups mentioned above. In addition to the two prostacyclin analogs mentioned above, United Therapeutics with its subsidiary Lung Rx has a third PAH drug in development, Aviptadil, which is a synthetic version of Vasoactive Intestinal Peptide (VIP). A Phase II study of aviptadil in PAH was recently completed, the agent does not appear in clinicaltrials.gov. The EMEA has given it orphan drug status for the treatment of acute lung injury and sarcoidosis. Some other agents, e.g., a rho-kinase inhibitor, have been mentioned in animal studies for some time but have not made it into humans as yet.A novel serotonin 5-HT2B receptor antagonist, PRX-08066, had good trial results in 2006 but the sponsor, Epix, was unable to obtain funds to continue its development program. It could re-emerge in another company's portfolio. A study of Dehydroepiandrosterone, the androgen DHEA, is the subject of a 4-center study in France that explores its efficacy in COPD patients with PAH (mean PA pressure > 25 mmHg) who have received 6-months of oxygen supplementation (and presumably failed to benefit). Exercise capacity will be the primary outcome (NCT00581087). The study seems well designed and appropriately targeted for a COPD indication. While researching this topic, I learned that DHEA is a pulmonary vasodilator and inhibits chronic hypoxia-induced PAH by upregulating soluble guanylate cyclase (Oka M et al. Cardiovasc Res 2007; 74:377-87). The relevance of soluble guanylate cyclase in vascular tone is illustrated by the next investigational PAH treatment.
One of the most interesting and novel entrants into the PAH field is Riociguat (BAY63-2521), a Bayer product. Riociguat is a stimulator of soluble guanylate cyclase (sGC), a key signal-transduction enzyme responsible for promoting the synthesis of cyclic GMP that leads to relaxation of vascular smooth muscle. sGC is physiologically activated by nitric oxide (NO), however impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of PAH. Thus, direct stimulation of sGC by agents like riociguat represents a promising therapeutic strategy for the treatment of PAH. Previous sGC stimulators developed by Bayer demonstrated beneficial effects in experimental models of PAH, but were associated with unfavorable drug metabolism and pharmacokinetic properties. Riociguat represents an improvement in these respects according to Bayer, and early clinical studies show beneficial clinically based outcomes such as improved exercise capacity. The agent, which is orally active, is currently in Phase III for PAH (not listed in clinicaltrials.gov).
To summarize the issue of vasodilator use in PAH secondary to COPD, WHO group III, it seems clear that effective agents already exist, some are already available and, if more are needed, there are numerous truly novel molecular entities in development. These will likely bring great benefit to patients with primary PAH, WHO group I. What is much less clear is whether the PAH due to COPD, WHO group III, should be treated with pulmonary vasodilators except in rare instances. I mention two ongoing trials (above) that one hopes will help us answer that question. It would be unfortunate if a new pulmonary vasodilator that was safe and effective for WHO group I PAH were approved and were to be so successful that it were used indiscriminately in more than a small minority of WHO group III patients. (I thank my colleague Bimalin Lahiri MD for invaluable assistance with the PAH report).
Newly Initiated Studies
BioPharm Insight's monthly report of all clinical studies initiated in January and February 2010 (when this column was written) includes a total of 1,108 new trials. Of these, 18 were for a COPD indication. Two that seem the most novel and interesting are studies from AstraZeneca and from QuatRx, the latter being a small biotech company. AstraZeneca's study is a Phase II study of its oral neutrophil elastase inhibitor for COPD, AZD9668. The primary outcome will be airway wall thickness as determined by multi-slice CT scan (MSCT) after 12 weeks of treatment (NCT01054170). MSCT is becoming widely used as a non-invasive imaging research tool, particularly in cardiovascular research. There are about 20 cardiovascular studies listed in clinicaltrials.gov that use MSCT of the coronaries or aorta to detect even subclinical arterial disease (NCT00455793).
MSCT is now also being used in pulmonary research to detect bronchiectasis (NCT00524095), to measure “patient specific geometries of the central and peripheral small airways…” in COPD (NCT00966459), and in alpha-1 antitrypsin deficiency (AATD) to follow the progression of lung density measurements during 2 years of AAT replacement therapy or placebo (NCT00263887). Its use to measure airway wall thickness in response to therapy in asthma and COPD, as in the AZD9668 study, if the resolution and reproducibility are sufficient, may signify the arrival of a new and important outcome tool for drugs that target airway inflammation.
The QuatRx Pharmaceuticals study is a Ph II study of fispemifene, “a new, selective estrogen receptor antagonist that is being developed as an oral treatment for testosterone deficiency and associated disorders in men”. The rationale, according to the sponsors, is that “by blocking estrogen feedback to the pituitary with a drug like fispemifene, the pituitary increases LH and FSH secretion which increases testosterone secretion.” The company claims to have evidence to support this physiology. The present trial is not yet listed in clinicaltrials.gov so one does not yet know its purpose; its stated indication in the BioPharm Insight listing is COPD. All the outcomes of a previously completed trial of this drug by the same company in COPD patients list only serum hormone and lipid levels as outcomes. One guesses that the drug may be positioned for the management of weight loss in advanced COPD and that exercise studies and pulmonary rehab studies are being planned when the phase II dose-finding studies are completed.
Also of significant interest is a large 1–3-year NHLBI trial of simvastatin vs. placebo with frequency of acute exacerbations of COPD as the primary outcome (NCT01061671). Exclusionary criteria require that enrollees neither be receiving statins already, nor have a condition for which a statin would be indicated (and not to be drinking too much green tea either). Not stated in the announcement, but very likely I believe, is that the new investigational AECOPD instrument called EXACT-PRO (United BioScience Corp) will be used to assess the outcomes. The trial, which is planned to complete in 2013, will be called STATCOPE.
Other newly initiated studies are a pair of Phase III studies of the Almirall/Forest LAMA aclidinium using a b.i.d dosing regimen, evidently the previous once-a-day expectation was not quite met; they also sponsor a Phase II trial of fixed dose combinations of aclidinium with 2 doses of formoterol inhaled b.i.d. Pearl has just initiated two Phase II studies using their proprietary HFA delivery system, one of formoterol HFA versus Foradil DPI, the other a fixed combination of formoterol-glycopyrrolate HFA versus the monocomponents, as well as Foradil, and Spiriva, and placebo. GSK has initiated 3 Phase III studies of its once-a-day ultra-LABA DPI, GW642444, in fixed combination with fluticasone fuorate. The Hospital Clinic of Barcelona has initiated a study of sildenafil in combination with pulmonary rehabilitation versus pulmonary rehabilitation alone in patients with COPD and pulmonary hypertension. The outcome will be exercise endurance.
AstraZeneca has initiated a Phase I study of an oral agent for COPD, AZD6553, about which I have no further information. ScheringPlough has a CXCR2 antagonist, SCH527123, that inhibits sputum neutrophilia in animals and is now entering Phase I. Novartis has a Phase II study of QAX028, which I believe is a once-a-day LAMA. Novartis is also initiating a study of its ultra-LABA indacaterol with single- and multi-dose DPI administration. I believe this will be the 34th clinical study of that agent reported in clinicaltrials.gov.