The COPD Pipeline XIII

Keywords: :

• Pharmaceutical research
• Palovarotene
• Weight loss
• Sun11031
• Tesamorelin

Pharmaceutical Research Today

All aspects of the pharmaceutical industry and new product development are changing quite radically. Information that industry itself regularly publishes shows some of those changes, changes that will soon affect our daily practice (data from the 2011 Pharmaceutical R & D Factbook, which covers 80% of the industry's global R & D, and is mostly about major pharmaceutical companies). Salient points are:

• Fewer new molecular entities (NME's, those excluding me-too's, changes of formulation, combinations of approved drugs, etc.) are reaching approval, -only 21 in 2010 as compared with a fairly consistent 25–30 in previous years. The one NME approved for COPD, roflumilast, is our first in some 2 decades.

• The numbers of drugs entering each of phases I, II, and III in 2010 were lower by about 50% than the corresponding numbers in previous years

• Expenditure on R & D by industry fell to $68 billion in 2010, having increased every year until a decline set in after the peak in 2008.

• At the same time, total drug sales reached an all-time high of $856 billion in 2010. Unless my calculator is malfunctioning that means that R & D accounts for only about 8% of sales revenue.

• The failure rate of drugs in phase III, -the pivotal stage, -last year more than doubled compared with the 2005–2007 average. These failures are terminations during the study, and there were 55 of them. The reasons for termination are not provided, but were presumably not all due to unacceptable or unpredicted adverse events.

• Among NME's entering clinical trial phase, oncology is the only category to see positive growth.

The story these data tell is fairly clear, although the reasons are not. One interpretation is that companies see the path of a NME from discovery to approval to be too expensive, too long, too uncertain and too hazardous. Also, my understanding from industry is that they are much more sensitive to emergent problems during development. They are more likely to discontinue development or even pull the plug on an ongoing trial if there is any whiff of failure. As is often said, aspirin could never be approved in the present climate.

It seems then that industry feels more comfortable spending its R & D dollar on a me-too than on an unknown entity. It is safer, easier, and quicker and the 505(b) regulatory route, -the route for approval of a me-too, is a well-worn one. One consequence is that very few companies are interested in developing new antibiotics, as I and many others have reported before. “The antibiotic pipeline is dry” one hears. Also, they are becoming more selective in the indications they develop for. Oncology and neuropsychiatric disorders, particularly Alzheimer's, are relatively safer fields, respiratory not so safe.

However, there is one welcome report that in the Autoimmune/Inflammatory area, the focus of research is shifting from rheumatic disorders to respiratory “with asthma and COPD seeing the highest levels of activity” (Drug Discovery & Development May 10, 2011). This activity refers specifically to COPD trials which now outstrip those for asthma. The success of fixed ICS-LABA combinations for COPD and the box-warnings about LABA use in asthma probably account for much of this movement.

Palovarotene

This is an oral, gamma-selective retinoid agonist being investigated for emphysema that I have written about before (1). Its rationale is that it may “promote structural and functional improvement”, in the words of a Swiss investigator. A trial in humans with alpha1 antitrypsin deficiency in Europe (the REPAIR study) did not show meaningful improvements in lung function or CT lung density, according to a report at the ERS meeting of 2010. However, a subsequent double-blind, randomized, phase II, placebo-controlled trial (TESRA, NCT00413205) was reported at the ATS 2011 annual meeting (2). At the end of 2 years’ treatment with 5 mg/day palovarotene or placebo, there was a modest reduction in the loss of FEV1 in the active-treatment group vs placebo. Each of the secondary outcomes, -the change in DLco, 6-minute walk, and acute exacerbations, but not CT lung density, also showed modestly better results in the active-treatment group. All changes were of more benefit in the subgroup with predominantly lower lobe emphysema. In the dosage used, the drug seemed to be well tolerated and without major adverse events. These results were considered to be suggestive of a disease-modifying effect. The sponsor, F.Hoffmann-La Roche Ltd., is undergoing some reorganization but one hopes that development will continue.

Weight Loss

As we know very well, weight loss is a serious complication of advanced COPD, particularly in patients with predominant emphysema. It is also a predictor of a poor prognosis and the risk of impending respiratory failure. Fortunately, it occurs in only a minority of our COPD patients, -less than 25% of patients is the highest estimate one can find, and probably less than half that number in reality. However, in those whose BMI falls below 17 (males) or 14 (females) there is a major loss of fat-free mass, considerable limitation of activity and a poor and deteriorating quality of life and health status. Its mechanism is almost entirely obscure (3). One theory has been that the work of breathing is so great that these patients are essentially calorie depleted, -undernourished. This mechanism has been tested many times and found not to be a plausible explanation. Recently, for example, Renvall and colleagues found that, rather than being malnourished, caloric intake was increased and inversely related to body mass (4). In one's clinical experience, it has also been difficult if not impossible to reverse the cachexia of emphysema by aggressive refeeding. An altered metabolic state has also been considered. Anabolic steroids, androgenic or non-androgenic, have sometimes been shown to increase muscle bulk and fat-free mass but not exercise capacity. A short course of megestrol, for example, increased body weight but did not improve the 6-minute walk, MRC dyspnea scale, SGRQ or BODE indexes (5). Besides, much of the weight gain due to megestrol appears to be due to adipose tissue rather than fat-free mass.

Likewise, blood levels of inflammatory mediators, although often increased in COPD, are not inordinately elevated in the weight-losing emphysema patient. Anti-TNF-α immunotherapy, ghrelin, and anti-oxidants have not been beneficial. The problem, therefore, remains a major unmet need in the subset of COPD patients who experience this dire complication.

Recently pharmaceutical companies have become aware of this unmet need and, although a successful treatment could only receive an indication for a minority of COPD patients, the disease is so prevalent that even a small segment would constitute a substantial number of patients. There are, in fact, currently 5 trials on the clinicaltrials.gov site with weight loss or an equivalent term and COPD or emphysema in the title other than the completed megestrol trial mentioned above. NCT00094562 is a completed trial of a Phase II trial of a fish oil supplement, NCT00244192 is a completed Phase II trial of the anti-TNF-α agent infliximab (6), and NCT00852020 is a completed phase II trial of an oral nutritional supplement, NCT01014338 is an ongoing Phase IV trial of the ACE inhibitor fosinipril.

SUN11031 is a peptide hormone currently in a 12 week Phase II trial for the cachexia of emphysema or chronic heart failure. The sponsor is Asubio Pharmaceuticals (formerly Daiichi and before that a branch of Suntory). No details of the peptide itself are in the public domain, the agent is administered by twice daily subcutaneous injection and was due to complete in 2011 (NCT00698828).

Tesamorelin

This is an analogue of growth hormone releasing factor (GHRHHHh) that I previously reviewed (7). It was recently approved as a treatment for abdominal lipodystrophy in HIV patients under the brand name Egrifta. It is now about to enter a clinical trial as a treatment for weight loss in severe COPD.

In addition to the above drugs for ‘weight loss’ or ‘cachexia’ for COPD on the clinicaltrials.gov website, there are 25 ongoing interventional trials for ‘sarcopenia’ of any cause. Most of these focus on exercise and/or dietary supplements, only a few for an investigational drug. The conditions for which they are being studied are mostly age-related muscle loss and chronic disorders. None are specifically for COPD.

In summary, weight loss in severe COPD remains an enigma of which we have little understanding and for which we don't yet have any effective treatments. Perhaps it should be designated an “orphan disorder.”