Retinoids. In a landmark study (Nat Med 1997;3:675–677), Massaro and Massaro showed that elastase-induced emphysema in rats was abrogated by administration of all-trans retinoic acid, atRA. Subsequent work has shown that retinoic acid and the biologically active metabolites of retinol play several key roles in alveolar development and regeneration post-injury. Most of that work has been done in mice and rats and its translation into humans is complicated by the fact, amongst other facts, that lung growth in humans, unlike in rodents, does not continue throughout life. Nevertheless, the possibility of regeneration of alveoli in the emphysematous human lung has lead to preliminary studies in humans. On the basis of some feasibility studies (Am J Respir Crit Care Med 2002;165:718–723; J Clin Pharmacol 2008;48:96–107), all-trans retinoic acid (atRA) and 13-cis retinoic acid were chosen for a 6-month NIH sponsored study called FORTE (NCT00000621). Although not designed or powered for clinically beneficial outcomes, small improvements in diffusion capacity and CT density were seen with the higher dose of atRA, warranting further study (Roth MD et al. CHEST 2006;130:1334–1345). In order to address problems that were seen with the bioavailability of retinoids in humans, synthetic retinoic acid receptor (RAR) agonists have also been developed. Of the several isoforms of RAR, RARγ appears to be the most promising target and a small molecule agonist developed by Hoffmann-La Roche, palovarotene, has recently completed a Phase II study in patients with moderate or severe emphysema (TESRA, NCT00413205). The outcomes included “measurements of exercise, gas transfer and lung densitometry” (Hind M, et al. Curr Opin Investig Drugs 2009; 10:1243–1250). Results are not available at the time of writing but may have become available by the time this column is published.
A search for patents relating to retinoids or RAR agonists for emphysema revealed several held by Roche in addition to palovarotene. There are several other patents for inhaled formulations of atRA and off-patent retinoids, but no other new retinoid molecular entities. Clinicaltrials.gov lists only the studies mentioned above.
Personalized Smoking Cessation. An interesting report in Molecular Medicine, [E-pub ahead of print] asks the question whether “genetic analysis can predict the success of a nicotine replacement strategy, or is that a pipe-dream?” (Their pun). The authors state that “genome wide association has identified groups of genomic markers that are associated with successful [smoking] quitting, allowing us to develop a “quit success” genotype score”. They report a relationship between the “quit success” genotype score and the level of nicotine dependence in a smoking cessation trial. If, as these results suggest, it were possible to predict the likelihood of success or failure with nicotine replacement therapy on an individual basis, it may be possible to personalize smoking cessation strategies by identifying those whose genotype score indicates they would not be candidates for NRT so that smoking cessation funds can be directed towards other methods in those subjects. No drug was involved, but it seemed a logical topic for a “Pipeline” column, [my pun].
New Clinical Trials in March and April 2010. According to BioPharm Insight, my source for new clinical trials each month, this was not a busy period. A total of 256 trials for all conditions were reported, (less than a quarter the usual number for a 2-month period), of which only 4 were for a COPD indication. Pearl initiated a Phase II study of a combination of formoterol fumarate and glycopyrrolate delivered by an HFA-propellant MDI system. Almirall initiated a similar Phase II LABA-LAMA combination study with formoterol and aclidinium delivered, one presumes, by their Genuair® DPI device. Novartis initiated a study of 4 different doses of their LABA indacaterol in a DPI formulation against salmeterol, which was designated as a Phase III study. (Indacaterol was approved in Europe last year and, as of May this year, has been launched in Germany, Ireland and Denmark under the brand name Onbrez Breezhaler. Novartis states they will file the NDA in US in the second half of 2010). Finally, there was a placebo controlled Phase IV investigator-initiated study of moxifloxacin for non-purulent acute exacerbations of COPD from the Hospital Clinic of Barcelona.
Biotech Companies. The first column in this series briefly reviewed the landscape of drug development. A year later it is time to look at an interesting corner of that landscape, -the biotech world. When the pharmaceutical rep calls on you with information about her company's new product, it is becoming more and more likely that the product began its life in the brain of an academic bioscientist and became a reality in some quite modest lab. It was nurtured through the preclinical stages by a persistent entrepreneur or two and survived the early proof-of-concept work and all the financial and practical challenges that killed off as many as 999 other candidates that were promising but that didn't quite have the right stuff. At some stage the product graduated into the larger world of conventional drug development after which it may have gone through ownership by more than one company before showing up as the product we could use in the clinic. We probably never have heard of the scientist(s) or entrepreneur(s) who conceived the product or funded the biotech company. It may no longer even exist; particularly if it was built on a single concept. This is the biotech world at its most modest. There are, of-course, a few much larger biotech companies which have matured and grown huge around a successful concept, -one thinks of the companies I mention below and the successful exploitation and commercialization of monoclonal antibodies, genetically engineered proteins, and small molecule inhibitors. But new ideas and biotech companies based on those new ideas are being spawned all the time, and my last item in this issue's column deals with one, ataluren.
Biotech companies, then, are those whose products or services primarily use biotechnology methods for their production, design or delivery (Wikipedia). At least 500, and there are probably many more, are recognized in the US with products that are intended for a medical use. They are usually founded by scientists who have a concept or technology that can be patented and exploited for a medical use but that needs development to get anywhere near commercial viability. Most are quite small with maybe 2 to 100 employees; Amgen is easily the biggest with more than 20,000 employees and revenues of more than $14 billion in 2006. The 90th largest biotech company has about 90 employees and annual revenues of about $20 million. The biggest have upwards of half a dozen approved products in the market and maybe 30 in the pipeline and are very profitable; the smallest have a single product in the pipeline and no approved product or sales. The former will be stable companies with every expectation of still being in business in a decade or more. The smallest may be looking only to get a promising Phase II trial result with a single product that will attract a buyout by a conventional pharma; –in other words, -built to be sold. It has been said that “..at one end biotech is just biological, at the other biotech is just another word for small pharma.”
What do biotechs produce? To quote the reference below, “Biotherapeutics account for 7.5 percent of all drugs on the market, comprise approximately 10 percent of the total expenditure for marketed drugs, and their use is growing at more than 20 percent per year.” About a third of all pipeline research programs are biotech drug candidates, and at least as many owe their existence to a concept that originated in academe and was first worked on in a biotech company. Annual biotech drug approvals were in single figures until 1996, after which the number abruptly climbed to around 20 per year, a level at which they have remained ever since. As total approvals have not increased significantly during that time period, biotech drugs constitute a progressively larger proportion of prescription drugs in the market. Unfortunately, new treatments for COPD are entirely absent from the pipelines of the 10 largest biotech companies, unless one includes 2 potential agents for pulmonary hypertension (Gilead) or a new alpha-1 antitrypsin formulation (Zemaira, CSL Pharma).
The commonest indication of biotech drugs is for a neoplastic disorder. This is followed by metabolic disorders, mainly diabetes. Other indications are for chronic disorders, -inflammatory diseases such as arthritis and psoriasis, multiple sclerosis, viral hepatitis and other chronic infections. Not a single one of the 25 top-selling biotech drugs in 2007 was for a COPD indication, unless one includes pneumococcal prophylaxis (Prevnar) and flu vaccine (Tamiflu) which come in at 14 and 15 respectively. In many cases this could be because when a biotech company's new molecule shows promise it leaves the biotech world to be acquired by a pharmaceutical company that has the resources to perform the hugely expensive phase III studies and to negotiate the regulatory issues. (Data from Biotechnology Drugs Report, 2009, BioWorld®, Atlanta).
Despite the absence of COPD drugs from the top of the biotech pipeline, I am not pessimistic. New treatments will have to come and our most pressing need, -a disease modifying treatment, -might well emerge from a biotech company before entering the pipeline of a major pharmaceutical company. Indeed, I see the main purpose of a “Pipeline” column as being to provide our subspecialty with advance notice of the advent of any such treatment even if it is only on the distant horizon.
Ataluren. Ataluren is described by its biotech developers, PTC Therapeutics, as a “potential protein restoration therapy”. In a few rare genetic disorders like Duchenne/Becker muscular dystrophy (DBMD) and certain forms of cystic fibrosis (CF), a vital protein fails to be correctly synthesized because of a nonsense mutation in the gene which results in a premature ‘stop’ signal and thus an incomplete, non-functional molecule. Ataluren is “a small molecule which allows the ribosome to bypass the premature stop signal and continue translation of the mRNA, resulting in a functional protein” (http://www.ptcbio.com/3.1.1_genetic_disorders.aspx). Ataluren could be called a “no nonsense” molecule—if you will allow me one more pun. Although it does not work equally well at all stop-codons, UGA being the most amenable apparently, it is somewhat miraculous, to my thinking, that such an agent exists at all. Orthodox molecular biology has it that the genetic code is holy doctrine. Not any more, it seems.
Ataluren is or was in 5 clinical trials for DBMD (one of which was recently halted for failure to meet expectations), and 5 trials for CF, including one in Phase III. If the concept of restoring synthesis of a functional protein in diseases due to a nonsense mutation proves valid, one anticipates it will be applied to other similar disorders including, one hopes, the rare forms of alpha-1 antitrypsin deficiency that are due to such mutations.
The sponsor of ataluren, PTC Therapeutics, exemplifies the biotech world. Founded by academic scientists in 1998, half its Board consists of PhDs, MDs, or both. It has 7 disclosed products in various stages, each based on the technology of post-transcriptional control of gene expression by small molecules, (PTC stands for ‘Post-Transcriptional Control’). I believe all its potential products have orphan drug status in the United States. Typically for a biotech of this size, it has partnered with a substantially bigger company, Genzyme, for its later stage clinical trials. It has no approved products and its financing is entirely due to grants from NHLBI, various CF and MD Foundations, the FDA's Office of Orphan Products, and investments by hedge-funds I presume, in all of which areas it seems to be quite successful, and necessarily so.
There are, incidentally, 583 orphan drugs currently in active development in the USA alone, with malignancy being the indication for over 100 of them. I will review those intended for a COPD indication (not many) in a future Pipeline column.
EXACT-PRO. On September 2, CRF a company that specializes in the development of patient reported outcomes in the life sciences, has received certification for 2 devices that address a long-felt need in COPD research, a consistent way to measure COPD exacerbations. Their press release states “the EXACT is a patient-reported outcome (PRO) measure designed to standardize the method for evaluating the frequency, severity, and duration of acute exacerbations of chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB). The devices use the Windows Mobile operating system. (Leidy et al. Published ahead of print on September 2, 2010 Am J Respir Crit Care Med 2010, doi:10.1164/rccm.201005-0762OC; http://www.fiercebiotech.com/press-releases/crf-health-achieves-exact-epro-vendor-certification-windows-mobile-systems).