Losartan

Losartan Drug Discovery, Development, and Commercialization

Losartan was developed rather unexpectedly by a group of chemist and pharmacologists who had just completed work for their PhDs. Losartan was a first in its class known as angiotensin II receptor antagonists. This class is used to treat hypertension. Pharmaceutical companies began focusing on the renin-angiotensin system in the 1970s, but DuPont, the company responsible for synthesizing the non-peptide, losartan, began their work around 1982 (Bhardwaj, 2006). One of the target options for this system was angiotensin-converting enzyme (ACE). It was targeted to “prevent the formation of Ang II and subsequent steps leading to hypertension,” (Bhardwaj, 2006). 

A scientist for DuPont, Taber, suggested Ang II as a target since most companies were focused on ACE inhibitors after the approval of captopril and hypothesized this target would be less toxic to the patient (Bhardwaj, 2006). Simultaneously, a chemist named JV Duncia was working for DuPont and had been assigned to work on Ang II receptors, too. He started by “making small peptide analogues of different fragments of Ang II to see if any would bind to the receptor and prevent Ang II from doing so,” (Bhardwaj, 2006). Ultimately, Duncia was unsuccessful in his search for a suitable peptide. 

However, the luck of these scientist began to change around 1982 when DuPont discovered Takeda Chemical Industries had two patents for compounds noted as imidazole derivatives that were nonpeptides and useful for Ang II antagonist activity (Bhardwaj, 2006). Around this same time, another chemist, DJ Carini, had been hired by DuPont and was assigned to see if the claims made by Takeda were true of these compounds, yet he concurrently decided to continue synthesizing peptides, too. In the meantime, two pharmacologists, Chiu and Wong, were also assigned to work on testing the Takeda compounds and found that they had a weak affinity for Ang II (Bhardwaj, 2006).  

Wong decided to complete more in vivo testing to confirm the results of an assay by mistakenly injecting a large quantity of the compound into a rat. He was unaware that the quantity mattered for drug discovery and use in humans. This error, however, showed that there was selectivity for Ang II by the compound despite the weakness it had displayed via the assay (Bhardwaj, 2006). This selectivity is what made losartan first in its class when compared to ACE inhibitors such as lisinopril. ACE inhibitors block the conversion of Ang I to Ang II which results in blood pressure lowering, but there can also be quite a few adverse effects such as hypotension, dizziness, cough, and increased serum creatinine and BUN levels. On the other hand, losartan -and other ARBs- is able to bind directly to Ang II to block its secretion and thus, lower blood pressure. Ang II receptor blocks also have decreased adverse reactions with cough being common if the patient experienced it with an ACE first in particular.  

Using computer modelling, the team realized that the Takeda compound was too small compared to Ang II, so they began the hunt of predicting the contact points of the receptor to attempt to discover a more realistic and stronger compound that could be synthesized. Duncia and Ripka, a computer analyst for the machine at DuPont, realized Ang II had a carboxylic acid and so did the Takeda compound. Duncia wondered if adding an additional acidic functionality to the compound would increase the potency and it did by 10-fold (Bhardwaj, 2006). Thus, the team continued to add and subtract different functional groups to the compound to increase potency and blood pressure lowering effects.  

Finally, in March 1986, a tetrazole acidic functional group was added to their latest compounded at DuPont, EXP-7711, and losartan was born (Bhardwaj, 2006). This functionality is what allowed further development of losartan into other compounds such as candesartan, irbesartan, telisartan, valsartan, and others. DuPont decided to join forces with Merck, a big-name pharmaceutical company, to further the research on losartan in clinical trials (Bhardwaj, 2006). In April 1995, the FDA approved losartan, brand name Cozaar, as the first Ang II receptor antagonist on the market.  

Since its approval in April of 1995, losartan has been indicated for 3 conditions and currently being studied for several others that will be mentioned a little later. The 3 current indications are the treatment of hypertension either alone or in combination with other antihypertensives, stroke reduction in patients with both hypertension and left ventricular hypertrophy and diabetic nephropathy in patients with type 2 diabetes and an elevated serum creatinine and proteinuria (Ripley, 2010). Amazingly, a look at the National Institutes of Health and ClinicalTrials.gov, there are currently three active trials for losartan involving its usefulness as an antifibrotic in the treatment of HIV infected individuals.  

Regarding the financial aspect of losartan, there was a much greater revenue for angiotensin receptor blockers than anticipated. At the time of the launch for Cozaar, the trade name of losartan, the estimated revenue in the U.S. was around $200 million dollars. By 2005, losartan was generating approximately more than $3 billion in the U.S. alone (Bhardwaj, 2006). The unfortunate part for DuPont is that they bought there share from Merck in the summer of 1998. The New York Times reported “DuPont would pay Merck $2.6 billion for the drug company's half of the DuPont Merck Pharmaceutical Company, the joint venture they formed in 1991,” (Deutsch, 1998). There was speculation on why Merck made the offer to disjoin, but DuPont agreed to the terms. Ultimately, DuPont left the pharmaceutical business in 2001 and Merck continues to be a name in the pharmaceutical industry.  

Also, there have been several studies designed to determine the economic impact losartan has had since being introduced on the market. One study, the RENAAL trial, discovered there was a cost benefit from losartan after 2-2.5 years and at a 4 year follow up in patients with end stage renal disease (Ripley, 2010). The cost savings that was seen by averting days in these patients was about $5,300 per individual in patients in the US (Ravera, 2006). In the Netherlands, the LIFE trial was used to evaluate the medication costs of losartan versus other drugs such as atenolol. It was discovered that losartan was more expensive than atenolol by $64, but the “net cost per life year gained was only $1,083,” which is well under the cost that is considered worth utilizing a treatment (Boersma, 2010). Therefore, losartan has stood its ground on many formulary list as one of the preferred ARBs by many insurance companies across the world.  

Despite the wonderful impact losartan has had on the lives of many hypertensive patients, there have been a few recalls since its release. As of 2017, there have been a total of 12 FDA recalls regarding losartan initiated by the FDA or the manufacturer themselves. All 12 of the recalls to date have been Class II meaning there is danger of death or serious injury, but it is not immediate. The largest recall took place in 2015 when Apotex recalled over 90,000 bottles with varying pill counts and dosages due to “failed content uniformity specs,” via MedPro disposal taken from the FDA. Overall though, losartan is a top ten generic medication with a relatively low recall rate.  

Lastly, losartan was approved in April 1995 as stated above and the Merck’s patent expired in April of 2010 in the United States and February and March of 2010 on the European Market. In 2009, losartan generated a revenue of about $1.2 billion for Merck, but the patent expiration in 2010 lead to an estimated loss of $2.1 billion via the U.S. Securities and Exchange Form 10-K for Merck & Co., Inc. Despite the losses associated with the patent expirations, Merck & Co., Inc. continues to rank as one of the top 10 pharmaceutical companies with total pharmaceutical sales around $35.4 billion dollars in 2017 (Merck & Co., Inc, 2018). Overall, I would argue the impact of losartan has been nothing short of amazing and even 23 years later, we are still able to study and develop it further to treat an array of other conditions. 

References: 

1. Bhardwaj, G. (2006). Drug Discovery Case History: How the antihypertensive losartan was discovered. Expert Opinion, 1(6), 609-618.  
2. Boersma C, Voors A, Visser ST, de Jong-van den Berg LT, Postma MJ. Cost effectiveness of angiotensin receptor blocker monotherapy in patients with hypertension in the netherlands: a comparative analysis using clinical trial and drug utilization data. Am J Cardiovas Drugs. 2010;10:49–54. 
3. Deutsch, C. H. (1998). DuPont to Buy Merck's Share of Venture. Retrieved from https://www.nytimes.com/1998/05/20/business/dupont-to-buy-merck-s-share-of-venture.html 
4. Full List of FDA Losartan Recalls Through 2017. (2017). Retrieved from https://www.medprodisposal.com/full-list-of-all-fda-losartan-recalls-through-2017 
5. Losartan Clinical Trials, Side Effects. (2010, September 10). Retrieved from https://aidsinfo.nih.gov/drugs/567/losartan/0/patient 
6. Merck & Co., Inc. (2010). 2009 annual report. Retrieved from https://www.sec.gov/Archives/edgar/data/310158/000095012310018679/y81622e10vk.htm#103 
7. Merck & Co., Inc. (2018, February 2). Merck Announces Fourth-Quarter and Full-Year 2017 Financial Results. Retrieved from https://investors.merck.com/news/press-release-details/2018/Merck-Announces-Fourth-Quarter-and-Full-Year-2017-Financial-Results/default.aspx 
8. Ravera M, Re M, Vettoretti S. Economic evaluation of angiotensin receptor blockers in type 2 diabetes, hypertension, and nephropathy. J Am Soc Nephrol. 2006;17(4 Suppl 2):S44–S48. 
9. Ripley, E., & Hirsch, A. (2010). Fifteen years of losartan: what have we learned about losartan that can benefit chronic kidney disease patients. International journal of nephrology and renovascular disease, 3, 93-8.