Tough times ahead for big pharma?
Currently it’s the financial industry that is in trouble. Will the pharmaceutical industry be next? This could well be according to business analysts, in a recent report in the Financial Times.
The reasons for the bad prognosis are expiration of patents coinciding with shrinking pipelines and increasing competition from generics. Furthermore, the counterstrategy of mergers and acquisition isn’t seems to be working as expected.
Meanwhile, drug regulations are getting tighter. Alternative medicine, dietary supplements, and homeopathic medications are conquering the market while biotechnology and stem cell research are not delivering the promised blockbuster therapies everybody is hoping for.
In 2007, Roche outperformed for the first time its Swiss archival Novartis in earnings. However, even Roche delivered lower than expected results in the first quarter of 2008 due to decreasing demand for Tamiflu.
Other drug companies are expecting tough times as the patent of their blockblusters are about to expire. GSK’s Lamictal goes off patent this year and Pfizer’s Lipitor in 2010. Other best-selling drugs whose patents are due to expire are Johnson & Johnson’s Risperdal, Astra Zeneca’s Seroquel and GSK’s Avandia, according to FT.
How Genetic Variation is Affecting Drug Development
In the March 2 issue of the Swiss newspaper “SonntagsZeitung” is an interesting article entitled “Pillen in Massanzug” which can be translated as “Custom-made Pills” [1]. The article basically explores how increased knowledge of human genetics is creating changes in drug development and speculates on the possibility of personalized medicine.
Here are some examples:
Carbamazepine
In December last year, The US FDA recommended genetic testing in connection with the prescription of the drug carbamazepine. Carbamazepine is commonly used for the treatment of epilepsy, bipolar disorder and neuropathic pain. Recently, certain patients – notably of Asian ancestry - were observed to develop serious skin disorders as adverse reaction to the drug. “Studies have found a strong association between certain serious skin reactions and an inherited variant of a gene, HLA-B* 1502, an immune system gene, found almost exclusively in people with Asian ancestry.” [2] Prior to this recent recommendation, genetic testing was recommended for all patients regardless of ethnicity. However, with the recent results of genetic studies, genetically high-risk patients have been narrowed down to an ethnic group, making life easier for health professionals and their patients, as well as the drug manufacturers themselves.
Statins
The use of the anti-cholesterol drugs statins has been associated with muscle pains and weakness. Researchers have recently identified the gene that may hold the key to statin-induced muscle toxicity. The atrogin-1 gene is associated with different types of muscle atrophy. In vitro and in vivo studies show that statins activate atrogin-1 gene leading to skeletal muscle damage [3]. Atrogin-1 gene expression may differ in different people, explaining the wide range of muscle symptoms (from very mild to debilitating) in statin users.
Trastuzumab
The anti-cancer drug Herceptin (trastuzumab) is a HER2/neu receptor antagonist and is indicated only for patients with HER2-overexpressing breast cancer. The drug specifically targets a gene (HER2) that causes breast cancer so that patients with other types of breast cancer cannot benefit from this drug. Considering the rather serious side effects involved (cardiomyopathy and pulmonary toxicity), HER2 gene testing is highly recommended before chemotherapy can be started. [4]
Ezetimibe
Ezetimibe is one of 2 combination drugs tested by the controversial ENHANCE trial. The study participants have heterozygous familial hypercholesterolemia, a genetic disorder characterized by cholesterol deposition and high plasma concentrations of low-density lipoprotein cholesterol [5]. Unfortunately, the trial results did not show any benefit from ezetimibe. However, drug testing on genetically distinct populations is becoming a common practice in drug development.
So how far are we from personalized medications? I personally think this will soon be technologically possible but whether it`s financially feasible is a different matter.
References:
1. SonntagsZeitung, 2 March 2008, p.73
2. FDA News, 12 December 2007.
3. Hanai et al. J Clin Invest. 2007 December 3; 117(12): 3940–3951.
4. Herceptin prescribing information, Jan 2008.
5. Yuan et al. CMAJ • April 11, 2006; 174 (8).
Latest approvals by the US FDA
• The proton pump inhibitor (PPI) Nexium (esomeprazole magnesium) is indicated for short-term treatment of gastroesophageal reflux disease (GERD) in children ages 1 to 11 years old. Nexium is manufactured by AstraZeneca [1].
• Xyntha Antihemophilic Factor (Recombinant) Plasma/Albumin Free is a new treatment for hemophilia A. Hemophilia A is a hereditary blood-clotting disorder that affects mainly males. It is caused by a mutation of the factor VIII, resulting in clotting factor VIII deficiency. Xanthia is a genetically engineered version of factor VIII. It is manufactured by Wyeth Pharmaceuticals Inc. [2].
• The Interleukin-1 blocker Arcalyst (rilonacept) is an orphan drug indicated for the treatment of two Cryopyrin-Associated Periodic Syndromes (CAPS) disorders. CAPS are very rare conditions of inflammation. Orphan drugs are drugs intended for the treatment of rare diseases. To make it worthwhile for drug companies to develop such drugs in the US, manufacturers of orphan drugs enjoy tax incentives and longer period of exclusivity as provided for by the US Orphan Drug Act. Arcalyst is manufactured by Regeneron Pharmaceuticals Inc. [3].
References:
Pediatric clinical trials: damned if you do, damned if you don’t
Drug regulators are in a quandary. On the one hand, they’d rather spare children from being used as test subjects in clinical trials. On the other hand, recent developments show an urgent need for pediatric testing.
There have been recent reports of adverse side effects, some of them fatal, attributed to OTC drugs for children. These concerned seemingly innocuous cough and cold medications containing active ingredients such as pseudoephedrine, paracetamol [1,2], and camphor [3]. But prescription drugs for children`s ailments such as asthma and ADHD are incriminated as well.
This brought to light how very little we actually know about pediatric pharmacology.
The problem lies with the fact that many drugs with well-established efficacy and safety profile have only been tested in adults. With an aging population and low birth rates in developed countries, the pediatric drug market is not really top priority for pharmaceutical industries. Very little money is allocated for pediatric R&D. Pharmacological results were simply extrapolated to pediatric population as “miniature adults.”
The issue is compounded by lack of test subjects. Very few parents in developed countries would ever consent that their children be enrolled in a clinical trial. Most pharmaceutical companies turn to developing countries for testing. Although there are strict guidelines regulating pediatric testing, there are still concerns about adherence to GCP in those countries.
The regulators are now scrambling to come up with solutions to plug this knowledge gap on pediatric drugs.
Last year, the US passed the Best Pharmaceuticals for Children Act 2007 and an amended version (2007) of the 2003 Pediatric Research Equity Act. The Acts empowered the US FDA to require drug companies to test new drugs on children before approval [4]. However, there is still a lack of knowledge on drugs approved before 2003.
In Europe, the EMEA is requiring a pediatric investigation plan for all new drug applications starting July 2008 (unless a non-pediatric use waiver is justified). In addition, it is funding research on off-patent drugs as well as looking into pediatric clinical data that may not have been previously published [5, 6].
In the meantime, millions of children need medications while drugs against cancer, infections, asthma, high blood pressure and hyperactivity currently available are waiting to be tested for pediatric use. Do we use these drugs or not ? Quandary for doctors and parents as well.
Damned if you do. Damned if you don’t.
References:
1. Wingert WE, Mundy LA, Collins GL, Chmara ES. Possible role of pseudoephedrine and other over-the-counter cold medications in the deaths of very young children. J Forensic Sci. 2007 Mar;52(2):487-90.
2. Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications–two states, 2005. Morb Mortal Wkly Rep. 2007 Jan 12;56(1):1-4.
3. Press Release, NYC Department of Health. January 17, 2008. Health department warns parents to keep camphor products away from children.
4. US FDA, Pediatric Drug Development. Retrieved 27 Jan 2008.
5. Sinha G.J. EU law mandates drug testing in children. J. Natl Cancer Inst. 2008 Jan 16;100(2):84-5.
6. EMEA Press Release Paediatric Committee (PDCO), 25 Jan 2008.
The newest beta-blocker: will it sell?
It is the 19th of its kind in the market. No wonder cardiovascular experts were not that excited when the US FDA approved the selective beta-blocker Bystolic (nebivolol) this month [1].
However, nebivolol has some characteristics that other beta-blockers don’t have.
Efficacy
Nebivolol offers a new treatment option for hypertension through its “added pharmacological properties of producing vasodilation and reducing total peripheral resistance brought about by modulation of nitric-oxide release.” These properties make the drug more effective than traditional beta-blockers [2].
Safety
Compared to traditional beta-blockers, nebivolol causes relatively lower incidence of side effects normally associated with this class of drugs [1,2]. “Nebivolol is a so-called vasodilating beta blocker. Thus, in contrast to traditional beta blockers, it is more patient friendly in that it maintains systemic flow and blood flow to target organs, lowers vascular resistance, and has very little, if any, metabolic adverse effects”, according to one expert [2].
Both the manufacturer (Mylan Bertek Pharmaceuticals) and the marketing company (Forest Laboratories) hope these properties would be the selling point to make the drug attractive to both doctors and patients.
The main competitors of nebivolol would be the similar but non-selective beta-blocker carvedilol as well as cheap generics.
Sources:
Recalls and OTC Disapproval: A Gloomy December for Merck
This is definitely not Merck’s month.
On 12 December 2007, Merck announced the voluntary recall of potentially contaminated batches of the influenza vaccines PEDVAXHIB and COMVAX. These vaccines are indicated for infants and young children for protection against the seasonal flu and hepatitis B. The affected batches were distributed in April 2007 [1].
On another front, a US FDA advisory panel voted against Merck’s application for the prescription drug Mevacor 20 mg to be sold over-the-counter. Mevacor (lovastatin) is indicated for the treatment of elevated cholesterol levels. It has been on the market as a prescription drug since 1997. The panel’s recommendation is based on concerns of the use of the drug by misinformed consumers who may not actually benefit from it. The recommendation is not binding and a final decision would be reached in January 2008 [2].
Merck News Item, 12 Dec 2007
Merck News Item, 13 Dec 2007
The STEP Trial: Discontinuation and Unblinding
The STEP Trial: The STEP study was a phase II multinational, randomized, double-blind, placebo-controlled clinical trial which was started in 2004.
The Investigational Drug: The V520 HIV vaccine candidate is a combination of 3 components made from a weakened adenovirus type 5. The vaccine serves as a vector of 3 synthetically produced HIV genes known as gag, pol and nef. These HIV genes would supposedly induce “an HIV-specific immune response through the body’s own CD8 T-cells, which become programmed to recognize and kill HIV infected cells.”
The Sponsors: The STEP trial was sponsored by Merck, the National Institute of Allergy and Infectious Diseases (NIAID), and the HIV Vaccine Trials Network (HVTN).
The The Study Population: 3,000 HIV-negative participants from different ethnic groups. They are aged between 18 and 45 years of age and at high risk of HIV infection. The trial was conducted in the United States, Peru, Brazil, Dominican Republic, Haiti, Jamaica, Australia, and South Africa.
The Efficacy Endpoints: The primary efficacy endpoints were to evaluate the ability of the vaccine to prevent HIV infection and to reduce virus proliferation in infected individuals.
The Discontinuation: On 21 September 2007, Merck announced the discontinuation of the STEP study due to poor efficacy profile. The vaccine did not prevent infection nor reduce viral loads in the bloodstream of HIV-positive individuals.
The Unblinding: In November 2007, Merck and HVTN announced their decision to unblind the trial based on concerns that the vaccine may actually have induced susceptibility to HIV infection in study participants. Sources:
HVTN Press Release 13 Nov 2007
Sanofi-Aventis Joins Forces with Regeneron
The French pharmaceutical giant Sanofi-aventis is joining the biotech bandwagon. Initially thought to be a slowmover in the biotech field, it is now stepping up its drug development program and is particularly concentrating on the development of therapeutic antibodies.
In order to attain these goals, Sanofi-aventis has decided to increase its stake in the biotech company Regeneron from 4% to 19%. As part of the payment, Sanofi-aventis will fund a big part of research costs in the next five years. Research will focus on the development of fully human monoclonal antibodies [1, 2].
Part of the colloboration portfolio are two promising drugs, namely:
- Antibody to Interleukin-6 receptor (IL-6R), indicated for rheumatoid arthritis, currently undergoing Phase I clinical trials.
- Antibody to Delta-like ligand-4 (Dll4), indicated for tumors, to enter clinical development in 2008.
From this collaboration, Sanofi-aventis aims to develop about 20 drug candidates annually and targets about 30 new drug submissions by the end of 2010 [1,2].
[1] 29 Nov 2007, Sanofi-aventis press release
[2] 29 Nov 2007, Regeneron press release