Recently, Reuters reported that “Drug companies generally don’t disclose all the reasons new medicines fail to win U.S. marketing approval, even though regulators often reject treatments over concerns about safety or effectiveness”.

Reporter Lisa Rapaport quotes Dr. Peter Lurie, FDA associate commissioner for public health strategy and analysis, saying “‘Only a minority of the press releases clearly stated that receipt of a complete response letter meant that marketing could not commence, and most findings associating the drug with a higher mortality rate went unmentioned.’” (emphasis added)

In her report, Rapaport notes that Dr. Lurie reviewed announcements by pharmaceutical companies following FDA disapproval released between 2008 and 2013 and found that “About half of the time, the complete response letters cited shortcomings in both safety and effectiveness. Out of 191 concerns about effectiveness raised in the letters, drugmakers disclosed a total of 30 in press releases, while companies shared 22 of 150 safety concerns.

Roughly half of the letters asked for new clinical trials to study safety or effectiveness; and in 59 percent of these cases companies disclosed this in a press release.”

This practice makes intuitive sense for drug companies, however cynical it is to admit. Why would pharma companies want to disclose precisely how a proposed product failed to meet FDA safety and efficacy requirements?

This actually raises an important issue for the FDA: should all proposed pharmaceutical products, not only approved drugs and devices, be a part of public knowledge?  Companies whose stock is traded on the open market are already required to detail drug rejections (as is noted in the aforementioned Reuters piece), but not all drug companies are publicly held.  Privately-held pharmaceutical corporations will argue that disapproved compounds consist in proprietary knowledge, and they may be right, public health concerns aside.

It nonetheless still is important to consider drugs that “may have been,” (or rather, drugs that failed to surmount the ever-weakening FDA approval process).  Many drugs sold in America are disapproved upon initial FDA review, and following simple adjustments to study design, methodology, or statistical rigour are approved without meaningful changes to drug design.  That is, the method used to test a drug’s effectiveness or safety can be adjusted, and a disapproved drug is made legal, without change to a drug’s chemical design.

With attention paid to disapproved drugs through open communication between pharmaceutical companies, the FDA, and the American public, consumers can understand more completely whether substantive changes were made to a drug’s design between initial disapproval and subsequent approval.

By no means would I suggest it is necessary, or would even be helpful, that the American populous attempt a measure of biochemical or pharmacological scrutiny when reviewing the FDA’s news ticker.  That is the task of science journalists and healthcare analysts.  As long is information regarding drug disapproval is available in full, dissemination to the public is possible, and that is a good thing.

Yesterday (1/16/2014) Reuters reported that an FDA advisory panel rejected a call by Johnson and Johnson to approve their anticoagulant Xarelto (rivaroxaban) for acute coronary syndrome by a vote of 10-0 with one abstention.

While Xarelto “is already used to treat and prevent deep vein thrombosis and pulmonary embolisms and to reduce the risk of stroke and blood clots in patients with an irregular heart beat that is not caused by heart problems”, due to a lack of data and a failure by the company to demonstrate the benefits of Xarelto outweigh the risk for bleeding associated with the drug, the FDA advisory panel decided that “Xarelto should not be approved to prevent further heart problems in patients who have recently suffered a heart attack”.

If the drug had been approved for acute coronary syndrome, it could be prescribed for “any condition brought on by a sudden, reduced blood flow to the heart, including heart attack and chest pain.”

Sadly, it seems Johnson and Johnson made its case based on evidence from only one research study.  Dr. Stephen Grant, consulting professor of medicine at Stanford University School of Medicine, gave an interview to Reuters, stating “Looking at the overall study it wasn’t robust enough in terms of statistical significance to be considered a positive study, and with that it was not possible to look at subgroups.”

“Dr. Stephen Grant, deputy director of the FDA’s division of cardiovascular and renal drugs, said the benefit of the drug met the criteria required to approve a drug based on a single trial – namely, proof it was superior in some way to existing products.”

On Thursday, January 9th 2014, MedlinePlus reported that gene therapy may be helpful to patients suffering from advanced-stage Parkinson’s disease, as demonstrated by new research.

According to the researchers, this therapy, “called ProSavin, works by reprogramming brain cells to produce dopamine, the chemical essential for controlling movement”. (MedlinePlus)

This research comes from an English company, Oxford BioMedica, where lead researcher Kyriacos Mitrophanous is quoted, stating “We demonstrated that we are able to safely administer genes into the brain of patients and make dopamine, the missing agent in Parkinson’s patients”.

Patients with Parkinson’s, a disease characterized by insufficient dopamine in the brain, suffer deceased muscle control which may begin as a slight tremor, but “also commonly causes stiffness or slowing of movement.” (Mayo Clinic)

“‘The ProSavin study was a positive and important first step for a potential gene therapy for Parkinson’s disease,’ said Dr. Michael Okun, national medical director at the National Parkinson Foundation. ‘The results of this preliminary study revealed a promising safety profile, and it will be interesting to observe longer-term benefits and how ProSavin will compare to other therapies such as deep brain stimulation.’” (MedlinePlus)

While ProSavin has not yet proven itself more beneficial than levodopa, the mainstay in dopamine therapy for Parkinson’s disease, or deep brain stimulation, a technique for boosting dopamine production using electrical stimulation with wires and an external battery pack, gene therapy carries at least one theoretical advantage.

According to Mitrophanous, as the disease progresses over time, patients require more and more medication.  With gene therapy, the body is “tricked,” if you will, into creating the dopamine it needs itself.

“Patients injected with ProSavin had mild to moderate side effects. The most common while on medication were involuntary movements (dyskinesias) and switching between mobility and immobility, called on-off phenomena, which occurs as levodopa wears off.”  However, “All patients showed significant improvements in motor scores in the 12 hours after they stopped taking their other medications and at six months and a year after surgery, the researchers found.” (MedlinePlus)

In recent pharmaceutical news, a new cancer drug from Peregrine Pharmaceuticals, Inc. called Bavituximab has earned Fast Track designation by the US Food and Drug Administration, The Wall Street Journal reports.

“The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration (FDA) that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days. Such status is often given to agents that show promise in treating serious, life-threatening medical conditions for which no other drug either exists or works as well.” (Wikipedia)

Bavituximab is used in the treatment of “second-line non-small cell lung cancer (NSCLC)” and “represents a new approach to treating cancer.” (WSJ)

This drug works by targeting immunosuppressive molecules known as phosphatidylserine (PS).  While PS molecules are found inside healthy cells, in cancer cells they lie on the outer membrane “of cells that line tumor blood vessels”, and make for a relatively straightforward target for cancer drugs.  Bavituximab seeks out PS molecules and binds with them, thus suppressing their immunosuppressant quality, if you will, and allowing the immune system to attack the cancerous cells. (WSJ)

The research explaining the mechanism by which Bavituximab targets PS molecules appears in an October 2013 edition of Cancer Immunology Research, the peer-reviewed publication of the American Association for Cancer Research.

“Bavituximab is currently being evaluated in several solid tumor indications, including non-small cell lung cancer, breast cancer, liver cancer and rectal cancer with a trial in advanced melanoma anticipated to initiate in the near future.” (WSJ)

Recently, National Institutes of Health reports that it has possibly discovered certain genes that can be targeted for the treatment of Parkinson’s disease.  Parkinson’s is a disorder of the central nervous system (which includes the brain and brain stem).  Early signs of the disease are shaking and impaired movement, while later signs may include problems with thinking, dementia, and depression.  Parkinson’s is mostly found in people over the age of 50.

Richard Youle is an investigator at the National Institute of Neurological Disorders and Stroke and is quoted saying, “We discovered a network of genes that may regulate the disposal of dysfunctional mitochondria, opening the door to new drug targets for Parkinson’s disease and other disorders”.  It is thought that Parkinson’s is brought about by the accumulation of damaged mitochondria that are not recycled by the body.  By understanding which genes are responsible for triggering the removal of dysfunctional mitochondria, we can seek to repair those apparently nonfunctional genes and thus curb Parkinson’s.

Mitochondria are the powerhouses of the cells, using oxygen to convert chemical fuels into energy that the human body can use.  This chemical fuel is called Adenosine Triphosphate (ATP) and is used by the cells to carry out their individual functions.  Certain proteins that are found inside of cells are there to detect when mitochondria are not working properly.  Once these proteins find a dysfunctional mitochondria they tag it and the body dissolves the mitochondria.  This is a crucial part that needs to function properly in order for the body to get rid of the unwanted mitochondria.

With the development of new technologies we are now able to have a better understanding of how the mechanism of a disease works, and this insight can help scientists develop new treatments for many disorders that are devastating for afflicted individuals.

A recent article by Bill Berkrot and Ransdell Pierson (published in Reuters) reports on restrictions being lifted from the use of the drug Avandia.  Avandia is a diabetes drug made by the company GlaxoSmithKline that was thought to increase the risk for heart attacks for people using the drug.  The U.S. Food and Drug Administration conducted an investigation into the safety of the drug and found there was not a significant increase in risk for heart attacks with Avandia, and their recommendation led health regulators to lift the restrictions of use for the drug.

Type I diabetes is an autoimmune disease that inhibits the body from properly controlling the amount of sugar in the blood.  Type I diabetics do not produce insulin, which acts like a key that allows sugar to enter the cells.  Cells gain energy from sugar, and will die without the proper supply.  Type II diabetes can come as a result of a poor diet and lack of exercise that causes the pancreas to form defective insulin molecules that do not adequately perform their function.  Both types of diabetes are serious medical conditions that can be fatal if not properly handled.

A 2007 report that claimed Avandia was dangerous prompted a halting of the distribution of the drug from Europe, and resulted in restrictions on the sale of the drug in the US.  The chemical name of Avandia is rosiglitazone had been one of the best selling medications for Glaxo, earning the company billions of dollars before rumors of the drugs dangerous characteristics came about.  Despite the fact that recent studies have shown there is no increased risk for heart attack while using Avandia, it is still assumed the drug will only be prescribed to patients who have tried other diabetes medications without success.  Only a small fraction of Americans continue to take Avandia since the restrictions were put in place.

Malaria is an infectious disease that affects millions of people throughout the world every year.  Most reported cases come from the Sub-Saharan Africa and Asia.  Thousands of people die each year from this disease, and people living in poor countries are at the highest risk.  Parasites from the genus Plasmodium use the biting of mosquitoes to spread from host to host.  Once these unicellular microorganisms enter the circulatory system of their host, they travel through the blood and eventually reach the liver.  In the liver, the Plasmodium parasites are able to reproduce and make their way to the rest of the body.  Typical signs and symptoms of Malaria include headaches and fevers.

Recently, researchers from the National Institutes of Health have found that a certain anti-malarial compound called imidazopyrazines can negate the functions of the protein “PI4K” that stimulates the development and growth of the Plasmodium parasites.  (Imidazopyrazine does not allow the parasite to mature and develop when it reaches the liver of its host.)

Dr. Winzeler, from the University of California, San Diego and Novartis Research Foundation, conducted a study that used imidazopyrazines for the treatment of infected mice with Plasmodium parasites.  They found that imidazopryazine was effective in preventing the malaria-causing parasites to develop and spread their disease.  However, the Winzeler study also found that some of the Plasmodium parasites formed an altered or deformed version of the PI4K protein that made them immune to the imidazopryazine compound.  Hopefully more research will be funded in this area.

As it currently stands, Primaquine is the only drug approved for the treatment of malaria.

Recently, a report published on the Director’s Blog at the National Institutes of Health website discussed new microRNA research on cholesterol.  Cardiovascular disease is one of the most common medical issues today, and cardiovascular health is heavily influenced by cholesterol levels.  There are two types of cholesterol, high-density lipoprotein (HDL) also known as “good” cholesterol, and low-density lipoprotein (LDL) known as “bad” cholesterol.  One of the strongest markers of cardiovascular health is the ratio of HDL to LDL.  Oftentimes statins are prescribed to adjust unhealthy HDL to LDL ratios.  These statins work by lowering LDL levels.

Researchers have explored different types of medications that work by increasing HDL rather than lowering LDL.  One new approach to increase HDL levels involves targeting microRNA (miRNA) which regulate protein production by disabling specific RNA templates called mRNA.  This theory was tested in mice; researchers blocked a specific miRNA and the animals’ HDL rose.  In humans however, HDL production is also regulated by another miRNA, so a team of researchers designed an anti-miRNA molecule that could inhibit both.  This treatment was tested in monkeys, and showed a 40% increase in HDL levels, without any major side effects.  Researchers are now evaluating its safety in preparation for possible human clinical trials.

This research is not only significant as a cholesterol therapy, additionally it is the first time that a single anit-miRNA molecule has been used to induce a therapeutic effect in primates.  This lays the groundwork for future development of therapies targeting other families of miRNA.  The author of this report, Dr. Francis Collins, stated that “one thing is clear: miRNAs are powerful regulartory molecules and may open the door to new treatments for cardiovascular disease, as well as many other conditions.”

Human immunodeficiency virus (HIV) infects more than 34 million people worldwide.  HIV is a virus that causes acquired immunodeficiency syndrome (AIDS), a condition, which does not allow the immune system to fight off other lethal infections.  HIV. The immune system functions by recognizing proteins on the surface of viruses and bacteria.  HIV is unique in that the human immune system cannot identify the protein on its surface.  This is due to the protein’s ability to rapidly mutate.  This also makes it difficult to create a vaccine.  Vaccines function by introducing the immune system to the protein of a harmful bacteria or virus, which allows the immune system to identify the protein in the future.

Recently, however, a team of scientists at the Scripps Research Institute and Weill Cornell Medical College engineered a more sturdy form of the protein.  This is significant because high resolution imaging of the protein had been elusive due to its complex and delicate structure. The results were published online in 2013, in the journal Science.

The team of scientists was able to determine the structure of the protein using cryo-electron microscopy and X-ray crystallography.  This finding may be critical in finally creating an HIV vaccine. One of the researchers, Dr. Ian Wilson stated “Most of the prior structural studies of this envelope complex focused on individual subunits, but the structure of the intact trimeric complex was required to fully define the sites of vulnerability that could be targeted, for example with a vaccine”.

Published Thursday, scientists at the National Cancer Institute wrote an article called “NIH Mouse Study Finds Gut Microorganisms May Determine Cancer Treatment Outcomes”.  The National Cancer Institute believes they may have found a connection between the presence of certain organisms living in the human gut and the success of cancer therapy.  Mice that had cancerous tumors were studied and the mice that did not have these microorganisms had an impaired ability to fight cancer growth and live longer.  These microorgansisms that live within the gut are called “commensal microbiota” and do not negatively affect their host.  Chemotherapy drugs such as oxaliplatin and cisplatin also had a diminished effect for the mice that lack commensal microbiota.

Some reports suggest that chemotherapy drugs harm the intestinal microbiota and affect the anti-tumor immune response intended by the drugs.  The bacterial composition in the gut does not return to normal after being treated with antibiotics and may permanently inhibit the effectiveness of anti-cancer therapy and people who have frequently used antibiotics throughout their life may be included for this decreased effectiveness of cancer drugs.  Researchers are now trying to determine how these microorganisms send messages to different parts of the body and increase levels of inflammation to infected parts; it is thought that this signal to change the type and level of inflammation in the infected body organ is related to the successful outcomes with cancer therapies.

The mice used for this study were raised in sterile environments so they did not acquire any bacteria and were given strong antibiotics to ensure they did not harbor any of the commensal microbiota.  Once the necessary precautions were taken to sterilize the mice, they were injected with cancer cells that would form tumors in the mice.  This study showed that the germ free mice did not respond well to the drugs meant to target their tumors.