As the weeks go by, we try to collect stories and news coverage regarding physician-industry collaboration and the breakthroughs and successes that come from such relationships. Below is a short summary of some recent physician-industry-academic-government collaborations and the impact they have had on individual patients, the U.S. healthcare system, and beyond.
In light of the recently proposed budgets for FY 2014, numerous scientific and medical groups have urged Congress and the Obama Administration to increase funding for research. The Pharmaceutical Manufacturers and Researchers of America (PhRMA) recently noted that its member companies have invested approximately $550 billion since 2000 in the research and development of new therapies for a wide range of diseases such as diabetes, heart disease and HIV/AIDS. PhRMA members alone invested an estimated $49.5 billion in 2011 in discovering and developing new medicines.
Diabetes
In mid-February of this year, NIH announced that “More people are meeting recommended goals in the three key markers of diabetes control, according to a study conducted and funded” by NIH and CDC.
The report, published online February 15 in Diabetes Care, shows that, from 1988 to 2010, the number of people with diabetes able to meet or exceed all three of the measures that demonstrate good diabetes management rose from about 2 percent to about 19 percent. Each measure also showed substantial improvement, with over half of people meeting each individual goal in 2010.
Improved cholesterol control was likely due to the increase in the use of statins, a type of cholesterol-lowering drug, from about 4 percent of people with diabetes during 1988-1994 to 51 percent during 2007-2010. Glucose control was worse in Mexican-Americans and in younger adults. Only 44 percent of Mexican-Americans met A1C goals, versus 53 percent of whites and blacks in 2007-2010 data. People between 20-49 years old were less likely to meet A1C goals than older people.
On Friday, March 29, 2013, FDA approved Invokana (canaglifozin) tablets, used with diet and exercise, to improve glycemic control in adults with type 2 diabetes. Type 2 diabetes is the most common form of the disease, affecting about 24 million people and accounting for more than 90 percent of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness, and nerve and kidney damage.
“Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors,” said Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research. “We continue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions that impact public health.”
Invokana, manufactured by Janssen Pharmaceuticals, a Johnson & Johnson company, works by blocking the reabsorption of glucose by the kidney, increasing glucose excretion, and lowering blood glucose levels in diabetics who have elevated blood glucose levels. Its safety and effectiveness were evaluated in nine clinical trials involving over 10,285 patients with type 2 diabetes. The trials showed improvement in hemoglobin A1c levels (a measure of blood sugar control) and fasting plasma glucose (blood sugar) levels.
The FDA is requiring five postmarketing studies for Invokana: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the Pediatric Research Equity Act (PREA), including a pharmacokinetic and pharmacodynamic study and a safety and efficacy study.
Rare Diseases
National Institutes of Health (NIH) Director Francis Collins recently wrote in a blog post about Alex Barton, a recently turned 17-year-old boy, who was born with Neonatal-Onset Multisystem Inflammatory Disease (NOMID). NOMID is the most severe form of an autoinflammatory disease spectrum called Cryopyrin-Associated Periodic Syndromes (CAPS). In 2001, researchers discovered the cause: a genetic mutation in a gene called NLRP3, which makes a protein called cryopyrin. Cryopyrin is part of a sensor in white blood cells that detects bacteria, harmful chemicals, and proteins produced by stressed, damaged, or dying cells. When the sensor detects these danger molecules, it launches an inflammatory response by activating a potent inflammatory protein called interleukin-1β.
When Alex came to the NIH in 2003 at age six to participate in a clinical trial, he was covered in a head to toe rash, had partial hearing loss, vision problems, and couldn’t walk. Dr. Raphaela Goldbach-Mansky, a rheumatologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, launched a clinical trial together with other NIH specialists to test a drug called anakinra (Kineret®), which the FDA had approved for rheumatoid arthritis (RA). Anakinra hadn’t been very effective for RA, but Goldbach-Mansky knew its mechanism should allow it to block cells from responding to IL-1β, curbing the inflammation that was destroying Alex’s body.
Just a few hours after Alex got his first injections of anakinra, the rash disappeared. Six days later, Alex was back on his feet and walking out of the NIH Clinical Center, where he recently came back to visit for his 10-year checkup. Goldbach-Mansky says that the results are truly astonishing. Of the estimated 80 or so children with NOMID in the United States, 53 are in her clinical trial on the NIH campus. Many of these patients were in such severe pain that they needed daily pain medication to sleep. After just a couple days of anakinra injections, these children were pain-free.
Based on Goldbach-Mansky’s trial data, the FDA approved the use of anakinra for NOMID. Collins noted that “anakinra and other related drugs are now also being tested for conditions like gout, type 2 diabetes, and heart disease—diseases that also involve inflammation and that together affect tens of millions of people nationwide. If IL-1β triggers inflammation in these diseases, as it does in NOMID, then anakinra and other IL-1β blockers might prove to be an effective treatment.”
HIV/AIDS
Back in early March of this year, NIH announced that “A two-year-old child born with HIV infection and treated with antiretroviral drugs beginning in the first days of life no longer has detectable levels of virus using conventional testing despite not taking HIV medication for 10 months, according to findings presented today at the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta.”
This is the first well-documented case of an HIV-infected child who appears to have been functionally cured of HIV infection — that is, without detectable levels of virus and no signs of disease in the absence of antiretroviral therapy. Further research is needed to understand whether the experience of the child can be replicated in clinical trials involving other HIV-exposed children, according to the investigators. The case study was presented at the CROI meeting by Deborah Persaud, M.D., associate professor of infectious diseases at the Johns Hopkins Children’s Center in Baltimore, and Katherine Luzuriaga, M.D., professor of pediatrics and molecular medicine at the University of Massachusetts Medical School in Worcester. These two pediatric HIV experts led the analysis of the case.
In July 2010, the child was born prematurely in Mississippi at 35 weeks, to an HIV-infected mother who had received neither antiretroviral medication nor prenatal care. Because of the high risk of exposure to HIV, the infant was started at 30 hours of age on liquid antiretroviral treatment consisting of a combination of three anti-HIV drugs: zidovudine, lamivudine, and nevirapine. The newborn’s HIV infection was confirmed through two blood samples obtained on the second day of life and analyzed through highly sensitive polymerase chain reaction (PCR) testing. PCR tests conducted on separate occasions that indicate the presence of HIV in an exposed infant are considered to have confirmed the diagnosis of infection.
The baby was discharged from the hospital at 1 week of age and placed on liquid antiretroviral therapy consisting of combination zidovudine, lamivudine and co-formulated lopinavir-ritonavir. This drug combination is a standard regimen for treating HIV-infected infants in the United States.
Today, the child continues to thrive without antiretroviral therapy and has no identifiable levels of HIV in the body using standard assays. The child is under the medical care of Hannah Gay, M.D., a pediatric HIV specialist at the University of Mississippi Medical Center in Jackson. Researchers will continue to follow the case. “This case suggests that providing antiretroviral therapy within the very first few days of life to infants infected with HIV through their mothers via pregnancy or delivery may prevent HIV from establishing a reservoir, or hiding place, in their bodies and, therefore, achieve a cure for those children,” said Dr. Persaud.
In related news, NIH announced that “For children who have had HIV-1 infection since birth, the combination drug therapies now used to treat HIV appear to protect against the heart damage seen before combination therapies were available, according to researchers in a National Institutes of Health network study.”
In the early 1990s, children with HIV were not treated with anti-HIV therapy or were treated with only one drug. In recent years, children, like adults, have been treated with combinations of three or more anti-HIV medications. This combination approach is called highly active antiretroviral therapy, or HAART. Before the widespread use of HAART, many children with HIV had chronic heart disease. In fact, heart failure was the underlying cause of death for 25 percent of HIV-infected children who died after age 10.
“We know that before today’s robust treatments were available, HIV-positive children were more likely to have heart infections and inflammation; many also died from heart failure,” said Dr. Lipshultz. “This research followed a rigorous protocol, and the findings suggest that HAART, in addition to being good for treating HIV, does not appear to adversely affect the heart’s function.”
Parkinson’s Disease
Lastly, the Michael J. Fox Foundation recently announced a $1 million grant to Addex Therapeutics, a Swiss-based company, to help fund continued human clinical testing of dipraglurant for the treatment of Parkinson’s disease levodopa-induced dyskinesia (PD-LID) this morning. The Fox Foundation has been a pioneer in funding research for an effective treatment for levodopa-induced dyskinesia, as this is an area of significant unmet need for PD patients and could greatly improve the quality of patients’ lives. The Foundation has invested more than USD $26 million in dyskinesia-targeted research to date.
“Dyskinesia is a top priority for our Foundation because of its significant negative impact on patients’ quality of life,” said Todd Sherer, Ph.D., Chief Executive Officer of The Michael J. Fox Foundation. “Candidates such as dipraglurant and other innovative therapies in development offer the possibility of improved quality of life through better symptomatic treatment of Parkinson’s. Dipraglurant targets a molecular mechanism that our Foundation has been investing in since 2005 and we are pleased to take part in its continued progress to the clinic. We are enthusiastic about funding this work and hopeful that it may offer patients relief from a longstanding issue with the treatment of their disease.”
“We are extremely pleased to receive this grant from The Michael J. Fox Foundation supporting the further development of dipraglurant,” said Bharatt Chowrira, Ph.D., Chief Executive Officer of Addex Therapeutics. “We believe the successful completion of the Phase 2a study offers some promise that dipraglurant has the potential to significantly change both the way patients are treated as well as their quality of life. The work we will be able to pursue with this grant is critical to our continued advancement of this important approach to the treatment of PD-LID. Ultimately, we hope to see dipraglurant become the first drug to alleviate all PD-LID symptoms.”
Dipraglurant is an oral, small molecule allosteric modulator that inhibits selectively the metabotropic glutamate receptor 5 (mGluR5), a Class C G-Protein Coupled Receptor (GPCR). Dipraglurant holds potential to be used in combination with levodopa or dopamine agonists, or as a standalone treatment for PD-LID, PD-related motor symptoms, dystonia, non-motor symptoms of PD and other movement disorders. Data from a Phase 2a showed that dipraglurant met the primary objective of the study by exhibiting a good safety and tolerability profile.
Dipraglurant also demonstrated a statistically significant reduction in LID severity with both 50 and 100 mg doses. Dipraglurant appears to reduce dystonia severity in addition to chorea, the two major LID components. In a double-blind, placebo-controlled study conducted in the US and Europe, the primary objective was to demonstrate safety and tolerability in PD-LID patients. In addition, the trial was designed to evaluate exploratory efficacy as a secondary objective. Efficacy was measured using the modified Abnormal Involuntary Movement Scale (mAIMS), patient diaries documenting “off-time” (impaired voluntary movement), “on-time” (with or without dyskinesia) and sleep. The trial was supported by a grant from The Michael J. Fox Foundation for Parkinson’s Research.