Research and development
Pfizer has announced that the FDA accepted for review a supplemental New Drug Application (sNDA) for its first-in-class CDK 4/6 inhibitor, IBRANCE (palbociclib). The sNDA supports the conversion of the accelerated approval of IBRANCE in combination with letrozole to regular approval and includes data from the phase III PALOMA-2 trial, which evaluated IBRANCE as initial therapy in combination with letrozole for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer. This is the same patient population as the randomized phase II PALOMA-1 trial upon which the accelerated approval of IBRANCE plus letrozole was granted in February 2015.
The sNDA was granted Priority Review status, which accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing.1 The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in April 2017.
“Since its introduction in 2015, more than 45,000 patients have been prescribed IBRANCE by more than 9,000 providers in the U.S.,” said Liz Barrett, global president and general manager, Pfizer Oncology. “We are pleased that the PALOMA-2 trial has further demonstrated the significant clinical benefit of IBRANCE in the first-line setting, providing additional evidence for its continued use as a standard of care medicine.”
PALOMA-2 is a randomized (2:1), multicenter, double-blind phase III study that evaluated a total of 666 women from 186 global sites in 17 countries. The study demonstrated that IBRANCE in combination with letrozole improved progression-free survival compared to letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. The adverse events observed with IBRANCE in combination with letrozole in PALOMA-2 were generally consistent with their respective known adverse event profiles
In an early-phase clinical trial of a new oral drug, selumetinib, children with the common genetic disorder neurofibromatosis type 1 (NF1) and plexiform neurofibromas, tumors of the peripheral nerves, tolerated selumetinib and, in most cases, responded to it with tumor shrinkage. NF1 affects 1 in 3,000 people. The study results appeared Dec. 29, 2016, in the New England Journal of Medicine.
The multicenter phase I clinical trial, which included 24 patients, was led by Brigitte C. Widemann, M.D., acting chief of the National Cancer Institute’s (NCI) Pediatric Oncology Branch, and was sponsored by NCI’s Cancer Therapy Evaluation Program. The study, conducted at the NIH Clinical Center and three participating sites, took advantage of techniques developed by Dr. Widemann’s team that enabled very precise measurement of the plexiform neurofibromas. Experiments in mice that developed neurofibromas due to genetic modifications were performed at Cincinnati Children’s Hospital in the laboratory of Nancy Ratner, Ph.D. NCI is part of the National Institutes of Health.
Plexiform neurofibromas develop in up to 50% of people with NF1. The majority of these tumors, which can cause significant pain, disability and disfigurement, are diagnosed in early childhood and grow most rapidly prior to adolescence. Complete surgical removal of the tumors is rarely feasible, and incompletely resected tumors tend to grow back.
The primary aim of this clinical trial was to evaluate the toxicity and safety of selumetinib in patients with NF1 and inoperable plexiform neurofibromas, and, encouragingly, most of the selumetinib-related toxic effects were mild. At present, no therapies are considered effective for NF1-related large plexiform neurofibromas, but, in this trial, partial responses, meaning 20% or more reduction in tumor volume, were observed in over 70% of the patients.
Responses were observed in tumors that were previously growing at a rate of greater than 20 percent per year, as well as in non-progressing lesions. Tumor shrinkage was maintained long term, for approximately two years, and, as of early 2016, no disease progression had been observed in any trial participant. Additionally, anecdotal evidence of clinical improvement, such as a decrease in tumor-related pain, improvement in motor function, and decreased disfigurement, was reported.
“Some may say that a 20% volume reduction is too small to be meaningful, but to me, just stopping the growth of these devastating tumors is an important achievement,” said Dr. Widemann. “The difference we see in these patients is truly unprecedented.”
The disease-causing gene for NF1 was first identified in 1990 by two independent teams, one of them led by NIH Director Francis S. Collins, Ph.D., M.D., who at the time was chief of Medical Genetics at the University of Michigan. The other team was led by Ray White at the University of Utah. Research to understand the gene’s function revealed that deregulation of the RAS signaling pathway was the most likely cause of tumor development. Numerous drugs that target RAS-related signaling pathways have been tested in patients with NF1 in phase I and phase II clinical trials, with disappointing results, hence the interest in selumetinib.
Selumetinib, provided for the study by AstraZeneca, is a selective inhibitor of the MEK protein, a part of the complex network of RAS signaling pathways. The drug has demonstrated activity in some advanced cancers, but it is not yet approved by the FDA for use in the U.S. It is manufactured in capsule form to be taken orally.
Trial enrollment began in September 2011 and 24 children (11 girls, 13 boys) participated. Twice daily doses of the medicine were taken continuously, over a median of 30 month-long treatment cycles. The majority of patients are still continuing with therapy, some for as long as five years, and the long-term treatment has had no observed adverse effect on their development or overall health.
Experiments in mice with similar neurofibromas confirmed the inhibition of the MEK protein function in the tumors. Inhibition of the MEK protein diminished as early as two hours after drug administration. In addition, the animals received treatment with regular interruptions and still demonstrated tumor responses. This indicates that even limited MEK inhibition could cause tumor shrinkage in this disease.
“In the future, we may wish to look at intermittent dosing in patients to minimize toxicity and retain maximal outcomes,” said Dr. Widemann.
In some patients, a loss of response to selumetinib with slow regrowth of tumors was observed, particularly after dose reductions. The researchers believe that additional studies are warranted to characterize tumors that no longer respond to selumetinib. NCI is currently sponsoring an ongoing phase II trial of the drug for adults with NF1, in which serial tissue samples are being obtained. This study should provide information about possible mechanisms of resistance to selumetinib.
In addition, a larger phase II pediatric trial is enrolling patients and should help establish the efficacy of selumetinib treatment in children. In this trial, in addition to tumor volume measurements, evaluations are being performed to assess the effect of selumetinib on plexiform neurofibroma related disfigurement, pain, quality of life, and function.
This research was supported by NCI’s Center for Cancer Research and the Cancer Therapy Evaluation Program; by the Children’s Tumor Foundation to Michael Fisher to support participating sites other than the NCI; by AstraZeneca providing selumetinib and funding for the pharmacokinetic analysis; and by grants from the Children’s Tumor Foundation and the Neurofibromatosis Therapeutic Acceleration Program (to Dr. Ratner for the mouse preclinical trials).
With Indian market benefiting from quick product regulatory approvals in bio-similars, the recent revision in guidelines by Central Drugs Standard Control Organisation (CDSCO) has made it more aligned with global regulations.
Besides this, regulatory landscape for biosimilars has been evolving with the global pioneer European Medicines Agency (EMA) also setting the trend, say experts.
Biosimilars are copy versions of already approved originator biologics that are marketed after patent expiry for the originator product. As the safety and efficacy of the innovator product is already established, copy versions are allowed to be developed and evaluated using an abbreviated pathway established on biosimilarity principles.
Since the first set of over-arching guidelines for biosimilars were released by the European Medicines Agency (EMA) in 2005, there has been much development in this space. The US Food and Drug Administration released its first set of draft guidelines in 2012, which have since been finalised. Additional guidelines were released in 2014-15. China FDA released its biosimilars guidelines last year.
However some experts like Dr Charu Manaktala, senior medical director, Biosimilars Centre of Excellence, Strategic Drug Development, QuintilesIMS Asia pinpoint, “The general principles of what the regulators expect, such as step-by-step development, focus on robust comparability and functional interests, pharmacovigilance – all of these are aligned with other guidelines.
She says that some points in the recent provision are contentious like the number of subjects required for different phases of development, but we need to have a more pragmatic view.
Compared to the pre-2012 era, she adds, “We have made significant progress. There is scope for revisions to further align our guidelines with the world view, but we are in a relatively good position.
“The basic regulatory framework for biosimilars registration has been established fairly well by 2016. The year also marked the 10th anniversary for approval of the 1st biosimilar in the EU. A number of regulatory guidelines are in place as well as a good amount of experience has been gained on a number of biosimilars ranging from simple proteins to complex monoclonal antibodies. Some of the other highly regulated markets such as Japan, South Korea, Canada, Australia among others have adopted EU biosimilar guidelines to a large degree,” Dr Manaktala concludes.
In addition to the revision of some of the earlier guidelines, the EMA published guidelines for pharmacovigilance of biologics in 2016. The US FDA has published a guidance on the labelling of biosimilars in March 2016.
The naming of biologicals and interchangability of biosimilars continue to be hotly debated topics. The EMA has approved biosimilars under the same non-proprietary name as for the reference product. In 2015, the US FDA issued draft guidance on the subject of non-proprietary naming of biosimilars. This guidance recommends that all biologicals should have non-proprietary names that includes a four-letter suffix to distinguish them from each other. The suffix would be composed of four lowercase letters and not carry any meaning.
The proposed approach is intended with a view to clearly identifying biological products to improve pharmacovigilance, and, preventing any unintended substitution. However, a number of industry stakeholders, including the USP have requested for alternative approaches to be considered.
While the interchangability guidance from the US FDA is awaited, Sandoz recently reported study findings that show lack of safety and efficacy impact from multiple back and forth switches between the it’s etanercept biosimilar and the originator product.
“We expect to see more products obtaining marketing approval on the basis of lean clinical data packages especially where validated PD markers are available, supported by strong quality comparability, in vitro biological activity evidence and clinical PK-PD studies,” adds Dr Charu Manaktala.
Asian manufacturers, especially from South Korea, continue to be key players in the current biosimilars landscape, with rich product pipelines as well as a number of approved products in both the EU and US.
South Korea is reported to have a goal of controlling 22% of the global biosimilars market by 2020. This goal is supported by the Korean government by way of providing capital as well as regulatory assistance to the domestic bioplharmaceutical companies.
In a major fillip to India’s efforts to globalise ayurveda and other traditional medicines, the US department of health and human services’ premier National Institutes of Health (NIH) and National Cancer Institute (NCI) have expressed interest in documenting ayurveda’s success stories in treating cancer.
Dr G Gangadharan, director, MS Ramaiah Indic Center for Ayurveda and Integrative Medicine, Bengaluru, who was part of an Indo-US joint delegation working on traditional medicine, said: “Some time in June, the US institutes expressed interest in documenting the success of ayurvedic treatment for cancer.” The delegation concluded in March 2016 its first meeting with the agenda ‘Collaborative Research on Traditional Medicine’.
Another integrated medicine expert with his own institute in Bengaluru, Dr Issac Mathai, who was also part of the delegation, said: “After the meeting in Delhi, the NIH and NCI teams visited the Ramaiah Centre and another facility.”
Gangadharan said several issues pertaining to traditional medicine, especially ayurveda, were discussed at the meeting and the expression of interest to document case studies will go a long way in taking this form of medicine to the world.
“While there is a lot of research in ayurveda, none of it is helping the traditional form. All of it is focused on identifying new molecules for modern medicine. The need of the hour is in proving how effective it is,” he said.
Although India has over 40,000 formulations in ayurveda, the Indian patent office has issued only 200 patents so far – of which 11% have gone to foreign entities with China leading the pack. Five patents have been granted for procedures to treat cancer and one has gone to a legal representative of a client in the US. The patent is for ‘Nutraceutical for the prevention and treatment of cancers and diseases affecting the liver’.
Although no generally accepted cure for cancer using ayurveda has been recorded officially in India, a recent test of a drug by AIIMS, Delhi showed improvement in the quality of life of cancer patients’, something the US is also aiming to enhance through President Obama’s Cancer Moonshot.
Mathai said there’s a lot of work in the field and once it materialises, partnership with the US will take ayurveda a long way.
The office of Dr Edward Trimble, director, Center for Global Health, NCI, confirmed the development. Soon after the March meeting, Trimble had said in a statement issued by the Union Ayush ministry: “The collaboration was a great opportunity to bring to the table from the US side NCI and NIH expertise in laboratory and clinical evaluation of traditional medicine and from the Indian side an impressive commitment to building the evidence base for traditional Indian medicine.”
The NIH research database shows over 3,574 papers on curcumin (a member of the ginger family) and cancer, and 1,161 papers on turmeric and cancer.
There are 2,500 studies on ginger, while there are 668 papers on fennel and 582 on cumin. According to a 2015 report of the National Center for Health Statistics (NCHS) under the Centre for Disease Control and Prevention (CDCP), the number of US citizens who have used ayurveda has jumped to 2.41 lakh in 2012 from 1.5 lakh in 2002.
An NHI factsheet on ayurveda says a few clinical trials in 2011 have shown some results for treating cancer using ayurveda. However, it says: “Most clinical trials of ayurvedic approaches have been small, had problems with research designs, or lacked appropriate control groups, potentially affecting research results.”
A new type of antibody therapy appears to have completely blocked the primate equivalent of HIV in infected monkeys.
More than two years after the treatment, the monkeys are now drug free, have no symptoms, and there are almost no traces of the virus in their systems. The results are so impressive that clinical trials have already begun with human patients in the US.
“We have good reasons to believe that the therapy will work similarly in humans,” said lead researcher Lutz Walter from the German Primate Centre in Göttingen. “It would be a breakthrough for the future treatment of HIV patients.”
In the trial, rhesus macaques infected with simian immunodeficiency virus (SIV) – the primate version of HIV – were given a standard antiretroviral drug for 90 days, before being treated with an antibody called Vedolizumab for 23 weeks.
After completing the therapy, all monkeys showed sustained control of the infection, and there were almost no traces of the virus in their blood or gastro-intestinal tissues.
Impressively, two years later, the “viral load remained low, the immune system intact, and the rhesus macaques healthy”, a press release explains. The monkeys, for now at least, are in “sustained remission“.
“This finding could become a blueprint for an alternative therapy for HIV, which could make it so someone would not need to continuously take antiretroviral drugs,” said one of the researchers, Aftab Ansari, from Emory University School of Medicine and Yerkes National Primate Research Centre in the US. “It could also help us craft more effective vaccines.”
Once HIV infects someone, it immediately hides in their gut, hijacking a group of immune cells called CD4+ T-cells and using them to replicate itself and spread around the body.
Antiretroviral drugs are already the most common form of treatment for patients with HIV, and taken regularly, they can help to keep this infection under control for decades . But they never remove HIV from the body altogether, so they have be taken permanently, and often cause side effects such as chronic inflammation, poisoning symptoms, and accelerated ageing.
That’s why researchers are trying to combine this approach with the use of antibodies, to develop a treatment that’s longer lasting.
Antibodies are a specific type of protein that our bodies produce in response to a certain antigen. They’re the proteins used in vaccines that tell our immune systems “Hey, I recognise this virus and it’s not good” – and researchers have spent years actively trying to develop antibodies that take down HIV.
But although there have been impressive results in the past, they’ve all been short-lived, and required ongoing injections of antibodies, because HIV is a master at hiding and disguising itself in its hosts.
Which is why this new approach is so promising.
“The aim of the study was to find a new therapeutic approach for the treatment of infections with immunodeficiency viruses, which would permanently prevent the proliferation of the viruses even after only temporarily application,” said Walter.
To figure this out, the team took 18 rhesus macaques infected with SIV and gave all of them antiretrovirals for 90 days, before giving 11 of them Vedolizumab every three weeks, and seven of them a generic antibody to serve as a control group.
Three of the monkeys in the treatment group were discounted from the study because their immune system fought back against Vedolizumab, but the other eight went on to have the virus pretty much erased from their system – while still maintaining healthy levels of T-cells in the body. This means the drug wasn’t just wiping out the immune system.
Barton F. Haynes, a Duke University immunologist who wasn’t involved with the study, told the LA Times that the antibody “allowed animals to control the infection” on their own. “That’s what was tantalising and surprising.”
Even better, Vedolizumab is already used in humans in Europe and the US to treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, so it doesn’t need to go through the extensive safety testing that most new drugs would need to.
The antibody works by attacking a specific receptor on T-cells that are known to be susceptible to HIV infection – in inflammatory bowel diseases this helps to calm down an over-active immune response. And in monkeys with SIV, it seems to wipe out all the T-cells that HIV is hiding in, while leaving healthy ones intact.
More research is needed to be done now to verify exactly what Vedolizumab is doing to infected T-cells, and extensive clinical trials will have to take place before we know whether this works in humans.
But so far, it’s looking pretty promising. And Phase I clinical trials testing the same combination of Vedolizumab and antiretrovirals in 15 HIV-infected humans have already begun in the US, with the researchers looking to extend them to more countries soon.
The research has been published in Science.