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Yearly Archives: 2014
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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EffRx Pharmaceuticals receives FDA orphan drug designation for EX404
EffRx Pharmaceuticals has received US Food and Drug Administration (FDA) orphan-drug designation for its proprietary metformin-based product, EX404, for treatment of paediatric polycystic ovary syndrome (PCOS).
Also known as Stein-Leventhal syndrome, PCOS is a heterogeneous disorder of chronic anovulation and hyperandrogenism.
The syndrome is believed to occur due to hormonal imbalance caused by increased levels of androgens and insulin in the body.
EffRx Pharmaceuticals chairman and CEO Christer Rosén said the FDA’s orphan drug designation of EX404 is a significant step forward in the clinical development programme.
Immunomedics’ IMMU-132 Gets Orphan Drug Status For Small Cell Lung Cancer
(RTTNews) – Immunomedics, Inc. (IMMU), a biopharmaceutical company focusing mainly on the development of monoclonal antibody-based products for the targeted treatment of cancer, autoimmune and other serious diseases, said its antibody-drug conjugate for solid cancer therapy, IMMU-132, has received orphan drug status from the Office of Orphan Products Development of the U.S. Food and Drug Administration or FDA for small cell lung cancer or SCLC treatment.
Immunomedics has received orphan drug designation from the US Food and Drug Administration’s (FDA) Office of Orphan Products Development for its IMMU-132 for pancreatic cancer therapy.
IMMU-132 is Immunomedics’ antibody-drug conjugate in clinical development for treatment of patients with solid cancer.
Immunomedics president and CEO Cynthia Sullivan said that this is the second orphan designation from FDA for IMMU-132, which has demonstrated activity in patients with advanced pancreatic cancer, as well as partial responses in five other types of solid cancer.
“The humanised antibody internalises into cancer cells following binding to TROP-2, making it a suitable candidate for the delivery of cytotoxic drugs.”
The FDA previously granted orphan drug designation to IMMU-132 for treatment of small-cell lung cancer patients.
In an ongoing Phase I/II clinical study, IMMU-132 has resulted in partial responses in patients with colorectal cancer, esophageal cancer, triple negative breast cancer, and small-cell and non-small-cell lung cancers.
IMMU-132 is composed of a humanised antibody, hRS7, that binds to the trophoblast cell-surface antigen (TROP-2), also known as the epithelial glycoprotein-1 antigen (EGP-1).
The humanised antibody internalises into cancer cells following binding to TROP-2, making it a suitable candidate for the delivery of cytotoxic drugs.
In preclinical studies, IMMU-132 has demonstrated that it delivers 120-times the amount of SN-38, the active metabolite of irinotecan, to a human pancreatic tumor xenograft than when irinotecan is given.
IMMU-132 significantly improves survival and tumour regression in various animal models of human cancers.
TIC 10 structure established……Synthesis: Structural misassignment stems from long-standing use of incorrect recipe to prepare anticancer agent
Misassigned (top) and corrected (bottom) structures of bioactive TIC10.
PIC FROM
Don’t forget the chemistry
In a bit of a whoopsie it has come to light 1 that a compound TIC10, a stimulator of gene expression for TRAIL and in PhI/II clinical trials has in fact got an incorrect structure or rather the compound that was protected in the patent was assigned the incorrect structure. It was patented in a single compound patent 2 – which might ring alarm bells for some – were they really that confident they had the best compound. A quick look at the patent revealed large amounts of in vitro work but none in vivo again begging the question how good is this single compound. The compound had been identified by a group at Pennsylvania State University and licensed to Oncoceutics from screening of the NCI compound collection but the team, as reported, only attempted structural characterisation by MS. This would be unlikely to differentiate regioisomers which is what the problem turns out to be. It does however seem strange that the patenting error was not detected during resynthesis and scale-up for progression to the clinic. The error was picked up when a group from the Scripp’s 3 who synthesised the patented compound but found it inactive while they found the NCI batch to be active. They characterised the patented (inactive) and non-patented (active ex NCI) structures by crystallography and total synthesis. The corrected structure has now been patented by the Scripps group and licensed to Sorrento.
Of course this is all a bit embarrassing for those concerned but also more seriously could end up with extensive patent litigation, wasting money and discouraging investors from supporting the work until the patent situation is clarified causing delay in progressing the asset. Please please talk to medicinal chemsist early in a project this one looks like no one did which has led to an expensive mistake.
1. S. Borman Chem Eng News 2014, May 26 page 7
2. US Patent US8673923
3. N. T. Jacob et al Angew. Chemie. Int. Ed., Article first published online: 18 May 2014 DOI: 10.1002/anie.201402133
The fog is beginning to lift on how a mistake in the structural analysis of a promising drug candidate occurred and was sustained for so long that the agent was nearly in human clinical trials before the error was discovered.
Kim D. Janda and coworkers at Scripps Research Institute California recently discovered that the structure of a promising cancer drug candidate, called TIC10 or ONC201, had been misassigned in the agent’s patent (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201402133). The biotech firm Oncoceutics, which has licensed the patent (U.S. 8673923), is sponsoring Phase I/II human clinical trials for the agent, which are currently in a prerecruitment phase. But Scripps has applied for a patent on the corrected structure and has licensed it exclusively to another company, Sorrento Therapeutics (C&EN, May 26, page 7).
TIC10 originated with a 1973 German patent (2150062) owned by C. H. Boehringer Sohn, in Ingelheim, now called Boehringer Ingelheim. The now-expired patent covers a family of 43 compounds, one of which is now called TIC10, and their possible use as antiseizure medications. It also contains a recipe for synthesizing the compounds.
At some point, the National Cancer Institute (NCI) picked up TIC10 for its publicly accessible Diversity Set II database, which researchers can screen freely to find agents with interesting activities. The compound’s structure shown in the database listing was the same as in the German patent—with three rings fused in a linear fashion.
Wafik S. El-Deiry of Pennsylvania State University and coworkers discovered that NCI’s TIC10 sample had potent anticancer activity (Sci. Transl. Med. 2013, DOI: 10.1126/scitranslmed.3004828). They used mass spectrometry to try to confirm that the structure of the compound was the same as that listed in the NCI database. But MS is inadequate for structure confirmation when used on its own.
Penn State was granted a patent to use TIC10 to treat cancer, and it licensed the patent to Oncoceutics for development. The company used the Boehringer recipe to develop a production process to produce sufficient amounts of the compound for study and eventually for clinical trials.
When Janda’s group decided to study TIC10 for possible use in a combination therapy, they opted to synthesize the three-ring linear structure from scratch, instead of using the Boehringer recipe. The compound they made that had that structure was bioinactive, so they ordered the compound from NCI and found that agent to be bioactive. When they then analyzed the bioactive agent carefully, they found it to have a structure in which one of the three fused rings is at an angle to the other two. They then synthesized this angular structure from scratch, applied for a patent on it, and relicensed it.
The reason the structural problem with TIC10 persisted so long is that until Janda’s group joined the TIC10 game, others all seemed to be using the Boehringer recipe to make it and were thus synthesizing a bioactive but structurally misidentified compound.
Oncoceutics Chief Business Officer Lee Schalop notes that all of the company’s research on ONC201, including studies required for approval of the agent’s Investigational New Drug Application with the Food & Drug Administration, were carried out with the bioactive agent. Oncoceutics did not reply by C&EN press time to an inquiry about what techniques it used to characterize ONC201 during its studies.
A number of reagent suppliers have also been marketing TIC10 for research purposes. A search of Chemical Abstracts Service databases in May showed that eight companies were selling CAS Registry Number 41276-02-2, the compound with the misassigned linear structure. (CAS is a unit of the American Chemical Society, which publishes C&EN.)
Sigma-Aldrich, one of the companies offering TIC10, hired a contractor to synthesize TIC10. But the company didn’t officially launch the compound for sale and didn’t ship any to customers. In response to the Janda publication, Sigma-Aldrich halted the product launch.
Sorrento patent attorney Jeff Oster tells C&EN that a meeting between Oncoceutics and Sorrento had been scheduled to begin untangling some of TIC10’s patent and licensing issues. But Schalop says Oncoceutics has no plans to meet with Sorrento.
EMA publishes final QP Declaration Template
EMA publishes final QP Declaration Template
The European Medicines Agency (EMA) has published the Template for the Qualified Person’s declaration concerning GMP compliance of the active substance used as starting material and verification of its supply chain – “The QP declaration template”.
Read more.
Researchers discover new form of cancer
This is the story of two perfectly harmless genes. By themselves, PAX3 and MAML3 don’t cause any problems. However, when they combine during an abnormal but recurring chromosomal mismatch, they can be dangerous. The result is a chimera—a gene that is half of each—and that causes biphenotypic sinonasal sarcoma. The tumor usually begins in the nose and may infiltrate the rest of the face, requiring disfiguring surgery to save the individual. Because Mayo Clinic pathology researchers have now described the molecular makeup of the rare tumor, several existing cancer drugs may be targeted against it. The findings appear in the current issue of Nature Genetics.
In 2004, Mayo Clinic pathologists Andre Oliveira, M.D., Ph.D., and Jean Lewis, M.D., first noticed something unusual about a tumor sample they were analyzing under the microscope. By 2009, they had seen the same pathology several times and had begun collecting data. In 2012…
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Grape consumption may offer benefits for symptomatic knee osteoarthritis
New research presented last week at the Experimental Biology conference in San Diego, California, suggests that regular grape consumption may help alleviate pain associated with symptomatic osteoarthritis of the knee, and improve joint flexibility and overall mobility. Researchers attribute these potential benefits to the polyphenols found in grapes.
The sixteen week clinical study, undertaken by Texas Woman’s University, was designed to investigate the benefits of grape consumption on inflammation and osteoarthritis outcomes. 72 men and women with knee osteoarthritis (OA) were assigned to either consume grapes in the form of a whole grape freeze-dried powder, or a placebo powder.
The study results, presented by lead investigator Shanil Juma, Ph.D., showed that both men and women consuming a grape-enriched diet had a significant decrease in self-reported pain related to activity and an overall decrease in total knee symptoms. This beneficial effect was more pronounced in females. Additionally, age-related differences were observed:…
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Molecular imaging gets to the root of rheumatoid arthritis
Rheumatoid arthritis causes chronic pain for almost half of adults by the time they retire, but a new molecular imaging technique can visualize inflammation in the joints, giving doctors a clear read on chronic pain and possible joint destruction, say researchers at the Society of Nuclear Medicine and Molecular Imaging’s 2014 Annual Meeting.
In order to image arthritis inside the joints, researchers used multiple molecular imagingsystems, positron emission tomography (PET) and single photon emission tomography (SPECT), both of which image physiological processes with the help of specialized detectors that pick up signals from injected radionuclide imaging agents. In this case researchers evaluated anti-fibroblast activation protein (FAP) antibodies involved in the inflammation associated with rheumatoid arthritis. This was made possible with radiotracers that combine the molecular compound 28H1, which can bind to FAP in the body, with the radionuclides In-111, used in conjunction with SPECT imaging systems, and Zr-89…
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Dr. Reddy’s avoids pitfalls of Ranbaxy, Wockhardt by cutting workers out of production Read more: Dr. Reddy’s avoids pitfalls of Ranbaxy, Wockhardt by cutting workers out of production
The execs at Dr. Reddy’s Laboratories have taken notice as some of its competitors in India have run afoul of the FDA over loose manufacturing standards. The actions have meant banned plants and plummeting revenues for Ranbaxy Laboratories and Wockhardt. To avoid that fate, Dr. Reddy’s and some other Indian drugmakers have decided it is worth investing hundreds of millions of dollars for new plants and equipment in a country that has traditionally relied on cheap human labor.
Contrave: Is This The Weight Loss Drug We’ve Been Waiting For?
Will the FDA finally approve Contrave, Orexigen’s hot new diet drug, this week? Expectations are high for this new weight loss medication, which could prove an important anti-obesity aid. The ruling is expected as soon as tomorrow.
Now temporarily renamed NB32, Contrave was eagerly awaited when it got a startling thumbs-down from the FDA in 2011. The agency demanded additional research into cardiovascular risks.
by
Melanie Haiken
New Drug Approvals 