Pharma’s Cutting Edge

For whatever it’s worth here’s my year-end list of the top pharma innovations of 2006.  In order to qualify for the list, the innovation must have been approved for human use by the U.S. FDA this year. 

To all my readers, I wish you a very happy, healthy and prosperous new year.  Talk to you in early 2007, when I’ll review the year past and ahead.

1. Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine (Gardasil, Merck).  2006 might very well be remembered as the year of the cervical cancer vaccine–deservedly so.  The idea that a virus was the cause of cervical cancer seemed heretical 40 years ago, but Harald zur Hausen and others persisted in their belief, fueled by tantalizing experimental evidence.  This persistence paid off when a postdoc in zur Hausen’s lab cloned HPV-16, one of the HPV serotypes responsible for cervical cancer, in 1983.  These and other findings led directly to Gardasil and provided the rationale for future prophylactic vaccines against other virus-induced cancers.
2. Ranibizumab (Lucentis, Genentech).  Prompted by evidence that retinal ischemia-induced iris neovascularization (the hallmark of “wet” age-related macular degeneration) requires vascular endothelial growth factor (VEGF), scientists at Genentech engineered ranibizumab, a humanized monoclonal antibody against VEGF, and quickly advanced it into the clinic.  Some eight years after its synthesis, Lucentis is widely anticipated to become the standard of care for wet AMD.
3. Sitagliptin (Januvia, Merck).  The discovery by DPP-IV in the mid-1960’s set the stage for the development of DPP-IV inhibitors, of which sitagliptin is the first to be marketed for human use in type 2 diabetes.  Sitagliptin was synthesized by Merck scientists.  It inhibits DPP-IV selectively, effectively increasing the body’s production of insulinotropic peptides (i.e. incretins, particularly GLP-1) in response to ingestion of food.  The decreased metabolism of incretins enhances food-induced insulin secretion and satiety and diminishes glucagon secretion and gastric emptying, leading to reduced postprandial and fasting blood glucose without weight gain in patients with type 2 diabetes.
4. Zoster vaccine, live (Zostavax, Merck).  Building on their experience with Varivax in children (the only previously licensed varicella virus vaccine in the U.S.), Merck developed Zostavax to prevent herpes zoster in older adults.  This population has been unserved by an effective means to prevent this very painful and debilitating condition.  Zostavax, with an immunogenic potency 14-fold greater than Varivax, filled the bill, reducing the burden of herpes zoster illness in an elderly population by about 60%.
5. Sunitinib (Sutent, Pfizer) and dasatinib (Sprycel, BMS).  These multi-receptor tyrosine kinase inhibitors were both approved this year, for different types of cancer.  Pfizer and BMS built on the foundations created by Novartis’ Gleevec, but these drugs represent a divergence from the traditional one-kinase/one-inhibitor thinking that gave birth to Gleevec.  Neither Sutent nor Sprycel will win any awards for their brand names or their immediate impacts to prolong cancer survival, but they represent an exciting new wave of TK inhibitors for cancer treatment.
6. Vorinostat (Zolinza, Merck).  Originally known as SAHA (suberoylanilide hydroxamic acid), vorinostat was acquired by Merck when it purchased Aton Pharma in 2004.  Aton was co-founded by SAHA’s discoverer (PA Marks).  It is the first histone deacteylase (HDAC) inhibitor approved for treatment of a malignancy.  HDAC inhibitors “open up” chromatin, but the specifc mechanisms of their anti-neoplastic effects are incompletely understood.  Zolinza is indicated in the relatively rare cutaneous T-cell lymphomas and is being studied clinically in a wide variety of solid organ and blood malignancies.

Amidst the depressing industry news that has been crossing my email lately–allegations of rampant fraud and public deception at BMS and Lilly, respectively, among the more disturbing–I’ve decided to focus one of my final posts of the year on some refreshingly positive basic research news of high therapeutic relevance.  I’d classify these two independent research findings, both in the metabolic-disease arena, as genuine breakthroughs.

The first breakthrough, based on research led by Michael Dosch and his colleagues at the Hospital for Sick Children in Toronto, opens up a very promising, novel approach for prevention and early treatment of autoimmune diabetes mellitus (Type 1) and some other autoimmune diseases and, even maybe for Type 2 diabetes mellitus.  The research is published in the December 15th issue of Cell.

In short, Dosch’s group, in collaboration with a group from the University of Calgary, has discovered that transient receptor potential vanilloid-1(TRPV1)-secreting afferent sensory neurons play a crucial role in islet inflammation and beta cell function.  Islet inflammation is characteristic of Type 1 diabetes, and impaired beta cell function with variable islet inflammation characterizes type 2 diabetes. 

Specifically, the group determined that removal of TRPV1+ neurons abrogates immune cell infiltration into the islets of mice genetically prone to developing autoimmune diabetes (called NOD mice), without affecting the autoimmune properties of the immune cells themselves.  In other words, the sensory neurons were found to be responsible for accumulation of the destructive autoimmune cells into the pancreatic islets.

Sequencing of the TRPV1 sequence of NOD mice revealed DNA mutations resulting in two amino acid exchanges compared with wild-type that resulted in hypofunctional afferent sensory neurons in NOD mice.  These neurons secrete the neuropeptide substance P (sP), which was found to have accumulated in the dorsal root ganglia of NOD mice, consistent with reduced secretion in these animals.  Treatment of the NOD mice with sP or selective removal of TRPV1+ neurons prevented immune cell infiltration and the other manifestations of autoimmune diabetes, suggesting that a partially functioning TRPV1-islet cell circuit is causing the disease, and that either replacing the missing neuropeptide(sP) or eliminating the neural circuit can essentially prevent the diease. 

This opens up an entirely new prevention/treatment strategy for type 1 diabetes (and prehaps some types of type 2 diabetes, especially the so-called LADA subtype) that has potential to be more effective and far less risky that generalized immunosuppression, which is currently being studied clinically.

Read the rest of this entry »

Here’s an idea.  I’m sure you’ve read on more than one occasion that medication errors continue to be a source of patient morbidity.  Hospitals have instituted a variety of procedures to cut down on errors, but what about the poor schlub self-administering meds at home.  Lots of folks take multiple meds, and you know what, they’re damn hard to tell apart from each other, especially when generic meds are inter-mixed.  It’s easy to miss a dose of one and double the dose of another, simply due to product confusion.

So, here’s a simple, no-added cost approach that might reduce risk a bit: stamp them with dosage (and name when practical).  Innovators tend to brand their capsules and coated tablets with the drug name and sometimes the dosage, but you’re lucky to get even a brand icon on a tablet, and good luck remembering which icon goes with which drug name.  Generic houses rarely include either the generic name or dosage on anything they sell, imprinted or stamped, opting instead for company and product codes, and they love those white, round tablets that all look exactly alike.

If both innovators and generic houses agreed to imprint the brand (or generic) name and dosage on suitable substrates and to stamp at least the dosage on tablets and other compacted forms, it might ease the confusion.  I know that if I saw a big “20″ on one round white tablet and a big “80″ on another it would alert me that they were different drugs, and if I were fortunate enough to remember which drug I took in 20-mg doses and which I took in 80-mg doses, I’d be all set.

It’s easy to do, it costs no more than stamping or impriniting a code, and its common sense.  You don’t need a regulation to compel you to do it; just do it.

Google has launched its Google Patents search beta.  I use Google quite a bit.  Google itself is my customized home page, and I frequently use Google News, Google Ads, Google Analytics, Google Scholar, Google Print, Google Maps, etc in my daily work and play.  It’s well known that Google releases new tools to the public early after their development, while in beta testing, so I expect some deficiencies and bugs at first.  Sometimes these deficiencies are addressed; sometimes not.

I’ve been awaiting a free patent search tool that improves upon the existing U.S. and international patent office tools and was gratified to learn that Google was taking on the task of developing one.  I put it through a quick test.  I wasn’t impressed.

Sure the tool allows you to search for and within documents using the ultra-quick Google engine, but other than that I can’t find much to recommend its early adoption for people who count on comprehensive, accurate search results or who want results sorted in a usable way.

First off, Google’s service is far less comprehensive than some other free internet-based tools.  Google has indexed the USPTO patent data, but none of the international patent databases have been indexed.  The USPTO makes for a good starting place for pharma/biotech patent searches, but most researchers will want to look at international filings.  They’ll need to use another search engine like espacenet to do that.  Also, only granted patents have been indexed.  A comprehensive service must also index patent applications.

As far as accuracy, I ran identical searches for three major pharmas on Google Patents and nearly simultaneously on the USPTO site.  In each case, the Google search yielded far fewer “hits”.  Eli Lilly, for instance, yields 1,084 patents on Google and 3,468 patents on USPTO.  It would have been nice to compare the two search engine results directly, but I couldn’t do that easily, because Google returns its findings in a non-sortable Googley way, the same way it returns results for its other services…according to Google’s search algorithm’s idea of relevance.  USPTO returns its search results sorted by date, most recent first.  The USPTO data are also not easily sortable, but at least the output makes some sense to the end-user who needs to find a specific patent.  The Google results display contains a bit more information for each patent than the USPTO display but not enough to give it a practical advantage.

Finally, Google scans the full USPTO patent text into its database as images over text, allowing within-document search.  I found the within-document search to work quite well, finding chemical terms nested within longer chemical names that included numbers and symbols.  The USPTO doesn’t offer within-document searching, but it displays text as HTML, which may be searched by a browser.  The USPTO output can also easily be saved as text.  Google’s output is an image of okay quality (figure quality is sub-par though) that may be saved and printed, but getting that image onto your hard drive as text requires additional manipulation with likely loss of information.

I’ll check back with Google Patents again in the future and will let readers know if my opinions change.

FDA’s mandate as far as human drugs are concerned is to ensure that drugs sold in the U.S. are safe and effective for their intended usage.  So when faced with criticisms that their rules prevent some very ill patients from receiving life-saving medicines, FDA was faced with a challenging problem–how can regulators ensure that only safe and effective medications are sold while also ensuring that patients don’t die or suffer unnecessarily during the investigational period?

It’s a tough problem.  Too much weight given to the needs of ill patients can jeopardize completion of the investigational program.  This is a particular concern for therapies aimed at rare diseases, where clinical-trial subjects are few and far between.  Delay or non-completion of an investigational program leaves sponsors without a timely marketed product and jeopardizes therapy access to a broad population.  Too much weight given to the evidenciary requirements of regulators, and the patients who might benefit most from investigational drugs could be left inadequate therapeutic options.

Rules already exist for access to investigational drugs, but these rules are somewhat vague in their criteria for implementation and provide for treatment use of investigational drugs in circumstances that make it difficult for individual physicians to intervene on a patient’s behalf, namely the treatment IND (aka “treatment protocol”) and emergency use.  I won’t go into detail about existing rules.  You can read descriptions of them in the proposed rule (expandedaccess).

In the proposed rule, FDA keeps the older terminology (but clarifies its meaning) and adds two new expanded access protocols aimed at addressing the needs of individual patients and intermediate-sized (~10 to ~100) patient populations, respectively.  Evidentiary requirements for treating seriously ill individual patients with investigational drugs are  lowest (with animal data often sufficing for those with life-threatening diseases), with increasing evidence of safety and efficacy required for intermediate-sized pools of patients and larger groups (under the treatment IND).  Individual physicians will still have to work with sponsors and collect drug disposition and adverse event data, but cooperative sponsors can include treatment protocols for individual patients in an amendment to their existing IND.  Physicians won’t have to convince sponsors to open a treatment IND or provide drug under emergency use.

FDA has also wisely created checks that should ensure that investigational drugs’ paths to the market are not unnecessarily delayed, for example by limiting treatment to patients with serious diseases who have no other approved-treatment options.  FDA will also maintain oversight of treatment and will have 30 days to review each IND amendment.

Overall, I think both sponsors and patient advocates should be pleased with these new rules.  FDA’s mandate to protect patients by ensuring the safety and effectiveness of marketed therapies is fulfilled without jeopardizing the health of patients for whom marketed therapies are not an option.  Well done.