Category → Pharma in the News
Last week, the FDA approved Zelboraf (vemurafenib), co-marketed by Roche and Daiichi Sankyo, for the treatment of melanoma characterized by genetic mutation BRAF V600E, which occurs in a subset of the overall patient population. Treatment of late-stage melanoma patients with Zelboraf increases their survival around five months longer than traditional chemotherapy. Cancer-stricken families believe this extra time justifies the $9400 / month price tag for the treatment, considering the dearth of treatments currently available for these near-terminal patients (for a more detailed look into the people who brought vemurafenib to market, read Amy Harmon’s New York Times article series from 2010).
Vemurafenib went from concept to approval in just six years, lightning-fast for pharma, which usually takes decades to bring a drug to market. So, what’s the secret behind its success?
Vemurafenib, developed initially by San Francisco pharma company Plexxikon (acquired in 2011 by Daiichi Sankyo) shows all the hallmarks of rational drug design. Initial screening of a 20,000-member compound library against the ATP-binding site of 3 kinases (Pim-1, CSK, and p38) yielded a 7-azaindole lead structure. This approach, known as fragment-based lead discovery (FBLD) – the concept that a drug can be built up from a tiny piece as opposed to a high-potency binder – may represent a first for the industry, as pointed out by Dan Erlanson of blog Practical Fragments. Further synthetic modification of this azaindole fragment, supported by computer binding studies, showed that a hydrophobic (nonpolar) pocket on the enzyme surface could best be filled by a difluoro-phenylsulfonamide group. Biochemical assays confirmed that a ketone linker (in place of the 3-aminophenyl group shown above) between the azaindole and the sulfonamide increased potency. Additionally, a 5-chloro residue on the azaindole eventually became a 4-chlorophenyl group; it’s unclear how this relatively non-polar group helps improve binding, since early active-site models suggest it faces out towards the watery cell cytoplasm.
How is Zelboraf halting melanoma growth? It all comes down to kinase inhibition, a topic covered with both a story and a Haystack post here at C&EN last year. B-RAF, a common gene overexpressed in melanoma cells, produces a protein kinase that is selectively inhibited by Zelboraf. Once shut off, this pathway reinstates a “lost” negative feedback loop for the BRAF V600E tumor cells, resulting in a cascade failure of growth factors further down the line. Cell growth arrest or apoptosis (cell death) follows, but only for the targeted melanoma cells, with no effect on non-cancerous cells.
In an interesting twist, a review published in July shows that inhibitors of Raf kinases (the family of kinases that includes the product of the B-RAF gene) can be developed for either the “activated” or “resting” forms of the enzyme. These two forms of the same enzymatic target show remarkably different clinical applications: Zelboraf targets the “activated” Raf kinase. Bayer’s Nexavar (sorafenib), a “resting”-form Raf inhibitor, was approved in 2005 for treatment of kidney and liver cancer, but shows little activity against BRAF V600E melanoma.
Update (4:30PM, 8/25/11) – Deleted “in silico” from screening description. Assays were run in vitro using AlphaScreen beads (PerkinElmer).
As reported by Nature News and Forbes’ The Medicine Show on July 20, dapagliflozin, a BMS-developed diabetes drug marketed with partner AstraZeneca, was given a “thumbs-down” by an FDA review panel on July 19. After the 9-6 final vote, panel members commented favorably on the drug’s new mechanism, but evidently felt that the safety profile could not be overlooked: the FDA committee meeting statement mentions increased risk of breast and bladder cancer, increased genital infections, and perhaps most seriously, potential for drug-induced liver injury (DILI).
Dapagliflozin has been one of the rising stars of the new class of Sodium-Glucose cotransporter 2 (SGLT2) inhibitors for diabetes treatment, whose development roster includes Johnson & Johnson, Astellas, Boehringer Ingelheim, Roche, GSK, and Lexicon (Note: see Nat. Rev. Drug Disc. 2010, 551 for a full recap). The excitement behind these drugs comes from a relatively new idea for diabetes treatment: inhibition of the SGLT2 enzyme stops the kidney from reabsorbing sugar, leading to excretion of the excess glucose in the urine, which in turn lowers blood sugar. Dapagliflozin, like most SGLT2 inhibitors, is a glucose molecule with a large aromatic group attached to the carbon atom in the spot chemists call the anomeric position. Such so-called C-glycosides are thought to have improved staying power in the bloodstream relative to O-glycosides (where the linkage point is at an oxygen atom, a more common scenario in sugars), since they are less susceptible to enzymatic breakdown.
Janet Woodcock, head of FDA’s drugs center, had a few things to say about obesity drugs at Monday’s Reuters Health Summit in New York. Some of her comments weren’t surprising. But some of them might offer a sliver of hope to companies hoping to succeed where Arena Pharmaceuticals, Orexigen Therapeutics, and Vivus have so far failed– in bringing a new diet pill to market.
For diet drugs, Woodcock said companies might find success by showing benefits beyond weight loss such as a decrease in blood pressure or reversal of diabetes.
“Those would be benefits you might accept more risk for,” Woodcock said. The FDA recently rejected diet drugs with various safety issues from Arena Pharmaceuticals Inc (ARNA.O), Orexigen Therapeutics Inc (OREX.O) and Vivus Inc (VVUS.O). The agency also asked Abbott Laboratories Inc (ABT.N) to withdraw its diet medicine, Meridia, from the market due to heart risks and the company agreed.
It’s not surprising to hear Woodcock say that a potential weight loss pill’s risks must be balanced by clear benefits. Having positive effects on things that can be consequences of obesity, such as blood pressure and blood sugar control, is one way of achieving that balance. Another way is to show FDA that your risks aren’t all that risky. On that topic, I was intrigued to read Arena’s announcementthat it isn’t conducting the 12-month study FDA asked for to evaluate how its obesity drug candidate lorcaserin caused tumors in rats, and is conducting a three-month study instead.
Now, what really caught my eye in Woodcock’s statements was this gem: Continue reading →
Last week, Lisa wrote a story about India-based Cadila Pharmaceuticals becoming a partial investor in a proposed drug manufacturing site in Rwanda. This guest post from C&EN reporter Linda Wang explains another partnership in that vein.
Cameroonian billionaire entrepreneur Celestin Tawamba is hoping that the enormous success he’s had in building a pasta empire in central and sub-Saharan Africa can be replicated in his latest endeavor—to establish a state-of-the-art generic drug production facility in his native Cameroon.
In April 2010, Tawamba, who is widely known as “the pasta king,” launched Pharmaceutical Industrial Company (Cinpharm S.A.), in Douala, Cameroon. With financial backing from foreign investors such as Cipla, India’s largest pharmaceutical company, cinPharm has started blister packing and distributing generic drugs, including paracetamol, ibuprofen, metronidazole, amoxicillin, and cotrimoxazole. Continue reading →
Today I posted a news story about the debut of the structure of PLX4032, a promising melanoma drug developed by Berkeley, California startup Plexxikon. This drug’s story has already been given the narrative treatment courtesy of the New York Times. And when the results of a Phase I clinical trial of PLX4032 came out, it got covered in many other news outlets as well. But we here at The Haystack are most interested in PLX4032′s chemical backstory. And when I contacted kinase expert Kevan M. Shokat for his opinion on the work, he said the story has another dimension- clues about how to pick the right kinase targets to treat diseases. Continue reading →
Back in 2007 and 2008, tainted heparin from China was responsible for the deaths of over 80 people in the U.S. If you had some sort of warm and fuzzy reassurance that authorities were looking into the matter, a new congressional probe should quash that feeling pretty quickly. Today the Wall Street Journal reported that the probe, by two congressmen from Texas, has found that China never looked into the heparin scandal at all. This is despite repeated warnings from FDA, as C&EN wrote last year.
The probe comes ahead of FDA Commissioner Margaret Hamburg’s first trip to China in her new official capacity. The congressmen, Reps. Joe Barton and Michael Burgess, urged the commissioner to bring the issue up during her trip. According to the WSJ, a spokeswoman for China’s State Food and Drug Administration said the results of the probe were “not true.”
It’s a shame this scandal had to happen at all- all because heparin, a drug so many people rely on, is easier to harvest from a pig intestine than it is to make in the lab. Continue reading →
This AM, Reuters released a special report about the state of drug R&D. Overall, I enjoyed reading the piece. Though there isn’t a whole lot in there that C&EN’s readers who work in the area won’t already know, I think the article does a great job of capturing how scientists- and young scientists in particular- feel about their job situation. The folks quoted in the article are feeling more than a little frustrated.
That said, there were a couple of statements in this article that were unfair, misleading, or downright pessimistic. In the section on biotech, we have this generalization:
Biotech’s “large molecule” protein drugs, made using genetic engineering, have proven superior at fighting complex diseases like cancer to many conventional “small molecule” chemical drugs.
That argument is a little hard to swallow. You might say that the side effects from a protein drug are more benign than those of traditional chemotherapies like 5-fluorouracil. And Herceptin, a biologic drug, has made a big difference for women with a specific type of cancer. But what about Gleevec? If you have cancer driven by a certain genetic mutation, Gleevec works-and it’s a small molecule.
Look closely at Herceptin or Avastin-a biologic cancer drug the Reuters article mentions in its next paragraph- and you’ll notice that for treating some cancers they must be taken with small molecules- carboplatin, paclitaxel, or something else. Both parts of the treatment- the small molecule and the protein- are necessary for the treatment to work its best.
Maybe cancer isn’t the best example- after all, every cancer is a different challenge. What about other diseases? In the past, we’d written about how biologic drugs are the best we’ve got for multiple sclerosis. Humira, a biologic treatment for rheumatoid arthritis, is another success story that the Reuters article mentions.
But what about HIV? There are an awful lot of small molecules on this list of approved HIV drugs, and when used correctly, they keep the disease at bay for years.
Yes, there’s some wiggle room in the Reuters statement because of the use of the word “many”. Maybe it’s the organic chemist in me speaking, but I get pretty miffed when I hear pessimistic statements about small molecules.
A smaller nitpick but a nitpick nonetheless- the article seems to use the words “biotech” and “biologic” interchangeably, which might confuse someone who isn’t familiar with the area.
By 2014, the world’s two top-selling prescription drugs won’t be tablets sold in blister packs but needle-based biotech treatments — Avastin for cancer, sold by Roche, and Humira for rheumatoid arthritis, from Abbott Laboratories — according to consensus forecasts compiled by Thomson Reuters.
Lastly, I wish the article hadn’t ended back in an academic setting. Instead, I would’ve liked to hear more about the scientists who migrated to Parexel, the company that conducts clinical trials for drugmakers. That academic ending was a downer to me- it represents a narrow-minded view about what the skills of a scientist trained to work in pharma are good for.
The American Society of Clinical Oncology (ASCO) meeting in Chicago has been dominating pharma news for the past few days. And while much of the cancer-drug-related news coming out of the meeting is about biologics, the small molecule crizotinib is in the spotlight, too. Crizotinib is an experimental drug that Pfizer is developing for the treatment of lung cancer in a very specific set of patients.
Much of the crizotinib coverage focuses on its targeting of anaplastic lymphoma kinase. While many “targeted” drugs have reached the market in recent years, very few types of cancer are driven by a single genetic mutation, so the drugs’ effect has therefore been limited. One of the rare exceptions is Novartis’ drug Gleevec, which targets a protein kinase called BCR-ABL. Gleevec has been called a miracle drug for its ability to halt a rare type of leukemia; some scientists now think crizotinib could be another of those rare exceptions. Robert Langreth at Forbes quotes Mark Kris, a scientist at Memorial Sloan-Kettering Cancer Center, who likens crizotinib to Gleevec.
While it’s too early to compare an experimental therapy like crizotinib to Gleevec, a successful marketed drug that has had a major impact on cancer research, at a molecular level, Kris is right, since both drugs do go after kinases.
Crizotinib is designed to work on the ~3-5% of lung cancer patients with an alteration in the ALK gene- that’s roughly 10,000 people in the USA, according to the Wall Street Journal. WSJ has articles on crizotinib here and here.
Now, when I see the word kinase, the first place I hunt for information are the archives of KinasePro. That didn’t disappoint- and revealed some more details of the drug’s story.
According to a discussion on KinasePro, the patent literature reveals that the series of compounds that included the future crizotinib was discovered by scientists at Sugen, a company which Pfizer acquired. We alluded to the fact that Pfizer inherited many such molecules in our coverage of drugs targeting Met, a tyrosine-kinase receptor implicated in many cancers. As the WSJ noted, crizotinib’s activity against Met, which was the reason Pfizer acquired it in the first place, has so far turned out to be less important than its effects on ALK. It’s worth noting that Gleevec targets other kinases as well- it’s not perfectly selective for BCR-ABL.
Is there a lesson for cancer research in here? Is high selectivity for one molecular target necessarily a good thing in drug development?
Bonus: If you want to get a real feel for the ‘needle in the haystack’ exercise that pharma is, try downloading the 2004 patent that KinasePro cites as the earliest mention of the series. It’s 300 pages long and packed with compounds, most of which will never get anywhere near a person, let alone a pharmacy shelf.
I am always on the lookout for news in the obesity drug area. But lately two of the molecular components of experimental obesity drugs in late-stage clinical trials-naltrexone and topiramate- are in the news for other reasons.
Alkermes announced this morning that it will receive priority review from FDA for VIVITROL, an injectable extended-release formulation of naltrexone, for treating opioid-dependent patients, with a PDUFA date of October 12, 2010. The idea is that a once-monthly injection of VIVITROL would be given to lower cravings in people with a dependence on opioids such as heroin, Vicodin, or Oxycontin. VIVITROL is already approved for treating alcohol dependence.
It’s Alkermes’s formulation that’s new. Naltrexone as a chemical entity has been around for some time. DuPont originally marketed it as Trexan in 1984 but that form is now off-patent, as C&EN’s Ann Thayer wrote back in 2006. I also promised that there was an obesity connection here, and indeed there is. Naltrexone is one of the two components in Orexigen’s experimental obesity medication, Contrave, as I explained last year. Orexigen has developed its own proprietary sustained-release formulation of naltrexone and the experimental drug’s other active ingredient-bupropion, an antidepressant and smoking-cessation aid that boosts dopamine signaling.
Ortho-McNeil Pharmaceutical, a subsidiary of Johnson & Johnson, has agreed to pay $81 million (that’s $6.1 million in criminal fines and $75.37 million from civil suits) for promoting its epilepsy medication Topamax for several uses not approved by FDA. This story has been in the news for nearly a month now (see Pharmalot’s entry about it here) but the company pled guilty to the illegal marketing just last Friday, placing this item back at the top of my Google News list.
One of the off-label indications J&J was promoting turns out to be obesity, according to the whistleblower who brought the case. Read the legal documents here [pdf format]. Thanks to Jim Edwards at BNET for posting these.
Topiramate (the active ingredient in Topamax) is one of the two active ingredients in Vivus’s experimental obesity drug Qnexa. But Vivus’s formulation uses topiramate at a much lower dose than would be taken as a standalone drug.
Been focusing on Chicago and this year’s BIO extravaganza all week? Here’s a sampling of news you might have missed.
In a surprisingly twist, FDA refused to approve InterMune’s lung treatment pirfenidone, despite a positive recommendation from its advisory committee. The agency wants another lengthy trial to better demonstrate pirfenidone is effective at treating idiopathic pulmonary fibrosis, a debilitating and ultimately fatal lung disease for which there are no approved treatments in the U.S. or Europe. InterMune’s stock fell over 75% on the news. Check out this piece in Forbes’ health care blog on whether FDA is these days less likely to listen to its advisory panels.
Birth Control Pill Exalted
The mainstream media celebrated as “The Pill” turned 50. Technically, they’re celebrating the 50th anniversary of its approval by FDA. C&EN covered the chemistry story of the pill in “The Top Pharmaceuticals That Changed The World” special issue, back in 2005. Don’t miss the classy 1950s era photo of Carl Djerassi.
Resveratrol Trial Halted
A GlaxoSmithKline clinical trial studying a reformulated version of resveratrol was suspended on April 22 due to safety concerns, but company officials say the complications may or may not be related to the drug. The big question remains-what does this all mean for the effort to make drugs out of resveratrol, the trace component of red wine that’s been touted as a cancer fighter and a fountain of youth in a bottle? Continue reading →