Contributor: Joanne Graham

The US and European approval of Bristol-Myers Squibb’s Yervoy earlier this year followed by the prompt FDA approval of Roche’s Zelboraf last week has been welcomed; European approval of Zelboraf is anticipated in the next few months. However, the reality is that there will remain a substantial proportion of patients that will not be impacted by these new drugs. The oncology team at Decision Resources Group has engaged in much cogitation, debate, discussion and analysis to determine how the dynamic malignant melanoma market will play out over the next few years.

The BRAF inhibitor - a success story of a targeted therapy where the target was identified initially through the human genome project (Davies H., 2002), is precisely that - targeted, albeit to a large proportion, 47% of patients with the mutated BRAF gene (Chapman PB, 2011; Jakob JA, 2011; Menzies AM, 2011; Long GV, 2011). The aim will be for the majority of patients with BRAF mutated disease to receive Zelboraf as soon as they are diagnosed with metastatic disease, it should prolong the time before their disease progresses, and current data shows a superior 6 month overall survival rate (84% versus 64% for dacarbazine (Chapman PB, 2011): experts are optimistic that median overall survival benefits will be realized when data mature. Patients with wild-type BRAF will be eligible for Yervoy - won’t they? Well yes, in the U.S., and yes, eventually - on failure of a traditional, largely ineffectual treatment, in Europe - if the current label for previously treated advanced melanoma is strictly adhered to.

Yervoy should be celebrated as the first drug to demonstrate an overall survival benefit, 3.7 months over control arm, in a previously treated population and 2.1 months better than dacarbazine in a first-line trial. However, this does not reveal the entire story as there is a proportion of patients who experience long, durable responses extending towards two years. Typically, the pay-off with Yervoy is the side-effect profile, and many patients may either be ineligible for treatment, or not complete the planned four injection course of Yervoy, with the consequence of compromised efficacy. In addition, and in contrast to Zelboraf, precisely which patients will derive benefit is difficult to predict.

And of course to price; many melanoma patients are young, and, in the US, will not be covered by Medicare so the uninsured will face reimbursement hurdles. It seems unlikely that Yervoy with an anticipated UK price tag of £75,000 a course ($123,000 exchange rate 24th August 2011) even in the light of an overall survival benefit, will jump the NICE barrier unless a cost-sharing or reimbursement structure is agreed. The UK has melanoma patients aplenty who may not be able to access this treatment.

So despite these exciting, novel new agents there remains ample room for more drugs to make even more gains, and increase treatment options, in this deadly indication. GlaxoSmithKline are steaming ahead with the clinical development of their BRAF and MEK inhibitors, dabrafenib and trametinib respectively, and the data from the trial that combines the two drugs are particularly eagerly anticipated. And of course there is the adjuvant setting - a much larger, and therefore commercially attractive, patient population, with in Europe in particular, low treatment rates due to a dearth of effective therapies, and high rates of recurrence to locoregional, in-transit, and metastatic disease. Yervoy is currently being explored in the adjuvant setting, and vaccines – currently explored by Amgen and GSK amongst others, as always are the great hope in this low tumor burden setting. So let’s celebrate these important advances, but let’s also hope more buses come along soon.

Contributor: Allison Thrower

While thinking about the upcoming Oncology seminar this September in Boston, my thoughts inevitably wandered to some of my favorite local restaurants and, more importantly, which would best satisfy my penchant for shellfish. Harbor-adjacent and only a few hours from Maine lobsters and Rhode Island clams, it hasn’t been hard for Boston, Mass to establish itself as the hub of New England seafood. And, while everyone’s familiar with the Legal Seafoods that line the Financial District, you don’t have to go far to find home-grown seafood eateries that boast fresher scallops and fewer tourists. So, for those looking to go beyond the beaten path, here are some of Boston’s best, lesser known seafood restaurants:

B&G Oysters – South End
While Boston’s South End boasts a myriad of diverse, high-end and equally delicious dining options, few locations can hold a candle to B&G Oysters’ seafood cuisine. Founded by local celebrity chef Barbara Lynch, B&G offers a knowledgeable wait staff, expertly picked wine list and wide array of edible bivalves. Their staple items come from the raw bar, and their fish entrees, which change seasonally, are simple to emphasize freshness and flavor. Don’t count on public transportation for any South End excursion. Instead, let the Walking City live up to its name; this historic neighborhood can be a nice backdrop for an after-dinner stroll.

Boston Sail Loft - Waterfront
If for no other reason, come to the Boston Sail Loft for their free Oreo cookies at the bar. While not as fancy as some of its neighboring wharf-side restaurants, BSL’s cozy atmosphere and home-style preparations make it a great place to enjoy a late-season Red Sox game, such as the September 23-25 series at Yankee Stadium. Their clam chowder is touted as the best in Boston, but the fish and chips are also a must-try. Avoid sitting on the deck on any moderate- to low-temperature day out. Although BSL has an outstanding view of the harbor, the waterfront location will leave you shivering despite the 70-degree weather just a few blocks into town.

Atlantic Fish Co. – Back Bay
Between the pretentious and overpriced cuisine of Newbury St., and the standard pub fare one street over, it is no surprise that Atlantic Fish Co. stands out as one of the area’s finest. Step away from the crowded streets of the Back Bay shopping district to find the spacious, welcoming and surprisingly warm atmosphere that Atlantic Fish Co. has to offer. Their menu is printed daily to advertise the freshest available fish on the market in addition to countless static items, from surf ‘n’ turf to soup. Anything from the raw bar is a safe bet at Atlantic Fish Co., but don’t write off their chowders, bisques and fish stews to start. For entrees, try the Lobster Ravioli drizzled in a basil cream sauce or the San Francisco Cioppino, an assortment of fresh shellfish swimming in a spicy saffron broth. All in all, Atlantic Fish Co. is pleasantly consistent for such an expansive menu, and any of their daily catches are sure to delight even the most discerning piscavores.

Neptune Oyster – North End
Nestled in the North End amongst predominantly Italian eateries, Neptune Oyster is undoubtedly the most well-known of the bunch and arguably the best. Their most popular dish is the Maine Lobster Roll – served hot with butter or cold with mayo; and, while both are delicious, butter is decidedly better. Pickings are slim for the non-fish eater, although the Neptuneburger – topped with cheddar cheese, garlic mayo and relish – is even better than some of their seafood options. It would be ill-advised to attempt this restaurant on a weekend night, as Neptune does not take reservations. There’s no better way to meet local Bostonians than by rubbing elbows with them in a three-hour wait line. My advice: make it a lunch date; your lobster roll will be just as good mid-day.

Honorable Mentions – More great seafood that didn’t quite make the cut…

East Coast Grill & Raw Bar - The menu oddly yet comfortably splits between seafood and BBQ (both of which are done well). The Sunday-morning brunch crowd flocks to ECG for their make-your-own Bloody Mary Bar. If you’re around on a Sunday evening, be sure to pop in for the weekly pig roast.

Union Oyster House – Union Oyster House didn’t make the list purely because it’s a tourist hot spot. That being said, history buffs can appreciate it as the oldest continuously operating restaurant in the United States, and their corn bread paired with clam chowder isn’t too bad either.

The Barking Crab – A little kitschy and a lot of fun, The Barking Crab is Boston’s go-to for fresh seafood without the pretense. And, while you may have to share your picnic table with a few families and tourists, the service, harbor view and shellfish dining options more than adequately compensate.

If you need an excuse to come to Boston, join us on September 22 for the Competitive Landscape Seminar Series on Oncology and be sure to reserve some time to check out one of these great restaurants.

Contributor: Kate Sullivan

The quest for a new obesity agent was dealt a further blow last week when Amylin and Takeda announced that they are ceasing development of their pramlintide/metreleptin combination. Clinical trials were suspended earlier this year owing to antibody-related laboratory findings, and the companies said their decision to halt development altogether was based on a reassessment of their commercial prospects as well as taking into consideration the “evolving dynamics” within the field of obesity drug development.

Despite its injectable mode of action which would likely deter some patients, the pramlintide/metreleptin combination had shown particular promise, given the double-digit weight loss efficacy it had demonstrated in Phase II studies. The suspension of this promising agent follows in the wake of the FDA’s recent rejection of three other obesity compounds: Vivus’s Qnexa, Arena/Eisai’s Lorqess and Orexigen/Takeda’s Contrave over a variety of safety issues, and it is likely that these failures weighed heavily in the decision to discontinue pramlintide/metreleptin.

So, what remains in the obesity pipeline? Of the three aforementioned agents which received Complete Response Letters from the FDA last year, Qnexa is the only one that we believe is likely to convince the FDA of its favorable risk:benefit profile. Lorqess’s poor weight loss efficacy, in combination with question marks over its safety, mean that this agent is unlikely to gain approval, and the requirement for Orexigen to carry out a preapproval cardiovascular outcomes study on Contrave means that a launch for this agent is no longer realistic.

Medical experts who lament the lack of safe and effective obesity treatments, have called for clearer guidelines in the development of obesity agents. The FDA is planning a general advisory committee meeting early next year to discuss requirements for cardiovascular assessments of obesity drugs. Thought leaders interviewed by Decision Resources predict that the drug development guidelines for obesity drugs are likely to become more aligned with those for type 2 diabetes agents, which will mean a requirement for large cardiovascular safety trials, and we believe this may act as a further deterrent to companies seeking to develop agents to treat obesity as a whole.

So, again, what is left in the pipeline? One agent that is showing promise in Phase III trials is Novo Nordisk’s GLP-1 analogue Victoza, which is currently marketed as a treatment for type 2 diabetes. This agent combines weight loss with excellent HbA1C control, and may prove effective in preventing the onset of type 2 diabetes. Given the high safety bar demonstrated by the FDA, it’s likely that an agent that addresses “medical need” in addition to providing weight loss will have a better chance of gaining approval. The fact that Victoza has already passed regulatory requirements for diabetes is also promising, given next year’s FDA meeting to discuss regulatory guidelines. Looking to the future with other obesity agents, interviewed thought leaders suggest that the development of agents which address the obese patients’ associated medical needs, such as diabetes or sleep apnea, in addition to providing weight loss, may be the best path forward for gaining regulatory approval. Therefore, we need to keep an eye on the diabetes pipeline for future development in the obesity space.

Contributor: Rachel Webster, D.Phil, M.Sc.

Dendreon’s Provenge (sipuleucel-T) faces a rocky road ahead following the company’s announcement of its second quarter 2011 financial results. What does the future hold?

On August 3, 2011, Dendreon reported net revenue of $78 million for the first half of 2011 (ending June 30, 2011), representing a significant a significant reduction on company forecast for Provenge. Consequently, the company withdrew its prior forecast of $350-400 million for 2011, but rather expects “modest” growth for the remainder of the year without being too specific as to their 2011 sales expectations.

Provenge became the first personalized therapeutic vaccine to gain major market regulatory approval for any oncology indication in April 2010. The path to regulatory approval was turbulent. Success in gaining FDA approval was however widely regarded as a milestone in clinical development for both prostate cancer and the field of oncology. At the time of FDA approval there was much enthusiasm and optimism for this novel agent and within the first year following its approval there has been high patient demand. However, penetration of the prostate cancer market has been slow, not least because of Dendreon’s limited patient-specific manufacturing capabilities. Although manufacturing constraints for Provenge now appear to have been alleviated, growth in sales has been considerably lower than expected.

Dendreon primarily attributed a lower 2011 sales projection to cautious physician prescribing, especially in the community setting, due to physician concern over gaining reimbursement for this highly priced therapy. The company stated that the high “cost density” associated with Provenge (i.e., Provenge’s high price [$93,000] and administration over a short period of time [one month]) has created considerable reimbursement uncertainty among physicians. This is so, even though the Centers for Medicare & Medicaid Services (CMS) recommended that Provenge be covered nationally for all Medicare beneficiaries according to the FDA approved label, in June 2011. Unless physicians gain more confidence that they can be reimbursed for the cost of Provenge, and quickly, it is likely that the high cost of this novel therapeutic and the current reimbursement environment will be prohibitive in its uptake. Indeed, physicians and payers surveyed by Decision Resources reveal that the high price of Provenge and its patchy insurance coverage is a barrier to uptake¹.

Although clinical data supporting Provenge as a first-line treatment for asymptomatic and minimally symptomatic castrate-resistant prostate cancer (mCRPC) are robust, Provenge has failed to demonstrate a significant improvement in time to disease progression over placebo. As such, the time to the requirement to treat with chemotherapy for symptomatic disease is likely not significantly different with Provenge treatment than with placebo. Experts interviewed by Decision Resources tell us that there is a subset of patients who are deterred from receiving Provenge, with this knowledge. Furthermore, there is no way of assessing which patients will most likely benefit from Provenge. These issues also likely contributed to the slower than anticipated uptake of Provenge, and are unlikely to remain unresolved in the near future.

The announcement of lower than anticipated sales is undoubtedly a setback for Dendreon, and the company faces a challenging time ahead. In addition to addressing physician confidence in Provenge’s reimbursement environment, other novel therapeutic agents are on the horizon and are poised to threaten Provenge’s current position in the prostate treatment paradigm. Most notably, Johnson & Johnson’s Zytiga (abiraterone) – FDA approved in April 2011 as a treatment for mCRPC patients who have received prior docetaxel (Sanofi’s Taxotere) – is being assessed as a treatment for the same subset of patients that Provenge is approved for. If Zytiga significantly improves overall survival and progression-free survival, and we expect that it will do, this novel hormonal agent could hit Provenge hard. Pivotal Phase III data for Zytiga in the first-line mCRPC setting is eagerly awaited.

There are perhaps now more questions than answers about the future of Provenge. Not least, with significant investment in a European manufacturing site, what does the future hold for Provenge in Europe? Lower than anticipated sales of Provenge in the United States certainly do not bode well for sales of Provenge in more cost-constrained European markets. However, there are likely many lessons learned from the developmental and commercial pathway of Provenge, and its woes post-approval. Developers of therapeutic vaccines in particularly – for prostate cancer and other oncology indications – could gain much from recent events.


¹ U.S. Physician and Payer Perspectives on Provenge, the First Therapeutic Cancer Vaccine: The Proof is in the Prescribing. Decision Resources, Inc. Physician and Payer Forum, June 2011.