DRugwatch Blog > January 2012

Matt KileenContributor: Matthew Killeen, Ph.D.


After a testing last year for Multaq (Sanofi’s dronedarone) – in 2011, its major PALLAS study was terminated and safety alerts were issued by the FDA and European Medicines Agency – 2012 offers a ray of hope for the antiarrhythmic drug. In January 2012, at the Boston Atrial Fibrillation Symposium, plans for a new clinical trial, testing a combination of Multaq and Ranexa (Gilead’s ranolazine) in AF patients were unveiled – a development strategy that Decision Resources had predicted over a year ago. Combination antiarrhythmic therapy for AF is a novel treatment approach that could deliver key benefits to patients, but developing such an agent poses a series of unique challenges. Given these factors, and the competitive landscape for antiarrhythmic drugs, what are the prospects for success of a Multaq and Ranexa combination therapy?


The HARMONY trial will investigate the effects of Multaq in combination with Ranexa in approximately 150 patients with non-permanent AF and implanted pacemakers – the enrollment of these patients will allow for investigators to quantify the therapy’s effects on AF burden. Although a small study, the results from HARMONY could lead to a paradigm shift in the treatment of AF.

Based on preclinical data, we believe that a Multaq and Ranolazine combination therapy could be well positioned to offer important benefits over current agents, which suffer from limited efficacy and/or safety concerns. Multaq and Ranexa have different modes of action and research in an animal model of AF showed that treatment with both agents yields synergistic antiarrhythmic effects. We expect that this finding prompted the choice of lower drug doses in the HARMONY trial (for example, only 150-225 mg of dronedarone will be tested vs. its current label of 400 mg twice daily). Additionally, Ranexa benefits from a strong safety profile; previous, intensive safety testing and Phase III research have shown that it poses no risk of major adverse events, particularly cardiac toxicity. Furthermore, although Multaq’s hepatic and cardiac safety profiles have been recently scrutinized, lower doses of the drug may reduce the risk of encountering these adverse events.

Despite the potential therapeutic benefits afforded by a Multaq and Ranexa combination therapy, it may face a number of regulatory and commercial challenges during its late-stage development and following its launch.  For example, given the risk of developing QT prolongation with both drugs, and Multaq’s prior history in the ANDROMEDA and PALLAS trials, the FDA is likely to demand a broad range of safety data in the form of dedicated studies (e.g., a thorough QT test) and at least one large outcomes-based trial. Selecting the optimal suite of safety studies and patient populations to enroll will prove crucial in demonstrating and reinforcing the combination’s safety to regulatory agencies and the medical community. The design of a subsequent Phase III program will also be pivotal in shaping physicians’ and payers’ perceptions of the combination’s efficacy and merits over existing agents; however, overcoming current perceptions of Multaq’s profile could prove challenging. Based on primary research conducted by Decision Resources, we believe that Multaq’s Phase III data from its ATHENA trial, which used an unconventional efficacy end point for AF (cardiovascular hospitalization), failed to resonate with prescribers and contributed to its modest uptake. Surveying cardiologists in the major markets to gauge the importance assigned to different efficacy end points in prescribing decisions could provide key insight into designing a Phase III study to fuel post launch uptake.

According to thought leaders interviewed by Decision Resources, the availability of safer and more effective antiarrhythmic drugs is a pressing unmet medical need in AF and, based on our current knowledge of the Multaq and Ranexa combination, we believe that it has the potential to offer important advantages over current agents. Nonetheless the combination therapy may face competition from key emerging drugs, such as oral vernakalant (Merck/Cardiome) and NTC-801 (Bristol-Myers Squibb/Teijin). The launch of Multaq, and the challenges it faced, provides the developers of new agents, including the combination therapy, with important learning opportunities regarding the design of late-stage AF trials, optimal end points to use, key patient subpopulations to target, and the best approaches to addressing regulators’ concerns. At this early stage in the combination’s development, harnessing this new insight to inform its future clinical pathway could play a major role in shaping its commercial success.
Posted on: 1/20/2012 2:12:09 PM | with 3 comments

Contributor: Allison Thrower

The pharmaceutical and entertainment industries have been abuzz since word dropped this week of Paula Deen’s type 2 diabetes diagnosis. The announcement offered an unexpected twist: the queen of Southern cuisine has also signed an endorsement deal with Novo Nordisk for its diabetes medication Victoza. The campaign called “Diabetes in a New Light” is meant to support healthy lifestyle changes in conjunction with the therapy – a stark contrast to Deen’s traditional tableau that consists of fried burgers on a glazed doughnut bun. A bold move by Novo, no doubt, but it’s certainly not the first of its kind.

Controversy aside, celebrities have been in the biopharma and healthcare spotlight for years – Bob Dole for Viagra, Sally Field for Boniva, Rob Lowe for Neulasta and now Paula Deen for Victoza. What other celebrities have successfully held sponsorships in the drug arena?

If time and tradition are any indicators, this will be an advertising trend for years to come. But still stands the question: just how efficacious or appropriate is this approach to drug promotion? And now that Deen’s endorsement has garnered public interest beyond the industry, how will celebrity pharmaceutical tie-ins be viewed or utilized in the future?
Posted on: 1/19/2012 6:15:13 PM | with 1 comments

Matt KileenContributor: Amy Duval

Doxil, who is being affected?

The ongoing shortage of Doxil is impacting both patient treatment and the progression of clinical trials, meaning its effects are not only being felt now, but drug development for future treatments is also being impacted.

In the United States, Doxil is licensed to treat ovarian cancer, AIDS-related Kaposi’s sarcoma, and multiple myeloma. Undoubtedly the shortage of Doxil is having a resounding impact on the treatment of all these diseases. In ovarian cancer, Doxil can be used to treat patients whose disease has recurred after initial therapy. In the current Doxil shortage, oncologists have to turn to therapeutic options, which may not typically be their first choice for patients.

The impact this is having on patient quality of life is almost impossible to tell, but certainly oncologists must be feeling the strain of not being able to prescribe their therapy of choice. Patients are undoubtedly feeling shocked and disappointed – to have either be told part-way through treatment that Doxil is no longer available, or to realize they are receiving a different agent because Doxil is not available, rather than out of physician choice.

Doxil’s supply shortages are also beginning to impact clinical trials for ovarian cancer. Because Doxil is frequently used to treat the disease, several clinical trials of emerging therapies for ovarian cancer use Doxil as a comparator. Furthermore, an emerging drug may be tested in combination with Doxil, with the aim of adding to its benefit. This issue has affected Endocyte, who are developing the emerging therapy EC145 for the treatment of recurrent, platinum-resistant ovarian cancer. EC145’s pivotal Phase III trial (PROCEED) is studying the drug in combination with Doxil versus Doxil alone. Owing to the shortage in Doxil, the PROCEED trial is now on hold, and in a company presentation Endocyte confirmed that new supplies of Doxil were not being given to the trial. It’s more than likely that other clinical trials utilizing Doxil are suffering a similar fate.

Doxil, what’s the delay?

In June 2011, Centocor Ortho Biotech (now Janssen) issued a letter to U.S. healthcare providers detailing a shortage of the drug Doxil (pegylated liposomal doxorubicin, or PLD). This shortage was caused in part by production delays at a specialty manufacturing plant, Ben Venue Laboratories, for Doxil.

The shortage of Doxil has been far-reaching as the affected plant is the sole manufacturer of Doxil, meaning its supply difficulties have affected markets worldwide. In August 2011 in Europe (where PLD goes under the brand name Caelyx), the European Medicines Agency issued a letter detailing the likely shortage in supply of the agent due to the manufacturing problems in the United States. The Ministry of Health, Labor, and Welfare in Japan issued an announcement in November 2011 that no new patients should start on Doxil therapy, as there would be a shortage of the agent in 2012.

The story continues. Since these initial announcements of the PLD shortage, further announcements have been made, and the delay to the expected date for new Doxil supplies has pushed further away. Few shipments of the drug have been dispatched since mid-2011, and as a result the Creating Awareness and Reinforcing Education Support (CARES) physician access program has been set up in the United States. The CARES program will deliver PLD to physicians as it becomes available, and is also in place to prevent supplies of the drug being hoarded.

In a further twist, November 2011 saw Ben Venue Laboratories announcing that it had temporarily suspend manufacture and distribution of products made at the plant (including Doxil, but also affecting a number of other chemotherapies) in order to complete site-wide assessments after it found that maintenance and requalification was overdue for some of its manufacturing equipment. In December 2011 Ben Venue Laboratories did not anticipate any Doxil from the manufacturing plant would reach physicians until the end of 2012. Janssen have released statements confirming that they continue to investigate alternative short-term solutions to create a reliable supply of PLD, and that in the long-term they will transition to an alternative supplier (following news that Ben Venue Laboratories will transition away from contract manufacturing services).
Posted on: 1/17/2012 4:47:06 PM | with 0 comments

Matt KileenContributor: Donny Wong, Ph.D. Director, Metabolic Disorders

Last week, we examined key happenings in the diabetes drug development arena from the first half of 2011. According to Decision Resources’ Metabolic Disorders team, here are the most influential events to impact the diabetes market in the second half of 2011.

To read part one of this list, click here.

4. In June 2011, the French and German regulatory agencies withdrew Takeda’s PPAR-gamma agonist Actos because of bladder cancer concerns. These concerns arose after several registry studies, including the FDA's Adverse Event Reporting System and the French national health insurance body's database, linked use of Actos to an increased risk of developing bladder cancer.  The drug remains on the market in other European countries, Japan, and the United States, although cautions about its use in patients with known or suspected bladder abnormalities have been added to the drug's prescribing information.

Winners and losers: While at the surface level it looks like the withdrawal of Actos from France and Germany is a loss for Takeda, the fact that the drug was allowed to remain on the market in the United States (and in Japan) is a win considering that French and German sales for Actos comprised only 2% of total G7 major-market sales for Actos. Similar to how Januvia benefited from the decline of Avandia following the publication of several meta-analyses linking Avandia to elevated cardiovascular risk, the negative publicity surrounding Actos and the elevated risk for bladder cancer will be a boon for the DPP-IV inhibitors, which are viewed by many physicians as safer options. However, the real losers will be the generics manufacturers who have lined up to market generic pioglitazone once the drug loses marketing exclusivity in Q3 2012; these companies will face diminishing demand for pioglitazone. Other drugs in the diabetes pipeline may also end up on the losing side, as the bladder cancer issue will cause regulators to increase their level of scrutiny for cancer signals, as we observe for the SGLT-2 inhibitor dapagliflozin (see #5 below).

5.  In July 2011, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee cast a 9-6 vote against approval of Bristol-Myers Squibb's and AstraZeneca's (potentially) first-in-class SGLT-2 inhibitor dapagliflozin. The negative vote resulted primarily from an imbalance in the number of breast and bladder cancer cases observed from pooled Phase II and III data in patients exposed to dapagliflozin, and a possible case of Hy's law (signifying potential drug-induced liver injury). The original PDUFA date for dapagliflozin was October 28, but was delayed by the FDA until January 28, 2012 following a request for additional data from ongoing clinical trials. Mechanistically, the imbalance in the cancer cases doesn’t make a lot of sense. But regulators cannot deny the numerical imbalance (18 breast and bladder cancers in the dapagliflozin group, 1 case in the control group) and therefore we anticipate that the additional data that BMS and AstraZeneca have delivered to the FDA will be insufficient. Instead, we expect that dapagliflozin will receive a complete response letter from the FDA requesting a safety study to demonstrate that there is no elevated cancer risk or hepatoxicity. We expect that fulfilling this request will result in at least a two-year delay for dapagliflozin.

Winners and losers: BMS and AstraZeneca stand to lose the lucrative first-in-class advantage for dapagliflozin owing to the regulatory delays we are anticipating. This opens the door for Johnson & Johnson's canagliflozin and Boehringer Ingelheim and Eli Lilly's empagliflozin, which are both in Phase III development—and we now expect all three drugs to launch around the same time. This delay will also benefit the DPP-IV inhibitors, which will not face the challenges posed by a new drug class until the first SGLT-2 inhibitors enter the market in 2014. However, the burden of proof is on other developers of SGLT-2 inhibitors to demonstrate that their compounds are not associated with elevated cancer risk—and if subsequent imbalances are found, then the entire class may be at risk. 

6.  In September 2011, Novo Nordisk filed applications for regulatory approval of insulins Degludec and Degludec Plus in the United States and in Europe. Degludec has a longer halflife than Lantus or Novo Nordisk’s Levemir, and is therefore a truer once-daily long-acting insulin analogue than either Lantus or Levemir. Also, Degludec is associated with a 25% lower rate of nocturnal hypoglycemia than Lantus and can be dosed more flexibly (i.e., at any point in the day).

Winners and losers: I would have to go out on a limb and say that Novo Nordisk will end up the most likely loser here. The company also has the most to gain, but there are too many chips stacked against widespread use of Degludec. Do we really need another long-acting insulin, especially as biosimilar formulations of insulin glargine are looming in the not-too-distant future? Novo Nordisk has also been fairly quiet about the thrice-weekly option that they had been championing over the past couple of years. While the need for fewer injections will be welcomed by patients, the thrice weekly option left most physicians scratching their heads, as a weekend “drug holiday” doesn’t exactly help a patient’s best interests. However, the proof will be whether payers will reimburse for what boils down to just improved safety and convenience. The one wild-card will be the Degludec-Victoza combination, which is currently in Phase III development. This duo will become a strong contender if it demonstrates good safety and efficacy (which we expect based on each drug’s individual profiles), and if the dosing can be optimized (i.e., via a single injection). The Degludec-Victoza combination also got a boost when Sanofi announced a delay to the development of its own basal insulin + GLP-1 analogue combination (Lantus + Lyxumia).

7.  In September 2011, Eli Lilly and Boehringer Ingelheim announced that they were delaying the launch of Trajenta (linagliptin) in Germany due to ongoing discussions about reimbursement with German reimbursement authorities following the passing of AMNOG (Germany’s Pharmaceutical Restructuring Act) earlier in the year. The companies’ concern was that generic antidiabetic drugs such as metformin or the sulfonylureas might be used for reference pricing for Trajenta, which would result in a low price for Trajenta. However, why the rest of the pharmaceutical industry needs to take notice of this development is that there can be serious repercussions beyond Germany, given that many other countries use German pricing as an external reference.

Winners and losers: In the short term Eli Lilly and Boehringer Ingelheim are losing revenue to other DPP-IV inhibitors by not launching Trajenta in Germany. However, the entire pharmaceutical industry may end up being the losers in the long term if German reimbursement officials do end up benchmarking novel therapies like Trajenta against low-cost generics like metformin or the sulfonylureas. The only potential winner here is the German healthcare system. One potential fallout to keep an eye open for is the possibility that BI and Eli Lilly will refuse to launch Trajenta in Germany at all. We’ve seen this happen in the past when AstraZeneca abandoned its plans to launch Crestor (rosuvastatin) in Germany in 2005. (However, AstraZeneca did eventually launch the drug in 2008, a full five years after its first launch in other European markets).
Posted on: 1/9/2012 8:04:20 PM | with 0 comments

Matt KileenContributor: Donny Wong, Ph.D. Director, Metabolic Disorders

As we start up the new year, it’s time to take a look back in time to examine some of the key events that occurred in the world of diabetes drug development in 2011. The past year was full of surprises and for each of these events I’ll re-cap who I think the winners and losers were, and provide a view of potential future outcomes. By the way, these events are in chronological order rather than order of importance—out of the thousands of minor and major news items that appeared over the wire during 2011, these events were what the Metabolic Disorders team at Decision Resources considered to be the seven most influential events, with long-reaching implications that will affect the entire diabetes drug market in 2012 and beyond.

1.  In January 2011, Eli Lilly and Boehringer Ingelheim announced a joint venture to co-develop and market five diabetes drugs worldwide. These five drugs included an insulin glargine product (i.e., biosimilar version of Sanofi’s Lantus), a novel basal insulin product (LY-2605541), the SGLT-2 inhibitor empagliflozin, the DPP-IV inhibitor Tradjenta (linagliptin), and a TGF-beta inhibitor drug in early-phase development for chronic kidney disease (LY-2382770).
Winners and losers: It’s still too early to say—although in the short term it looks like Lilly has ended up with the short end of the stick. BI is a newcomer to the diabetes market, so the deal gives BI access to Lilly’s strong diabetes marketing experience and sales force.  Meanwhile, Lilly has already made a $300 million up-front payment to Boehringer Ingelheim to gain access to two oral diabetes therapies, which complement Lilly’s injectable insulin franchise. However, as a third-to-market DPP-IV inhibitor in the U.S. (and despite Tradjenta’s marginally improved safety profile compared to other DPP-IV inhibitors), the drug will not be able to approach even a fraction of the market success of Merck’s first-in-class Januvia franchise, which achieved over $3 billion in 2011 sales.

In the longer term, the deal may become a win-win situation for both parties. An anticipated delay for Bristol-Myers Squibb/AstraZeneca’s SGLT-2 inhibitor dapagliflozin opens the door for empagliflozin, although it is still unclear how each of the SGLT-2 inhibitors in the pipeline will be able to differentiate from one another. But more importantly, the partnership gives Eli Lilly access to BI’s European sales and marketing expertise generated by BI’s strong European presence in the cardiovascular space, which will in turn provide the necessary reach for Lilly’s biosimilar insulin glargine product to compete against Sanofi’s Lantus and the host of other biosimilar glargine products waiting in the wings.

Also, keep an eye open for LY-2382770. This compound is only in Phase II development for diabetic nephropathy and chronic kidney disease, but will target a market with tremendous unmet need, where any drug able to convincingly demonstrate disease-modifying properties can expect strong sales.

2.  In March 2011, Eli Lilly and Amylin Pharmaceuticals released the results of the DURATION-6 head-to-head trial which pitted Bydureon against Victoza. In this study, Bydureon was unable to demonstrate superiority over Novo Nordisk’s Victoza.  This result was yet another disappointment in a long line of setbacks for Bydureon. The drug was already delayed twice by the FDA—once with a request for a clearer Risk Evaluation and Mitigation Strategy (REMS) and more recently with a request for a thorough QT (tQT) cardiac safety study. Together, these delays cost the manufacturers 18 months of market access, which we estimate has diminished Bydureon's market potential by approximately $1 billion per year. Without these delays for Bydureon, Victoza would have only had six months on the market before Bydureon’s originally anticipated entry date. Now Victoza will get a two-year lead over Bydureon in the U.S. (assuming Bydureon gets the nod from the FDA at the end of this month.)

Winners and losers: The clear winner here is Novo Nordisk. In the past, we had forecasted that Bydureon would own the GLP-1 analogue space shortly after its launch because of its once-weekly dosing schedule and strong glucose-lowering and weight-loss efficacy. Not any more. The tides have now turned and by the time Bydureon enters the U.S. market (expected in Q1 2012), not only will Victoza have been on the U.S. market for two years, but patients will have gotten used to the thin-gauge needles used to administer Victoza. Suddenly the prospect of a once-weekly drug may not be so appealing to physicians, especially if a large-bore needle is required, and if the net result, as demonstrated by the DURATION-6 trial, is that Victoza offers at least comparable (if not better) efficacy. It’s clear that this is a huge setback for Bydureon, so perhaps the divorce between Eli Lilly and Amylin Pharmaceuticals doesn’t look like that bad of a situation for Eli Lilly after all.
3.  In May 2011, a third nail in the quest for an immunomodulatory therapy for type 1 diabetes hit the coffin when Diamyd Medical and Ortho-McNeil-Janssen’s Diamyd vaccine against GAD-65 (an auto-antigen found in a large proportion type 1 diabetics) failed to meet its primary end point in a European Phase III trial. The company subsequently terminated both the U.S. Phase III trial and the follow-up to the European Phase III trial. The previous two nails were the October 2010 announcement that MacroGenics and Eli Lilly’s anti-CD3 mAb teplizumab had failed to meet its primary end-point in the Phase III PROTÉGÉ  study and the March 2011 announcement from Toleryx and GlaxoSmithKline that their anti-CD3 mAb otelixizumab had also failed to meet its primary end point  in the Phase III DEFEND-1 study.

Winners and losers: Unfortunately, there are many losers connected to this event and no clear winners other than the major insulin manufacturers. In fact, the future looks bleak for the entire immunomodulatory approach, and as the demise of these frontrunners in the race for a disease-modifying therapy for type 1 diabetes sends a strong signal that we still do not understand the factors that trigger the development of type 1 diabetes as well as we previously thought.
To read about the other key events in the 2011 diabetes drug market and beyond, click here for part two.
Posted on: 1/6/2012 5:25:06 PM | with 0 comments

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