Category Archives: Development

posts about current or developmental therapies

Good Lancet Article on Qnexa

 

Metabolic Markets commented a few months about about the structure of the risk mitigation approach from both a label and distribution control standpoint for Qnexa and what approach would would give the FDA confidence (code for: “political cover”) to approve.   An article in the LANCET recently dove into the advisory panel vote.  In particular, it was interesting to note the comments of the Qnexa panel chair, “”This risk mitigation strategy probably is what was most important in terms of swaying the vote”, says Abraham Thomas, endocrinologist at Henry Ford Hospital, Detroit, MI, USA, and chairman of the advisory panel.”

We still have about 5 weeks until the FDA is scheduled to render a decision on Qnexa.  While Wall Street seems to be convinced of an approval, we are not as bullish, but two powerful forces, time and bureaucracy, will soon tell.

Two other  important dates upcoming for industry are the panel FDA public discussion on obesity / cardiovascular safety trial design and a report to the Senate on how the  FDA is taking steps toward obesity agent development.

Below is the full Lancet text

Panel meeting prompts excitement for antiobesity drug

Asher Mullard

pg. 882 Vol. 379 No. 9819 ISSN: 0140-6736

 

An FDA advisory panel has recommended approving Vivus’s weight-loss drug, potentially paving the way for the first new obesity drug in the USA in 13 years. Asher Mullard reports.

In a highly anticipated US Food and Drug Administration (FDA) panel meeting about Vivus’s antiobesity therapy Qnexa at the end of last month, independent advisers voted 20-2 in favour of approving the therapy. The final decision now lies with the FDA, who are due to either approve or reject the drug by mid-April, but the vote nevertheless raised hopes that new antiobesity agents are on the horizon.

“I think it will now be approved, but probably with a label that restricts use and advises patients to discontinue treatment early if they aren’t losing weight”, says Arne Astrup, anobesity expert at the University of Copenhagen, who has acted as a consultant for drug developers including Vivus.

Vivus’s Qnexa is a combination of the appetite suppressant phentermine and the antiepileptic topiramate. In clinical trials it induced average placebo-adjusted weight-loss of up to 9·3% of bodyweight, leading to a first filing with the FDA in 2009. At a panel meeting held at the time, experts voted 10-6 against the drug, noting that it increased pulse rate, carried a risk of cleft palette in babies conceived by mothers on the drug, could potentially cause memory problems and depression, and induced a teratogenicity signal in rats, leading the agency to reject the drug.The therapy was refiled last year, however, leading to a second advisory meeting in February, 2012.

Although many of the same key concerns remain-including lingering uncertainty over Qnexa’s cardiovascular profile and birth defects-Vivus presented some new data that shed new light on the risks. The company also proposed a strategy to minimise adverse events by educating patients and physicians, limiting drug dispensing to specified mail-order pharmacies, and recommending monthly pregnancy tests. “This risk mitigation strategy probably is what was most important in terms of swaying the vote”, says Abraham Thomas, endocrinologist at Henry Ford Hospital, Detroit, MI, USA, and chairman of the advisory panel.

Vivus also said it is possible to identify non-responders early on, which could further minimise risks. And it plans to run an 11 000 patient trial to resolve the heart safety uncertainty issues. Panellists agreed that such a trial will be necessary, and most felt that given thedrug’s clear efficacy signal it could be started after approval.

Although the final positive tally of the vote suggests that the combination therapy should now be a shoe in for approval, the numbers belie the complexity of the debate. “I was surprised that the vote was so overwhelmingly positive”, said Thomas. The final decision, consequently, remains far from certain. The agency rejected another antiobesity agent, Orexigen’s Contrave, in 2011, despite a positive advisory panel vote.

Because just over a third of the US adult population is considered to be obese, and because an approved drug could be misused, regulators have historically held antiobesity agents to particularly high standards. Even the few products that have run the gauntlet have struggled to gain a foothold. GlaxoSmithKline and Roche’s lipase inhibitor orlistat, as well as generic phentermine as a monotherapy, have had limited uptake due to their side-effects. Abbott’s serotonin-norepinephrine reuptake inhibitor sibutramine was withdrawn by regulators in 2010 after it was linked to heart attacks and stroke. And Sanofi’s cannabinoid receptor rimonabant was pulled off the market in the European Union in 2008 after it was linked to severe depression and suicidal thoughts (the drug never got the green light in the USA).

Some hope that an approval for Qnexa might represent a shift in the regulatory stance to antiobesity drugs, although each drug is of course reviewed on its own benefit:risk merits. Arena is pushing for approval of its serotonin receptor agonist lorcaserin. The drug, which has the lowest efficacy of the potential newcomers, was first filed in 2009 as well, but was rejected due to carcinogenicity and efficacy concerns. Lorcaserin was resubmitted with the FDA last year, and a decision is now expected by the end of June. Orexigen, meanwhile, will run a 10 000 patient study to address the cardiovascular safety of Contrave, a combination of opioid receptor antagonist naltrexone and antidepressant bupropion, potentially paving the way for a 2014 approval. Other upcoming events may also help broadly define the future for antiobesity agents. At the end of March, the FDA will hold a 2-day public panel meeting with its independent advisers to discuss the cardiovascular safety requirements for weight-loss drugs, potentially defining the safety benchmarks for experimental agents. The agency is also due to report to the Senate Appropriations Committee on the steps it is taking to support the development of antiobesitydrugs by March 30, reflecting the growing governmental pressure to address the obesity endemic.

Post-Qnexa Panel, is the FDA bamboo or will they finally break in obesity?

The surprising 20-2 advisory panel vote in favor of Qnexa’s approval has uncorked media coverage of the obesity issue.  Countless news stories and editorials have been published in the last week.

The overwhelming vote may have forced the FDA’s hand to approve Qnexa, breaking under  the mounting pressures in recent years to approve an obesity agent.  This returns to a refrain of Metabolic Markets for some time, is Qnexa the drug the agency wants to have as the first obesity agent in 13 years?

It will be interesting to watch the news flow and messages coming from the popular press until the FDA action in April.  It already feels like increasingly articles detailing the concerns and potential issues are replacing the exuberance of last week.  Please read this story from Fox News today (I know it is Fox, but stay with me).    It is a very direct discussion highlighting the risks associated with Qnexa and the challenges for Vivus or the FDA to control inappropriate utilization?  And if inappropriately used, does this re-open the pandora’s box of litigation seen post phen-fen, and likely delaying or raising the regulatory bar on a truly novel obesity agent even further?

 

BYDUREON. IT IS HERE. AND SO FAR, SO GOOD

Persistance.  it has paid off for Amylin.  And so far, so good.

Late Friday, Amylin announced the approval of Bydureon. Although roughly a year late, it seems that the preparation time has paid off.

The market has reacted positively to the news and to the investor conference call late Friday.  this is in stark contrast to the original Byetta approval in 2005 when AMLN went down on approval.

We wish our friends at Amylin very well.  We are excited for you and the prospects of Bydureon.  It is a good drug, good data, and without the Lilly involvement, so far we have seen good execution.

 

Tick tock goes the Bydureon PDUFA clock

With the sglt-2 shot down last week, that has cleared the fda’s calendar for Bydureon. The official pdufa is january 28, but fda watchers have told me the fda doesn’t like to let things linger. So will tomorrow be the day?  Or as Garth sings “if tomorrow never comes….”  we wish our friends at AMLN all the best in their efforts to deliver Bydureon to the world.

Dapagliflozin – FDA says “Not so fast, my friend”

In the least surprising FDA news in some time, dapagliflozin has been sent packing,   Metabolic Markets has been watching and commenting on various efforts to pump up dapa’s chances which you have read about in this space, including the Cleveland Clinic’s listing of dapa on its “Top 10 innovations for 2012.”  As we commented when that story first broke, the curious bullishness of Dr Nissen who said about dapa, ““My guess is that within the next year, this will get over the goal line. This is as good as anything we’ve seen.”

As “good as anything we’ve seen.”  Except for a 9-6 panel vote against and unexplained safety signals.  A cursory PubMed search for dapa data outlines a good, but distinctly not great oral agent, in Metabolic Markets opinion.  Modest A1c and good weight loss, but not earth-shaking. Edward Chao has a very good (and free) summary of the SGLT-2 class and data if you really want to know more than you will ever need.

So is this a death knell for the class?  There are several others in mid-stage development, with J&J’s canagliflozin the next one up.  As we have learned over the years, intra-class variation is not uncommon, but will this mean the FDA will require additional data for any of those in the class?

Until then, BMS/AZ seem to be saying they will have the data soon to address the FDA.  Watching what happens in Europe will be quite telling.  Do they “withdraw” their application, which is the polite European way of saying “you don’t have a chance.”

 

Arena / Locaserin – we can’t say they are not trying…….

Arena announced yesterday the submission of their complete response letter to the FDA, based on  the October 2010 Complete Response Letter.

Although every case should be judged on its own merit and circumstances, considerable parallels can be drawn from the Vivus discussion in this space last month.  The FDA has provided a path forward for each to respond to the Agency’s concerns, but will it be enough to outweigh the Agency’s risk assessment, real or perceived?

Neither Vivus nor Arena has much choice but to invest the resources and respond.  And maybe through a large risk mitigation program or an austere label, approval is possible, but it seems unlikely.   Efficacious and SAFE treatments for obesity are needed, but are these the best industry has to offer?

 

 

 

For Takeda’s alogliptin, the waiting is the hardest part…….

With apologies to Tom Petty, the world will have to wait a few more months to learn alogliptin’s fate.

Just a few weeks ago, we were discussing the very active late January scheduled for the FDA with three new agents PDFUA dates scheduled, alogliptin, dapagliflozin and exenatide QW.

Takeda announced last week the the FDA has re-scheduled the action date for April 25.  Three months will seem like a blink of an eye for Takeda, who received a complete response letter in June 2009.

Nevertheless, 2012 is stacking up as a great year for industry watching.   We are about two months away from the news on dapa and exenatide QW. Tick Tock!

Victoza is still the champ in the A1c battle, at least….

 

GSK announced today results of their albiglutide trial against Novo Nordisk’s Victoza (liraglutide).  And once again, Victoza (QD dosing) was called into the ring to take on a QW dosing GLP-1 and has come out victorious.  In this case, Albi lowered HbA1c 0.78% compared to 0.99% for lira.

This is the second time that a QW GLP-1 manufacturer has attempted a non-inferiority trial against liraglutide.  You might remember a few months ago, Lilly and Amylin announced a similar result for exenatide once-weekly against liraglutide, -1.28% compared to -1.48%.

One thing jumps out in both trials, is the consistency in rates of nausea, both the once weekly versions had roughly 9%, compared to the 20% and 29% reported for liraglutide.  It is always VERY dangerous to compare different studies, particularly when the HbA1c impact was markedly different, indicating considerably different baseline characteristics.

Is it too early to conclude something physiologically about GLP-1?  In essence, is there a reason the body releases GLP-1 when food is ingested, resulting in the glucose dependent insulin response seen in a non-diabetic state?  Is there something else going on in the body?  Good questions for the academics to figure out on rats.

In here the real world, will the potential for modestly lower HbA1c difference in the QWs be offset by the reduced nausea that has plagued the class?  Or will the once weekly administration be the trump card, even if the once weekly is offered a large gauge needle for administration?  Or are the results seen in the QWs to date the best we will see and be prepared for an even further fall from grace?

Secondly, what does this mean for companies like Intarcia, developing a micro-implant for GLP-1 administration?

Lastly, is there actually room for everyone in the space, and there won’t be any real “champ”, but much like professional boxing, a hodgepodge of manufacturers claiming their own spin on superiority, and secretly, Don King is behind it all for the pay-per-view ratings?

Late January 2012 will be a busy, busy time for the FDA, pharma and lunch caterers

As we mentioned earlier, January 28, 2012 is the FDA action date for both the new SGLT-2 agent, dapafligozin as well as exenatide once weekly.  A few days ago, Takeda announced that the FDA has given them an action date of January 25, 2012 for alogliptin and the FDC alogliptin/pioglitizone.

The FDC of an glucose dependent insulin stimulating agent of a DPP-IV paired with an insulin sensitizer is a physiologic combination.  Mix in the pending patent expiry for pioglitizone in 2012, it is a well played franchise extension maneuver.  It will be interesting to watch how Takeda prices the FDC, if they “give away” the pio portion, or do they ask for a premium over the current DPP-IVs.

It will be a very busy time for the FDA to move all of these agents through the process by end January.  Two agents (dapa & exenatide QW) have some distinct safety baggage, and this is Takeda’s second time down the aisle with the FDA for alogliptin.  Will anyone take a bet on if the FDA starts the year with a clean sweep of approvals, rejections, or a mixed bag?  See the poll for your predictions….

Is the DPP-IV battle shaping up to be “what combination can you develop?”  We have Juvisync (sitagliptin + statin), alogliptin+pioglitizone, and the other DPP-IV manufacturers have an arsenal of hypertension and cholesterol agents at their disposal.  Mix-in depression, erectile dysfunction, Alzheimer’s, we could be looking at a multitude of combination therapies with a DPP-IV for years. I’m no product development / toxicologist guy, and I am sure there are limitations, but I would assume that the relatively benign profile of DPP-IVs and now with years of patient experience, may lead it to be the backbone of multiple different combinations that address the various co-morbid conditions of diabetes.

Drop me a line, let’s discuss  aaron@metabolicmarkets.com

Everything ends badly, otherwise it wouldn’t end……

And yes, in honor of today’s Amylin / Lilly Breakup, I have quoted one of my favorite really bad movies of all time, Cocktail.

An old man goes to the Wizard to ask him if he can remove a curse he has been living with for the last 40 years. The Wizard says, “Maybe, but you will have to tell me the exact words that were used to put the curse on you.” The old man says without hesitation, “I now pronounce you man and wife.”

Bad humor better left for the golf course aside, today’s announcement brings to an end a tumultuous 9.5 year marriage that brought the world a terrific advancement, although much like a horribly spoiled child, required constant attention, and eventually doomed the relationship.

Lilly’s commitment to the treatment of diabetes can not be questioned, and nor for the matter should Amylin’s.  so why didn’t this relationship work out?  On a slide, it looks beautiful; a large pharma with considerable history in the disease state but in need of novel technology, a biotech with leadership born/bred of the same large pharma holding a high value asset already in mid-stage development.  What could go wrong?  In short, probably quite a bit, and you can ask Lilly’s other “partners” over the years that they had acquired with disturbing regularity.

Is it a “Lilly Thing” or was Amylin ill-equipped? Or did the product ever have a chance/reason to be sold in a primary care environment?  Novel and elegant science, a premium priced agent, is that better left to biotech?   It is an open question, and subject to a ridiculous amount of bar side quarterbacking over the years.

So what does the new arrangement mean? Investors were not excited as evidenced in the reaction today. Although much of that is driven by the “what do we know” financial implications of the divorce.  The market’s-10% reaction also generally tells me that investors didn’t give much credit to the relationship.

There is much more to be written on this subject, and it will be a absolutely fascinating start to 2012.  At Metabolic Markets, we can hardly wait.

Drop me a line, let’s have coffee and discuss, aaron@metabolicmarkets.com