Close Concerns Weblog

Conjuchem - abandoning GLP-1 daily product

Conjuchem put out a press release a few moments ago that indicated that the company is abandoning its GLP-1 daily product- dilutent didn't work and the GI/drop out problems were severe with this one (we wrote about in a DCU last year for anyone who you'd like to see history who hasn't). While the prospects for the product weren't bright based on the side effect profile and high number of drop-outs, this appears to confirm there is no development potential for DAC GLP-1.

As such, Conjuchem is moving forward only with once-weekly GLP-1 compound, which will enter clinic in first half 2006 - so would assume anything of note would be done post 2010. We aren't sure why this is being called a phase 1/2 program.

The company has been discussing potential big pharma partnerships for some time; it sounds like the current hope is to have a partnership in place by mid-2006, when initial once-weekly data will be announced.

Recall that Novo had announced a delay of its own GLP-1 product last year - this reinforces for us Amylin's strength in the area with Byetta and LAR as well as the complexity in making these products. Even in the best case scenario, given this morning's setbacks, it would seem that the company couldn't have a compound marketed before 2011 or beyond.

MONTREAL, Sept. 30 - ConjuChem Inc. (TSX: CJC) today announced that
further development activities for its DAC(TM):GLP-1 compound have been put on
hold pending completion of the Phase I study in patients with
PC-DAC(TM):Exendin-4 in the first half of 2006.
The Phase 1 single dose trial in patients with diluent (D23) improved the
tolerability profile of the in vivo DAC(TM):GLP-1 compound. However, the
three-month D23 toxicity studies in animals failed to provide sufficient
safety margins to advance D23 as a diluent into chronic dosing regimes.
Additionally, the pharmacokinetic and pharmacodynamic profile of
DAC(TM): GLP-1, using diluent D23 did not lend itself to once weekly dosing.
"ConjuChem's goal is to develop a best in class GLP-1 analogue," said
Dr. Jean Paul Castaigne, ConjuChem's COO. "The data generated to date with
PC-DAC(TM):Exendin-4 program indicates that this compound has the strongest
potential to emerge as the leader in the GLP-1 class of drug therapies. Proof
of concept data in patients is expected in the first half of 2006."
PC-DAC(TM):Exendin-4 will be administered to Type 2 diabetic patients in
a Phase 1/2 clinical program starting in Q1 2006. To date, the pre-clinical
data has been very encouraging, demonstrating a significantly extended
half-life of 30 fold relative to native exendin-4. This longer half-life
resulted in a longer duration of therapeutic activity. Full glucose control
was obtained for more than a week after a single injection of
PC-DAC(TM):Exendin-4 in ZDF rats (ZDF rats are obese rats with Type 2
diabetes). Finally, a significantly better tolerability profile was observed
compared to exendin-4 in two independent rat models, which assessed GI
tolerance and nausea. PC-DAC(TM):Exendin-4 is expected to be stable at room
temperature, thus being highly convenient for patients.
Developed to treat Type 2 diabetes, exendin-4 is a close analogue to
GLP-1, the human body's most potent insulinotropic hormone. It has been shown
to normalize blood glucose levels by a) stimulating insulin secretion and
lowering glucagons secretion in a glucose-dependent manner; b) delaying
gastric emptying; c) induces Beta cell proliferation (demonstrated only in
animals to date); d) restores Beta cell sensitivity to glucose; and
e) increases peripheral sensitivity to insulin . Moreover, it appears to have
a very attractive safety profile, with a low probability of inducing
hypoglycemia.

About ConjuChem
ConjuChem, developers of next generation medicines from therapeutic
peptides, is creating long-acting compounds based on bioconjugation platform
technologies. When applied to peptides, the Company's systemic DAC(TM)
Technologies enable the creation of new drugs with significantly enhanced
therapeutic properties as compared to the original peptide. The Company is
developing compounds to treat various disorders including diabetes, human
growth deficiencies, HIV/AIDS, and congestive heart failure.
Detailed descriptions of the Company can be viewed on the Company's
website www.conjuchem.com.

Novo (Novo!) downgraded due to LAR strength

JP Morgan's pharma analysts downgraded Novo Nordisk (Novo!) due to perceived strength of LAR. This downgrade is huge - pharma (not biotech) analysts are beginning to figure out the score. For them to acknowledge biotech - enormous!

They noted that competition from non-insulin competitors (read: Byetta) will slow the growth of the US insulin market volume from 5% to flat by end of the decade. But not only THAT - they say that of greatest concern is LAR, Amylin's once weekly injectable GLP-1 analog, which will have the potential to transform the management of diabetes (note - they don't mention for any particular segment) .. this leaves Novo vulnerable.

Diabetes care and kids ~ 8.5 and stuck!

September is nearly over and we wanted to dig into recent Diabetes Care issues before the very end of the month so ... this month we focus on articles about kids. Some heartening and disturbing news ~

First off, Mohsin et al, published an article on an investigation into how the DCCT and new methods to achieve glycemic control have affected adolescents with diabetes and microvascular risk.

878 type 1 diabetic adolescents aged 12-20 years of age were assessed at the Children’s Hospital at Westmead in Sydney, Australia from 1998-2002. During this span of time three groups were matched for age and duration of diabetes. The authors found that the prevalence of retinopathy and nephropathy (measured by early elevation of albumin excretion rate - AER) declined in the post-DCCT era among this group of adolescents, while the prevalence of peripheral nerve function abnormalities increased. Surprisingly, no documented change in hypoglycemia was found. There was no change in A1C (median A1C remained 8.5% throughout the entire study, well above target) despite an intensification of insulin therapy.

We’re happy to hear that retinopathy and nephropathy declined over time. However, the increase in peripheral nerve abnormalities - neuropathy - and a mean A1C unchanged from 8.5% emerge as surprising and disappointing results.

Metabolic syndrome-- a problem in type 1 diabetes

While the metabolic syndrome (MS) is usually discussed in relation to type 2 diabetes and has been shown to be a risk factor for early mortality in type 2 diabetic patients, the prevalence of the metabolic syndrome in the type 1 diabetic population is less well-known. Yes, who knew!? In a study published in August's Diabetes Care, Thorn, et al. estimated the prevalence of MS in 2,415 adult Finnish type 1 diabetic patients, using National Cholesterol Education Program guidelines. They also assessed whether MS is associated with diabetic nephropathy or poor glycemic control.
The prevalence of MS in the study participants was 39%, which about three times higher than the prevalence seen in non-diabetic subjects in the Finnish population - although it was significantly lower than the prevalence of MS observed in type 2 diabetic patients (78-84%), nearly 40% is pathetic!

Unsurprisingly, glycemic control correlated closely with the prevalence of the metabolic syndrome. Patients with MS tended to be older, to have had an early onset of diabetes, and to have had a long duration of diabetes, compared to patients without MS. Patients with MS had higher rates of retinopathy and nephropathy compared to patients without MS (see above!). In fact, hose with the metabolic syndrome had a 3.75-fold increased odds ratio for diabetic nephropathy compared with those without MS, after adjusting for age, sex, smoking, and A1C.

Stresses...

This one was also surprising - stress affects post-prandial numbers more than fasting numbers? In August's Diabetes Care, Wiesli et al published an article entitled, “Acute Psychological Stress Affects Glucose Concentrations in Patients With Type 1 Diabetes Following Food Intake but not in the Fasting State.” Stress may play a large role in explaining why patients with type 1 diabetes often report glucose excursions that seem inconsistent with carbohydrate intake and insulin dosing. Wiesli et al., investigated how the effect of acute psychological stress on glucose concentrations differs between the fasting state and postprandial state in patients with type 1 diabetes. 40 type 1 diabetic patients attending the University Hospital of Zurich participated in the study. The first 20 patients underwent a psychological stress test, the Trier Social Stress Test (TSST), in the fasting state. The second 20 patients underwent the TSST in the postprandial state. The authors found that the effect of acute psychological stress on glucose concentrations in type 1 diabetic patients differs depending on whether the patients are in the fasting state or have recently eaten a meal. Acute psychological stress had no effect on glucose concentrations in the fasting state but induced a significantly delayed decrease of glucose concentrations 20 minutes after the onset of stress in the postprandial period.

Byetta update - wow!

This was in this morning from Dr. Joe, who writes frequently on diabetes. He comments here on use of Byetta in his 130 patients on the drug - 150 mg/dL as a ceiling for blood glucose is quite incredible, no?! Eight pounds down on average for ten weeks for n=130 is also quite something. Here is Dr. Joe's post in its entirety - if you want to subscribe to his musings, see http://www.endocrinemetabolic.com/programs/.

"As we enter the fourth month of Byetta, what do we see? The glucose excursions appear normal. Where has the diabetes gone?

Phone calls “I can't get my glucose up!” really represent the fact that it won't go over 150 no matter what you eat. That was from a person with zero C- peptide who was on 120 U of insulin daily when he started.

“ How much insulin are you on now?” I yelled into the phone. “4 Units” he replied. “Four? You’re just jerking my chain” I replied. “Cut in to one unit until we check your C - peptide” I said but I stopped worrying about him from that night on.

We will be measuring the C- peptide over the next 30 days. I can't “weight.” Of the 130 people on Byetta now, we have lost over 1.000 lbs in the last two and a half months. It is hard to believe."

Dr. Joe, The Diabetes Doctor

Novartis pipeline update - LAF237 fails to show non-inferiority to Metformin ~

Novartis said today it will file LAF-237 in the first half of 2006 - this is its DPPIV inhibitor. Talk at EASD focused on safety of the class, particularly in the wake of the FDA panel on inhaled ~ lots to watch out for. (By the way! Did anyone really focus on the fact that two out of the nine votes that were _no_ were both from pulmonary specialists and that there were only three pulmonary specialists total?)

I liked how Novartis discussed LAF-237 in depth on its pipeline update call BUT the most critical element of the drug, the long-term safety, wasn't really addressed in depth in my view. They discussed how there are fewer GI side effects with this drug vs Metformin, etc. but they didn't address the worries that many have, what else (<--italics) is being inhibited with this compound.

Surprisingly, and unfortunately for Novartis, metformin worked very well in the studies presented, so much so that the primary endpoint, non-inferioritity vs metformin, wasn't met (as it were). In 52-week study of about 750 people, the high dose of LAF237 resulted in an A1C drop from 8.7 to 7.5, while metformin had a drop from 8.8 to 7.1. This was statistically significant. The headline on this slide said "52 week data with monotherapy confirm early and sustained A1C reductions..." It is true the reduction is a good reduction, but not versus metformin's reduction (which was better than some would have expected, at over 1.6 points). They noted then that LAF237 is better tolerated. True, in the sense of traditional annoying side effects, but we think there are still some uncertainties on the long term impact of this new class, and without it beating traditional therapy, this isn't a place a company wants to be, in our view.

Novartis also did an Actos comparison and on this one, Actos had a 1.9% A1C drop, while LAF237 (100 mg) had a 1.6% drop. And this was using 30 mg of Actos not 45 mg! We're not major TZD fans overall (but we are for the right patients) but doing a study not using a fully powered dose seems wrong. Lest you note how impressive nearly 2 points drop is, we point out this is from a 10 A1C - impressive, yes, but it's not like the baseline was 7.0.

There was one 12 week study that was pretty impressive - the only point was to show dose-proportional drops in A1C, and that they did, but on the 50 mg and 100mg arms, they got drops of 1.0 and 1.2, respectively, from baseline A1Cs of 7.4.

Then! They had an add-on insulin trial that showed a non-wow 0.5 drop for LAF237 vs 0.25 drop for placebo plus insulin, over 24 weeks. What was impressive here was that there were six (count 'em six!) hypo events for the insulin group (defined at 3 mmol or less - that is 3x18=54 mg/dL for those that also always forget how to translate mmol).

Novartis also said it's working on a range of products with the FDA, one on manufacturing methods, a secnd on biomarkers to develop new therapies, and a third, interestingly, to look for "the simultaneous development of a particular therapy and a diagnostic test kit that would enable the identification of patients who are most likely to benefit from the particular therapy."

LAF237 appears to be weight neutral, which is better than insulin, but not as positive as Byetta.

Our main issues with the data summary is that they make a very big deal about LAS237 being well tolerated, but they don't say anything about unknown side effects that could be issues longer term AND they try to position as "ideal profile as first drug of choice" - this would never be first drug of choice given what isn'tknown and it seems irresponsible to position it as such.

At the start, Novartis positioned current oral therapies as not addressing multiple defects in type 2 - right! - but GLP-1 (Byetta) has been shown to address two labeled as "unmet need," namely inadequate glucagon suppression (beta cell dysfunction) and beta cell decline.

They also show key requirements for new therapies: 1) clinically meaningful a1c drop; 2) sustained a1c reduction; 3) weight neutrality; 4) well tolerated; 5) low hypos. We agree these are great requirements but they need to show what recently approved drugs can do, in our view.

Other problems: 1) they showed Novartis as the most productive big pharma company - in terms of approvals, they didn't give Lilly any credit for Byetta, which we thought was wrong; 2) They say there are 150 mm type 2 patients worldwide, but 194 million is a widely quoted number; 3) we don't necessarily know if this drug should be approved or not, but the panel meeting will hopefully focus on some of the uncertain safety issues and we would hope the panel would be very well informed. On that note - the FDA should in our view use more experts on panels that are close to industry but just get them to promise they are unbiased. Among the smartest endos in our view are the ones driving the studies, and it seems patently absurd to exclude them due to a suspicion they cannot put forward unbiased views.

Third to last comment - the name that seems to be catching on for this class is incretin enhancer - that's a great name.

Second to last comment - very interesting studies upcoming, including diabetes prevention (this will be very tough indication to get) in about 2009 and reduction of CVM complications in about 2011. Excellent!

Last - Novartis does a great job at melding CVD and diabetes. Just overall, the call really reinforced how hot diabetes is becoming/has become in Big Pharma. There is some chatter that the cardiologists are taking over, and we have certainly started to see it. This is happening at the same time that medical students aren't entering endocrinology as it is such a poorly-reimbursed speciality. Overall, we look for more and more critical data to be presented at CVD meetings rather than diabetes meetings ... onward!

EASD day four - posters!

EASD day three - Guardcontrol!

The days here are amazing - sweltering but optimism is in the air. Especially on the device side, it feels to us that we are turning the corner.

Guardcontrol data was presented Tuesday - this 150-person, three month multicenter study showed a 1.1 A1C drop, and a meaningful reduction in severity and frequency of hypoglycemia. How excellent is that!! We loved the way that the study was presented - all about things that matter to the patient. No one was getting caught up in error grids, discussion of random variables, etc. Our takeaway is that the device helps improve life meaningfully to patient. Lots of questions remain - we would love to see sub-group analysis, and in spite of ourselves, we are very interested in seeing more on sd, aucs, mard, etc - but this was an excellent start. Terrific to see the investment by Medtronic in trials like this - we hope the industry shows more, because we imagine more will be needed in order to get to the holy grail - not the product itself, but reimbursement and coverage for the product.

EASD day two - Proactive! ~ hypoglycemia ...

Proactive results are out
It was a negative study, surprisingly!
The press is highlighting it as a breakthrough study, but we point out that on the primary endpoint, mortality was 21% while in the placebo arm, it was 23.5% - risk reduction of just 10%. The study was powered to show 20% and 30%-40% would've reppresented a home run.

Yet and still, of course, for many it's a great drug - it decreases blood glucose, it improves important lipids in diabetes, and it affects known markers of cardiovascular risk. As the excellent Finnish independent commentor noted, for those for whim CHF isn't a problem, for them, it is an excellent drug!

Safety news

Actos has been treated in over 7 million patients since 1999, with over 50 million prescriptions. No new safety concerns have been raised by the PROactive study BUT, we do point out one troubling note - bladder cancer occurred in 14 people in the treated group, compared to 6 people in the placebo group. We know that intensive cardioginicity studies are now required by FDA, but back then they weren't.

More to follow on this !

“Glycemic Control of Type 2 Diabetes Mellitus”

R.J. Heine: “Exenatide achieved equivalent glycemic control to insulin glargine, with weight reduction and less nocturnal hypoglycemia, in metformin and sulfonyurea-treated type 2 diabetes”

This session was packed, reflective of the high interest in Amylin’s gila monster-derived GLP-1 compound. As an option for patients who have failed to achieve glycemic control on oral medications, exenatide has been pitched as an alternative to insulin glargine. This study of 549 patients used HbA1c as an endpoint and found no difference in glycemic control between glargine and exenatide, with each dropping HbA1c by approximately 1.1%. The slide that was perhaps the most striking, however, depicted the weight changes between the two groups of patients during the 26 weeks of the study. While the exenatide group lost approximately 2.3 kg, the insulin group gained 1.8 kg. This difference of 4.1 kg—or nine pounds!—certainly will matter to patients and physicians when choosing between two injectable therapies that affect glycemic control similarly.

While the insulin dosage was titrated, exenatide was delivered as a fixed dose, earning it points for simplicity. The study did find significant GI-related adverse events, with 57% of patients in the exenatide group experiencing nausea. Other parameters were a toss-up: exenatide achieved tighter post-prandial control, while the glargine group won out for fasting glucose scores; exenatide had less nocturnal hypoglycemia, glargine less daytime hypoglycemia.

Poster session: Hypoglycemia

While we all know hypoglycemia is a barrier to intensive therapy and effective glycemic control, quantitative information on this topic is often difficult to come by. This poster session shed a bit of light on the prevalence and character of this phenomenon. Some studies that caught our collective eye:
• A UK-based group attempted a mailed survey of 1241 patients with type 1 diabetes, inquiring about the frequency of severe hypoglycemic episodes and affect on their quality of life. We have the results—about 2.2 events per person per year—but we put little stock in the methodology. The response rate was only 21.9%, with nearly 1000 patients failing to respond. While the self-selection bias and vague definition of “severe hypoglycemia” used in the study makes the study less than compelling, the study is a starting point.
• More convincingly, one study of hypoglycemia studied silent hypoglycemia using Medtronic’s CGMS system. This study found shockingly high rates of so-termed silent, or asymptomatic, hypoglycemia, reporting that it comprised 76% of all hypoglycemia episodes. If three out of four hypoglycemic episodes are truly undetected, this means our current estimates of hypoglycemia are only a fraction of the true frequency. So what, you ask? The study found that episodes of asymptomatic hypoglycemia were not correlated with episodes of severe hypoglycemia, and some physicians questioned the clinical relevance of silent hypoglycemia if is not a proxy for severe hypoglycemia. We feel patients would prefer to avoid such silent episodes, especially nocturnally, or say while driving, but we question the high rates. After all, we know that continuous systems have questionable rates of accuracy in the low range—so should we trust the data? In response to our questions on this front, researchers pointed out the lower “conservative” threshold used for hypoglycemia (2.2 mmol/l, or 40 mg/dl) and added that they had examined surrounding data points in the study.
• Another presentation addressed recovery time for cognitive functions following hypoglycemic episodes, finding that rapid decision making is impaired for prolonged time period (40 minutes). The message from this poster session overall is that researchers are increasingly interested in trying to quantify hypoglycemic episodes, including subsets of nocturnal, silent, or severe hypoglycemia, and in trying to understand how this affects patients glycemic control and quality of life. This data may prove critical in supporting a need for continuous technology, so we applaud research on this front.

EASD Day One - PROactive, GuardControl, Abbott’s Navigator, and Rimonabant

1. EASD: Focus on PROactive, GuardControl, Abbott’s Navigator, and Rimonabant.
• PROactive – The conference has begun! Our schedule is on our website, as noted – we’ll be back with a full report next month, along with our AADE review. Biggest news likely to come from this trial – stay tuned.
• Guardcontrol – So ISPAD took place in Krakow, Poland from August 31 to September 2. Diabetes Close Up was represented by Paris-based Jean-Philippe Gaetan who covered everything from patient empowerment to insulin sensitizer use in kids to problems behind obesity. Our larger report for the company will come next issue but in the meantime, we can say that the Medtronic results make us very eager to see the full Guardcontrol data. ‘A1C isn’t everything’ was definitely a message working its way through the conference – Medtronic management adeptly pointed out that A1c misses glycemic instability, nocturnal hypoglycemia, postprandial hyperglycemia, and glucose patterns/excursions.
• Navigator – There were a slew of great symposia, but Abbott’s at the sexy Metropolitan Hotel took the cake. Dr. David Klonoff showed the history of continuous monitoring, Jen Block, CDE at Stanford, showed prospective vs retrospective CGM “clinical application and utility,” followed by Abbott’s Geoff McGarraugh, a leader on the chemistry side, discussing real time continuous technology, closed out by Dr. Andreas Pfeiffer on the outlook toward the future. This was all followed by cocktails on the roof, where everyone continued to remark on how great Jen’s numbers looked! On the positive side for Navigator, we learned that Navigator is intended now for five-day wear rather than three-day wear (with only four calibrations – hours, 1, 10, 12, and 72); on the flip side, we also learned that the device will be blinded the first ten hours in order to improve the technology among all users. On balance, we view the change as positive as it will help support all the scores. In the best moment of the evening, the very poised Ms. Block shared her glycemic patterns with us – half a week with Navigator off, and half a week with it on – the line in the end looked incredible and we could just feel her delight - in fact, we were feeling it too, in shared anticipation for what looks to be quite the technology.
• Rimonabant: So besides PROactive, the other word of the game here is Rimonabant, or Acomplia. The Rimonabant sanofi-sponsored symposium was packed, with perhaps 1500 people filling a room equipped with five large screens, audience-polling equipment, and mass quantities of well-dressed sanofi personnel. The big draw focused squarely on attention on the big drug. The polling devices revealed that the crowd was truly international—almost half from Western Europe, with significant representation from Eastern Europe, Africa, and Southeast Asia, and few from North America. A welcome by Chairman Matt Riddle included two major talking points: 1) the great variability in the presentation and care of diabetes, both between different countries and between different ethnicities in the U.S., and 2) the need for earlier, more widespread use of insulin therapy in type 2 diabetes. Polling the audience, Prof. Riddle showed that most there (79%) thought less than 40% patients in their area of the world were achieving an HbA1c of less than 7 (they’re right). Likewise, 46% of the audience said that 20-40% of patients in their region already had complications at the time of diagnosis with type 2 diabetes. Right, again. The first speaker Prof. Paul Zimmet of Australia put the polling devices to a more subversive use, asking the controversial question: do you believe in the metabolic syndrome? In defiance of the recent EASD/ADA rejection of this diagnostic category, a stunning 88% of the audience responded positively. This affirmed one of the major messages of the day, which was that metabolic syndrome is a valid and important disease condition. One presenter attacked this question with such force that a nearby physician described him as “evangelical.” Almost as shocking, the second major theme of the day was abdominal fat—shocking not perhaps in concept, but more in presentation, as we saw multiple photos of obese abdomens. Dr. Robert Ross drove home the point that clinicians should be measuring waist circumference, not merely BMI or body weight. This measure of abdominal obesity serves as a surrogate measure for visceral fat, which corresponds to risk level for mortality and CVD, and it also can change with exercise when weight may not. With respect to treatment, Ross spoke to the benefits of a healthy lifestyle…
• Rimonabant, Part 2: Closing out this section, Prof. Luc Van Gaal of Belgium presented results from rimonabant trials, positioning it as an all-powerful drug: affecting the hypothalamus, adipose tissue, muscle, liver, and GI tract, rimonabant is believed to decrease food intake and lipogenesis while increasing glucose uptake, adiponectin, and satiety signals. Results from the four concluded RIO studies have shown a reduction in waist circumference and weight, with 39% of women on 20mg of rimonabant losing >10% of their body weight throughout the 2-year trial, compared with 12% on placebo. Rimonabant was also shown to dramatically cut the incidence of the controversial metabolic syndrome—from 42% to 21.5% in the group on 20mg of rimonabant (p <0.001). Concerns about tolerance remain, with the primary side effects psychiatric (depression), gastrointestinal, and related to the nervous system. This appears especially important given exclusion criteria (strong) – many at ADA said merely ‘oh they’re messed up on CNS anyway’ – exaggeration at best, we believe. The crowd seemed to respond well to the presentation, although strangely there were no questions asked during the “rimonabant Q&A.”
• Rimonabant, Part 2: Dr. Julio Rosenstock described his protocol for using the treat-to-target method in type 2 patients, again highlighting the need for more aggressive therapy here. He noted that HbA1cs are “too high,” insulin given is “too little” and “too late.” He suggested that insulin should be started when the HbA1c is above 7.0% despite maximum dosage oral medication. In keeping with the tone of the day, Dr. Rosenstock noted that he was hopeful that insulin glargine plus rimonabant might prove an excellent therapeutic combination.

And it's YES for inhaled ...

Before a packed room at the Holiday Inn in Silver Spring, Maryland, the Endocrinologic and Metabolic Drugs Advisory Committee met to discuss approval for Pfizer’s inhaled insulin drug Exubera. The drug was summarily recommended for approval for type 1 and type 2 patients with diabetes after a wide-ranging discussion focused more squarely on questions related to safety than efficacy, in our view. Efficacy was basically assumed, and by the end of the day, although the tone was muted, it didn't seem to us anyone could come up with a convincing reason as to why patients shouldn't be offered the choice.

Some points of interest from the day:
• A benign opening! Rather than open the discussion with admonitions about the importance of safety, Dr. David Orloff opened the discussion more benignly, and we felt that there was almost the assumption of approval, despite the major questions still at hand. We were also surprised that there wasn’t ultimately more lobbying for oversight or surveillance.
• Recommendation to approve Exubera in type 1 and 2 diabetes: Ultimately, despite extensive discussions about safety of Exubera, the panel voted 7-2 in favor of approval for both type 1 diabetes as well as type 2 diabetes. Additionally, the panel voted 7-2 that there was enough clinical trial evidence that Exubera could be effectively applied to an “intensive” glycemic control regimen and that the efficacy of Exubera had been adequately assessed in patients with type 2 diabetes. Interestingly, the dissenting votes in each case were different.
• Ultimately we’re happy that patients have another option to try, given outcomes are so poor, although we’ll watch the safety front very carefully. One thing we do know – restrictions and recommendations are generally quite difficult to enforce.
• Importance of training highlighted again and again: Throughout the day, panelists pointed out how important training of doctors, nurses, and patients would be – we second this, especially for patients who start at ground zero, carb counting! Interestingly, even the “no” votes weren’t necessarily due to safety alone, but even here, training was emphasized (one panelist voted no because he doesn’t believe training will take place). Yes, education was stressed by many doctors today, and we suspect Pfizer will need to invest extensively on this front – we also believe they are well prepared to do it, although we do question what overall drug profitability will be. They haven’t set pricing yet, and we look forward to information on this front!
• Medical need well articulated: Another thing that really set the tone for the day was Dr. William Cefalu’s cogent talk on medical need. He made it very clear that current therapies aren’t doing the job and that more options are needed! At the end of the day, while there were some very real discussions about lung cancer, it’s impossible to predict that risk with the available information – by contrast, much of the information focused on cough, and panelists probably just didn’t feel that they could hold back on cough grounds!
• Hypoglycemia not an issue to delay approval: The panel said that the safety of Exubera and hypoglycemia had been adequately assessed in type 1 intensively managed patients as well as in type 2 patients. We were surprised about this since hypoglcyemia is typically such a hot button.
• Next, the panel also conveyed its belief that there was sufficient evidence to assess pulmonary safety in patients without underlying disease.
• By contrast, the panel voted that it did not have enough data to assess pulmonary safety of Exubera in patients with underlying lung disease. We would’ve been shocked had this been negative. This vote was 5-4 and we were actually more surprised that anyone said they had enough evidence on this front. Bottom line, we think that it is probably very difficult to generalize about lung health of such a varied population and that probably drove the yes votes. In particular, there was major concern expressed about people with viral upper respiratory infection, asthma, COPD, and smoking. The panel had fewer worries about clinical concerns and recommendations on titrating and going back and forth between inhaled and sub-cu insulin.
• Our overall take was while the panel wasn’t absolutely enthusiastic about Exubera, mostly due to lingering questions about safety (some of which can’t be answered for years), it still felt squarely that it did not have enough evidence to hold the drug from the market.
• Challenges remain: We believe that many challenges face Pfizer as it scales up for commercialization. We would expect a positive approval decision by the end of October and then we would look for next challenges to be associated with pricing, reimbursement, coverage, uptake, and profitability. As noted, we don’t necessarily think that the drug is as simple as it appears and this will prompt problems for PCPs, who have very limited patient time as it is.
• Other musings/items of note/speculation:
o Panel members asked to see a sample of the Exubera device and the sponsor, Pfizer, didn’t have one! This struck us as very odd.
o Many complained that the size of the device is too big – while we agree about the need for miniaturization, we also feel that it’s a first generation device and size won’t hurt too much at this stage since it’s first in class. Alkermes and Mannkind both have much sleeker devices – we would expect Pfizer/Nektar is probably very closer to filing one of its own as well!
o What will pricing be? We would look for at least 3x the cost of Lantus but likely lower than 5x the price, based on profitability needs combined with not limiting demand.
o There was extensive discussion of variability among patients and the impact of inhaled insulin – why so variable, everyone asked? We reckon there’s probably substantial variability with patients taking traditional insulin analogs – we just never hear about it!
o There will be a lot of people contraindicated from use, including all smokers, all people with asthma, anyone with COPD, etc. One can use Exubera if one is an “ex-smoker” – how does one define ex-smoker? Five years without a drag? Six months? And then what is people surrounded by passive smoke are contraindicated? How is that defined?
• Look for approval by the end of October, a pricing decision shortly thereafter, and then the education should reach full throttle! We’ll be staying tuned and watching for implications on