GLG News by Eric Gruff, PhD MBA

Implications: The recent publication of new cases of pancreatitis that are occurring in patients taking Byetta (exenatide) can't be good for Amylin/Lilly. While Byetta and investigational GLP-1 analogs are still very viable therapeutics for Type 2 Diabetes, prescribers will have to reassess the risk-benefit ratio for many patients given the new information. The long-acting form of Byetta (LAR) may suffer the most since its long half-life will make reversal of pancreatitis that much more difficult and may lead to additional damage.

Analysis: While Byetta (and other GLP-1 analogs) still offers promise for many Type 2 Diabetics, the recent appearance of acute pancreatitis at a seemingly higher frequency than previously thought will lead to a more cautious use of these agents. High-risk patients (those with morbid obesity, severe hypertriglyceridemia, and significant alcohol consumption, for example) will particularly be at risk. Diabetics as a group already are at increased peril of this potentially fatal disease.

The benefits of GLP-1 analogs, such as sustained weight loss, will still motivate many prescribers to use this class of drugs. However, they'll have to decide if the benefits still outweigh the risks with this new and potentially severe adverse drug reaction now more prevalent. Overall, the combination of twice-daily injections (for Byetta) and risk of pancreatitis will offer manufacturers of competing drug classes (notably DPP-IV inhibitors) more room for positioning with regard to safety and compliance.

Where I believe the most damage may have been done to Byetta is the LAR (long-acting release) formulation. Byetta LAR was a boon to the major objection of patients using exenatide - namely the need for twice-daily subcutaneous injections. By switching to a once-weekly administration, much of this issue would have been removed. Now, anyone at risk of pancreatitis likely won't get the chance to try LAR. With a therapeutic half-life measured in days rather than hours, if LAR leads to pancreatitis, there will be no way to limit damage by immediately removing the causative factor. Most physicians won't want to risk three or four days of potential damage in at-risk users.

Overall, my feeling is that Byetta will continue to be used, albeit in more limited patient populations. The big hit to the franchise may likely come when competing GLP-1 analogs hit the market, especially if they have marginally improved dosing regimens (once daily, for example) without days-long half-lives, or if they eventually demonstrate a reduced risk of pancreatitis. Of course, the FDA will raise the bar for approval on these agents now, and will almost certainly require a "black box" class warning regarding the elevated risk of pancreatitis.

Implications: Regardless of the reason (greed, carelessness, incompetence, etc.) that Chinese heparin became tainted, the end result will be increased scrutiny on imported raw materials and other ingredients, not only from China, but from all 3rd World suppliers. How the FDA and other regulatory agencies actually intend to step up the scrutiny is still open to debate, but the ultimate responsibility lies with the license holder.

Analysis: The US FDA is now saying that it believes that heparin sourced from China and distributed in the US by Baxter was intentionally contaminated. The motive purported by the FDA was economic benefit - substituting or dilution with a cheaper ingredient. This theory has precedence in China - in recent history ethylene glycol (the main ingredient in automotive antifreeze) has been used in place of glycerin, with catastrophic results.

No matter what the root cause of the tainted heparin, the FDA (and other world drug regulatory agencies) must take steps to prevent a repeat from occurring. The current financial environment is extremely tight for the FDA, so the possibility of stepping up on-site inspections in international locations isn't there. Besides, the biannual inspection program undertaken by the agency is not likely to stop situations like the current one from occurring. Rather, pharmaceutical and biotech companies will have to increase their scrutiny of overseas suppliers. This is not a new requirement - the FDA has always expected that sponsors (i.e., those holding the drug approvals) are taking appropriate steps to ensure the quality of raw materials and processing steps produced/undertaken in their own factories and by contractors. It's very likely that the FDA and international counterparts will turn to requiring increased scrutiny by sponsors. The big question is how will this be achieved.

If you're interested in my thoughts on the next steps, please contact me via GLG.

Implications: The 3-month reduction in HbA1c demonstrated by AGI-1067 is promising, but I still have many questions regarding the design and outcomes. There are many existing therapies that lower A1c - many have undesireable side effects like weight gain or hepatotoxicity.

Analysis: Lowering HbA1c by 0.5% at the highest dose makes for a good press release, but what was the starting level? There's a big difference between patients starting at 9.5% and those at 7.5%.

Also, I am troubled by the elevated liver enzyme results, even if they are sporadic. The most scary liver toxicities are those that are difficult to predict from a population genotype/phenotype standpoint. DPP-IV inhibitors like Januvia lower A1c by as much as 1.0% and don't appear to be hepatotoxic or cause weight gain. How will AGI-1067 compete with these?

Implications: The news that Cubist's Cubicin has been contaminated with 2-mercaptobenzothiazole (MBT) has caused great concern for patients. It appears that the MBT has leeched out of the Cardinal Health ReadyMED drug pumps that are used for delivering Cubicin. Regardless of who is at fault, everyone involved (Cubist, Cardinal, the FDA, doctors, and patients) have good reason to worry.

Analysis: Cubist is fairly sure that the ReadyMED pumps are responsible for the leeching of MBT into Cubicin solutions. Cardinal Health is currently investigating whether this is actually what happened. If the pumps are the source of MBT, then both Cardinal and Cubist are to blame.

Makers of drugs must perform extensive compatibility testing with approved delivery devices (syringes, pumps, tubing, etc.) to ensure that the drug formulation doesn't do exactly what Cubicin seems to be doing. If a change to the formulation isn't practical or desired, than a warning should be part of the drug product labeling (It's very likely that one will become part of it now).

Cubist may point the finger elsewhere, but at the end of the day, they are going to need to change their own practices and take responsibility for the usage of their products.

Implications: The pharmaceutical industry continues to lay its collective head on the chopping block by pushing drugs like Vytorin that demonstrate at best marginal activity. Insurers have a fiduciary duty to push back against the poor judgement of drugmakers who take advantage of confusion and DTC advertising to make money.

Analysis: I earn my living as a member of the pharmaceutical industry and am proud of the many lifesaving and life-enhancing products that we've produced. However, I am quite dismayed at the number of questionable products that continue to be touted via DTC advertising. The latest, and possibly most egregious example is Vytorin. At best, it's a mediocre competitor to the statins, with less experience available regarding safety. Of course, if it turns out to be true that Vytorin confers less benefit than say, Lipitor, then patients taking Vytorin are depriving themselves of the potential benefit of the proven statin drug.

Merck and Schering continue to take out full page ads in city newspapers that imply that Vytorin should be considered when trying to lower LDL and prevent cardiovascular events. Insurers will, in many cases, pay for this more expensive therapy as patients ask their doctors for Vytorin. Of course, another option is to refuse to pay for the more expensive treatment. While unpopular with patients, it will save them money on premiums in the longer term. It will also serve notice to drugmakers that just because a treatment is approved, that doesn't mean that it will be covered if it doesn't demonstrate a meaningful improvement over existing (and presumably cheaper) therapies.

A paradigm shift? Yes and no. European countries have pushed back forcefully against paying more for what they deem to be equivalent therapies. Witness Pfizer's situation in Germany and England. Germany set much lower prices on many drugs, including statins, and under free trade policy within the EU, distributors could export cheaper German drugs to England. Pfizer basically shut off shipments to Germany to preserve sales in England at the higher price. The US Government might step in via Medicare after the general election in November, but it wouldn't hurt for private sector insurers to take the first big step for mankind.

Implications: While disappointing for patients and caregivers, Pfizer's loss of a late-stage treatment for melanoma casts an even darker shadow on the ability of pharmaceutical and biotech companies to successfully bring new treatments to market. Coupled with other recent Phase 3 failures, this latest outcome points to the need for even more investment in better biomarkers.

Analysis: Pfizer's recent announcement that tremelimumab, an antibody therapeutic intended to treat advanced melanoma, was not better than the current Standard of Care (SOC) was surprising and disappointing to many. In the past year or two, Pfizer (torcetrapib) and others have reported the failure of promising candidates that had reached Phase 3 clinical trials.

While not shocking that late-stage candidates fail, it is troubling that these programs, which have presumably shown Phase 2 efficacy and tolerability, can be so hard to successfully move through Phase 3 to approval. The increased use of biomarkers for both safety and efficacy has been touted as the next big breakthrough in boosting drug development success. Oncology has been an area where biomarkers are well defined and expected to be predictive of successful clinical outcomes. Yet we still see failures like tremelimumab in Phase 3. 

Implications: A recent study by ConsumerLab.com suggests that some generic versions of pharmaceutical products may not be bioequivalent to their brand name counterparts. The difference seems to be in the release rates for extended-release (ER) dosage forms as determined by in vitro ("test tube") analysis of dissolution. Patients who report a difference could suffer from the Placebo Effect, or there could be a real and possibly harmful difference.

Analysis:

A recent article by ABC News suggests that generic drugs may not be bioequivalent to their innovator (brand) counterparts. This is a very serious claim - the entire basis for the existence of generics is that they are truly the same as the brand name drug that they replace in every way except price. 

ConsumerLab.com has reported differences in the in vitro ("test tube") dissolution values for some extended release (ER) generic drugs, and the ABC News article implies that this difference could lead to patient harm. The FDA's primary focus in approving ANDAs is that bioequivalence has been demonstrated. This is almost always done via an in vitro dissolution test. Even across batches of a branded drug, there often will be small differences in release of the active in the first hour, but these are deemed insignificant. For a particular drug such as Wellbutrin, once steady-state blood levels are achieved, small differences in dissolution shouldn't have much, if any, impact on the drug's efficacy. One wonders how much the placebo effect comes into play in cases like this.

As a long-time member of the branded pharmaceutical industry, I'm confident that generic drugs are equivalent to their brand name counterparts. The system that has been established to assure generic drug quality is the same system that is in place for branded drugs, and I have no reason to think that the folks who manage or work in the generic industry have any less concern for the quality of their product than those in the innovator companies.

Implications: Wyeth's acquisition of Haptogen, a Scottish biotechnology company specializing in novel protein-based therapeutics, is a promising development for Wyeth's biotechnology pipeline. This is a welcome addition for Wyeth, but the key will be translating the increased pipeline into additional drugs on the market, something the entire pharmaceutical industry has struggled with over the past several years.

Analysis: Haptogen will certainly add value to Wyeth's discovery efforts, and will increase the number of biological candidates entering the post-discovery pipeline. Coupled with Wyeth's efforts in Translational Medicine, one would hope that Wyeth will be able to squeeze another one or two new drugs per year from their pipeline. On the other hand, the entire pharmaceutical industry has suffered from an inability to successfully clear the safety and efficacy hurdles needed to replenish their shrinking revenues as existing drugs go off patent. One needs only look at Pfizer to see how serious this situation really is.

Many industry insiders believe that biologics will be more successful than small molecule therapies for several reasons. Notably, many biologics lack the off-target toxicities that small molecules are prone to. On the other hand, delivering biologics to their targets in therapeutic concentrations has not been without difficulty. Another question for more complex (and costly) therapies is to what level reimbursement will be available, especially for diseases that have existing pharmacological treatments on formularies.

Implications: Microsoft's HealthVault will store medical information in an encrypted database available via the Web. In addition, there will be access to health information available to the public. Putting secured health data online seems like a great idea provided that personal information remains out of reach of those that will take advantage of it.

Analysis: The benefits of putting secure medical information on the web are appealing. Not only can individual data be made available to a physician no matter where a patient may be, but emergency personnel will be able to quickly review medical histories, drug allergies, and other critical information. Taken further, statistical analysis can be obtained for patients using a particular medication or after a new type of medical procedure.

On the other hand, the potential for abuse of this system leads to some truly frightening possibilities. Phishing scams, hackers, and even unethical health care professionals with purportedly legitimate access will certainly gain access to some data. Once this personal information is in the wrong hands, there will be no putting the genie back in the bottle. Simply changing account numbers won't do it, and there is no way for personal information to be retrieved once exposed. If hereditary predisposition to illness exists, this information could be used for blackmail or as a basis for discrimination.

Of course, great rewards often carry great risks. The key for Microsoft (or anyone else) is to demonstrate that the benefits outweigh the risks. In order to be of most benefit, a health database system will need to be set up as an internationally recognized standard that can be used with existing health systems. Microsoft's track record in providing open source software is spotty at best, so it remains to be seen how much acceptance the HealthVault system will garner among insurers, health care providers, and others who will be the users of the information.

Implications: A recent Chicago-area study has made it clear that diabetics view the daily-injection routine as being equally as onerous as many of the long-term complications from the uncontrolled disease. In addition to multiple daily injections, diabetic patients usually take several concommitant medications every day. While patients greatly fear the most severe end-stage complications like blindness, kidney failure, and stroke, many indicated a willingness to give up years of life (or quality of life) to avoid daily treatments.

Analysis: Healthcare practicioners have always known that the most onerous part of treating newly-diagnosed diabetics is making the leap to insulin injections. The pharmaceutical industry has a variety of programs that are looking at alternate means of delivering insulin: oral, transdermal, intranasal, and of course, inhaled. At present, none of these alternatives would enable insulin-dependent diabetes to completely free themselves from daily injections.

The advent of GLP-1 analogs (exenatide, liraglutide, etc.) has certainly garned excitement in the medical community because of the excellent glucose control coupled with meaningful weight loss. Of course, these compounds are all administered with a needle, thus reducing the appeal to the patient.

Oral diabetes drugs, including the newly available DPP-IVs, aren't cures for diabetes, and pharma has an intense focus on coming up with therapies that not only control glucose, but preserve or restore pancreatic beta cell function, reduce the risk of neuropathy, retinopathy, and nephropathy, and provide a cardioprotective effect. Having a combination of these factors in only one or two drugs would be icing on the cake. My opinion is that a medium pill burden would still be far preferable to a daily injection for most patients.

Of course, the key to any diabetes treatment being successful is a patient who is compliant with their therapy and who makes the appropriate lifestyle modifications to ease the burden on their body. It's not a stretch to think that modern medicine can completely cure diabetes, but only if the causal factors are removed at the same time that the symptoms are treated. In many ways, the situation with diabetes is not unlike that experienced by HIV patients in the 90s. Once HAART made HIV a chronic, treatable disease instead of a death sentence, patients began to clamour for more well-tolerated and convenient therapies. Diabetics deserve the same thing.

Implications: The results of two Phase III trials conducted by Novo Nordisk on liraglutide, a once-daily dosed GLP-1 analog, indicate significant glucose lowering efficacy and weight loss. On a positive note, Novo has to be relieved that they are seeing the same magnitude of HbA1c reduction and weight loss as exenatide (Byetta) with less-frequent dosing. However, given the ADA's refusal to include exenatide (and by inference, other GLP-1 analogs) in first-line therapy, it's hard to get too enthusiastic over this incremental improvement to Byetta, especially since the once-weekly form of Amylin's therapy (Byetta LAR) is roughly a year away from the market.

Analysis: Novo Norodisk has released data from two Phase III studies that examine the glucose and body weight lowering efficacy of their GLP-1 analog liraglutide. In the first study (LEAD 1), liraglutide was added to a sulfonylurea (glimepiride) regimen and compared to glimepiride alone or in combination with the TZD rosiglitazone. The second study (LEAD 2) compared the combination of liraglutide and metformin against a metformin only or metformin/glimepiride combination. Each study ran for 26 weeks and enrolled Type 2 Diabetics (mean initial HbA1c of about 8.5%) that had previously failed one or two oral antidiabetic therapies.

The data indicate that liraglutide provided superior blood glucose control to rosiglitazone in the patient population tested. In patients that had failed one prior oral therapy, the effect was more pronounced, with approximately 50% of liraglutide treated subjects achieving an HbA1c level of 7% or lower. When compared to the metformin regimen, comparable reductions in HbA1c were noted. In both studies, patients on liraglutide lost between 2 and 4 kg compared to placebo.

While encouraging, the results are very similar to those obtained with exenatide (Byetta), Amylin's already-approved GLP-1 analog. From a compliance standpoint, the knock on Byetta has been the need for thrice-daily injections, and Amylin is currently running a 30-week equivalence study using a new once-weekly formulation (Byetta LAR). This study is expected to complete by the end of 2007, and given favorable results, the long-acting form of the drug could be on the market in late 2008. Perhaps more importantly, the ADA's recently issued Clinical Practice Recommendations do not recommend a GLP-1 analog as part of first-line pharmacologic therapy for Type 2 Diabetes. The weight loss is meaningful, but not overwhelming, especially given Byetta's already proven efficacy in this area. Diabetics are going to have to make significant lifestyle changes to make a significant impact on their conditions no matter what pharmacologic therapies they use. The GLP-1 analogs at least avoid the weight gain seen with other oral medications for Type 2 Diabetes.

Given the current situation, it's not unreasonable to expect that Novo Nordisk will sell a few hundred million dollars worth of liraglutide in 2008 and beyond. I would be quite surprised, however, if the drug ever reaches any type of significant sales. Remember, there are many new oral therapies (notably DPP-IV, but others to come) for diabetes that may confer additional benefit around beta cell health, cardiovascular protection, etc., and these are the potential blockbusters. If nothing else, I'd like to see an oral GLP-1 analog hit the market in order to give patients and doctors something to be excited about in the relatively near term.

Stay tuned...