Merck's Januvia Approved For Type II Diabetes

Diabetes is an insidious disease that affects over 20 million in the US and 200 million world wide. The epidemic of diabetes seems to be growing rapidly around the world and doesn't seem to be abating at all. Primary contributors of increase in diabetes around the world is the influence of western food habits and sedentary lifestyle. With globalization of the economy, this cultural change is inevitable and we are likely to see a further increase in the incidence of diabetes. This is what creates an opportunity for diabetes drugs.

Sulfonyl ureas and metformin have been the main stay of diabetes treatment in US and elsewhere. Both class of agents act by pumping more insulin out of the pancreas, but metformin also seems to sensitize the body to the insulin. Unfortunately both categories are rather old and suffer from major side effects such as weight gain, and eventual loss of insulin secretion. Merck's Januvia is a welcome addition to the anti-diabetic armamentarium of the physicians.

Januvia: How does it work?

Our body cells needs glucose to function, and this glucose is made available to the cells in one of two ways – nutritional intake, or production of glucose in the liver by a process called called gluconeogenesis. DPPIV inhibitors seem to work on the former pathway.

When food is ingested and reaches the intestine, the endocrine cells in the intestine produce a small peptide called GLP1, which exhorts the pancreas to produce insulin. It is this insulin that is responsible for a quick metabolism of the glucose ingested in the form of our food intake.. As useful as this is, if our body continues to produce insulin long after the sugar levels have come down, we would hyperinsulinemia and its related side effects. Therefore our bodies have a unique mechanism to roll back the insulin level by inactivating GLP1. This enzyme which inactivates GLP1 is called DPPIV, and it helps to maintain a very delicate balance between production of insulin when needed and switching it off when not needed.

It turns out that the diabetic patients actually have malfunction in this delicate balance. They tend to produce excess DPPIV enzyme, which essentially results in lack of insulin production even when food is ingested. So, the theory was that if you were to inhibit this enzyme long enough to allow the GLP1 levels to go up, the body might produce enough insulin to metabolize the glucose. Januvia is the first proof of principle of this theory. Or in other words, Januvia is a DPPIV inhibitor, which by inhibiting the DPPIV enzyme, allows for continued availability of GLP1, and in turn continued production of insulin, and in turn continued metabolism of glucose.

So why is it such a big deal? For one thing, Januvia is a new mechanism of action, which has demonstrated solid efficacy in clinical trials. Another reason is that unlike sulphonyl ureas, Januvia does not act directly on the pancreas, and acts in a more natural way. This promise could mean that in the long run, patients pancreas may not get exhausted the way they do with sulfonly ureas. Long term data on this is currently not available. Finally, since GLP1 is produced only when food is ingested, Januvia should act only in the presence of food, which is a good thing.

Home run, but not out of the woods yet

Approval of Januvia is a nice home run for Merck, which has taken its lumps in the market place recently including the Vioxx debacle, and failure to launch Muroglitazar with Bristol-Myers Squibb. But Merck needs more such home runs – Januvia alone won't do it. One reason for that is that Januvia is being launched in a generic market place saturated with generic sulfonyl ureas and metformin. So, Merck has the challenge of convincing the prescribers that Januvia is better than these generic compounds.

Januvia also has competition breathing down its neck. Novartis is expected to get approval for Glavus, its own DPPIV inhibitor not too much into the future. While this competitive threat is real, it may not be all bad, as Novartis could also help Merck in its efforts to raise the "noise-level" on this new class and overall boost the share of the class itself in diabetes. Think back to the launches of Pravachol, Zocor and Lipitor and what they did to the HMGCoA Reductase inhibitor class.

DPPIV inhibitors may be the future of diabetes treatment, and Merck has once again demonstrated its industry leadership by delivering Januvia as the first of this new class of agents.

Sutent, Active in GIST

Sutent seems to be active against GIST. Results of a Phase III study published in Lancet this week seemed to indicate that in Gleevec failed patients, treatment with sunitinib increased meadian time to progression from 6 weeks to 27 weeks.

This is of course a good news for the GIST patients who are failing Gleevec because there is nothing available for them right now. Gleevec itself works in only about 75% of the patients, and when it does, it starts failing in about 18-24 months. But Novartis must be worried. The obvious next step for Pfizer is to move Sutent into first line, which means competition for Gleevec.

With Dasatinib breathing down Gleevec's neck in CML, and now Sutent chasing it in GIST, Novartis will need all of its marketing muscle to keep Gleevec sales chugging.

You can expect a Sutent indication for GIST in next 6 to 8 months.

Genentech Doldrums

One would think that with Avastin recieving NSCLC indication, Genentech stock would be on an uptick.

The FDA has approved the use of Avastin for lung cancer combination treatment with carboplatin and paclitaxel chemotherapy for first line treatment. Avastin is now approved for the most common lung cancer - locally advanced, recurrent or metastatic, non-squamous, non-small cell lung cancer (NSCLC).

But no, rather Genentech seems to have hit the doldrums. And the reason for this is sales of Avastin. Although Genentech met the earnings expectations, sales of Avastin slowed down a bit, and this sent the investors into a tizzy.

Add to this the announcement by Genentech that it would cap the annual cost of Avastin to $55,000 to some "eligible" patients, it seems like Avastin sales might not grow as previously thought.

But Genentech is doing a sensible thing by introducing a self imposed price cap. With Lung cancer patients likely to be taking Avastin for 12 or more months, and the cost per dose for lung cancer patients being twice ($8800) that of Colorectal cancer ($4400), it seemed like Genentech would have become a prime candidate for criticism. What it means to overall Avastin sales remains to be seen, but Genentech may have taken the sting out of the price pinch.

Changes Changes Changes at Imclone

So, Imclone announced the resignation of its Chairman Kies and board member William W.

A company regulatory filing said their decisions weren't the result of any disagreements with ImClone over operations, policies or practices.

Yeah right!

The market thinks otherwise, and its betting that Imclone will be sold for a price far higher than the $35 or 36 that Kies agreed to sell out for. Well, when you play with fire, there is a good chance you'll get burnt. And if Mr. Icahn isn't fire, what would he be?

And Fire is nature's way of implementing a long overdue change. 

Glaxo Files Tykerb in Europe

Just a month after filing the NDA for Tykerb in US, Glaxo has filed for its approval in Europe. Tykerb or lapatinib, a small molecule HER2 inhibitor, has been studied in breast cancer in patients who failed Herceptin treatment. In patients who failed Herceptin treatment, Tykerb, incombination with Xeloda was found to double to Time to Progression. This from the Glaxo press release...

....Phase III international, multicenter, open-label trial randomized 324 women who had advanced or metastatic breast cancer with documented HER2 overexpression and whose disease progressed following treatment with Herceptin and other cancer therapies, to TYKERB and Xeloda or Xeloda alone. In this pivotal trial, the combination of TYKERB and Xeloda versus Xeloda alone nearly doubled median time to progression (36.7 weeks [8.5 months] in the combination arm versus 19.1 weeks [4.4 months] with Xeloda alone, p=0.00008).

All this is great news for the patients IF the health authorities in UK and elsewhere in Europe allow easy access to Tykerb. I can only hope that the Herceptin story is not repeated again with Tykerb.

Merck Gets Zolinza Approved. Proof of Principle for HDACs

Well, what do you say about this...the big bad pharma industry is back
swinging. Merck, the venerable big Pharma that got itself into hot
waters over Vioxx, is back in the game. This time the drug is Zolinza
or vorinostat, which was approved by the FDA today for treatment of
Cutaneous T cell Lymphoma. Zolinza is a HDAC inhibitor which is
likely to find use in a broad array of tumors.

While this is a big deal for Merck, and is a signal of its seriousness
to enter into Oncology market place in a big way, the drug actually
came to Merck from the labs of Aton Pharmaceuticals, a small biotech
which Merck bought in late 2003. Still, belegured Merck will welcome
this news as it takes the bite out of the Vioxx nastiness.

HDAC inhibitors are particularly attractive anti-cancer agents because
of their potent activity and relatively benign side effect profile.
Merck seems to have beat other HDAC inhibitors to the market,
especially the one from Gloucester Pharmaceuticals' FK228 also called
Romidepsin. At 2006 ASCO both Merck and Gloucester had shared the
data in CTCL which started the horse race between them.

While the CTCL indication is hardly going to be producing billions of
dollars, especially with Gloucester breathing down Merck's neck, the
real payoff will come when Zolinza trials in other tumors come
through. Currently Zolinza is being studied in a broad range of
tumors including Lung cancer, breast cancer, colorectal cancer and
many other solid tumor malignancies.

This news is big positive for Gloucester too. Now that the proof of
principle on HDAC has been established, this small privately held
biotech will suddenly be seen as an important target by all the top
pharma companies with dry pipelines, to provide them the lead in HDAC
inhibitor space. Gloucester is now in drivers seat to fetch the best
price for partnering with a big pharma.

Sometimes good things do happen to people that wait!

Mello and Fire Discovery Fires Up Nobel Committe

Drs. Craig Mello and Andrew Fire of U Mass, and Stanford respectively, have won the 2006 Nobel Prize for medicine.  The duo wins the Nobel for their discovery of  RNAi, which is implicated in turning genes on and off.  RNAi or interference due to bits of RNA is a relatively new discovery.  Mello and Fire, working with C. elegans model, discovered that unlike the conventional belief (that RNA simply acts as a messenger of the code present in the DNA), RNA can play a role in turning certain genes on and off.  Since the discovery, RNAi have been found to be present a wide range of plants and animals.

It is postulated that RNAi and dsRNA (double stranded RNA) potentially could be used as a theraputic treatments.  Several companies, including Merck are interested in this new technology, but it will be a while before we start seeing drugs on the market.