Isis Pharmaceuticals' Obesity Buster an Enormous Finding

Logic may dictate that Isis Pharmaceuticals' largest multibillion-dollar blockbuster drug is its anti-lipid drug Mipomersen. After all, Genzyme (GENZ) has already paid Isis 325 million dollars upfront, and is scheduled to pay an additional 1.575 billion dollars in milestone payments.

True, Mipomersen has already proven to reverse atherosclerotic plaques in the murine model at unprecedented efficacy (up to 92%). It has also been able to lower lipid levels never achieved with traditional medicines in patients afflicted with homozygous hyperlipidemea.

I would even venture to say when fully approved, it would beat Pfizer's (PFE) Lipitor in gross annual sales and profits. So shouldn't Isis' Mipomersen be its largest medicinal candidate in terms of gross revenues and profitability potential?

No, not at all. While Mipomersen will turn out to be wildly successful, Isis' hidden gem is its obesity-busting diabetic drug ISIS 113715, a second-generation antisense inhibitor of protein tyrosine phosphatase 1b. It is this enzyme that inhibits insulin receptors in type 2 diabetics. This is no small feat, as there are over twenty-two million Americans suffering from this disease.

Even more important, a whopping 63% of Americans, or roughly 191 million people, according to the CDC, are overweight. A third of those are obese. And it is this drug that normalizes glucose but does not cause hypoglycemia like some oral diabetic agents. It also decreases circulating lipids to the point of decreasing the amount of fat in an over satiated (overfed) individual.

This effect has been noted in several scientific publications discussing inhibiting tyrosine phosphatase 1b. The problem was finding a specific antisense molecule that inhibited this individual phosphatase and not the general class of 1b phosphatases. Isis owns that particular antisense molecule.

I cannot overemphasize the importance of this finding. This medicine could be America's answer to its obesity epidemic.

Disclosure: Long ISIS

Comments

[User 59050]

this is the kind of knowledge i am looking for. thank you so much for sharing.

[Rallos]

I don't believe that ISIS themselves are heavily pushing the anti-obesity potential of this compound as there was no statistically significant change in bodyweight in the phase 2 study (it didn't involve diet or exercise but obesity drugs in development have shown a significant change without any lifestyle intervention). I think this is partly a result of the distribution of the molecule and its particular concentration in tissues such as the liver rather than its exposure to the CNS.

Preclinical studies have emphasised that peripheral action is mainly what contributes to the anti-diabetic effects of PTP1b inhibition while central inhibition is what's needed for the effects on bodyweight.

Genaera appears to be the only other company with a clinical PTP1b inhibitor and it is a small-molecule central and peripheral inhibitor. It is currently in Phase 1 trials with both an anti-obesity and an anti-diabetes IND

[southshoreinvestor]

First, let me say that when AMGN and DNA were just small start ups, the large pharma companies whose focus was on traditional small molecule drugs probably didn't foresee the success of the protein-based drug market. That's likely because a single success doesn't prove a "platform's" potential. Of course, AMGN and DNA over a long time "have" proven themselves to have pursued a successful platform bringing many new drugs to market using it.

Since it is not the individual drug that will make a start-up or the investment in one have great potential but rather the ability to bring many new drugs forward, then it is important to assess the platform more than the individual drug.

With that said, companies like ISIS, and to a lesser extent MNTA, stand today at the forefront of a new "platform" for drug discovery and the strength of each remains to be be seen.

My specific comments are:

1) Mipomersen is an injectable (not oral) preparation. Thus, the ability to expand its market share to Lipitor-like sales could be held back until ISIS launches an oral formulation. It is my understanding that ISIS intends to pursue this, but that doesn't mean it will be easy, cheap, and/or safe. Competition from generic statins should make marketing shy of attempting to expand here unless the clinical data shows benefits not seen in the statins in general. Perhaps the efficacy in reducing the plaque as stated in your blog will offer cardiologists a new tool used prior to arterial stents and/or bypass surgery.

The counter argument (a positive) would be that a once per month injection would be preferable to the patient over taking 3 pills a day, every day, along with 3 or 5 other daily medications. This would increase patient compliance. And since many seniors already visit their doctor/HMO frequently, then an injectable formulation might not be black-listed by the HMO's/insurance co's because of increased office visits per patient.

2) Bayer brought to market (thus passed the FDA clinical trials) the anti-cholesterol drug Baycol, which was later recalled for toxic side effects. Baycol was highly bioavailable (meaning it could be found throughout much of the body's tissues) whereas all of the other statin drugs including Lipitor were retained in the liver. Retaining the drug in the liver prevents the toxic side effects of sterol inhibition elsewhere in the body. As yet, it is unclear if ISIS can effectively produce an oral formulation that is retained by the liver (for Mipomersen) or the reverse, if their formulation technology can be engineered to make other potential drugs highly bioavailable (as they might need to be).

Thus, can ISIS make oral formulations that are tailored to the needs of the tissue target? This has implication as to how successful the ISIS platform will be - not just how Mipomersen can be advanced or its use expanded.

Having demonstrated proof-of-concept with Mipomersen and many of the patents in the area is a good sign, though.

Just my 2 cents,

[johnar]

I know so many people who cannot get out of bed two days a week due to muscle pain from statins. They are constantly in doctor's offices anyway due to their hearts. An injectible once or twice a month would be much better than what they have now. ISIS is not looking to make this an oral drug. Neither is Genz. They are also not going after the statin market. The 20 million they are going after are the ones that can't move on statins due to muscle pain. They'll take the shot.

[User 217910]

The notion that arterial plaque can be reduced could be pretty significant. Statins can reduce plaque buildup but I am not aware of any credible claims of reversal by statins, just a slowing of progression.

If I could get reversal with no adverse side effects, I'd give it a "shot."

[BioInvestor]

southshoreinvestor, actually major pharma got involved very early with both AMGN and DNA. Partnerships with J&J and Eli Lilly, respectively, helped move the initial programs along. Of course, J&J missed out on the big market for Amgen's first drug.

A non-oral form of a drug will be an impediment to its widespread acceptance. In the obesity market, not too far from ISIS in Southern California, one finds Arena Pharmaceuticals. Arena (ARNA) has an oral anti-obesity drug that's currently in phase III. To date, its safety profile looks good; however, until the Phase III results are published, there is risk associated with investing in this company.

[southshoreinvestor]

Re: Bioinvestor. Actually, big pharma invests in most promising new platforms in a rather unique way - in a press release, with a transfer of money, rights to regional distribution, and in exchange for a percentage of the company they're investing in. So they do share in the profits of the successful ventures, and they also lose their investment in those platforms that are not viable. Even the big pharma's were taken during dot.com bubble.

As you correctly said, upstart biotechs must partner away early products in order to build a revenue stream that will power growth of their future pipeline. Most fail. Also, AMGN and DNA are now struggling as they've picked most of the low hanging fruit.

A non-oral form of Mipomersen will discourage its wide spread use, but if the formulation can be produced in an extended release form or packaged in a pen-style injection similar to AMLN's Byetta, then this might change.
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Specifically regarding Mipomersen, a reversal of plaque would be a significant benefit and would provide ISIS with an expanded use. Prevention of cardiac disease surgeries would be a significant savings to the HMO system (not to mention the impact on patients and families).
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Generally regarding ISIS, they have a potential platform that applies a new drug type to old and new disease targets. The old targets are the most promising since these are already validated, have probably come off patent, and are abundant. Plus, ISIS will not have to spend much money or time on early-phase discovery or legal. Targeting PTP-1b with small molecules for instance was tried to death by every pharma and is the poster child for each new drug platform. The platform for ISIS is the bull case for investing here. Mipomersen is the proof-of-principle product.

Toxic side effects, drug-delivery issues, competition, and production costs are the bear points.

Long-term, ISIS is a speculative buy - to me. IMO.