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|Includes: Insmed, Inc. (INSM)

After Insmed announced results from phase 2 clinical trial evaluating Iplex™ (mecaser-min rinfabate) on patients with myotonic muscular dystrophy ("MMD"), investors instigated a hysterical sell off of INSM on a very high volume. Capital is a coward, we know, especially in shaky economies, yet aggressive negative reaction to news based on fear only might not echo reality, which is much better sensed through an honest search for facts.       

To begin with, investors should not have overlooked the fact that phase 2 clinical trial with Iplex on MMD was exploratory. The objective of this trial was to let researchers learn more about Iplex’™ as a therapeutic. The important polypeptide in Iplex is the insulin-like growth factor IGF-1, which scientists know now that in nature, it is involved, among other tasks, in children’s growth and in sustaining the muscle strength then after, i.e., it has an adult anabolic effect. It also has to do with glucose and lipid metabolisms. Researchers now recognize that using the free IGF-1 as therapeutic is limited by its toxicity at effective doses. That’s why the combination in Iplex of IGF-1 with its predominant binding protein IGFBP-3 has demonstrated much better results than using the free growth factor in short stature children and had promising results in other neurological diseases where other products failed.  

Myotonic muscular dystrophy ("MMD") has complex symptoms, which comprise progressive muscular weakness and myotonia, cardiac arrhythmias, cognitive defects, endocrine disturbances including insulin sensitivity, testosterone imbalance, as well as deregulated lipid metabolism, gastrointestinal and reproductive deregulations and pain.  

No rational professional analyst should have expected full accurate confirmatory results from a short-term exploratory trial with Iplex on a few patients suffering from MMD. That’s why the primary endpoint was not predefined. As a matter of fact, the trials were, yes, incapable of demonstrating positive effects of Iplex on the functional measure of endurance, muscle function and muscle strength, but were positive on other MMD complications. So, while investors reacted hysterically against the stock because of the negative side of the results, they totally overlooked the positive results of the drug on other important MMD complications, including, improvement in standard measures of insulin sensitivity - reductions in fasting glucose, fasting insulin, and on cholesterol and triglyceride high levels. They also closed their eyes on the results demonstrating that the use of Iplex rhas esulted in increasing body mass index and testosterone level.  

These positive results confirm that Iplex has the same effect as the natural body insulin-like growth factor (IGF-1) without toxicity, thus, it can be used in diseases where the natural IGF-1 is deficient, or not sufficiently protective. Needless to repeat that the combination of IGF-1 with its binding protein IGFBP-3 enables administering the drug safely at higher therapeutic doses with no side effects as those produced through the use of free IGF-1 developed by other firms.      

The data from phase 2 trial also tell scientists that if they wanted to reproduce the same effects as that of the natural IGF-1 in the body, the only current available drug for them is Iplex. We have no doubt that researchers at Insmed and at other firms interested in providing a therapeutic IGF-1 will do their best in finding effective Iplex combinations for debilitating neuromuscular, neurological and other diseases that have yet to find specific effective treatments.

Insmed is designing a new phase 2 trial that focuses solely on those patients who suffer from severe insulin resistance and are expected to benefit from the drug as seen from the unveiled results. Insmed intends to apply for a grant from the Muscular Dystrophy Association ("MDA"), which has largely supported the exploratory trials. The firm has considered using alternative methods that can demonstrate the effect of Iplex on muscle function.   

Why do we need a therapeutic IGF-1?  

The discovery of cytokines and growth factors and the developed of state-of-the-art tools for gene expression analysis have dramatically changed the understanding of many diseases. They handed scientists new tools that help them use natural body growth factors as therapeutics - a task that has been  difficult to achieve.

Insulin-like growth factor 1, (IGF-1), for example, which was once called somatomedin C, and is part of Insmed’s complex drug Iplex™ is a polypeptide similar in molecular structure to insulin. IGF-1. It plays an important role in childhood growth and continues to have ananbolic effects in adults. IGF-1 activates the AKT signaling pathway, stimulates cell growth and multiplication and inhibits programmed cell death. It affects every cell in the human body, especially muscle cells, nerve cells, cartilage cells,  bone, liver, kidney, skin and lung cells. IGF-1 and promises regulating cell nerve cell growth and development.

No wonder then why scientists dream of using this polypetide as therapeutic for growth related issues, for neuromuscular diseases and for metabolic diseases, especially diabetes.        

Why Iplex?

Developing Iplex™ as a complex of recombinant human insulin-like growth factor-I (rhIGF-I) and IGFBP-3 (rhIGFBP-3) was a genius approach by Insmed. The complex solved the problem of dose restriction, enabled the drug to cross the blood brain barrier, increased its half life and freed it from the side effects that the free IGF-1 (Increlex and Myotrophin) – drugs developed by other firms.  Iplex is given once a day, while free IGF-1 must be administered twice a day in a much lower dose.

Iplex™ was approved in the United States in December 2005 for the treatment of children with growth failure due to severe primary IGF-I deficiency. The advantages of this drug, however, convinced scientists’ that Iplex™ could be the drug the would play major roles in the treatment of serious neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), myotonic muscular dystrophy (NYSE:MMD), type 1 and type 2 dia-betes, retinal diseases, such as retinopathy of prematurity (NYSE:ROP) and HIV adipose redistribution syndrome (HARS).

Amyotrophic lateral sclerosis (ALS): Insmed is currently providing Iplex in Italy through Expanded Access Program to physicians for ALS patients with promising re-sults. No other drugs, including free recombinant insulin-like growth factor-I (rhIGF-I), succeeded in inducing any improvement on the symptoms of this deadly disease. Many physicians are now putting their patients on Iplex™ in Italy. When the FDA heard the news about the Italian experience, it gave physicians the green light to use Iplex™ on compassionate basis on ALS patients in the U.S.

HIV adipose redistribution syndrome (HARS): Preliminary results from a phase 2 study conducted at the University of California, San Francisco on HIV patients suffering from HIV-associated adipose redistribution syndrome (HARS) showed that treatment with Iplex 0.5 mg/kg/day for three months only resulted in increasing IGF-I levels 3-fold.  The administration of Iplex seems to be associated with significant improvements in fasting glucose levels, in the amount of insulin secreted during oral glucose tolerance test, and overall insulin sensitivity. Additionally, there was a significant reduction in patients’ trunk fat and lipid profiles.   

If such a low dose of Iplex increased IGF-I levels 3-fold and positively impacted abnor-mal glucose metabolism, dyslipdemia and abnormal fat distribution, it is then fair to assume that a higher dose would have a better impact on improving glucose homeostasis. Competitors’ products have failedl to alter glucose homeostasis. It is important to note that abnormal glucose metabolism and dyslipedemia are present in a significant number of HIV patients treated with highly active antiretroviral therapy.

Retinopathy of prematurity (ROP

Premacure is developing iplex™ as a potential treatment for Retinopathy of Prematurity (ROP) via a Material Transfer Agreement with Insmed. It seems that IGF-1 predominant binding protein IGFBP-3 (rhIGFBP-3), increased serum IGF-I levels into the normal range in significantly premature infants. These most recent study results were re-ported at the European Society for Pediatric Endocrinology 47th annual meeting, Istan-bul, Turkey, by Investigators from the Harvard Medical School, Boston MA, and the University of Gothenburg, The Karolinska Institute, Stockholm and Lund University, Sweden in a poster entitled "Pharmacokinetic study of recombinant human (rh) insulin-like growth factor/rh IGFBP-3 complex administered to very low birth weight infants. 

Commenting on the Results

Lois Smith, Professor of Ophthalmology, Harvard Medical School, Children's Hospital Boston said, "The possibility of preventing ROP and other complications of prematurity by replicating the in utero environment after infants are born prematurely and lose the factors normally provided by the maternal environment is very exciting. This work shows that it is now possible to raise the serum level of IGF-1 and IGFBP-3 to normal in utero levels in these fragile infants with IGF-1/IGFBP-3 deficiency, which is a critical step in the development of interventions that prevent ROP. Since we have shown that low IGF-1 is associated with ROP, this offers the first possible intervention to prevent this blinding disease."

Ann Hellstrom, Professor in Pediatric Ophthalmology, Sahlgrenska Academy, Gothen-burg, Sweden said, "Our research focuses on promoting neural, vascular and metabolic development in premature infants. While in this study we are attempting to identify the benefits of IGF-I for ROP, our findings are also likely to be applicable to many aspects of complications of premature birth and could provide benefits for a lifespan."

Prevention of ROP

Low levels of IGF-I are known to contribute to the occurence of ROP. The objectives of the investigator-sponsored clinical study were to determine whether intravenous admini-stration of rhIGFI/rhIGFBP-3 (IPLEX™ could increase serum levels of these proteins in at-risk infants to levels seen in normal infants, and to evaluate the drug's safety and tol-erability. Due to consistency in response, the study was finalized after five infants. Treatment with IPLEX™ took place on the infant's chronological age day 3 and the investigators reported that the protein complex effectively raised serum IGF-I levels into the physiological range and that the drug's administration was well tolerated, with no acute adverse events.

With a drug like Iplex™ one cannot be pessimistic by results from trials that are not meant to prove but teach. We do believe that Iplex™ will, indeed, play a role in the treatment of many diseases, alone, or in combination treatments and as adjuvant to other treatments.

Insmed has agreements with Pharmacia AB’s portfolio of regulatory filings pertaining to rhIGF; and an agreement with NAPO Pharmaceuticals that gives NAPO the right to develop, manufacture, and commercialize masoprocal products for various indications relating to diabetes, cardiac disease, vascular disease, metabolic disease, and syndrome X.

Insmed also engages in various oncology programs, including INSM-18, an orally available small molecule tyrosine kinase inhibitor that has demonstrated selective inhibition of IGF-1 and human epidermal growth factor receptor; and rhIGFBP-3, which is in early clinical development stage for breast, prostate, liver, ovarian, and colon cancers.

The firm has around $120 million in cash reserves and is looking forward to continuing to explore Iplex™ possibilities with its strategic financial advisor, RBC Capital Markets.

ROP is a disease of the eye that affects prematurely born babies. It is thought to be cau-sed by disorganised growth of retinal blood vessels, which may result in scarring and retinal detachment. ROP can be mild, but may lead to blindness in serious conditions. It is one of the most common causes of visual loss in childhood and can lead to lifelong vision impairment and blindness. As such, all preterm babies are at risk for ROP, and very low birth weight is an additional risk factor.

Premacure AB, based in Sweden is dedicated to the development of diagnosis and prevention of complications in neonates due to premature birth. The first of several indications to be developed is Retinopathy of Prematurity (ROP).   

What do you think? Do we hope that Iplex succeeds as therapeutic, because we need a safe and effective IGF-1 drug?

Disclosure: No positions