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PROLOR: The Added Value Of Reversible PEGYlation

Prohost Biotech - Wednesday, March 30, 2011

When Professor Irving Boime and his team at Washington University in St. Louis observed that human chorionic gonadotropin (hCG) has a longer half life than other natural hormones, researchers’ curiosity led them to discover that a carboxyl terminal peptide (CTP) linked to the hormone molecule increases its half life. Experimenting with CTP on other proteins left no doubt in the minds of the researchers that linking Nature’s CTP to protein therapeutics could be safe and effective in extending their half-life. When it comes to reproduction, Mother Nature does not err and does not cause harm. It selected CTP to link to the hormone, which without it, pregnancy would have never been possible. Read also The Value of CTP Technology

Washington University in St. Louis granted  Prolor Biotech (PBTH) an exclusive license to use the CTP technology with the exception of four proteins; follicle stimulating hormone (FSH), human chorionic gonadotropin (hCG), luteinizing hormone (LH) and thyroid stimulating hormone (TSH), which ended up in Merck’s lap. Having secured the rights to CTP, Prolor’s priority has been to develop long acting versions of approved protein therapeutics that have the least troubling clinical trial requirements, which would be money draining and time-consuming. Modifying approved therapeutic proteins requires less time for preclinical and clinical development than molecules that have yet to be proven safe and effective.

As Prolor’s products were advancing in clinical trials, the firm made a surprising announcement; declaring it has secured the right to a new technology dubbed Reversible PEGylation. While granting the right to this state-of-the-art technology to Prolor was the envy of many drug delivery firms and other pharmaceutical companies, it looked as if many investors missed noticing the breakthrough nature of this elegant technology that, when added to the CTP technology, would tremendously increase of the number of modified products in Prolor’s pipeline.

What’s is the story? Why is Prolor interested in extending the half-life of proteins, peptides and other small molecule therapeutics? Why did this firm add another technology to its safe and effective CTP technology?
Short half-life and poor bioavailability of parenteral therapeutic proteins and peptides renders them unstable, poorly effective and plagued with adverse effects. The tremendous increase in the number of protein and peptide therapeutics following the establishment of the biotech industry necessitates the discovery of modifying technologies that would prolong the half-life of these molecules without compromising their mode of action and efficacy. Unfortunately, despite the introduction of many technologies, the badly needed safe and effective approaches towards prolonging the half-life of these molecules remain badly needed. Of the many therapeutic proteins and peptides that have been approved and generating billions of dollars in revenues, a few only were modified, making them safer, less expensive and more convenient for the patients. Here comes the role of CTP and Reversible PEGylation technologies, which ended up in the hands of prominent scientists at Prolor Biotech.

By imitating nature and attaching CTP to existing therapeutic proteins, Prolor was able to stabilize and extend the half-life of therapeutic proteins without impacting their desired biological activity or therapeutic efficacy. The new approach has been validated through various clinical trials and, more importantly, by the approval in Europe of Elonva®, an extended release follicle stimulating hormone (CTP-FSH), one of the four products licensed to Merck by Washington University St. Louis. Elonva is used together with a gonadotrophin-releasing hormone (GnRH) antagonist in women undergoing fertility treatment. One subcutaneous injection of Elonva has replaced many injections required daily for other recombinant follicle stimulating hormone (rFSH) preparations to do the job.

As Prolor’s CTP product pipeline is growing, trials are further confirming the safety and efficacy of the approach. The firm’s lead product (CTP-rhGH) is a modified version of the recombinant human growth hormone, which is approved for children and adults. In children, it is prescribed for long-term treatment of growth failure due to inadequate endogenous growth hormone. For adults, hGH is approved for severely hGH-deficient adult patients. CTP-rhGH is now in phase II trial after demonstrating in Phase I trial that two monthly injections can replace daily injections of the conventional hormone. Results have also demonstrated that the treatment has increased IGF-1 level, an evidence-based proof of CTP-hGH activity. The IGF-1 levels are agreed upon marker of hGH activity. This is good news.

Prolongation of rhGH action has long been recognized as a necessity for all the reasons mentioned above, but more importantly for the sake of children, who are enduring a shot everyday for a long, long time. It needed CTP to be attached to the hormone to make it easy for short-stature children to comply with the treatment, as it did thousands of years ago to chorionic gonadotropin, which enabled children to exist in the first place.

In early February, an Independent Data Safety Monitoring Board decided that the drug is safe and recommended continuing the trials as they have been planned. This is good news. It indicates that the firm’s trial plans are good enough to provide all the necessary data that a Phase II trial must provide. The results are expected in the third quarter of this year. This is another good news. We are optimistic. The market is large and is still growing, especially for adults. The market for hGH has been stretched several times in the past; the largest was when it was approved in the U.S. for HIV-related wasting. High doses of hGH have been found to increase the weight and lean body mass in people with AIDS. The loss of lean body mass is the form of wasting is most closely related to an increased risk of death.

Prolor’s current pipeline includes additional CTP-formulated products, which include interferon beta candidate (IFN-B-CTP); Factor VIIab (FVII-CTP); an erythropoietin candidate (EPO-CTP); a product for type 2 diabetes (GLP-1-CTP) and the obesity candidate OBES-CTP (MOD-1002).

On January 18, 2011, Prolor announced it entered into a definitive license agreement with Yeda Research and Development Company Ltd. Upon the agreement, Prolor would use the state-of-the-art novel Reversible PEGylation technology to develop sustained release small molecule peptide and protein therapeutics. Following the announcement, some investors expressed an uneasy feeling towards the news, while others that we mentioned in the beginning of this article have been totally indifferent to it. Some shareholders did not like the fact that Prolor is using the Reversible PEGylation technology in developing an obesity drug. A series of recent FDA rejections of obesity drugs have misled investors into falsely believing that, for one reason or another, the FDA has decided to make it extremely difficult approving obesity drugs, regardless of their safety and efficacy. Some investors thought that Reversible PEGylation is the conventional PEGylation approach, which is described as inefficient for the modification of proteins and peptides.

To clarify the confusion, we thought investors should know more about Yeda, about Reversible PEGylation and about the obesity drug. To begin with, the technology belongs to Weizmann Institute of Science (WIS) – a world leader in research and graduate education. The Institute’s state-of-the-art technologies and research have led to many discoveries and inventions that have huge commercial potential. In 1959, WIS established Yeda as a research and development company, which, in due course, has become one of the World's most successful technology organizations for the transfer of breakthrough discoveries. So Yeda is not a small, unknown company, but a viable arm of WIS. The mere fact that Yeda decided to grant Prolor the right to the Reversible PEGylation is that the Weisman Institutes of Science viewed Prolor’s scientists as highly qualified to effectively use the technology in developing and commercializing breakthrough therapeutics.

Reversible PEGylation is a breakthrough technology developed to boost the half-life and biological activities of small molecule candidates as well as peptides and proteins without changing the mode of action of the therapeutic molecules and improving their pharmacokinetics. The worst problem in PEGylation is the fact that the polyethylene glycol polymers block the active sites of the therapeutic molecules. In Reversible PEGylation, PEG polymers are attached to the drug with chain-like structures held in place by chemical bonds that gradually dissolve in the bloodstream, enabling the PEG molecules to detach in a measurable way from the drug. As they detach, the native molecules are released into the blood in a slow, constant, and predictable manner.
Many scientists, including Prolor’s have validated this genius approach. As a matter of fact, Prolor was able to negotiate its exclusive license for reversible PEGylation after its success in developing a preclinical-stage long-acting oxyntomodulin anti-obesity candidate using Reversible PEGylation platform under an option-to-license agreement. Having accomplished its job successfully, Prolor was awarded the right to use Reversible PEGylation, not only for the drug in hand, but for all therapeutic indications except hemophilia and insulin.

With regard to obesity, Oxyntomodulin, which Prolor is actively developing into a sustained release formulation, is totally different from the drugs that were denied FDA approval. The rejected drugs had little or no effect on weight loss, or failed the reward versus risk test, especially for a non-terminal stage sickness. Oxyntomodulin is a natural peptide hormone that is released by the digestive system following food ingestion. It acts as a natural satiety signal to reduce food intake and increase energy expenditure. Prolor has chosen a natural, safe body product to fight overeating. Previous human studies conducted by other groups have demonstrated the potential of oxyntomodulin in reducing appetite and food intake, leading to significant weight loss with minimal side effects. As oxyntomodulin has a short half-life, which requires frequent dosing that is arduous for the drug takers, it needed modification that prolongs its half-life. Reverse PEGylation was the option of choice for extending oxyntomodulin’s half life, making the drug user friendly, i.e., easy for the patients to take, so they would comply with the prescribing directions.

Adding Reverse PEGylation to CTP technology enables Prolor to realize its vision of filling its pipeline with modified approved therapeutic proteins and peptides that are already generating billions of dollars in revenues and other molecules, small, or large, that promise blockbuster drugs.

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