The new biological science is evolving at the speed of light. As a matter of fact, the bright penetrating light of the genomic revolution is effectively reaching the dark corners where the utmost reality remained hidden since millions of years. The new light enabled the insight to match the sight in divulging the buried secrets of body at the molecular level. With the most advanced tools ever created by human minds, scientists have reached a stage where they can spend much less effort in solving much more puzzles on the road towards solving the problems of diseases at their root-origin. The successful are those researchers who keep their eyes open and their minds prepared.
New Therapeutics For Chronic Life-Threatening Diseases
Until a few years ago, nobody knew about the impact of an enzyme known as PCSK9 on the cholesterol serum level. Now, we know that PCSK9 is a protein encoded by the PCSK9 gene and plays a major regulatory role in cholesterol homeostasis. PCSK9 binds to the epidermal growth factor-like repeat A (EGF-A) domain of the LDL receptor (LDLR), causing the receptor’s degradation. The reduced LDL receptor levels prevents the uptake of cholesterol into the cells, decreases LDL metabolism, hence results in an increased level of serum LDL (the bad cholesterol), a condition dubbed hypercholesterolemia.
Essays published in scientific journals as recently as 2008 predicted that one day in the future, we might see in the pipelines of some biotech firms drugs that antagonize PCSK9. Et voilà, the future seemed to have become past, as a few PCSK9 antagonist drugs are already in the pipelines of biotechnology firms, one of them is in Phase 2 clinical trials.
On various occasions, specialists in metabolic diseases have expressed great enthusiasm towards these novel drugs. They believe that targeting PCSK9 is evidence-based practice that has been confirmed through many studies and validated by many others. They believe that the time has come for improving the treatment of high cholesterol, in addition to preventing cardiovascular disease. They also think this new approach will do a great job, unprecedented in magnitude as described by others. While hoping that the drugs targeting PCSK9 would pass the safety and efficacy tests, many observers are optimistic and predict that the PCSK9 regulating drugs are expected to reduce heart attack and stroke risk and, used with lower doses of the currently available statins would cause 25 to 30 percent LDL lowering of cardiovascular risk beyond that caused by the use of statins alone.
The PCSK9 - lowering drugs under development by the biotech firms include:
REGN 727: This drug is a monoclonal antibody developed by Regeneron (REGN). It is already in Phase II clinical trials. Analysts believe that Regeneron is well equipped and could be the most well oriented to deal with the cholesterol problem. This belief is based on the fact that the firm’s Chairman, P. Roy Vagelos, MD, has been President, Chief Executive Officer and Chairman of Merck during the time when Merck was in the process of bringing the billions of dollars in sales statin drugs into the market. The firm has also on its board two Nobel Prize winners, Michael Brown and Joseph Goldstein whose research led to the discovery of statins.
AMG 145: A human monoclonal antibody developed by Amgen (AMGN). The drug is in Phase I trials and expected to begin Phase II soon.
ALN-PCS: An RNAi-based drug developed by Alnylam (ALNY). The drug aims at silencing PCSK9 gene through blocking its messenger RNA (mRNA). According to Alnylam, the drug has the potential to lower tissue and circulating PCSK9 levels resulting in increasing the LDL receptor levels in the liver, and subsequently, lowering the LDL (bad cholesterol) levels. Preclinical data with ALN-PCS have demonstrated specific silencing of PCSK9 mRNA with a decrease in serum PCSK9 protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) of approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDL, which was rapid and durable, lasting for weeks after one dose.
In July 2011, Alnylam filed a Clinical Trial Application (CTA) with the Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase I clinical trial with ALN-PCS.
Of course safety should pass the tests and so the drugs’ efficacy at safe dosage. Yet, many observers are optimistic and believe that targeting PCSK9 protein, in addition to the promise of becoming a game changer in the treatment of hypercholesterolemia, it also promises to be a blockbuster of unparalleled magnitude.
Currently, we have interest in REGN and AMGN