Newest Hopeful In Cholesterol Lowering Landscape

Just weeks after the biotech world celebrated the approvals of two new cholesterol-lowering PCSK9 inhibitors, Regeneron/Sanofi’s Praulent and Amgen’s Repatha, a potential future rival arrived in style. Enter Alnylam (Cambridge, MA), with its RNAi-based experimental drug ALN-PSCsc, which just completed Phase I with positive results.

What makes PCSK9 inhibitors so hot, and why are the new cholesterol drugs on the market clutching their pearls over ALN-PSCsc? Let’s find out why the PCSK9 and RNAi are creating a buzz in biotechnology.

On The Market: PCSk9

The body naturally keeps bad cholesterol in check with low-density lipoprotein (LDL) receptors. These receptors bind to excess LDL, which the liver cell absorbs. The liver breaks down the cholesterol and recycles the receptor back to the cell surface, where the LDL receptor can bind to and remove more LDL.

PCSK9 is a protein that also binds to the LDL receptor, which also triggers the liver cell to absorb the pair. However, the entire complex is degraded and the receptor is not recycled—sort of like a murder-suicide. This results in fewer LDL receptors, impeding the process of LDL removal.

Repatha and Praluent are monoclonal antibodies (mAb) that work by attaching to PCSK9, which prevents the protein’s interaction with low-density lipoprotein receptors on the surface of liver cells. By preventing the degradation of these critical receptors, PCSK9 inhibitors lower LDL levels and lessen the risk of a cardiovascular event. Clinical results report lowering of LDL levels by as much as 60%. One key advantage of the new PCSK9 inhibitors is their safety profile—in clinical trials, the adverse events observed were equivalent to that of the placebo.

RNai Technology Explained

Recall from high school biology that RNA is single-stranded (ssRNA) and is the set of instructions from the gene to the ribosome to make protein. Simply put, RNAi technology creates a double-stranded RNA (dsRNA) by introducing an RNA sequence into a cell which is complementary to the RNA for the particular gene to be silenced. When both ssRNAs meet, dsRNA is formed. The cell recognizes dsRNA as foreign and destroys it—because dsRNA is seen as a “mistake.”

Short Interfering RNA (siRNA)

When researchers introduce a dsRNA, it is processed by the cellular enzyme DICER and produces a “short interfering RNA” , or siRNA. This siRNA then binds a second enzymatic complex called RNA-induced silencing complex, or RISC, which then recruits cellular mRNA whose sequence is complementary to the guide RNA. RISC then destroys both RNA strands—thereby preventing the production of the protein coded for by the targeted mRNA.

The RNA-based therapeutics field has a history of failed candidates due to delivery problems—getting the drug in the right place at the right concentration to be therapeutically effective. The efficacy and durability of ALN-PCSsc is a significant accomplishment in the RNAi world.

In Development: ALN-PCSsc

Instead of inhibiting PCSK9 after its production in the body (like the mAbs on the market), ALN-PSCsc blocks the production before it even starts. Early clinical study results suggest that this is as effective as the mAb therapeutics—and the efficacy is long-lasting, with the potential for quarterly or even biannual dosing, as opposed to twice-monthly for Repatha and Praluent.

Alynylam’s approach was to create an RNAi molecule that targets the PCSK9 mRNA, and attaches the synthetic RNAi to a sugar called “GalNac.” GalNac, in turn, binds a receptor on the surface of liver cells, called the asialoglycoprotein receptor (ASGPR)—resulting in very efficient uptake of the RNAi. In order to increase stability, the RNAi has been modified to be resistant to cellular enzymes that would normally break it down, making it possible for patients to one day be on a longer dosing schedule—potentially increasing compliance. With the buzz around ALN-PSCsc getting even louder, all eyes will be on Alnylam every step of the way through their clinical trials.

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