The Science Behind The Blockbuster Drugs Of Tomorrow

Emily BurkeBiologics, Business of Biotech, Cardiovascular Disease, Clinical Trials, Drug Approvals, Drug Targets, Easily Confused, FDA, Mechanism of Action, Monoclonal Antibodies, Small Molecule Drugs, The WEEKLY

Billion Dollar Mechanisms Of Action

The Most Promising Drugs of 2015—a Thomson Reuters Cortellis Competitive Intelligence report—includes several new drugs with predicted sales of $1 billion plus by 2019. Those on the list are well on their way to winning or have recently won FDA approval and the fervor around their potential has caught the biotech world by storm. While stock gurus are passing predictions on to investor circles, we here at WEEKLY wonder: what exactly is the science propelling the market into overdrive? Let’s discover the mechanisms of action driving the top three drugs on the list.

OPDIVO By Bristol-Myers Squibb

Drug type: Monoclonal antibody.
Drug class: PD-1 inhibitor.
Indication: Approved by the FDA for melanoma and lung cancer.

Opdivo belongs to the new class of immunotherapy drugs known for their inhibition of the PD-1 protein found on T-cells. Under normal conditions, the PD-1 protein is used by the immune system to prevent an attack on the body it is charged with protecting. When PD-1 encounters a cell with PDL-1 proteins, it identifies the cell as “self” and signals the T-cell to hold back and not attack.

Some cancers have a sneaky tendency to overexpress PDL-1 in their cells and this helps tumors to survive and thrive by evading T-cell detection. By inhibiting the expression of PD-1 with Opdivo, the T-cell does not have the means to read the signal from a PDL-1 protein and the T-cell attacks the tumor cells.

PRALUENT By Regeneron and Sanofi

Drug type: Monoclonal antibody.
Drug class: PCSK9 inhibitor.
Indication: High cholesterol.
Pipeline: FDA decision expected this summer.

Praluent works by binding to the PCKS9 protein, which plays a key role in cholesterol metabolism. The PCKS9 protein manages to trigger the degradation of low-density lipoprotein (LDL) cholesterol receptors on the surface of liver cells. The function of a LDL cholesterol receptor is to “mop up” circulating LDL and their deterioration results in higher levels of LDL in the patient’s blood. By preventing the degradation of these critical receptors, Praluent lowers LDL levels to lessen the risk of a cardiovascular event.

LCZ696 By Novartis

Drug type: Small molecule drug combination.
Drug class: Angiotensin-neprilysin inhibitor.
Indication: Heart failure.
Pipeline: FDA decision expected in August.

LCZ696 is a combination of the drugs Valsartan and Sacubitril. This dynamic duo work together to lower blood pressure, effectively reducing the strain on the heart and lessening fluid accumulation in the tissues (such as the lungs)—all key symptoms of heart failure.

Valsartan is an angiotensin II receptor inhibitor—it stops angiotensin II. When angiotensin II attaches to the angiotensin receptor, blood vessels constrict and blood pressure rises. Think about it like this: it takes more work to push fluid through a long narrow tube than through a wide one.

Angiotensin II also promotes the release of a second hormone, aldosterone, which increases sodium retention by the kidneys and further drives up blood pressure. Valsartan blocks the angiotensin receptor so angiotensin II has nowhere to land, resulting in no reaction cascade, no blood vessels constriction and ultimately blood pressure is lowered.

Sacubitril is a neprilysin inhibitor—it stops neprilysin. Neprilysin naturally breaks down natriuretic peptide, a hormone whose job is to get rid of sodium and dilate blood vessels. By inhibiting neprilysin, Sacubitril allows the hormone to reign free and blood pressure is lowered.

By combining an angiotensin II receptor inhibitor and a neprilysin inhibitor, LCZ696 drives drown blood pressure and decreases the rate of heart failure.

Easily Confused: Agonist vs. Antagonist

An agonist is a chemical that binds to a receptor and activates it to produce a biological response. An antagonist blocks the action of an agonist—in other words, it acts as an inhibitor. The three drugs featured in this WEEKLY, as well as with a majority of drugs currently on the market, are antagonists.

Want to bend your mind a bit further? An inverse agonist causes a biological response opposite to that of the agonist.