By Mary Carpenter
ABOUT one-quarter of new medications approved in recent years are “biologics” — large, complex molecules made from living cells — of which a recent entry is Regeneron’s monoclonal antibody treatment for Covid. Also for Covid, last week Merck submitted an application to the FDA for its new antiviral, the “small-molecule” – i.e., traditional — drug molnupiravir.
The Regeneron drug (REGN-COV2) highlights issues surrounding most biologics that have emerged since the first one, “human insulin”—developed using recombinant DNA in the early 1980s: higher effectiveness along with much higher price tags. For insulin, the average list price increased 11% annually from 2001 to 2018, with average annual per person insulin costs now approaching $6,000.
Among other recently approved biologics, two (Praluent and Repatha) have dramatically lowered LDL cholesterol—and the corresponding risk of heart attack and stroke—in patients for whom statins proved insufficient. And Aduhelm (aducanumab) may help with the treatment of early-stage Alzheimer’s disease. Most biologics require administration by injection or infusion “because they are proteins that are quickly digested and inactivated if given by mouth,” according to Medicine Net.
Biologics provide “precision” or “personalized” therapy because they target a single step in the inflammatory process— a specific antibody, molecule or cell — and thus can avoid unwanted side effects of more broadly acting medications. On the other hand, some side effects of biologics include higher risk of common infections—upper respiratory, urinary tract and skin infections —as well as of non-melanoma (basal and squamous cell) skin cancers.
Most candidates for biologics are people with moderate to severe forms of certain, usually chronic diseases, who have been insufficiently responsive to standard or traditional drugs. These diseases, such as, asthma; many autoimmune diseases such as rheumatoid arthritis, psoriasis, Crohn’s disease and ulcerative colitis, and multiple sclerosis; and cancer, can be difficult to treat because they present differently in each patient.
In “allergic asthma”— afflicting about 70% of asthma patients —inflammation occurs when inhaled allergens and pollutants interact with cells in the airway, leading to activation of several components of the immune system that can differ for each individual.
For the 5% of these asthma patients with uncontrolled, severe disease, the most commonly prescribed biologic is omalizumab, which targets the allergy antibodies known as IgE. Asthma specialist Michael Wechsler at National Jewish Health in Denver told the New York Times: “Everyone’s asthma is a little different, with different underlying mechanisms…It is now considered a syndrome with many different characteristics.”
All five biologics currently approved for treating asthma are cocktails of monoclonal antibodies —biologics distinguishable by the suffix “-mab” at the end of the generic names. The other two categories of biologics are non-MAB products and vaccines. The worldwide bestselling biologic —and one of the best-selling drugs regardless of category —is Humira (adalimumab), used to treat the inflammation that wreaks havoc in autoimmune diseases, including rheumatoid arthritis, Crohn’s disease, ulcerative colitis and several kinds of psoriasis. Humira cannot reduce the overproduction of TNF (tumor necrosis factor) that causes inflammation, but instead binds to and blocks the action of TNF in the cells.
Humira is also a leader in high price tags for biologics—costing more than $50,000/year, with some staying on the medication for years but others able to stop after several months. Insurance covers anywhere from as low as 10% to 99% of these specialty drugs. A “biosimilar” —like generics for drugs, but for biologics —expected in the next few years could topple Humira from the top, as could a new biologic called Keytruda, used for treating many kinds of cancer.
Biologics account for only 2% of all prescriptions written in the U.S. but are responsible for 37% of drug spending. Although biosimilars have been approved for many biologics, their market penetration is poor in the U.S.—compared to Europe — because of messaging from drug companies and affiliated groups that it is “potentially dangerous to switch patients [to biosimilars],” writes Joel Lexchin, community medicine physician at the University of Toronto, on Jama Network.
For Covid, a good alternative to the Regeneron biologic is the new antiviral from Merck—because the drug, molupiravir, is taken by pill versus the hour-long infusion of Regeneron, which is cumbersome for physicians’ offices. Also, molnupiravir could cost the government about one-third as much as the biologic —about $700 vs. over $2,000. In trials, the antiviral was less effective than Regeneron but still reduced by half the risk of hospitalization or death from Covid.
The best description for molnupiravir is “high risk, high reward,” writes Derek Lowe in Science. Like the other antiviral drugs on the market—used to treat HIV and Hepatitis C — the Merck formulation interrupts replication in the body’s cells that is critical for RNA viruses in order to reproduce and cause infection.
On the other hand, antivirals risk altering the body’s DNA, although Merck has said its drug is not capable of inducing genetic changes in human cells; and it can be cytotoxic, causing damage to cells in the liver, kidneys and other organs. Current authorization for molnupiravir would cover only “high-risk adults”—those over 60 or younger people with underlying conditions; and fully-vaccinated individuals may also be ineligible because they were not included in the clinical trial.
Like all current medications for treating Covid, molnupiravir has a limited timespan for administration–within the first five days after the onset of symptoms, which can be a problem because of difficulties getting tested for Covid. The Regeneron drug must be given within ten days of diagnosis; and the earlier antiviral drug remdesivir, requiring I.V. administration, is approved only for Covid patients already in the hospital.
Despite the drawbacks, mostly of high cost, biologics are making enormous contributions. There is new vocabulary: first, the updated group name for medications — to include both drugs and biologics, both small and large molecules —is “new molecular entities” (NMEs); and, “antisense” refers to strategies of biologics, which block the communication between cells resulting in production of unwanted proteins.
But the greatest contribution of biologic medications may be hope for anyone confronting diseases, both chronic and deadly, that have no better alternative for treatment. While Covid and cancer are scary, other diseases in their severe and intractable forms have presaged a lifetime of misery—before the advent of biologics to offer new hope.
—Mary Carpenter regularly reports on topical subjects in health and medicine.