Barbara Hesselgrave

Use hand sanitizers, cover your mouth, wash your hands, wear a mask-the byword messages of public health agencies are upon us once again as temperatures drop. In an era of increasingly drug-resistant pathogens, widespread efforts to prevent the spread of infectious disease are laudable.

Nonetheless, providers who treat severe respiratory illness say it is particularly troublesome for older people whose bout with influenza often results in community-acquired bacterial pneumonia (CABP). Depending on the bacterial strain, resistance is widespread, making the infection a tough contender to cure at any age-but especially in older people. 

This season, however, providers will have a new and better choice for the treatment of CABP, a disease whose risk not only increases with age but is a significant burden of illness for about 5 million people in the U.S. each year. A study of claims data from nearly 2 million individuals 65 years and older enrolled in a Medicare Advantage Plan found that, in 2015, the CABP-related hospitalizations incurred medical costs in excess of $18,000 with an average length of stay of 5.6 days.

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In August, the FDA approved XENLETA (lefamulin, Nabriva Therapeutics plc), a new antibiotic that is forecast to have a significant impact on patients with CABP and is hailed as a significant breakthrough for the treatment of antibiotic-resistant disease. 

Nabriva’s chief commercial officer (CCO), Francesco Maria Lavino, PharmD, reports, “This is tremendously exciting as not only is XENLETA a new molecule, it is a new molecule in a brand-new class of IV and oral anti-infective drugs, and this has not happened in almost 20 years. And, it is also the first new-class antibiotic that has been approved in both oral and IV form which is very important because it gives physicians wider treatment options.”

XENLETA is available for oral (600 mg every 12 hours) and intravenous (150 mg every 12 hours) administration with a short 5-to-7 day course of therapy. 

He explains the unique mechanism of action of this novel molecule-lefamulin.

“The drug inhibits the bacterial protein synthesis by binding the 50S ribosomal subunits through multiple interactions, and it is in the way it binds to the ribosomal site that is different from any other antibiotic. This results in a low risk of developing resistance to XENLETA as well as a low risk of developing resistance to older antibiotic classes such as the beta-lactams, fluoroquinolone, macrolide, and tetracycline antibiotic classes.

“When you have multiple binding sites it becomes more difficult for the bacteria to mutate to prevent the antibiotic from working and at the same time, retain its fitness and ability to replicate. Overcoming drug resistance is a function of inhibiting bacteria that have created already-created mechanisms to resistance to other drugs. By inhibiting the bacteria with this type of interaction, which is the hallmark of this new molecule, we achieve both effective treatment outcomes and overcome propensity toward resistance at the same time.” 

 reported on the efficacy of lefamulin as the first semisynthetic pleuromutilin antibacterial for intravenous and oral treatment of community-acquired bacterial pneumonia. Results from the 2015-1016 SENTRY Antimicrobial Surveillance Program state that XENLETA (lefamulin injection, tablets) was highly active against the most common pathogens in pneumonia-including strains that are multidrug resistant. 

, professor of medicine, and chief, Division of Infectious Diseases at the University of Louisville underscores the need for a new class of antibiotics that fight resistance. 

“The bacteria that have caused CABP have remained the same, but each one of these bacteria have developed the capacity to fight against the antibiotics that we regularly use to treat pneumonia.”

He says the bacteria that cause pneumonia typically classified as either typical or atypical pathogens. 

“To treat these two groups of bacteria in hospitalized patients, sometimes we use two different classes of antibiotics. The advantage of XENLETA is that we can treat these two types of bacteria with a single antibiotic. Once patients are hospitalized with CABP, we can start IV XENLETA as a single antibiotic therapy; once patients improve, we can use the same antibiotic in an oral formulation and achieve an early hospital discharge.”

Ramirez says the launch of XENLETA is very important as it offers a new class of antibiotic with documented clinical efficacy in patients with CABP.

“This is a very common infection and is considered one of the primary infection-related causes of death in the U.S.,” he says.

Lavino underscores this importance for new options, saying the drug is “going to be an ideal choice for CABP patients and will give providers a well-tolerated and effective option, particularly considering that 30% to 60% of S. pneumoniae are reported to be macrolide resistant.”

From a clinical perspective, he says physicians can offer patients who show up to the ER an opportunity to initiate therapy with an oral medication and prevent hospitalization if their condition does not warrant admission.

“Even if they are admitted for a day or two, they can start on the IV XENLETA and then go home and continue on the oral therapy. Many times, physicians will admit patients, but they know that macrolide treatment has resistance and while the efficacy of broad-spectrum fluoroquinolones on CABP are excellent, there are many boxed warnings that often deter a physician’s use of this drug.” Lavino adds that this continuity of treatment-the same drug from hospital to home-is important. 

, vice chairman of Orlando Regional Medical Center Department of Emergency Medicine says he is “very excited to have XENLETA added to our pneumonia armamentarium.”

The drug, Giordano says, is particularly exciting because it plays into the trend of moving patients into outpatient management as much as possible. “Outpatient management reduces costs, increases patient satisfaction, and avoids exposing patients to nosocomial infections.”

“Currently, many patients with CABP are admitted to the hospital solely because of the lack of confidence in currently available oral agents. The introduction of a new antibiotic with potency, ease of use, and a safety profile that clinicians can be confident in will increase the opportunities for outpatient management,” Giordano says. 

, showed that in just five days of monotherapy XENLETA’s effectiveness for CABP is the same as seven days of moxifoxicin.

“Along with the appropriate spectrum of coverage for the right bugs, this is another important principle of stewardship, to treat in the shortest duration to be effective,” says Lavino. “So you can send more patients home and prevent hospitalizations and the costs incurred, as well as the stress and risk of that event upon the patient.” He adds that the current median length of a CABP-related hospital stay is three to four days and that direct costs of pneumonia is estimated to be approximately $17 billion in the U.S.

He reports that Nabriva “initiated a lot of pre-work to the launch by profiling the main accounts and the managed care team has been engaging payers to accelerate coverage. XENLETA is covered by Medicare for inpatient use and most commercial plans follow that lead since most hospitalizations are treated under a DRG single payment system and in the next few months we expect the majority of commercial plans to review and approve the drug.” 

The company says the wholesale acquisition (WAC) price is $205 per IV treatment day and $275 per oral patient treatment day.

However, adopting a new therapy often poses reimbursement challenges to the system and Giordano says, “Differences in the way hospitals add to their formularies can affect the adoption of a new intravenous drug. When an oral form is available in the case of XENLETA, adoption is not formulary dependent and can begin immediately by ED physicians, internists, and pulmonologists for their pneumonia or even suspected pneumonia patients.”

Contraindications include patients with known hypersensitivity to XENLETA or pleuromutilin and XENLETA tablets are contraindicated for use with CYP3A4 substrates that prolong the QT interval. Warnings and cautions state that the drug has the potential to prolong the QT interval and should not be used in patients with known QT prolongation, ventricular arrhythmias, or who are taking drugs that may prolong the QT interval. 

“CYP3A is a route of metabolizing the drug, and other drugs share that same metabolism,” Lavino explains. “So you can be taking an inducer which would render XENLETA less effective, or you could be taking an inhibitor, in which case you have more drug in the blood. The label is clear on warning against concomitant use of inducers or inhibitors of this metabolic pathway”

The FDA granted approval of both the oral and IV form of XENLETA via their Qualified Infectious Disease Product (QIDP) and Fast Track designations. The QIDP guidance is designed to encourage the development of new antibiotics to address the growing microbial resistance problems in treating disease.  

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The drug comes at a time when antibiotic resistance worries are high. Here’s why it matters.

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The science of modifying human DNA to correct defective genes has come a long way since the first studies in the late 1970s. More often these attempts were considered failures than successes.

However, the approval of viral vector-delivered Zolgensma (onasemnogene abeparvovec-xioi), for infants with spinal muscular atrophy (SMA), changed everything. It not only targets the defective motor neuron cells, but alters them permanently so they function properly. It is not a treatment, it is a cure, and a new benchmark in gene therapy. 

In May, Zolgensma, developed by Illinois-based AveXis, a Novartis company, was approved by the FDA for SMA. With a single one-time infusion therapy costing more than $2 million, it was labeled the most expensive treatment in the world. 

 offers some background that lead to the discovery of this unprecedented, life-saving therapy.

“We were studying gene therapy for decades under the assumption that, with the Human Genome Project, gene therapy would be right around the corner. But the reality was it took decades to figure out how to deliver the therapy safely and effectively, and get FDA approval.”

SMA is a disease that affects 1 in 6,000 to 10,000 live births. The most severe form, SMA 1, causes death usually before age 2, but some people with other forms of SMA live to adulthood and, in one form, do not show symptoms until after early childhood. It is caused by a genetic defect in the SMN1 gene that codes for the protein necessary for survival of motor neurons. In its most severe form, SMA Type 1, there is rapid motor neuron loss, muscle degeneration, and a need for permanent ventilation support in the child. Zolgensma is basically the functional gene needed to replace the defective one, Lennon says.

“Delivery is a one-time intravenous infusion, given over an hour. It’s pretty straightforward and uneventful. But you have to get this to patients as soon as they are diagnosed, as loss of motor neurons is permanent.”

The life-saving effects of Zolgensma are there, but its price of $2.125 million has added to the media attention and debate about drug pricing for this new gene therapy. 

, RPh, MBA, CEO of NCPA, sees Zolgensma as a call to action for pharmacists.

“First of all, this drug deserves a big hoorah; thank goodness it exists, and thanks to the scientists that led us to figuring out this technology and process to cure this terrible disease. That is the top line,” he says. 

“Second, is how we pay for it. When gene therapy becomes mainstream, which I believe it will, then those costs will be absorbed by a wider population. Then there will be less individual expense associated with a respective disease as costs are spread out and borne by employers and insurance companies.”

Hooey adds that the payer world will need to catch up with these breakthrough therapies.

“They’re used to reimbursement models of chronic, ongoing care, often for the life of the patient. Now, we are looking at a very near future where a high-cost one-time treatment like this drug potentially eliminates or vastly reduces those lifetime costs.”

The dialogue about Zolgensma’s price harkens back to an earlier, similar scenario.

, recalls when AZT was launched in 1987. Keville, co-founder of the 1995 AIDS Drug Assistance Program (ADAP) Working Group, explains: “This was the first and only treatment for HIV/AIDS at the-then outrageously steep price tag of $15,000. At that time, no one had ever challenged the market, and it took unheard of collaboration with the manufacturer, AIDS activists, and policy makers to create the ADAP program for patient access and drug reimbursement,” she says. 

“But we did it, and it wasn’t long before newer and better drugs were approved and a new payer system, ADAP, was in place. Today, reimbursement programs are commonplace, but we were the first to lay that groundwork.”

, agrees. “The entry of a million-dollar therapy can act as a stressor to the system and will spark a variety of innovations. Wright is the former chief medical officer of Advance PCS/Caremark, 

“The stakes are much higher as the investment of time and money to achieve these discoveries is high risk, but the innovations won’t stay isolated to million-dollar drugs, and as more discoveries enter the market prices will be lowered.” 

In rare diseases like SMA, Wright points out that a one-time high-cost treatment such as Zolgensma, in effect, eliminates the millions of dollars that would otherwise be spent on chronic therapy. “Which in the case of this disease, could be in excess of  $4 million in just the first decade of the child’s life.” 

AveXis is partnering with both government and commercial payers to accelerate decisions on how Zolgensma will be covered, Lennon adds. 

“We have established outcomes-based agreements with payers because we believe in the long-term value of Zolgensma and are willing to stand behind the therapy.”

One of those partners is the Massachusetts-based Harvard Pilgrim Health Care. 

, and chief medical officer of the healh plan, says that Pilgrim’s outcomes-based agreement with AveXis “helps ensure that we balance access and affordability for our members.” 

While there would be only a small number of newly-diagnosed patients with the rarer SMA Type 1 disease each year, Sherman adds, “We believe it is our responsibility to provide access to this lifesaving treatment.”

The real-time patient monitoring of a million-dollar drug is essential, says Wright. “Because it really matters that outcome goals are met; payers will be following this very closely.”

Addressing the high price of treatment, Lennon concurs, “In terms of cost, this is cost versus pricing. One question is, ‘what does it take to manufacture this product versus the pricing, which is driven by value?’ In this case, a very severe disease, patients will die if not treated, and the supportive care will be many millions to just stay alive. To produce this live-engineered virus is a huge production process to make enough to treat just one person, let alone hundreds or potentially thousands around the world.” 

In partnership with specialty pharmacy Accredo, AveXis is also offering a pay-over-time option of up to five years to help ease short-term budget constraints especially for states, small payers, and self-insured employers. There have now been instances where families have turned to their local communities for financial help. One group in Florida raised $2.2 million for a little girl in a few days.

To help patient families navigate Zolgensma treatment, AveXis has implemented a patient support program called OneGene. This program provides each patient family with a personalized and dedicated support team in matters of reimbursement assistance; coordinates financial assistance for eligible patients; and helps patients, caregivers and healthcare professionals with any Zolgensma needs and questions. 

In the meantime, NCPA’s Hoey says pharmacists must become much more familiar with pharmacogenomics. 

“They need to learn more about these specialty drugs; they are not mainstream now, but I foresee the day, not too far in the future, when they will be.” 

Because Zolgensma delivery will be handled by specialty pharmacy Accredo, “the likelihood of community pharmacists seeing this is very small, but it is a precedent, and I see this as a harbinger of things to come,” Hooey says.