Timothy O'Shea, PharmD

On May 24, 2019, the FDA approved onasemnogene abeparvovec-xioi (Zolgensma), the first gene therapy indicated for children with spinal muscular atrophy (SMA), a rare genetic disease that affects the motor nerve cells in the spinal cord.

 With its approval, Zolgensma became the most expensive drug in the world, priced at more than $2 million per patient.

Here are several key therapeutic areas with Zolgensma that every pharmacist should know: 

Zolgensma is indicated for the treatment of pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (

The safety and efficacy of repeat administration of Zolgensma have not been evaluated. Additionally, the use of Zolgensma in patients with advanced SMA (eg, complete paralysis of limbs, permanent ventilator dependence) has not been evaluated.

Zolgensma is only approved for SMA type 1. The safety and efficacy for SMA types 2-4 have not been evaluated.

Zolgensma is a recombinant AAV9-based gene therapy that is designed to deliver a copy of the gene that encodes the human SMN protein. The SMA disease is caused by a bi-allelic mutation in the 

 gene, which results in insufficient SMN protein expression; therefore, Zolgensma functions to ultimately replace the missing SMN protein.

Zolgensma will primarily be administered in the hospital outpatient setting. Unlike other gene therapy products currently on the market, Zolgensma will not be restricted to certain hospital sites. Despite this, it is expected that there will be a limited number of hospitals that will be administering soon after product launch, with a number of hospitals working on protocols to provide the drug in the future.

The manufacturer has partnered with 2 specialty pharmacies, Accredo and Orsini Pharmaceutical Services, to dispense Zolgensma. Accredo is reportedly offering a pay-over-time option to allow payers to defer the $2 million dollar cost over a 5-year period.

The recommended dose of Zolgensma is 1.1 × 10

vector genomes per kilogram of body weight. There are 22 kits commercially available that contain 1 or more 5.5 mL vials and/or 8.3 mL vials.

It is given as a 1-time, 60-minute infusion. Clinical study data suggest that administering Zolgensma as soon as possible following diagnosis may result in improved outcomes versus delaying treatment.

The efficacy of Zolgensma was assessed in 2 clinical trials. All patients experienced onset of clinical symptoms consistent with SMA before 6 months of age and had a confirmed diagnosis. Efficacy was established on the basis of survival, achievement of developmental motor milestones, and scores on CHOP-INTEND, which is an assessment of motor skills in patients with infantile-onset SMA. Survival was defined as time from birth to either death or permanent ventilation.

The first study was an open-label, single-arm clinical trial that enrolled 21 patients with infantile-onset SMA. The mean age at the time of treatment was 3.9 months.

As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (ie, event-free survival) and were continuing in the trial, 1 patient died at age 7.8 months due to disease progression, and another patient withdrew from the study. Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support and only approximately 25% of these patients would be expected to survive beyond 14 months of age.

The open-label, single-arm, ascending-dose clinical trial enrolled 15 patients with infantile-onset SMA, 3 in a low-dose cohort, and 12 in a high-dose cohort. By 24 months post Zolgensma infusion, 1 patient in the low-dose cohort met the endpoint of permanent ventilation and all 12 patients in the high-dose cohort were alive without permanent ventilation.

The most common adverse reactions of Zolgensma reported in clinical trials were elevated

aminotransferases and vomiting. The drug has a boxed warning for acute serious liver injury.

In clinical studies, there were 2 reported patient deaths. The first patient died from respiratory failure; however, an investigation found it was unrelated to the gene therapy. The second death was deemed possibly related to treatment by the investigator.

Zolgensma is given as a 1-time infusion listed at $2.125 million.

The only other product available for SMA is nusinersen (Spinraza), which was approved in December 2016 to treat SMA in pediatric and adult patients. It is administered intrathecally via 4 year 1 doses and then every 4 months thereafter. Spinraza costs $750,000 for year 1 and approximately $375,000 per year thereafter.

In April 2019, the Institute for Clinical and Economic Review (ICER) released a report assessing the comparative clinical efficacy and value of Spinraza and Zolgensma. They acknowledged that both products dramatically improve the lives of children with SMA. They voted unanimously that Spinraza is priced in such a way that it represents a low long-term value for money.

For Zolgensma, ICER concluded that to reach thresholds of $100,000 to $150,000 per life year gained, a value-based price benchmark for Zolgensma would range from $1.2 million to $2.1 million.

Zolgensma appears to be efficacious as a 1-time gene therapy for SMA. Upon its approval, Zolgensma became the 

 to be approved by the FDA and the first for SMA.

Although most pharmacists will never encounter Zolgensma due to the limited number of sites that will be administering the treatment and the overall low incidence of SMA (estimated that only 700 patients would eligible for Zolgensma treatment in the United States), it is important for pharmacists to keep up-to-date on gene therapy because it represents a paradigm shift from chronic, life-long treatment to treatment in as little as a single dose. Additionally, the pipeline is full of gene therapies for a variety of diseases, including hemophilia, Fabry disease, Huntington disease, sickle cell disease, and various types of cancer.

		Zolgensma [prescribing Information]. AveXis. Bannockburn, IL. May 2019

		AveXis Announces Innovative Zolgensma® Gene Therapy Access Programs for US Payers and Families. Novartis. May 24 2019. Available at: https://www.novartis.com/news/media-releases/avexis-announces-innovative-zolgensma-gene-therapy-access-programs-us-payers-and-familiesrapy-access-programs-us-payers-and-families

		Spinraza [prescribing Information]. Biogen. Cambridge, MA. October 2018. 

		Spinraza and Zolgensma for Spinal Muscular Atrophy: Effectiveness and Value. ICER. Updated May 24, 2019. Available at: https://icer-review.org/wp-content/uploads/2018/07/ICER_SMA_Final_Evidence_Report_052419.pdf.

Articles

Zolgensma is the first gene therapy indicated for the treatment of children with spinal muscular atrophy.

Clinical Insights: Zolgensma for Spinal Muscular Atrophy

 (HIV) is a viral infection that weakens the immune system by destroying white blood cells.

An estimated 1.1 million adolescents and adults were living with HIV by the end of 2015, yet about 15% of them had not yet received a diagnosis, according to the CDC.

Although the widespread availability of HIV medication has decreased the complications and progression of the disease, adverse effects, drug interactions with concomitant medications, and medication non-adherence remain concerns in achieving optimal outcomes.

In November 2017, the FDA approved Juluca, a fixed-dose tablet containing 2 previously approved drugs (dolutegravir and rilpivirine) to treat adults with HIV type 1 (HIV-1) infections whose virus is suppressed on a stable regimen for at least 6 months, with no history of treatment failure and no known substitutions associated with resistance to the individual components. With its approval, Juluca became the first complete treatment regimen containing just 2 drugs to treat certain adults with HIV-1.

Here are several key therapeutic areas with Juluca that every pharmacist should know: 

Julica is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the antiretroviral (ART) regimen in those who are virologically suppressed (defined as an HIV-1 RNA less than 50 copies/mL) on a stable ART regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Juluca.

Notably, Juluca is not indicated as initial treatment for treatment-naïve individuals with HIV-1.

The effectiveness and safety of Juluca in pediatric patients have not been established. Additionally, because of the potential for HIV-1 transmission, mothers should not breastfeed if they are receiving Juluca.

Dolutegravir is an integrase inhibitor that works by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration, which is essential for the HIV replication cycle.

Rilpivirine is an NNRTI of HIV-1 and inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase.

Juluca is formulated as a fixed-dose tablet containing 50 mg of dolutegravir, equivalent to 52.6 mg dolutegravir sodium, and 25 mg of rilpivirine, equivalent to 27.5 mg rilpivirine hydrochloride. Each bottle contains 30 tablets. Notably, Juluca is the smallest single-pill HIV-1 treatment available on the market.

Juluca should be stored and dispensed in the original package, while being protected from moisture. Do not remove the dessicant. Store at room temperature (68°F to 77°F).

The recommended dose of Juluca is 1 tablet taken orally once daily with a meal. If Juluca is co-administered with rifabutin, patients should take an additional 25-mg tablet of rilpivirine once daily with a meal for the duration of the rifabutin co-administration.

The efficacy of Juluca was assessed in 2 open-label, controlled trials [SWORD-1 and SWORD-2) in virologically suppressed patients switching from their ART regimen to Juluca.

Both studies were identical, 148-week, phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1024 adult HIV—1-infected subjects who were on a stable suppressive ART regimen containing 2 NRTIs, plus either an INSTI, a n

on-nucleoside reverse-transcriptase inhibitors

 or a protease inhibitor for at least 6 months, defined as HIV-1 RNA < 50 copies/mL, with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine were included in the analysis.

Subjects were randomized in a 1:1 ratio to continue their ART regimen or be switched to Juluca once daily. The primary endpoint was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at week 48. At baseline, the median age of subjects was 43 years (range 21-79), 22% female, 20% non-white, and 11% had CD4+ cell count < 350 cells/mm3.

Pooled study results showed no significant difference in the primary endpoint between each treatment group (95% in both). Treatment differences were maintained across baseline characteristics, including, age, baseline third-treatment-agent class, CD4+ cell count, gender, and race.

The most common adverse reactions of Juluca reported in clinical trials were diarrhea and headaches. Patients should be monitored for signs and symptoms of depressive disorders, hepatotoxicity, and severe hypersensitivity or skin reactions.

Drugs that induce or inhibit CYP3A4 or UGT1A1 may affect the plasma concentrations of the components of Juluca. Therefore, concomitant use is contraindicated with carbamazepine, dexamethasone, oxcarbazepine, phenobarbital, phenytoin, rifampicin, and St John's-wort. Additionally, use with proton pump inhibitors should be avoided, because increased gastric pH may lead to significant decreases in rilpivirine plasma concentrations and therefore loss of virologic response.

				Not for treatment naïve patients; switch adult patients only

				Indicated in adult and pediatric patients 12 years and older

This article highlights several key therapeutics areas with the prescription medication. 

Juluca for HIV: What Pharmacists Should Know

 previously about the pros and cons of refinancing student loans, but I think a couple points are worth repeating with thousands of pharmacy students graduating across the country this month. Additionally, this is a hot topic with interest rates starting to slowly increase

 from rates that have been at 10-year lows

and with the average pharmacy student graduating with nearly $160,000 in student loan debt.

All of this means if you’re like most pharmacy graduates with a significant amount of student loans, it’s time to seriously consider whether refinancing is right for you.

When talking to people about managing their student loans I find there is often confusion about the difference between consolidation and refinancing, so let’s take a closer look between the two terms.

This involves combining multiple loans into one giant loan. In general, consolidation can be subdivided into federal and private loan consolidation. 

Federal loan consolidation is a government program allowing you to combine multiple federal loans into one single loan. The interest rate on your new loan becomes a weighted average of the prior loan rates. Therefore, this process won’t end up saving you money or change your monthly payment (

assuming you don’t extend the repayment period

). The major benefit is convenience, as you will end up with fewer bills to pay and keep track of each month.

Private loan consolidation also allows you to combine multiple loans into one. The major difference is the interest rate on the new consolidated loan isn’t a weighted average based on your old loans, but rather calculated based on a number of different factors. In practical terms, when you consolidate student loans with a private lender, you’re also refinancing them.

This means you use a new loan to pay off one or more existing loans. Again, this process results in a new interest rate on the consolidated loan. The specific interest rate is based on your credit history, salary, total amount owed, and a number of other factors.

This can result in benefits including lowered monthly payments, paying off loans quicker, saving money on interest, and the convenience of paying only one monthly bill. Some private lenders will only refinance private loans, whereas others will refinance both private 

 federal student loans for additional convenience and cost savings. Additionally, if no co-signer is needed on the new refinanced loan, then parents can be removed if they had originally cosigned. Refinancing can be especially valuable for new graduates with interest rates on loans over 8-9%.

On the flip side, refinancing your private and federal loans together means giving up favorable repayment terms like IBR plans and public service loan forgiveness. Although these may not be commonly used repayment options for the majority of pharmacists, you should consider all your options before refinancing.

 extensively detailing my personal experience refinancing my student loans from pharmacy school. Essentially, once you decide that you may benefit from refinancing it’s time find some vendors to compare your options. There are a number of different banks and institutions available through a quick Google search. Getting a refinanced interest rate is easy and doesn’t require more than filling out a few forms.

, as I found them to offer the best resources, repayment plans, and interest rates. There are certainly other options to consider but again I can only speak to my personal experience.

In 2015, I graduated with over $150,000 in student loans from pharmacy school. At the time, it felt like an insurmountable amount of money to pay back, especially considering I took a substantial pay cut to complete a 1-year residency after graduating. The monthly payments were extremely high and to make matters more confusing, I had multiple loan providers between my private and federal loans, with some in my name and some in my parent’s name. The interest rates on these loans varied from 6.5% to 8%.

After finishing my residency, I knew I had to take a close look at my financial situation and make a plan to aggressively start paying off these loans. After extensive research, I decided to refinance my student loans through SoFi, an institution that offers a number of different loan types through a “nontraditional” approach.

While there are a number of vendors to refinance student loans, again I found SoFi to offer the best interest rates and resources. In particular, SoFI charges no fees to refinance, no penalties to make additional payments, and a variety of loan terms and rates. Refinancing through SoFI will save me over $15,000 in cumulative payments over a 10-year term by lowering my interest rate to 5%. It also provided the additional benefit of removing my parents from my loans. I personally did not need a co-signer on my loan due to my pharmacist salary and credit score, although this may vary based on your situation.

Refinancing your student loans from pharmacy school can potentially save you a significant amount of money while providing the convenience of making one payment a month. Keep in mind refinancing may not be for everyone. Individuals with a poor credit history, low salary from a pharmacy residency or fellowship, or those who want to keep the provisions in federal loans may want to closely consider their options before jumping right into refinancing their loans.

		Carrns A. Warning: Federal Student Loan Rates Are About to Rise. 

https://www.nytimes.com/2017/05/12/your-money/stafford-student-loan-rates.html

		Dickler J. Student loan interest rates edge higher and higher. 

https://www.cnbc.com/2017/07/18/student-loan-interest-rates-edge-higher-and-higher.html

		Carter M. What the fed's interest rate hikes mean for student loan borrowers April 24 2018. Available at: 

https://www.credible.com/blog/refinance-student-loans/feds-interest-rate-hike-means-student-loan-borrowers/

		Cooper P. Most Student Loan Interest Rates Fall To Ten-Year Lows. 

https://www.forbes.com/sites/prestoncooper2/2016/05/11/most-student-loan-interest-rates-fall-to-ten-year-lows/#4f15d288602b

		Macklin D. Student Loan Options: What is Refinancing vs Consolidation. 

. July 26 2016. Available at: https://www.sofi.com/blog/student-loan-smarts-consolidation-vs-refinancing-2/

If you’re like most pharmacy graduates with a significant amount of student loans, it’s time to seriously consider whether refinancing is right for you.

Now Is the Time to Refinance Student Loans

This article is the sixth part of a series on memorable pharmacists in television history. For part 5, 

Pharmacists are generally considered some of the most trusted and highly regarded professionals. In a 2016 Gallup poll, pharmacists were ranked the No. 2 most trusted professionals by American respondents, just below nurses, with 67% rating the honesty and ethical standards of pharmacists 'high' or 'very high.'

Despite this, pharmacists are often portrayed in movies and television in a negative light. In 2015, researchers conducted a study to determine whether pharmacist characters were depicted in a positive, negative, or neutral manner in films and TV shows available in the United States between 1970 and 2013. Their data found that of the 231 pharmacist portrayals identified, 145 (63%) were negative, 56 (24%) were neutral, and 30 (13%) were positive. Additionally, very few pharmacist characters were recurring ones on TV.

Here is a look at 6 more of the most memorable TV characters who are pharmacists:

Selina Cadell plays pharmacist Sally Tishell in the British medical comedy series 

. She appears in 41 of the series 62 episodes, which aired from 2004 to 2017.

Sally is the only pharmacist in the village of Portwenn, where the show takes place. She is a highly independent woman, as her husband Clive works on an oil rig at sea and is rarely home. Sally is also a big supporter of Dr. Martin Ellingham, the show’s main character, trying to impress him whenever possible, and finding herself falling in love with him throughout the series. Viewers of the show would describe Sally as a successful business woman, however she also is eccentric, and sometimes portrayed in a negative light.

For example, in season 5, episode 8, Sally rebukes her husband when he comes home, and suggests they both retire to spend more time together. Sally offers to watch Martin’s son James for the day, which he accepts. Under a cocktail of self-prescribed drugs, including paroxetine and modafinil, Sally mistakes a young couple coming into the pharmacy as a secret message from Martin, and then dispenses the wrong eye drop prescription to a local police officer, causing him to crash his car. Sally subsequently mistakes James as her own child, and takes him to a nearby home. Martin chases after her and pretends to profess his love for Sally to get his child back. It’s later explained that Sally experienced a psychotic episode due to excessive doses of prescription drugs.

Thanks to twitter user @mm_raymond for this suggestion.

 is a comedy series that details the lives of pharmacists, interns, and technicians as they fill prescriptions for customers at Gateway Drug and Surgical. The series aired its pilot November 2017 on Amazon.

The first episode introduces the staff of the pharmacy including Joe, a pharmacy technician who narrates part of the episode; the pill-popping, and ornery pharmacy owner Rich; his daughter and pharmacist Lisa; and pharmacy intern Doug. Throughout the episode, a number of angry, uneducated, and overreacting customers come into the pharmacy to complain about a variety of issues. Joe also interviews several people to replace him as pharmacy technician.

The show, unfortunately, falls into the Hollywood stereotype of displaying pharmacists as being inept and terrible at their jobs. For example, it’s revealed Lisa has been working unlicensed after failing her boards for 3 years, an obviously unrealistic, and problematic situation. Additionally, 2 of the technicians interviewed were awful, and unrealistic candidates.

Retail pharmacy can certainly be crazy, but this show doesn’t accurately represent the day to day in any sense. Granted, only 1 episode has aired, but it’s not off to a particularly good start.

There are several memorable pharmacist interactions in Larry David's comedy series 

which aired for 9 seasons, and was nominated for 38 Primetime Emmy Awards.

In season 5 episode 4, Larry enters Cal Oaks Pharmacy to pick up his father’s blood thinner prescription. After a brief hesitation, the pharmacist explains that there’s another drug on the market that he likes a lot better, and that his patients are much happier taking. The pharmacist offers to write down the name of the medication for Larry to bring to his doctor.

Larry subsequently debates the merits of the doctor versus pharmacist’s recommendation. Eventually, Larry leans on the side of the pharmacist, and states that he is going to request the other medication from the doctor. It’s a funny moment, although it could be argued whether or not the pharmacist was acting within his scope of practice to recommend a different medication, especially when he had little to no medical history of the patient. It’s also curious exactly what medication the pharmacist was recommending as the first novel oral anticoagulant wasn’t introduced until 5 years after the episode aired.

Larry: “But the doctor prefers this one.”

Pharmacist: “Yes, but I prefer the other one.”

Larry: “Doctor, pharmacist. Doctor! Pharmacist! I'll go with the pharmacist.”

was an American sitcom series that aired 202 episodes from 1976 to 1985. It features a woman named Alice who attempts to move with her son to Hollywood, in hopes of becoming a singer, after her husband dies in a trucking accident. Instead, their car breaks down in Phoenix, where she works at a local diner.

In the series, there is 1 notable pharmacist interaction in season 2, episode 14 titled 'The Pharmacist.' During the episode a young man named Howard Gillepsie walks into the diner looking for change to make a phone call. Howard is a pharmacist at Canyon Drugstore, and appears to be having a mental breakdown, after his wife left him and his dog died. He decides to place a phone call to President Jimmy Carter to air his grievances against food additives, which he believes are poison and an attempt at genocide of the American public.

After being unable to reach the President, Howard shows the diner staff that he has a cyanide pill, and threatens to swallow the pill unless the President calls him back. Initially, the diner staff tries to distract, and stall Howard. Flo, one of the show’s main characters, attempts unsuccessfully to seduce Howard while Alice, the main character, ultimately talks Howard out of killing himself, and instead encourages him to fight for his beliefs in more productive ways. After Howard leaves the diner, Alice gets a call back from Washington DC, where she relays Howard’s concerns to the Secretary of Health Education and Welfare.

Jesse Sturgis is third pharmacist to make the list from the long running series 

Jesse makes an appearance in season 14, episode 11, when she is arrested for allegedly killing her boyfriend, Tommy.

Several months prior, Jesse had been raped by a man she was seeing on the side named Michael Provo, after she found out he had a family, and wanted to break up their relationship. After assaulting Jesse, Provo told her that he was a cop, and that she would regret pressing charges. When Detectives Olivia and Nick questioned Jesse, she was scared to say who raped her, and instead made up a different story before eventually revealing the truth about Provo.

The Detectives track the owner of the gun used in the murder who initially says Jesse approached him to purchase a gun as her pharmacy was recently robbed and needed protection. Pressed further, the gun owner reveals that Provo was actually the one who purchased the gun, to frame Jesse.

After investigating the case further, the detectives learn that Tommy’s death was a conspiracy to get Jesse arrested for murder, so Provo would not be prosecuted for her rape.

 was an American comedy/medical crime series featuring Dick Van Dyke as Dr. Mark Sloan, a medical doctor who solves crimes with the help of his son Steve, a homicide detective.

The storyline in season 2, episode 11 features the search for the person who murdered the realtor of Dora, Mark’s sister. During their investigation, Mark and Steve learn that the man had high levels of cyanide and phenobarbital in his system, which initially leads them to suspect his secretary may have spiked his coffee at work. After clearing the secretary, the investigation leads them to a young pharmacist named Larry Maclan, who had previously assaulted the realtor after having lost a large amount of money from a bad business deal.

Mark and Steve ultimately discover that although Maclan was not the murderer, he did supply a coworker of the realtor with phenobarbital, which he believed she was using to help relax, but instead used to kill the realtor. Maclan confesses his role after having lost his pharmacist license, but not wanting to spend life in prison.

What TV pharmacists are missing from the list? Tweet them to me at @toshea125.

Yanicak A, Mohorn PL, Monterroyo P, Furgiuele G, Waddington L, Bookstaver PB. Public perception of pharmacists: film and television portrayals from 1970 to 2013. 

 2015;55(6):578-86. doi: 10.1331/JAPhA.2015.15028.

The Internet Movie Database. imdb.com. Accessed April 8, 2018.

This is the sixth part of a series on how pharmacy professionals have been depicted on TV, both in a positive and a negative manner.