Winter 2021 Edition - Ready or not, gene therapy is here

Ready or not, gene therapy is here

In the summer of 2019, Green Shield Canada (GSC) first started telling you about gene therapies and how these treatments are considered a game changer in terms of both value offered and dollars spent. You can read about it in The Inside Story^® or listen to episode 17 of our podcast. And keep in mind that gene therapies are just one example of ultra-high-cost treatments that are starting to emerge from the drug pipeline.

What is gene therapy?

To review, gene therapy aims to treat – and ideally cure – a disease by changing the patient’s genetic makeup instead of using drugs or surgery. This could involve:

• Replacing genes that are causing disease,
• Inactivating genes that aren’t functioning properly, or
• Introducing new or modified genes to help treat a disease.¹

There are two types of gene therapies: in vivo (inside the body) and ex vivo (outside the body). In vivo gene therapy involves direct delivery of functional genes into a patient’s target organ. Ex vivo gene therapy, on the other hand, involves removing cells from a patient’s body and then modifying them with genetic material in a culture. The gene modified cells are then reintroduced back into the patient.

Learning from the hepatitis C experience

In some ways, the advent of gene therapy is similar to the medical and financial impact of hepatitis C drugs several years ago. Like the hepatitis C drugs, gene therapy offers the promise of a cure, and if the cost of hepatitis C drugs raised eyebrows back in 2015, the cost of gene therapy is truly astonishing – up to millions of dollars per treatment – meaning gene therapies will end up having a comparable impact on health benefit plans.

One of the reasons for the high cost of gene therapies is that currently a main focus is helping patients with diseases where no treatment options exist. Some also aim to help patients who have tried all available treatments and where, without intervention, the prognosis is disability or death. For example, gene therapies have targeted rare or inherited disorders (a.k.a. orphan diseases) and advanced-stage cancers. In addition, gene therapies are also focusing on patients with conditions that require intensive and ongoing maintenance treatment.

With the ideal being a curative one-time treatment, gene therapies have the potential to deliver lifelong benefits to many with an otherwise dire prognosis. With traditional treatments, patients may have to rely on them for years, if not for the rest of their lives, often with difficult to handle administration and side-effects. Gene therapies, even with their eye-popping price tags, can potentially generate savings in the long run – similar to how a kidney transplant costs hundreds of thousands of dollars less than years of dialysis.

Currently approved gene therapies

Kymriah and Yescarta are two ex vivo gene therapies that are approved by Health Canada; they are chimeric antigen receptor T-cell (CAR-T) therapies and both are used in the treatment of cancer. However, while Kymriah was approved in September 2018 and Yescarta in February 2019, it’s only recently that they’ve been accessible for patients. Due to the complexity of delivery, among other factors, it is not surprising that the process of getting the first two gene therapies to market was a lengthy one. First the patient’s cells are sent to a laboratory, located out of the country, where they are modified; then the modified cells are returned and infused back into the patient. As well, the treatment sites of the organizations administering the procedure require certification by the Foundation for the Accreditation of Cellular Therapy.

Kymriah became available in Quebec in October 2019² (11 months after Health Canada’s approval) and in Ontario as of December 2019³ (15 months after approval). Yescarta is available as of December 2020 but only in Ontario⁴ so far. Alberta announced in August 2020 that it would be the third province to offer CAR-T therapy with cells manufactured in the United States.⁵ Alberta Health is funding a clinical trial using cells manufactured in Alberta as a step toward implementing its own gene therapy program.

The first-ever gene replacement (in vivo) therapy, Luxturna, was approved by Health Canada on October 13, 2020, and a second one, Zolgensma, was approved on December 15, 2020. Luxturna treats certain retinal diseases, and Zolgensma is a treatment for spinal muscular atrophy. While we may also see a delay from the time of approval to patient access for Luxturna and Zolgensma, we expect the delay to be significantly shorter than that seen for CAR-T therapies. GSC’s pharmacy team is currently going through the clinical review process for both drugs, and we expect to have a listing recommendation in Q1 2021. The per patient treatment cost (list price) for Luxturna is $1 million for treatment in both eyes and $2.9 million for Zolgensma. Given the rarity of the conditions for which these drugs are used, we have estimated that benefit plans can expect to receive two claims per 1,000,000 lives covered for Luxturna and one claim per 1,000,000 lives covered for Zolgensma in year one.

The coverage and affordability dilemma

GSC is currently developing a strategy to ensure these life-changing but ultra-high-cost drugs can be made accessible to patients, while ensuring benefit plans remain sustainable. As we saw with hepatitis C drugs, the huge cost of the drug is outweighed by the expected lifelong benefit, although with gene therapy the cost-benefit stakes are of a much larger degree of magnitude due to a significantly larger upfront cost than that of hepatitis C drugs.

Today, our industry’s benefits reimbursement model is designed largely for recurring claims and more predictable costs. One-time, curative treatments with large upfront costs can’t possibly be accommodated within this traditional framework; the timing of the payment doesn’t match the timing in which the benefit is being accrued. For example, if one $3 million payment is made for a gene therapy, the benefit is accrued over the plan member’s lifetime. However, under our traditional reimbursement model, the timing of claims payment and benefit for chronic medications corresponds over time.

Ensuring a positive plan member experience

Underlying all these concerns about the high cost of gene therapies and how to handle them under benefit plans are plan members afflicted with serious conditions and who are now being offered a cure.

It’s vital that all Canadians have access to gene therapies and that access is simple and transparent. This means a streamlined process to determine eligibility and no out-of-pocket costs to patients and their families. Gene therapies aren’t like other prescription medications: they’re not dispensed at pharmacies; instead they’re more like a one-time surgical procedure. This is why new approaches are needed. Establishing partnerships with manufacturers will ensure patients get timely access to the treatment they need without worrying about logistical and financial matters.

What’s next?

In the coming weeks, GSC will finalize the last details of our strategy for gene therapies. Watch out for a future GSC Update that will outline everything you need to know. In the meantime, direct any questions to your account team.

Sources
¹ What is gene therapy? U.S. National Library of Medicine website, Genetics Home Reference. Retrieved May 2019: https://ghr.nlm.nih.gov/primer/therapy/genetherapy.
² Novartis completes certification of initial sites in Quebec for first approved Canadian CAR-T therapy, Kymriah^® (tisagenlecleucel), media release. Retrieved January 25, 2021: https://www.novartis.ca/en/news/media-releases/novartis-completes-certification-initial-sites-quebec-first-approved-canadian.
³ Novartis completes certification of initial sites in Ontario for first approved Canadian CAR-T therapy, Kymriah^® (tisagenlecleucel), media release. Retrieved January 25, 2021: https://www.novartis.ca/en/news/media-releases/novartis-completes-certification-initial-sites-ontario-first-approved-canadian.
⁴ Kite’s YESCARTA^® (Axicabtagene Ciloleucel) Reimbursed in Ontario for the Treatment of Certain Types of Aggressive Non-Hodgkin Lymphoma, media release. Retrieved January 25, 2021: https://www.newswire.ca/news-releases/kite-s-yescarta-r-axicabtagene-ciloleucel-reimbursed-in-ontario-for-the-treatment-of-certain-types-of-aggressive-non-hodgkin-lymphoma-836786912.html.
⁵ Alberta becomes 3rd province to offer promising leukemia and lymphoma treatment, CBC News, August 24, 2020. Retrieved January 25, 2021: https://www.cbc.ca/news/canada/calgary/cancer-centre-care-shandro-calgary-investment-1.5697735.

Behind the counter

An update on COVID-19 vaccines

In our summer 2020 issue of Follow the Script, we talked to GSC pharmacist Leila Mandlsohn, about the development of vaccines and treatments for COVID-19. Now that vaccines have arrived in Canada, we’ve brought her back for an update on the imminent rollout.

FOLLOW THE SCRIPT: First of all, can you walk us through the vaccines that are going to be in the Canadian market and explain how they are different from one another?

Leila: In simple terms, traditional types of vaccines contain the germ – a virus or bacteria, the whole germ or a piece of the germ, live or inactivated – that the vaccine is going to attack. This is injected into a person, and their immune system recognizes it and mounts an immune response. Most vaccines we’re familiar with in our lives work like that, but the first COVID-19 vaccines approved in Canada use a different technology.

FTS: Those would be the two famous ones that we hear about – the vaccine from Pfizer-BioNTech and the one from Moderna? How exactly are they different from older-style vaccines?

Leila: They’re called mRNA vaccines. It’s not brand-new technology, but it had only been used in studies… until now there were no vaccines in the market that had been developed using mRNA technology. These vaccines don’t use actual SARS-CoV2 – the coronavirus that causes COVID-19 – instead the virus’s RNA is coded to instruct the person’s body to create a protein of the virus. That protein is recognized as a foreign particle, and the body then mounts a response. So it’s different in the manufacturing and how we get an immune response. But ultimately the end result is the same as a traditional vaccine.

FTS: Are there other vaccines in development that we might eventually see in Canada?

Leila: Yes, the other two in the pipeline are the University of Oxford-AstraZeneca vaccine and one from Johnson & Johnson. Right now there’s no timeline for when these are going to be available. Interestingly, these vaccines are adenovirus-based, meaning they use an unrelated, genetically engineered virus to deliver a piece of SARS-CoV2 DNA – instead of mRNA – which makes the vaccine more stable than mRNA vaccines. And the adenovirus vaccines can be stored for up to three months under regular refrigeration, as they don’t require the freezing storage temperatures that the mRNA vaccines need.

FTS: Do all these vaccines require two shots?

Leila: The Moderna and Pfizer vaccines are both two shots. For Pfizer, it’s three weeks between doses and Moderna is four weeks. Typically, with most vaccines, you need two shots. Johnson & Johnson is testing a single dose of its vaccine as well as two doses; recent data shows that the single dose was 66 per cent protective overall for moderate-to-severe COVID-19 infections and 85 per cent protective against severe disease. The trial results for a two-dose regimen aren’t expected until sometime in May.

FTS: If we had an option between all these vaccines with two shots and some with one shot, why would we go with two? Just in terms of logistics and patient compliance, isn’t the ideal to have one and done?

Leila: Sure, that would be ideal, but the problem is that you need two doses to really get a full immune response. I recently read a study that showed a minimum vaccine efficacy of 70 per cent was needed to prevent an epidemic and 80 per cent efficacy to end an existing epidemic – assuming 75 per cent of the population was vaccinated. Both Pfizer’s and Moderna’s vaccines have more than 90 per cent efficacy after two doses, and apparently Johnson & Johnson’s has 70 per cent after just the one dose. So the math speaks for itself.

FTS: Recently we’ve heard that some provinces are extending the amount of time between the two shots because of challenges in getting and distributing the vaccine. Is that OK?

Leila: The three or four weeks between shots is based on how the trials were designed, so that’s what’s recommended based on the data. But in general, when it comes to immunization, if you miss the second shot you still want to get it even if it’s a little bit later. So ideally you don’t want to extend the timeframe between the two shots but the CDC [Centers for Disease Control] in the U.S. has said that a person could even go six weeks between doses. They’re not recommending that be the protocol, but if there’s no alternative, it’s unlikely to make a difference in a person’s level of immunity. They also said it’s likely fine to mix the Pfizer and Moderna vaccines for the first and second doses. Again, it’s not recommended, but it’s better than not having a second dose.

FTS: Right now vaccination is happening for select groups of people, but once it starts rolling out for the general public, based on your experience, who do you think is best positioned to deliver this en masse: pharmacists, family doctors, public health clinics?

Leila: We’ve seen the benefits of having pharmacy provide flu shots as immunization has gone up since they started being administered by pharmacists. So I’d be surprised if pharmacists weren’t brought onboard for COVID-19 vaccination. I also think that public health is going to be very important. For the H1N1 vaccine, I remember going to get the shot at a public health clinic; it was convenient and well organized. If we only rely on doctors’ offices and hospitals, those health care professionals will be overwhelmed; to provide vaccination en masse, we need to use local pharmacies and public health clinics in places like community centres where people can just go get their shot and move on.

FTS: We’re speaking to you in early February, do we have any realistic idea today of when the general public will be able to get the shot?

Leila: My understanding is that already there’s a hold on production of the Pfizer vaccine because they want to make upgrades to increase capacity, so that’s delaying distribution in Canada as well as in other countries. So the plans for each province seem to be changing by the day. Right now, according to the Ontario plan, where I live, it doesn’t look like the general public will be getting shots until the summer. To start, the focus is on health care professionals, essential caregivers, long-term care home and retirement home residents, and First Nation communities. Then they’ll move on to older adults, people who live or work in high-risk congregate settings, front-line essential workers, and people with high-risk conditions. Then the rest of us after that, so we’re not looking at any time before July or August, depending on the province.

FTS: Are all pharmacists trained to give the vaccine? Could you give a
shot tomorrow?

Leila: I could, yes.

FTS: You wouldn’t have to get extra training?

Leila: No, because I’ve already had it. Pharmacists have to complete an injection training course and have CPR certification to be able to give vaccines. So once a pharmacist has done the training, then they can start giving shots. There is education and guidance that has been made available right now specifically for the COVID-19 vaccine and as a refresher for pharmacists who don’t give vaccinations regularly. But I think most pharmacists working in the community today have completed the training since patients have the expectation that they can walk in and get a flu shot.

FTS: We keep hearing there’s a certain segment of the population that is averse to getting the vaccine. So if a majority of Canadians – 70 or 75 per cent – got their vaccination by the end of the year, what happens to that 25 per cent who didn’t get it? Won’t the virus still circulate among that population?

Leila: There’s always a portion of the population who doesn’t get vaccinated, yes, but they can be protected because of herd immunity. So where the majority of people are vaccinated, people who are not vaccinated have a much lower risk of getting the virus and getting sick. But pockets of outbreaks can always happen. Is COVID-19 going to be eradicated like polio was eradicated? That would be great. Will this become something like the flu? Who knows? But to your point, anyone who’s not vaccinated will always be at risk if they come into contact with the virus.

FTS: Do we need to be concerned about the variants that are starting to show up?

Leila: I think it’s a concern from the perspective that we’re still learning about them. We’re at the beginning of February now, and so far three variants have been detected – from the United Kingdom, South Africa, and Brazil. From what I’ve seen, the Pfizer vaccine, for example, seems to protect against them. The other thing that seems to be better than it could have been is that the variants spread more easily but don’t cause more severe disease. Though that’s not necessarily good news because more people getting sick means more people admitted to ICUs and more people dying.

Viruses constantly mutate as they spread and anything could happen. We could get a variant that causes a more severe illness; we could also get a variant that’s less virulent – harder to transmit and causes mild illness. We’re still learning lots about this virus, so until it’s under control and mostly gone, vaccination along with social distancing and masks is our best bet.

FTS: Thanks for talking with us again on this topic, Leila. We’re all getting a bit tired of COVID-19, so maybe next time we have you back, we can talk about something else!

Drug Review at GSC

To give you an idea of what drugs might impact your benefits plan next, every quarter Follow the Script highlights some of the drugs recently reviewed by GSC’s Pharmacy and Therapeutic (P&T) Committee.

General Information

Prostate cancer is one of the most commonly diagnosed cancers among Canadian males. It can be categorized as castration-resistant or castration-sensitive depending on whether it responds to androgen deprivation therapy (ADT). In metastatic (has travelled to other sites of the body) castration-resistant prostate cancer (mCRPC), standard of care generally involves use of what is known as new hormonal agents (abiraterone or enzalutamide); however, once the disease progresses, standard of care becomes less clear. In approximately 16 per cent of patients with mCRPC, mutations in the BRCA or ATM genes (also referred to as HRR gene mutations) can be found which have been associated with more aggressive disease compared to wild-type (without the mutation).

Lynparza represents the first targeted therapy approved for use in mCRPC patients harbouring the HRR gene mutation. Lynparza has been approved by Health Canada as monotherapy for adults with deleterious or suspected deleterious germline and/or somatic BRCA- or ATM-mutated mCRPC who have progressed following prior treatment with a new hormonal agent. It is administered orally twice daily until disease progression or unacceptable side-effects. Treatment is given concurrently with a gonadotropin-releasing hormone analog, or patients should have had a bilateral orchiectomy (removal of the testicles).

General Information

Pancreatic cancer is an aggressive type of cancer with few symptoms until the cancer is advanced. Given the late diagnosis, there is very poor prognosis and low survival. Currently standard of care is generally chemotherapy until progression.

Lynparza represents the first targeted treatment option approved by Health Canada for the maintenance treatment of adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas whose disease has not progressed on a minimum of 16 weeks of first-line platinum-based chemotherapy. Lynparza is administered orally twice daily until disease progression or unacceptable side-effects.

General Information

Breast cancer can be classified by various factors each influencing a patient’s prognosis and treatment, including the hormone-receptor (HR) status and human epidermal growth factor receptor 2 (HER2) status. When breast cancer is HR-positive, the cancer cell has receptors that are sensitive to hormones (estrogen or progesterone) and benefits from the use of hormonal therapies to block or lower estrogen to slow cancer growth. Similarly, HER2-positive breast cancers lead to overexpression of the HER2 protein, so these patients often benefit from therapies targeting HER2. In patients with HR-positive and HER2-negative breast cancer, standard of care generally involves hormonal (endocrine) therapy; however, despite treatment, many patients do not respond or may experience disease progression. In those with advanced or metastatic breast cancer, despite initial benefits with first-line endocrine therapies, many patients acquire resistance within two to three years of starting therapy, with approximately 36 per cent of HR+/HER2- breast cancers developing resistance from PIK3CA mutations (a gene that plays a central role in the signalling pathway involved in cell proliferation, survival, and growth).

Piqray represents the first approved, targeted therapy for those with acquired resistance from PIK3CA mutations. It has been approved by Health Canada for use in combination with fulvestrant for the treatment of men and postmenopausal women with HR+, HER2-, PIK3CA-mutated advanced or metastatic breast cancer after disease progression following an endocrine-based regimen. It is administered orally once daily until disease progression or unacceptable side-effects.

General Information

Severe eosinophilic asthma (SEA) is a rare type of asthma marked by high levels of white blood cells (eosinophils).

Nucala represents the only biologic therapy approved for those under the age of 18 with SEA. Nucala was granted Health Canada approval for use as add-on maintenance treatment in those age six and older with SEA who are inadequately controlled with inhaled corticosteroids and an additional asthma controller(s) (e.g., LABA), and have specific blood eosinophil counts at initiation or in the past 12 months. It is administered by subcutaneous injection (under the skin) every four weeks.

General Information

Dayvigo is the first drug belonging to the new class of hypnotics known as DORAs (dual orexin receptor antagonists) which work by suppressing wake-promoting effects to help facilitate sleep. Given its differing mechanism of action, Dayvigo offers an additional treatment option that may be safer compared to other currently available hypnotic agents, which typically demonstrate signs of physical dependence, withdrawal reactions, or associated rebound following discontinuation. Dayvigo was approved by Health Canada for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance. It is administered orally once daily immediately before bedtime.

Notes:
¹ Traditional generally refers to small molecule compounds derived from chemical synthesis and also includes drugs not listed in Schedule D of the Food and Drugs Act; Biologic refers to drugs produced through biotechnology and listed in Schedule D of the Food and Drugs Act; High-cost refers to drugs subject to GSC’s High Cost Drug Policies; Specialty refers to drugs with an expected annual treatment cost of $10,000 or more (certain drugs approaching the threshold may also be considered if clinically warranted).
² Brand (generic)
³ Based on manufacturer list price, does not reflect pharmacy markup and dispensing fee. $ <1,000; $$ 1,000–4,999; $$$ 5,000–9,999; $$$$ 10,000–49,999; $$$$$ ≥50,000
⁴ Applicable to all formularies unless otherwise noted. PPN refers to GSC’s preferred pharmacy network program.