What Hemophilia and Sickle Cell Disease Reveal About the Future of Gene Therapy Access

Gene therapies promise unprecedented relief for patients with severe hematologic disorders, but the path to delivering them is anything but uniform. In a conversation with Pharmacy Times, Alex Wolff, PharmD, BCOP, FHOPA, breaks down how hemophilia and sickle cell disease—2 conditions with vastly different demographics, treatment histories, and socioeconomic profiles—illustrate the practical challenges of access, safety monitoring, and care coordination. From high upfront costs to the demands of ex vivo treatment models, Wolff outlines the nuances pharmacists must understand as gene therapy programs expand.

Q: You’re using sickle cell disease and hemophilia as case examples, which represent quite different patient populations and treatment contexts. What do these 2 diseases teach us about how gene therapy access and implementation challenges can vary, and are there lessons that apply more broadly across hematologic conditions?

Alex Wolff, PharmD, BCOP, FHOPA: I think in these 2 disease states, there are some commonalities, and there are a lot of differences. Some of the commonalities are, as with most gene therapies, [that] it is a genetic mutation they have had from birth. So this is something that the patients have—this burden of disease that they have known and have been managing at some level.

In both cases, it is the severe cases that would be [eligible] for gene therapy. The patients with milder symptoms, milder phenotypes, are not going to qualify for an expensive, invasive gene therapy. They are going to be managed through more conventional mechanisms. But the patients who have had morbidity and complications—long-term disability from bleeds into the joints, for hemophilia, for example, or organ dysfunction from vaso-occlusive crises, from sickle cell disease—those are the patients [who] qualify for gene therapy. So they are having significant impacts in their health and their quality of life already.

Those are some of the commonalities. Some of the differences are in the patient population. Because these are genetically linked diseases, naturally the patient populations are different. Hemophilia is almost exclusively men. It is an X-linked disease, so it is very rare to have a severe phenotype in a female because you have 2 X chromosomes, whereas the men only have 1. So the severe male phenotype predominates. It is largely a male group, which does not necessarily mean a lot; it is just that that is your population there.

What is different with them, too, is that they are typically used to frequent intravenous infusions, frequent health care interventions, because the conventional therapy for hemophilia is factor replacement, which is given intravenously, typically 2 to 3 times a week, [for] their entire life. It is a very expensive therapy. So it is not that they are new to a high-cost therapy. The idea, though, that they have to…get behind is that it is a very expensive upfront therapy with the goal that they come off their prophylaxis, and the cost is recouped over time. So it is a little bit of a different approach. As opposed to maintaining their factor levels over time, the body then is able to produce them with factor levels.

With sickle cell disease, I think…that population…is obviously a lot larger. The sickle cell community in the United States is about 100,000 individuals who are affected. If you take that to just the severe—just the ones who will qualify—you are looking at a much smaller number, but it is still a larger population.

We also run into a lot of socioeconomic differences in sickle cell disease. It is largely Black Americans or African Americans who carry the severe traits of those. They tend to have higher rates or higher percentages of patients on Medicare and Medicaid, government assistance, or government insurance. So the payer structures are going to be really important. These therapies cost in the multimillion-dollar range per treatment, so we have to think about that as a system, how that is going to affect things, and then access to care.

With the sickle cell disease gene therapies, those are the ex vivo therapies. Those require hospital admission. They require chemotherapy and then a 3- to 4-week hospital stay for count recovery. So when you are talking about patients who may have limited access to a treatment center—you have to be at a large transplant center—[who] have transportation needs, and you are going to have to follow up 2 to 3 times a week after that, they may have employment issues or caregiver issues.

The median age of patients in these trials was in their late 20s to 30s. Those are the working population. That is a patient population that typically has small children and has caregiver needs. So I think that the population itself has some unique aspects that we have to take into consideration. Because…as easy as it is to say, if you do not have childcare for 3 weeks, you cannot get that treatment; then that is not an option for you. So those are some of the considerations that you have to take into account.

Q: What are the most clinically significant safety signals pharmacists need to be prepared to recognize and respond to across gene therapy platforms, and how does that differ between viral vector-based and cell-based approaches?

Wolff: Yes. So the viral vectors, in general, tend to have more toxicities to the liver. What we saw in the hemophilia case—for Hemgenix (etranacogene dezaparvovec-drlb; CSL Behring), for example—[is that] 20% of patients had liver injury or elevations in their liver enzymes that required steroid treatments. The steroid treatments ranged anywhere from a couple of weeks to several months, but on average, most patients had about 3 months of steroid use in order to mitigate that inflammatory reaction. So it is an inflammatory response, and the viral vectors have a liver target for hemophilia in particular, but even some non–liver-associated diseases. So that is one of the biggest things that we need to watch for.

With the ex vivo cell-based gene therapies, the cells themselves actually have very little risk. They are your own autologous cells, the patient’s cells. We took them from them, we modified them, and we gave them back. So the body usually takes those pretty well. The immunogenicity risk is low. It is what we have to do to them to allow those cells to grow. They need 4 days of intensive chemotherapy to essentially wipe out their bone marrow stem cells, and that comes with a lot of toxicities. Their infection risk is high, their bleeding risk is high. Mucositis and mouth sores, fever rates, things of that nature; gastrointestinal toxicities, nausea, diarrhea—those things are very common, especially in that acute period for several months.

Long-term, we need to monitor for safety signals in both therapies. We have used these therapies, and the longest follow-up study on them has about 4 to 5 years of data. In theory, these are very durable responses, and you should get many years, a lifetime, of efficacy from this. But we do not have long-term safety data.

There are some signals with some of the cell therapies that use a viral vector to insert the gene that there could be oncogenesis, or the development of a cancer, because of the insertion of the gene therapy. So the viruses, although they are very good and very sophisticated with modern technology, can insert some material a little promiscuously. Sometimes they activate oncogenic DNA material that creates a cancer, or they may disrupt a tumor suppressor, and then it allows a cancer to occur. One of the products that is made with a lentiviral vector reported 2 cases of acute leukemia out of their couple of dozen patients. So it is something that we are definitely vigilant about, and those possibilities certainly exist.

Q: Gene therapies carry extraordinary price tags and are currently concentrated at a limited number of treatment centers. What role can pharmacists realistically play in navigating prior authorization, patient assistance programs, and care coordination to improve access for patients who could benefit?

Wolff: Yes, I think it is a team effort. It is something that we are not going to manage on our own. Most of these treatment centers are going to have their own financial coordination departments. The way that these are set up, with the high upfront cost, is typically going to require a case agreement either with that organization and the payer or a single case rate for that particular patient.

In the case of these ex vivo gene therapies, that is going to encompass more than just the gene therapy. It has to encompass the hospitalization and the chemotherapy, because that is a required component to get the gene therapy. So they are bundling these in group bundles of a certain period of postinfusion follow-up. How much of that is included is all negotiated. A lot of that is done with the financial groups.

I think as pharmacists, our role is to make sure that the things that they need also get covered. If they have persistent nausea or persistent diarrhea from the chemotherapy for their gene therapy, you need to make sure that that gets covered too. So advocating for that, working with authorizations for insurance companies, things like that.

And then I do a lot of providing education to our financial teams. They are not trained clinically. They have a code and a chart, and if it does not match, it does not go. So helping them understand—some of that we have done with our chimeric antigen receptor T-cell (CAR-T) therapy as…a model that we can use. They need chemotherapy prior to their CAR-T cell therapy. So they do not authorize just the code for the CAR T; they are going to need 3 days of chemotherapy, but that is part of the bundle. Providing that education to them is important because they see these codes just drop through the system, depending on how the system works, and may not understand that this is part of the same treatment. You cannot have A without B, and they both have to be covered. So we have to submit for all of that together.

Q: For a pharmacist attending this session whose institution is just beginning to explore a gene therapy program, what would you say are the first 2 or 3 concrete steps they could take?

Wolff: I think you need to identify a physician champion. You need to know what their goal is. Do they want to bring on all of the products in that space? Are they looking for a particular product? Most of the products are going to require some sort of onsite level of approval or authorization that your site is appropriate. So working toward seeing what is involved with that—whether it is related to storage and handling, processing, prior authorizations, those types of things—and then working toward that.

It is definitely a multidisciplinary group. You are going to need your contracting folks, your financial folks, your physician team on board, and then your pharmacy team ready to receive and prepare.