Hemophilia Gene Therapy Getting Closer to the FDA Approval Finish Line

Disclaimer: Mandeep Sohal, PharmD and Joshua Murdock, PharmD are employees of CVS Health. Any statements contained herein are solely the opinions of the authors and do not reflect the views of CVS Health, Aetna, CVS Caremark or any of CVS Health’s affiliates or subsidiaries.

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What is hemophilia?

Hemophilia is a type of rare genetic bleeding disorder that mainly affects males.¹ It can be categorized into two main types of hemophilia – hemophilia A and hemophilia B.¹

Both types of hemophilia are caused by a lack of ‘factor,’ a key component of the coagulation cascade, which is a step-by-step process that occurs in your body to stop bleeds by the formation of a blood clot. It is important to have a quantity of factor within a normal range to prevent bleeding episodes. Hemophilia A is caused by a lack of factor VIII (8) and hemophilia B is caused by a lack of factor IX (9).¹ Blood clotting is a part of normal bodily function, and many patients that lack factor suffer from bleeding into joints, muscles, and skin (bruising); repeated bleeding into joints can lead to disability.²

However, similar to other medical conditions, not all patients with hemophilia have the same symptoms. Some patients are more severe than others, which is usually related to how much the factor levels are under the normal range.² Due to these differences, treatment is individualized to the patient’s needs.²

The care of a hemophilia patient is complex and requires a number of healthcare professionals, like hematologists, nurses, pharmacists, and physical therapists. For the majority of patients who aren’t of a mild severity, treatment requires the use of factor drug products or antibodies that help improve symptoms.³ Some patients require the use of drug products on a regular basis, while others use them after bleeding episodes.

There are several different categories of drug products used to treat hemophilia today, two of which include the plasma-derived and recombinant replacement factor products.³ Plasma-derived products come from blood donors while recombinant factor products are made in a laboratory setting.³

The benefit to recombinant products is that they are often safer than plasma-derived products because they have a very low risk of carrying disease causing micro-organisms.³ However, one study did show that the use of recombinant products resulted in a greater incidence of inhibitor production.⁴ Inhibitors are antibodies formed in hemophilia patients that recognize the drug product as non-self. This causes the patient’s immune system to attempt to eliminate the foreign threat, the factor drug product, and prevents the factor drug product from working normally. Certain inactivation techniques have nearly eliminated transmission of disease causing micro-organisms in plasma-derived products, but there still exists risk for unknown viruses and prions (abnormal proteins) in these products.⁵

Furthermore, replacement factor drug products can also be divided into standard half-life vs. extended half-life products.² Standard half-life products typically need to be administered to a patient more frequently than extended half-life products, as they do not last quite as long in the patient’s body. As many patients using factor in a preventative manner need to administer drug product several times a week, extended half-life products are often preferred by patients as they need to be administered less frequently.

Additionally, there is an FDA-approved monoclonal antibody used for hemophilia treatment. Hemlibra (emicizumab-kxwh), while not a replacement factor product, is an antibody that helps reduce the frequency of bleeding episodes.⁶ It has been shown to be more effective than traditional factor products in one study, and it can be administered as an injection under the skin as infrequently as every 4 weeks.⁷ While we do see significant advances in hemophilia treatment options, we are at the cusp of a changing hemophilia treatment landscape in this decade.

While these are some of the current treatment options available for patients with hemophilia, there are other drug products currently being studied in clinical trials that have potential to help patients with hemophilia in a new way.

What is gene therapy?

Gene therapy is a new way to treat diseases, which can help many patients that have abnormal or absent gene function. For medical conditions like hemophilia, gene therapy is emerging as a treatment option.

Specifically, gene therapy is a developing therapy class that allows healthcare professionals to treat diseases by inserting a functional copy of a gene into a patient’s cells. As hemophilia is a genetic bleeding disorder caused by a single faulty gene, it is a reasonable candidate for this therapy class.² Today, hemophilia is treated by a number of different medications. However, for many with severe disease, frequent injections of replacement factor into a patient’s vein or antibodies under the skin is an inescapable reality.²

While there are currently no FDA-approved gene therapies for use in hemophilia patients, there are several drug products being studied that may change how hemophilia is treated in the future, including Roctavian (Manufacturer: BioMarin) and AMT-061 (Manufacturer: uniQure) among others.⁸ It is likely that we will see the approval of a hemophilia gene therapy in the near future. 

What is Roctavian (valoctocogene roxaparvovec)?

Roctavian is the brand name of the gene therapy valoctocogene roxaparvovec for hemophilia, which was previously known by the brand name of Valrox.⁹ It is one of many being studied for hemophilia treatment, today.

Roctavian uses a vehicle, a non-disease causing virus, called Adeno-Associated Virus Type 5 (AAV5), to deliver a functional factor gene to a patient. This is given by infusion into the patient’s vein.^9,10 This gene therapy, like many other existing gene therapies for other conditions, can only be tried a single time. Once administered, it causes the patient’s immune system to create antibodies to the vehicle.¹¹ If the therapy is given again, the patient’s immune response will neutralize the gene therapy, likely rendering it ineffective.¹¹

However, there are other new, innovative technologies in development, which can be given more than once, because they use a different type of vehicle.

For example, Generation Bio’s lipid nanoparticle has shown the possibility of redosing a gene therapy without provoking an immune response, which may alter how gene therapy is delivered in the future.¹² In other words, Generation Bio’s product may be administered to a patient more than once, but it is far from FDA approval and hasn’t yet been studied in humans. While it is unknown if future vehicles for delivery will be mostly viral or non-viral, it is likely that gene therapy will need to be given in a hospital setting, so patients can be monitored to help ensure that they tolerate the therapy.

In the Roctavian clinical study protocol (a document that describes study details), patients were initially screened and several examinations were conducted, including physicals, urine tests, and blood tests.¹³ After screening, Roctavian was administered to eligible patients via an infusion into a patient’s vein, and BioMarin estimated that the maximum infusion time would not exceed four hours.¹³ However, the patients were hospitalized for an entire day for observation to evaluate how they responded.¹³ Prior to being allowed to participate in a research study, patients have to meet certain requirements or criteria. While patients enrolled in the Roctavian study had to meet many criteria to be included, it may be useful to understand what some of the higher level requirements were.

It is important to note that this gene therapy is still being studied in clinical trials, and it has yet to achieve FDA approval. The final FDA-approved product, if approved at all, may or may not be used in an identical population to the study criteria. Furthermore, this is just the criteria for Roctavian for one study; the studies for other gene therapies to treat hemophilia may have different criteria.

Patients included in the study were males with severe hemophilia above the age of 18.¹³ These patients also had to have no inhibitors on two occasions within the last twelve months.¹³ At this time, BioMarin is recruiting participants for a study that does include patients with inhibitors.¹⁴ Furthermore, if patients had antibodies to AAV5, the vehicle, they were also excluded.¹³ This is a point of concern as many patients have been exposed to AAV during childhood and adolescence and already have formed antibodies as a result; the prevalence of neutralizing antibodies for AAV5 ranges from 4% to 50%, which would exclude many hemophiliacs from this therapy.¹⁵ Patients that were eligible and did receive therapy were quite significantly affected.

Roctavian treatment resulted in more than a 90% decrease in annual bleeding rate and more than a 90% decrease in factor VIII use 3 years after having received an effective dose of gene therapy. From a safety perspective, Roctavian did affect the patient’s liver enzymes, but the effect was temporary and non-serious. One patient was found to have experienced treatment related serious adverse events during the study, which included a high fever, muscle pain, and headache. Reassuringly, this patient’s symptoms resolved within 48 hours after receiving acetaminophen (Tylenol).

BioMarin, the manufacturer of this gene therapy, submitted their study data, but their application was denied in August 2020 due to differences in the submitted studies with concerns for how long the effect of the gene therapy would last after it was administered to the patient.¹⁶ FDA requested additional data from one of BioMarin’s studies.¹⁶ Now, BioMarin is working to obtain additional data, and they will likely resubmit Roctavian to the FDA for potential approval in the future.

While this class of therapy holds significant promise, many outstanding questions remain. At this point, it is difficult to say how long the effects of this gene therapy will last. For Roctavian, or any other gene therapy, factor levels would ideally be sustained over the entire lifetime of the patient. As adult patients, 18 years or older, were eligible for the trial therapy, the gene would have to be functional for several decades in order to be considered a curative success. Even with current data, it is not yet possible to know if this will happen. Only additional data and time will allow us to realize the true effect of gene therapy.

 Other gene therapies for various medical conditions will likely become available over time. Roctavian (valoctocogene roxaparvovec) for the treatment of hemophilia, although still being studied in clinical trials, is one example of many hemophilia gene therapies in the drug development pipeline.

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References:

1. What is Hemophilia? Centers for Disease Control and Prevention website. Accessed March 1, 2021. https://www.cdc.gov/ncbddd/hemophilia/facts.html
2. DiPiro JT, ed. Pharmacotherapy: A Pathophysiologic Approach. Tenth edition. McGraw-Hill Education; 2017.
3. Treatment of Hemophilia. Centers for Disease Control and Prevention website. Accessed March 1, 2021. https://www.cdc.gov/ncbddd/hemophilia/treatment.html
4. Peyvandi F, Mannucci PM, Garagiola I, et al. A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A. N Engl J Med. 2016;374(21):2054-2064. doi:10.1056/NEJMoa1516437
5. Teitel JM. Viral safety of haemophilia treatment products. Ann Med. 2000;32(7):485-492. doi:10.3109/07853890009002024
6. HEMLIBRA uniquely addresses the factor deficiency of hemophilia A. hemlibra website. Accessed March 1, 2021. https://www.hemlibra.com/hcp/about-hemlibra/mechanism-of-action.html
7. Reyes A, Révil C, Niggli M, et al. Efficacy of emicizumab prophylaxis versus factor VIII prophylaxis for treatment of hemophilia A without inhibitors: network meta-analysis and sub-group analyses of the intra-patient comparison of the HAVEN 3 trial. Curr Med Res Opin. 2019;35(12):2079-2087. doi:10.1080/03007995.2019.1649378
8. Gene therapy for hemophilia: So close, yet so far away. biopharmadive website. Accessed March 1, 2021. https://www.biopharmadive.com/news/hemophilia-gene-therapy-biomarin-uniqure-pfizer-roche/594168/
9. Roctavian (formerly Valrox/BMN 270). hemophilianewstoday website. Accessed March 1, 2021. https://hemophilianewstoday.com/bmn-270/
10. Grieger JC, Samulski RJ. Packaging Capacity of Adeno-Associated Virus Serotypes: Impact of Larger Genomes on Infectivity and Postentry Steps. J Virol. 2005;79(15):9933-9944. doi:10.1128/JVI.79.15.9933-9944.2005
11. Thwarting AAV-Neutralizing Antibodies Could Improve Gene Therapy. the-scientist website. Accessed March 1, 2021. https://www.the-scientist.com/news-opinion/thwarting-aav-neutralizing-antibodies-could-improve-gene-therapy-67981
12. Generation Bio Announces Two Non-Viral Gene Therapy Milestone Achievements: Target Levels of Factor VIII Expression in Hemophilia A Mice and Translation of Expression from Mice to Non-Human Primates. generationbio. Accessed March 1, 2021. https://investors.generationbio.com/news-releases/news-release-details/generation-bio-announces-two-non-viral-gene-therapy-milestone
13. Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med. 2020;382(1):29-40. doi:10.1056/NEJMoa1908490
14. Study 270-205. biomarin website. Accessed March 1, 2021. https://www.biomarin.com/clinical-trials/hemophilia-a/
15. Kruzik A, Fetahagic D, Hartlieb B, et al. Prevalence of Anti-Adeno-Associated Virus Immune Responses in International Cohorts of Healthy Donors. Mol Ther Methods Clin Dev. 2019;14:126-133. doi:10.1016/j.omtm.2019.05.014
16. FDA Delays Decision on Roctavian, Potential Hemophilia A Gene Therapy, for a Year or More. hemophilianewstoday website. Accessed March 1, 2021. https://hemophilianewstoday.com/2020/08/19/fda-delays-decision-roctavian-hemophilia-a-gene-therapy/