Hot Takes on Hereditary Angioedema: Clinical Care Options Independent Conference Coverage of the 2024 ACAAI Annual Scientific Meeting

Thursday, 7^th November 2024

Hot Takes on Hereditary Angioedema: Clinical Care Options Independent Conference Coverage of the 2024 ACAAI Annual Scientific Meeting

Dr. Marc Riedl (University of California): Hello, and welcome to this program entitled, Hot Takes on Hereditary Angioedema: Clinical Care Options Independent Conference Coverage of the 2024 ACAAI Annual Scientific Meeting. I am Dr. Mark Riddell. I am an Allergist Immunologist in the Division of Allergy and Immunology at the University of California, San Diego. It is my pleasure today to very briefly run you through some of the important data that was presented at the recent American College of Allergy, Asthma and Immunology meeting.

[00:00:40]

Updates on Long-term Prophylaxis for Hereditary Angioedema

We will start with some updates on long-term prophylactic therapy in hereditary angioedema.

[00:00:48]

VANGUARD OLE: Impact of Garadacimab on Quality of Life in Persons With HAE

The first data set I would like to review comes from the VANGUARD Open-Label Extension study. This was a poster on the impact of garadacimab on quality of life in persons with hereditary angioedema.

[00:01:01]

          VANGUARD OLE: Background  

By brief background, and we know that hereditary angioedema has a negative impact on patients and their quality of life, primarily due to the unpredictability and the debilitating nature of these angioedema attacks. Of course, we use both on-demand treatment and long-term prophylactic treatment strategies to try to control or manage hereditary angioedema and thereby improve quality of life.

Now, the data I will show you is from a study of garadacimab. This is a monoclonal antibody that targets Factor XIIA. This is an important component or active protein in the contact system that leads to these hereditary angioedema attacks.

Now the VANGUARD study was a randomized, double blind, placebo controlled trial, that data was published in Lancet and showed the efficacy and the safety of garadacimab and preventing HAE attacks.

What I will show you here is some open label extension data of garadacimab that really looked at health related quality of life, and compared patients who had zero attacks on this treatment to those that had a reduction in attacks but still had one attack or more. This included patients that were naive to garadacimab that had not been on the treatment prior, as well as some patients who had previous exposure from other studies and rolled into the open label extension.

[00:02:31]

          VANGUARD: Percent of Individuals Treated With Garadacimab Attack-free at Six Months  

Now, just as a reminder, if we talk about attack- free status, this is some data from the pivotal VANGUARD study on the left. This was a six-month study. You see in that trial, 62% of the patients were attack-free, had had no HAE symptoms during the study period, compared to zero in the placebo arm that were attack-free.

In this open-label extension study, which has a median exposure of 13.8 months of treatment, you can see 60% of these individuals in the study were attack-free, with no HAE symptoms while receiving garadacimab during the trial.

[00:03:10]

          VANGUARD OLE: Study Design  

Now if we move ahead to look at this entire population of study patients, I want to point out that there were patients here that had been on garadacimab either rolled over from the phase II or phase III trial of the medication and a group of patients that were naive to the treatment. So you see here some that rolled over from the phase III that got placebo during the randomized trial, or those who were entirely new to the study and enrolled for the first time in a garadacimab study.

And so these are two populations where the data was analyzed. Again, in open label studies, we primarily look at primary endpoint of safety or side effects. I am not going to spend much time on that because there were no new safety signals in this trial compared to the randomized, placebo-controlled study.

But what I will show you briefly are the exploratory endpoints, really again, focused on a number of quality of life outcome measures in these patients.

[00:04:09]

          VANGUARD OLE: Mean Improvement in AE-QoL Scores  

Here is an important outcome measure. This is using the AE-QoL, the angioedema quality-of-life score, which is a validated tool to look at angioedema quality of life. And what you will see here on the right is a couple of things. First of all, if you look at the garadacimab naive patients, which are in the orange, they experienced a significant improvement in quality of life.

So that means their AE-QoL scores went down. That indicates better quality of life. You see these significant improvements from their baseline to going on to the investigational drug, garadacimab. That improvement on the right in patients that were already on garadacimab was maintained into the open-label trial.

But what is also notable here is that if you look at attack-free on the left columns, compared to one attack or more on the right columns, you can see those quality of life scores are better, numerically better both in the garadacimab naive cohort and in the previously exposed cohort. So there does appear to be a clear benefit in quality of life if you have zero attacks compared to patients that still have a reduction but still have one attack or more.

[00:05:24]

          VANGUARD OLE: QoL Impairment at Month 12 In Individuals Who Were Attack Free vs 1 or More Attack

That is further highlighted by this rather busy slide. But shows on the top panel attack-free versus the bottom panel one or more attack. What we are looking for here is the very dark navy blue or the less dark royal blue. That indicates that there was never or rarely an impairment in these quality of life domains of functioning, nutrition, fatigue and mood and fears and shame.

And just eyeballing it without getting into all the comparison of statistics, you can see there is much more of the dark blue in patients that were attack-free compared to those that had one attack or more, meaning it was much more likely or prevalent that they never had an impairment in their quality of life if they were attack free.

[00:06:10]

          VANGUARD OLE: Conclusions

This study really highlights the benefits of being attack-free. Conclusions would be that, in HAE, garadacimab did improve health-related quality of life, most notably in those garadacimab naive patients that enrolled in the study, but also that this continue to persisted in patients that had previously been on the medication.

And then, as I highlighted, being attack-free really optimizes or reaches the best quality of life compared to even patients that have one or more attack. And so I think this is encouraging. This is an investigational medication, but one that really shows promise for not only safety and efficacy, but improving quality of life.

[00:06:51]

OASISplus OLE Interim Results: Donidalorsen for Hereditary Angioedema   

All right. Let us move along now to talk about another data set. This is a data on donidalorsen, specifically data on the OASISplus open-label extension study, looking at donidalorsen for prevention of HAE attacks.

[00:07:07]

          OASISplus OLE Interim Results: Background  

Again, by way of review, HAE is a condition that causes these very severe, protracted and often life-threatening angioedema events. We know this is mediated through the kallikrein/bradykinin system due to deficiency of C1 inhibitor.

Now donidalorsen is a unique medication. It is an investigational drug, but it is targeted specifically at RNA in reducing prekallikrein production in the liver. It does this through technology as an antisense oligonucleotide. So very specific, targeting the liver, reducing plasma prekallikrein production.

This has been shown to be effective and safe in a large, randomized, double-blind, placebo controlled trial that was published in the New England Journal of Medicine recently. What we will look at here is data that was presented in the open label OASISplus study, again looking at treatment-emergent adverse events, but also efficacy and quality of life over time.

[00:08:12]

          OASISplus OLE Interim Results: Study Design

This open-label study had two groups. Both got donidalorsen, but there was a larger group that got every four-week dosing. There was a smaller group that got every eight-week dosing of donidalorsen, and that occurred in patients who did well in the randomized, placebo controlled study where they got the every eight-week dosing and were attack-free for at least eight weeks on that regimen. Otherwise patients were on placebo or who got every four-week dosing or were had less control on every eight-week dosing, those were rolled into this Q4 week 80 milligram donidalorsen dose. And that accounts for the larger majority of patients.

Now again, open-label study, primary endpoint is always focused on safety and tolerability. So we look at adverse events, but importantly looking at efficacy and markers of angioedema control including quality of life.

[00:09:12]

          OASISplus OLE Interim Results: Baseline Characteristics  

So here is the baseline characteristics. You can see them split into the two cohorts. But overall these were largely adult patients, though, 8% were adolescents, mostly white population. And you can see the mean treatment exposure was about 228 days when this data cut was done. There were only two patients that terminated the study early, and this was not due to any adverse effects or adverse events within the trial.

[00:09:45]

          OASISplus OLE Interim Results: Primary Endpoint – TEAEs  

These are the treatment-emergent adverse events. Again, safety always an important outcome in these open label trials. And you can see there were no adverse events that led to study discontinuation. The vast majority of these adverse events were mild to moderate in nature.

The most common were things that we see very often in studies, including respiratory tract infections, headache, and, to a lesser extent, injection site discoloration.

[00:10:16]

          OASISplus OLE Interim Results: HAE Attack Rates With Donidalorsen Use   

This is the efficacy data. You can see the very dramatic reduction in HAE attack rates compared to baseline. The pink is the every four week dosing group. The blue is the every eight week dosing group. What you will notice is they are extremely comparable as you go out further into the study.

And for both of these dosing regimens, the mean change or the mean reduction in attack rate was greater than 90% during the clinical trial.

[00:10:48]

          OASISplus OLE Interim Results: AE-QoL and Disease Control (AECT)

Very importantly, quality-of-life. So a couple of measures here on the left panel shows the angioedema quality of life score. A reminder that a clinically significant change is 6 points or more. And you can see in both dosing groups, these very dramatic reductions in the quality-of-life score, which means improvement in angioedema quality-of-life.

28-point reduction or improvement in the every four week dosing, and a 24-point improvement in the every eight week dosing. So really remarkable improvement in quality-of-life with the donidalorsen treatment.

On the right is angioedema control. This is measured by the angioedema control test, where a score of 10 or more indicates good control or well controlled disease. You can see across the board for the every four week and every eight week dosing, and in particular, those that rolled over from placebo into this open-label trial, really remarkable control of angioedema, 91% in the every four week and 100% in the every eight week dosing groups.

[00:11:55]

          OASISplus OLE Interim Results: Conclusions

We can conclude here that in this open-label extension study, both every four week and every eight week dosing of donidalorsen had acceptable safety profiles. There were no treatment-emergent adverse events that led to discontinuation of the medication during the study. The attack rate reduction was very significant, greater than 90% for both dosing groups, and it was maintained throughout this open-label trial.

And for all patients, particularly those who were treatment-naïve, you see these clinically meaningful improvements in quality-of-life.

[00:12:33]

Impact of SDOH in Persons With HAE

Lastly, let us briefly look at some data on social determinants of health in patients with HAE.

[00:12:39]

Impact of SDOH in Persons With HAE: Background 

HAE is being a rare genetic disorder. There has been very little work in social determinants of health to determine if these factors might influence health outcomes in hereditary angioedema, what sorts of treatments, what sort of access to care patients may have.

So this was a study looking at some of these social determinants of health, to determine if they have an impact on treatment or outcomes in HAE.

[00:13:09]

Impact of SDOH in Persons With HAE: Study Design 

This used a cohort analysis of claims data from 2017 to 2021. This particular claims database was enriched for Medicaid patients, but it did include Medicare and commercial payers covered patients as well. You can see the inclusion criteria included this diagnostic code for HAE D84.1 or a code for angioedema, which was coupled with prescriptions for HAE specific medication.

Importantly, we are looking at social determinants of health, including income level, race or ethnicity, and location of residence, rural versus urban or suburban.

[00:13:50]

Impact of SDOH in Persons With HAE: Baseline Characteristics

These are the patient demographics quickly, predominantly female. And you can see a mix of ethnicities including white, African American, Hispanic and Asian. And as I mentioned, enriched for this Medicaid population, but also commercial and Medicare coverage.

[00:14:07]

Impact of SDOH in Persons With HAE: Proportion of Patients on Medicaid

What we see is that those patients that were covered by Medicaid, a high proportion of them were Hispanic or African American. You can see 63% of African Americans and 71% of Hispanic racial or ethnic background were on Medicaid.

There were a higher proportion of low-income patients on Medicaid, of course. No real difference in location rural versus urban on Medicaid plans.

[00:14:37]

Impact of SDOH in Persons With HAE: LTP Therapy Claims

If you look at long-term prophylactic prescription claims, again, you see this disparity, overall 26%, but only 12.8% of African Americans getting a prescription for long-term prophylaxis. Also, lower rates of low income patients getting prescriptions for long-term prophylactic therapy, and a somewhat decreased percentage of patients in rural areas.

In these boxes is access to specialty care, specifically allergist and immunologist. And you see the same trend, lower rates of access to specialists in African American patients, in patients with low income in particular.

[00:15:18]

Impact of SDOH in Persons With HAE: Odds of Having an ED Visit

Finally, emergency department visits. This is notable for the fact that African American and Hispanic patients, as well as low income patients had statistically significantly higher rates of emergency department visits for all causes compared to the overall population.

[00:15:38]

Impact of SDOH in Persons With HAE: Conclusions

So the conclusions here is that there is variability in healthcare utilization based on some of these social factors, including race or ethnicity, income and rural location for HAE patients. Those communities that were traditionally concerned about being excluded from usual health care, including low-income, African American and Hispanic patients, did in fact have more emergency department visits and lower use of long-term prophylactic therapies for HAE.

And this really highlights the need for additional research in social determinants of health, specifically in the high population.

[00:16:16]

          Key Takeaways

So we will wrap up this program with a few key takeaways. We recognize that there are continued advances in long-term prophylaxis, including the investigational drugs of garadacimab and donidalorsen that look very promising not only for reducing HAE attacks, but for improving quality of life.

It is important in the clinics that we consider these sorts of therapies, but also that we consider factors of patients, including socio-demographic factors when we choose, discuss and recommend treatment strategies for our patients with hereditary angioedema.

With that, I thank you for your attention. Do not forget to claim your credit by clicking on the link.

[END OF TRANSCRIPT]