iTTP Externally-Led Patient-Focused Drug Development (EL-PFDD)

On January 26, 2024, the Ree Wynn Foundation hosted a patient-focused drug development meeting for the US Food and Drug Administration (FDA). The meeting was supported by:

• James Wynn – The Ree Wynn Foundation/Co Moderator
• James Valentine – Hyman, Phelps & McNamara/Co Moderator
• A host of iTTP Warriors and caregivers who shared their experiences with iTTP

The meeting also welcomes the following guest speakers - here are the times and the topics for their presentations:

• 00:23:53 – FDA Remarks - Dr. Tanya Wroblewski, Deputy Director DNH
• 00:33:06 - Scientific Foundation for iTTP – Dr. Zheng Long, University of Kansas
• 3:17:13 - iTTP treatment overview - Dr. Adam Cuker, University of Pennsylvania
• 5:05:40 – Meeting Summary - Larry Bauer from Hyman, Phelps & McNamara

If you would like to learn about the experiences of iTTP patients, I recommend you watch the complete video. If you would like to learn about iTTP and treatments, please listen to the talks by Dr. Long and Dr. Cuker.

I thank the Ree Wynn Foundation for preparing and hosting this important meeting which is another step to support all iTTP Warriors.

Thanks, Bruce.
@BruceFightsTTP

ADZYNMA recombinant ADAMTS13 for cTTP Patients

Takeda has announced ADZYNMA (recombinant ADAMTS13) has been approved by the US FDA for chronic thrombotic thrombocytopenic purpura (cTTP) patients.

What is cTTP?

Takeda provides this answer.

cTTP is an ultra-rare, chronic, and debilitating clotting disorder associated with life-threatening acute events and debilitating chronic symptoms, or TTP manifestations. TTP has an estimated prevalence of 2-6 cases/million. The inherited form of the disease, cTTP, accounts for ≤5% of TTP patients. It develops due to deficiency in ADAMTS13, a von Willebrand factor (VWF) cleaving protease, which results in the accumulation of ultra-large VWF multimers in the blood. The accumulation of ultra-large VWF multimers leads to uncontrolled platelet aggregation and adhesion. This can lead to abnormal clotting in the small blood vessels of the body and is associated with microangiopathic hemolytic anemia and low platelet levels (thrombocytopenia).

cTTP has both acute and chronic manifestations (including stroke and cardiovascular disease) and when left untreated, acute TTP events have a mortality rate of >90%. cTTP can also cause ongoing widespread organ damage and other co-morbidities resulting from an ADAMTS13-deficient state.

What will ADZYNMA do?

ADZYNMA provides patients with a treatment option that replaces their deficient ADAMTS13 enzyme by injection instead of plasmapheresis. This means a cTTP patient will not have to repeatedly receive and react other people’s plasma. It means patients can have the process provided locally or even at home and not have to go to a rare apheresis clinic.

The ADZYMNA site indicates cTTP patients will have approximately 4- to 5-fold higher ADAMTS13 activity exposures compared to plasmapheresis.

What does this mean for aTTP patients?

There is no announcement yet, but since acquired TTP (aTTP) patients are the other ≥95% of TTP patients, I am sure ADZYNMA processes will be addressed for this group in the future. Imagine if an aTTP patient is tested with a low ADAMTS13 and only needs a series of injections to recover. Will the patients need Prednisone? Or the hard-to-get off label rituximab product?

Hopefully the process to provide recombinant ADAMTS13 will be extended to reduce the symptoms and suffering for all TTP patients.

TTP#6 – We were so close

This was unexpected. I have been working with my hematologist since February 2020 to measure my ADAMTS-13 enzyme activity. Good ADAMTS-13 activity means no Thrombotic Thrombocytopenic Purpura (TTP). The blood is sent to another facility, such as the Mayo Clinic, and its takes about a week to get the result. For many the months, the good news was greater than 100%, but in October 2021 it dropped to 78%. I suppose this is bad news, but I am a chronic-TTP patient, so we were expecting a change at sometime. The upside is I did not have TTP. The plan now was to monitor ADAMTS-13 and get rituximab to increase its activity before TTP sets in.

On May 17, 2022, ADAMTS-13 was at 25%, so the doctor prescribed rituximab with a dose on each Friday in June. In the third week I was not feeling very well. I had mild symptoms – a stomach-ache, some blurred vision, numbness in one arm. Since I was taking rituximab which will stop TTP, I was thinking side affects. On the Thursday night, I had a miserable headache which kept me up all night. My wife did not tell me, but she thought I had TTP. I went for the next rituximab dose on the morning of June 17, and advised I was not feeling too well. My doctor ordered a blood test, and my platelets were at 41, I had TTP again. Later we found my ADAMTS-13 was at 1%.

The same day I had the line put in my neck and we started plasmapheresis. We did plasma exchange for 6 days straight and 8 in total. The good news is the original discarded plasma was not dark, it was almost the same colour as the new plasma. I believe this means I was not suffering all the consequences of lack of platelets with items such as kidney issues, bruises and petechia. I recovered from TTP#6 faster than any previous TTP episode. The conclusion was the two does of rituximab which were provided on the first two Fridays of June helped for quick response. I was only admitted to the hospital for 5 days and with night passes only stayed one night in the hospital. This helped my family have a more normal life and was much better for eating and sleeping.

When I reviewed this TTP episode with my hematologist, she concluded we waited too long to administer rituximab. Next time, the plan will be to administer at a higher level of ADAMTS-13 activity.

We were so close, but I did get TTP for the sixth time, stopped working for 4 weeks and interrupted our personal life where we even missed my nephew’s wedding.

Thanks, Bruce.
@BruceFightsTTP

10 Years with TTP

It has been ten years since I was first diagnosed with Thrombotic Thrombocytopenic Purpura (TTP). I have learned a lot about TTP over the years plus I have also had the opportunity to make many new friends and support a charity which supports TTP research.

For some background, I have had TTP five times (2012, 2014, 2017, 2019, and 2019). The first incident was the worst. We did not react fast enough to go to the hospital. Luckily, I was diagnosed quite quickly and started plasmapheresis. Unfortunately, this was quite late - I had seizures and was induced into a coma for two days. Through treatments, they found I had an anaphylaxis reaction to regular plasma transfusion. This is bad when the treatment is to replace your plasma. Luck was there again as my hematologist ordered solvent/detergent plasma, even though it was not yet in use in Canada. The good news is that for subsequent episodes, we recognized the symptoms and thus had more time to get the tell-tale blood test.

What have we learned over the last ten years?

You don’t find out whether you are going to have TTP by measuring the platelets. Sure, your platelets are reduced when you have TTP, but that is a symptom. The cause is, for some reason, the ADAMTS-13 enzyme activity is reduced, which causes your blood to become sticky with clotting platelets. Measuring lack of platelets will just tell you that you have TTP. You need to monitor ADAMTS-13 activity to see if you will get TTP in the future. We never started monitoring ADAMTS-13 until the end of 2019. Now we monitor monthly.

TTP patients need Rituximab, which is not a TTP drug. Most governments including the US and Canada do not have rituximab approved as a TTP drug, it is a cancer drug. However, hematologists have been using rituximab for many years to help stop the recurrence of TTP. You can see from the USTMA Foundation treatment protocol that rituximab should be given immediately after plasmapheresis. For many Canadian patients, rituximab is not easily available until we find out how it will be paid for. This causes some delays, and I did not receive Rituximab twice after TTP occurrences. We need to work to make Rituximab readily available for chronic TTP patients as it can help ADAMTS-13 to return to normal levels to stop another occurrence of TTP.

A pharmaceutical company has developed a TTP drug called Caplacizumab. This drug will stop a TTP patient’s platelets from clotting. This gives the TTP patient time to respond to treatments such as plasmapheresis, corticosteroids, and rituximab. Caplacizumab is approved for use in the UK and US, but Canadian Agency for Drugs and Technologies in Health (CADTH) issued a negative recommendation for caplacizumab. As such, Canada is an outlier and does not support coverage and reimbursement for this drug. The AnsweringTTP Foundation has taken action to provide advocacy and awareness to Canada’s provincial health ministers for caplacizumab. Hopefully, we will have caplacizumab approved for Canadian TTP patients in the future.

So, in the last ten years I have found out what TTP stands for, what enzyme we need to test, and what drugs we to get. I hope we have even more progress in the next ten years.

 

Thanks, Bruce.
@BruceFightsTTP

2020 International TTP Day Wrap-up

I thought that this post might interest you and the supporters of Bruce Fights TTP and AnsweringTTP Foundation. This video is their announcement that they met their $30,000 fundraising target.

It also thanks the fundraisers, their supporting teams and provides a few fun facts about TTP. You will also see a few pictures of myself and some of the Bruce Fights TTP supporters in our t-shirts. Thanks Régimbal Promotions.

The video states that some fundraisers sold t-shirts to raise funds. Please note that the Bruce Fights TTP t-shirts were provided to me by our sponsor and were given to supporters as a thank-you. Supporters do where their t-shirts when we hold our annual International TTP Day walk. And if they cannot make the walk (or we have a pandemic), they are asked to send a photo in their t-shirt to help show support for AnsweringTTP and our many patients. As you can see in the video, we have many supporters.

Would like to extend a thank-you to all people who supported the International TTP Day fundraiser. Let's do it again next year.

Thanks, Bruce

@BruceFightsTTP

What I Learned from the USTMA Conference

The USTMA Consortium held their first annual conference for TTP patients on 22 August 2020. It was originally scheduled as an in-person conference in Chapel Hill, North Carolina, but due to COVID-19 it pivoted to a virtual conference.

The stated mission of the USTMA Consortium is to “improve outcomes in Thrombotic Thrombocytopenic Purpura (TTP) and other thrombotic microangiopathies (TMA), through observational studies, clinical trials of novel therapies and translational research in these rare diseases.”

The conference agenda covered the following items:

·         Welcome to USTMA

·         Preventing Relapse of TTP

·         TTP and the Brain

·         Congenital TTP

·         Coping with Strategies for Dealing with Chronic Disease

·         Women and TTP

·         Ask the Hematologist

·         What is Research?

·         The Doctors’ Golden Rules: Listen to your Patients, Learn from your Patients

So, what did I learn?

How to forecast TTP. I think my hematologist and I are now on the right track. In the past, we measured the level of the platelets to check that status of my blood. This is like looking out the window to forecast the weather. The platelet level tells if you have a problem or do not have a problem. To forecast TTP, it is better to measure the trend of the ADAMTS13 activity, one of enzymes in the blood, If the ADAMTS13 activity is trending down, then TTP could happen in the future. To monitor ADAMTS13 activity, it was recommended that ADAMTS13 activity be measured monthly for 3 months after TTP, then every 3 months for the first year, and then every 6-12 months. Currently we are measuring my platelets and my ADAMTS13 activity monthly. So far, so good.

How can we try to prevent relapse? The goal is to stay away from plasmapheresis and steroids (Prednisone). Plasmapheresis requires hospital time, nursing time, loads of plasma and either needles in your arms or a line in your jugular vein. Steroids are just bad as there are many side effects. As such if the ADAMSTS13 activity can forecast a relapse, it is recommended that the patient is prescribed Rituximab to help improve the ADAMTS13 activity. Additionally, Caplacizumab can also be prescribed as this drug will help to block platelet aggregation. Note Caplacizumab may not be approved for use in all countries, may not be known or used by your hematologist, and may not be prescribed due to its cost.

The conference discussed TTP and the brain and coping with chronic disease. Originally it was thought once recovered from TTP, the patient’s lives would return to normal. Unfortunately, studies have shown that TTP most significantly effects the brain, then the kidneys, and then the heart. As a result, many TTP patients do not fully recover. Due to the impact on the brain many patients become depressed. Discussions with recovered patients showed they are still dealing with the effects of the disease.

TTP does not impact people uniformly. About 75 percent of the time, TTP patients are woman. And is the US, about 50 percent of the patients are African American. There was no reasoning provided.

Stopping a TTP episode takes time. TTP is an auto-immune disease, so we first try to stop the auto-immune disfunction using Prednisone. This drug is quite effective, but like all other alternatives, it is slow. I have experienced this slowness. In 2017, my platelets were back to normal after 9 days and we stopped plasmapheresis, but 4 days later my platelets were 39 and I had retinal detachment. In 2019, we also stopped plasmapheresis after 9 days to allow me to go home for Christmas and Boxing Day. Unfortunately, my platelets dropped to 16 and we really had to start plasmapheresis all over again. We learned you need to taper away from plasmapheresis slowly to help prevent relapse.

All in all, the conference was successful. If you did not attend, you should watch some of the videos linked to the agenda above. I highly recommend you watch The Doctors’ Golden Rules section by Dr. James George.

 

Thanks, Bruce.

@BruceFightsTTP

 

TTP #5 Fooled Again

It all started on December 14, 2019. We were on our way down to see my sister but slept over halfway on our trip at my cousin’s place. We had a great dinner, a few beers and a good night’s sleep. In the morning, I took a shower and noticed a large bruise on my left bicep.

Now you would think that a person who has had TTP four times would have said, oh-oh, TTP again, but I didn’t. I assumed that I had bruised it from a workout in the gym on Friday morning. I had no other symptoms. I felt good. No headaches or stomach aches. No other bruising, no petechia. As a result, we went about our day and completed the trip to see my sister and her family. Fooled again.

The wonderful reason we went to see my sister was to hear her sing in a Christmas choir. It also gave us a chance to drop off some Christmas presents and to celebrate her birthday. We were only there for a day, but it was great to make the trip and catch up. Presence is a present.

I was still semi-recovering from TTP#4 from March 2019, so was still checking my blood on a regular basis and Monday, December 16 was the next date. So around 9 AM, I stopped at Dynacare for a blood check. At 6:20 PM, I received a call from a hematologist at the Ottawa Hospital. TTP was back, platelets were at 14, pack it up, get to the hospital, we are doing plasmapheresis tonight.

Not only was I upset about TTP, but we were close to Christmas. I didn’t want to be the guy that messed up Christmas. My youngest son and girlfriend were coming for Christmas. My oldest son and fiancée were coming for News Year’s. I really hoped this would work out.

From 16 to 24 December, I had plasmapheresis 9 times. My platelets went from a low of 9 up to 136 on Christmas Eve. I was doing so well that I was moved to out-patient status on December 20 and was able to celebrate with Christmas and Boxing Day off – no plasmapheresis. On December 27, my platelets had dropped to 20 and I was re-admitted to the hospital - it felt like we were staring all over again. My platelets did climb, and I was again an outpatient on New Year’s Eve. I had plasmapheresis 15 more times with the last one on January 15, 2020.

So, let’s think back to December 14, I had a bruise, what were my options? Well, I’m thinking 1) keep going to see my sister, 2) think that I have TTP and head to the Ottawa General (my wife’s choice) or 3) go and have the blood checked at Dynacare where I have an open requisition. With a map lookup, I can see that a Dynacare was only 16 km away which was open on Saturdays. It was really an option. Either way, options 2 and 3 would have seen treatment started two days earlier, but then I wouldn’t have visited my sister or seen her sing in the choir. Choices …

So, where did the bruise come from. I was in the gym the morning of December 16 and asked my personal trainer how I got the bruise and he said, not from the exercises you did. So how? I didn’t figure it out for a few weeks, when I was sitting in a chair with a what I think they call a Windsor back. Apparently, when I am sitting in this type of chair, I sometimes rest my left arm over the top rail of the chair. I bet that having those couple of beers with my cousin caused that bruise.

Next time I get the bruise there will only be two options – blood check or hospital …

Thanks, Bruce

@BruceFightsTTP