Straight Dope on Medicine: Graft vs. Host Disease in Children

Author

Scott Ganser
August 07, 2023

Australia isn’t big into biotech. Australia is an important source of export cereals, meat, sugar, dairy produce, and fruit. They are highly dependent on agriculture, (“riding on the sheep’s back”) and foreign investment.[i] Wheat, beef, lamb, dairy produce, and a range of irrigated crops also became important during the first century of European settlement.

This country down under only sports 3 successful biotech ventures: CSL, Cochlear and Resmed, valued on the sharemarket at $139 billion, $14.7 billion and $13.3 billion respectively.[ii]

What they do have is kind of sketchy.

Emyria is trying to commercialize MDMA (ecstasy) for treating PTSD and other mental illnesses, as well as cannabis. The company is burning $500,000 a month, has $2.7 million in the bank and is years from commercializing its treatments.

Avita Medical, which is commercializing the plastic skin invention of former Australian of the Year Fiona Wood, saw its share price surge nearly 50 per cent in February when it announced surprisingly strong sales in the United States.

I clicked on their link to check out plastic skin, but their server is down.

This only adds to the sketchiness.

Now I have to resort to Wikipedia, which itself sports a certain degree of sketchiness.

The first regenerative medicine product brought to the market by Avita Medical was ReCell spray-on skin for the treatment of burns.[1] The two latest products are ReNovaCell, for Aesthetics and Plastic applications including skin trauma, and ReGenerCell for the treatment of chronic wounds.[iii]

Now I would certainly like to vacation in Australia, but time and money are a bit prohibitive.

Fun comes at a premium don’t you know?

One of my favorite expressions is “Now I have to pay for all of this happiness.”

But let’s not get sidetracked on a tangent.

Mesoblast is about to blast off. They have some sizzling technology that they got from the states that is beginning to come into its own. I own some shares of this concern, so take what I am saying with a grain of salt. I have a stake in seeing some success.

Mesoblast is using its proprietary mesenchymal lineage cell technology platform to develop and commercialize innovative allogeneic cellular medicines to treat complex inflammatory diseases resistant to conventional standard of care.[iv]

The Company’s portfolio of Phase 3 product candidates is:

  • Remestemcel-L for steroid-refractory acute graft versus host disease (acute GVHD) in children

  • Remestemcel-L for moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 infection

  • REVASCOR® for advanced chronic heart failure

  • MPC-06-ID for chronic low back pain due to degenerative disc disease

No one cares about Covid anymore. Are they even testing for it?

Recently they have secured a date with the FDA on the steroid-refractory graft versus host disease that would be a first of its kind, if approved.

Mesoblast’s novel allogeneic product candidates are based on rare (approximately 1:100,000 in bone marrow) mesenchymal lineage cells that respond to tissue damage, secreting mediators that promote tissue repair and modulate immune responses.

Mesenchymal lineage cells are collected from the bone marrow of healthy adult donors and proprietary processes are utilized to expand them to a uniform, well characterized, and highly reproducible cell population. This enables manufacturing at industrial scale for commercial purposes. Another key feature of Mesoblast’s cells is they can be administered to patients without the need for donor–recipient matching or recipient immune suppression.

Remenstemcel-L

The FDA has accepted a resubmitted biologics license application for remestemcel-L as a treatment for pediatric patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD).

Acute GVHD occurs in about 50% of patients who receive an allogeneic bone marrow transplant. About 30,000 people globally receive an allogeneic bone marrow transplant each year, mostly during treatment for blood cancers. In patients with the most severe form of acute GVHD, Grade C/D or III/IV, mortality is as high as 90%. There are currently no FDA-approved treatments in the U.S. for children under 12 with SR-aGVHD.[v]

The resubmitted application for remestemcel-L contained long-term survival data from a phase 3 trial (NCT02336230) with 4 years of follow-up. In a group of pediatric patients with predominantly grade C or D disease, 63% receiving remestemcel-L survived after 1 year, and 51% survived after 2 years.

Additionally, the resubmission contained new outcome data on the agent's activity in high-risk disease by propensity-matching patients in the phase 3 trial and controls from the Mount Sinai Acute GVHD International Consortium (MAGIC) database who were stratified based on biomarkers. In the trial, 67% of pediatric patients with high-risk disease responded positively to remestemcel-L within 28 days and were alive after 180 days compared to 10% of control patients receiving other therapy in the MAGIC group.[vi]

What happens in your body when you have chronic GVHD?

Chronic GVHD CAUSES YOUR IMMUNE SYSTEM TO BECOME UNBALANCED. In people with chronic GVHD, the immune system overreacts, creating too many of some cells and molecules, and not enough of others. This leads to inflammation (swelling) and fibrosis (hardening, scarring).[vii]

My stem cell transplant[viii]

I had my transplant in February 2014 – I had been totally wiped out from the treatment for two weeks after, then I caught flu and spent further time in isolation. It was a bit like being in purgatory!

It was quite daunting; I didn’t really feel prepared for it. My sister was searching everything on Google, but I said, ‘what you get is what you get – let’s just deal with it!’

But if I could go back again and prepare myself a little better for treatment, I would. You need to put your serious head on for a few days and get ready for the onslaught.

 

The first signs of GvHD

I first noticed the acute graft versus host disease in hospital around three to four weeks after my transplant. I had a bit of redness on my legs; it started off with some red patches that my wife noticed.

We told the doctor when he came in to see me, and by the time he’d left the room about two to three minutes later the red patches had turned to purple – it was like someone had painted my legs and arms! I was put on steroids straight away, and it only lasted a few days.

I came home from hospital in early April. The sun was shining and I set the gazebo up in the garden, but I ended up sitting out in the sun covered up in a big coat, hat and gloves because even though it was warm - I felt cold!

l can remember feeling cold most of the time, and that can be part of the skin GVHD.

Paul on holidhy

The onset of chronic GvHD

By July I felt like I could have gone back to work and could cope with most things.

We went to Portugal on holiday in August. I’m not greedy, but I usually have a good appetite, and while we were there, I started to notice that I couldn’t finish my food. By the time I came back I was quite poorly.

And that was the onset of the chronic GvHD – I had problems swallowing food, couldn’t finish my food, and if I had a main meal, I couldn’t eat dessert as normal.

The first thing we did when I got back was report to the local hospital as I also had a fever, then mid-week I went to my transplant center and they confirmed the symptoms were chronic GvHD.

If there are 100 symptoms of GvHD – I’ve had 99. My skin, hair, scalp, eyes, mouth, lungs and intestines have been affected. I’ve had aching joints and muscles, sinus problems and thickening of the skin around my ankles – they look like my old nan’s legs now!

The most worrying is the lung problems – I get short of breath. I can walk reasonably well, but odd jobs around the house are difficult. I remember trying to repair a switch in the cooker this time last year. Even a simple job like that took me all day, because I was so breathless.

 

Paul and his wife Frances

Treatment for my GvHD

I’m having lots of treatment for GvHD – I’m still on the immunosuppression – ciclopsorin, as well as other regular medications. I have various creams for the skins, eye drops for the GvHD in my eyes. And I’ve been having a treatment called extracorporeal photopheresis (ECP) as well, which seems to be helping.

I also still suffer from fatigue now two years down the line – I’ve always had a manual kind of job, and decorated the house, been really hands-on. Now I do jobs in the morning so I can rest in the afternoon.

We did talk about GvHD before my transplant – the consultant went through it – but not in a great deal of detail. I feel like I’ve been lucky, though. All the GvHD has been running along in the background. I just take it as it comes, deal with it and get on with it.

I feel like now it’s just a fact of managing it; at moment I can handle it, and the treatments are keeping it under control.

I saw an advert on TV the other day that said you shouldn’t have to deal with cancer on your own – but I’ve never been lonely. My wife, daughter, family –everybody, really – has supported me. I could talk the hind legs off a donkey - to anyone who will listen! I’m of the opinion that sharing an experience will hopefully help someone else get through it.

Conclusion

It has been a long, long, long time coming for a cell-based therapy. The FDA has been totally corrupted and this might be exhibit A.

Why do I say that?

In 2020, the U.S. FDA Advisory Committee votes nine to one in favor of Remenstemcel-L (Ryoncil) for Efficacy in children with steroid-refractory acute graft versus host disease, but then their bureaucratic bosses decided to give them a complete response letter.[i] Committee That’s like your teacher giving you an A+ and then your principal removes it to give you an F instead.That’s like your teacher giving you an A+ and then your principal removing it and giving you an

Mesoblast Chief Medical Officer Dr Fred Grossman said: “Steroid-refractory acute graft versus host disease is an area of extreme need, especially in vulnerable children under 12 years old where there is no approved therapy.”

This week the FDA did it again. They gave a complete response letter to Mesoblast. That means total rejection. However, they did extend an olive branch. Mesoblast will have to do another trial with adults who are extremely sick.

That’s right. In order to get the indication for children 12 and younger, the FDA is demanding data generated in adults. That’s like vying to get approval for a product in cats, you have to validate it in dogs.

The FDA just doesn’t want to approval cell therapies.

And they will keep moving the goal posts to achieve it.

The biotech said it will hold a Type A meeting with the FDA within the next 45 days to finalize the details of the trial, for which the company plans to enroll adult patients at highest risk of dying from SR-aGVHD.[ii]

People are literally dying, and the FDA is indifferent. Maybe not indifferent, but actually hostile. The regulator hadn’t raised any safety issues with the more than 1,300 patients who have received remestemcel-L across various trials.

Safety is not an issue. Ego and corruption are.