What is graft versus host disease and why is it important to find therapies for it?
Kiadis is developing innovative and potentially life-saving therapies for patients with late-stage blood cancers who are in need of a transplant. Bone marrow transplants are used as a last-resort treatment for patients that have blood cancers like leukaemia. Allogeneic haploidentical stem cell transplants (HSCTs) are a potentially curative treatment for haematologic cancers and certain inherited non-malignant disorders. Haematopoietic transplants are con-ceptually simple; diseased stem cells in the bone marrow are eradicated with aggressive cytotoxic chemotherapy and replaced with donor-derived CD34+ stem cells, which recolonise the marrow and reconstitute production of healthy blood cells that are free from disease-driving mutations.
However, the fundamental problem with bone marrow transplants is the risk of rejection. Most people are familiar with the risks of transplanting organs like kidneys, where the new organ can be rejected by the patient’s immune system, but in this case the patient themselves can be rejected by the immune system of the donor, known as graft versus host dis-ease (GVHD). GVHD is a potentially lethal side effect that occurs in many allogeneic trans-plant patients.
GVHD occurs when mature transplanted donor T-cells recognise the patient’s tissue as ‘non-self’ and start attacking the patient’s body, causing skin damage, gastrointestinal tract malfunction, liver injury and other organ system impairment. It is an absolutely terrifying disease which can lead to permanent impairment of quality of life, and in many cases even death. Patients with GVHD often require prolonged immunosuppressive treatment which increases the risks for infections, organ damage, secondary malignancies and other complications associated with these medications.
Several employees at Kiadis have had family or friends who have experiences with transplants and leukaemia and they know how difficult it can be. This experience is a strong motivation towards our commitment to developing a potential life-saving treatment.
In fact, we recently had a patient who came to share her experience. She was transplanted 20 years ago with bone marrow from her sister and got acute GVHD, almost died, then was in a coma for about a month and has had chronic GVHD ever since. She can’t work, and she’s never been able to start a family. Half the time she can’t even leave her house, because her intestines have been destroyed and she has constant diarrhoea. She has to put artificial tears in her eyes every 30 minutes because the tear ducts have been destroyed – if she forgets in the evening, she can’t get her eyes to open in the morning. She said she often asks herself why she did this transplant and wishes she was dead. But the thing that really struck us was that whenever she feels bad she says, ‘Sis please stop’, because she was transplanted with cells from her sister, and although her sister saved her life she is also hurting her every day. It makes you realise that her sister must feel horrible about it too.
A lot of doctors are impacted by the experience. I’ve heard a number of doctors say they feel really bad about causing this disease. I described this patient’s case to one of our principal investigators and in his opinion this was a mild case. The very severe cases are in a much worse shape.
Luckily there are also some great examples where bone marrow transplants have done wonderful things. Olympic gold winning Dutch swimmer Maarten van der Weijden had leukaemia at the age of 19, received a transplant and then won the gold medal in open water swimming in 2008. He has been swimming to raise funds for cancer ever since.
What are the current ways to prevent or address GVHD?
One option is to use a genetically matched donor, but there’s a limitation to the number of patients for which they can find matched donors, and even with a genetically matched donor you still see GVHD.
An alternative that doctors are using more and more, is a protocol whereby they conduct a transplant with a genetically half-matched donor. This causes a massive T-cell attack in the patient. To suppress this attack, a strong dose of chemotherapy is given on days three and five after the transplant. This will destroy the activated immune cells from the donor and limit the T-cell attack in the patient.
With our lead programme, ATIR101, we essentially do the same, but outside of the patient. We remove the unwanted ‘bad’ T-cells that would attack the patient but we retain the ‘good’ T-cells that are needed for protection against infections and protection against relapse of the disease.
How does ATIR101 aim to address these problems?
ATIR101 is a patient-specific T-cell product designed to be delivered following a haploidentical hematopoietic stem cell transplant (HSCT) in order to support the patient’s newly transplanted immune system before it becomes fully functional.
We manufacture ATIR101 ex vivo from donor T-cells by selectively depleting harmful donor T-cells that can attack patient tissue and cause GVHD while retaining those T-cells that fight relapse and infections. We believe that ATIR101 can improve haploidentical HSCT outcomes and treatment options, thereby enabling the use of haploidentical HSCT in a broader range of patient groups and a broader range of diseases of the blood or immune system.
Bone marrow transplants can be curative, but the rejection problem is massive, and this is potentially a way to make it fundamentally safer and therefore more broadly applicable.
What has the phase II data shown?
The most relevant endpoint is called graft-versus-host disease free and relapse-free survival (GRFS) – which is designed to capture patients being alive and also having a reasonable quality of life. If you relapse after a transplant, your chances of survival are very slim. If you have severe GVHD after transplant, then again your chance of survival is reduced and you also could face a severely reduced quality of life. Currently GRFS is 30-40% one year after a haploidentical stem cell transplant based on literature data for the ‘Baltimore protocol’, where patients are given strong chemotherapy on days three and five after the HSCT. With our approach, based on the single arm phase II trial, GRFS goes up to over 50%.
What’s been the biggest challenge in the development of this therapy?
The fact that we’re dealing with a cell therapy has of course had an impact. Even just five years ago cell therapy was regarded as an unknown area. Historically this impacted the ability to fund the company, it impacted our progress, and the regulatory paths were not clear. It certainly was a bottleneck in the evolution of the company. Since June 2017 we have been able to raise over EUR 100 million for Kiadis and now have a cash runway into 2020. The company has also come a long way in establishing the technology and approach, the manufacturing process, and we have tailwind with CAR-T products recently being approved and cell therapies and regenerative medicine being recognised for their potential to improve the health of patients.
What are your plans for ATIR101?
The company expects a CHMP opinion in the first half of 2019. Following potential EU approval Kiadis intends to commercially launch ATIR101 in a first EU member state in the second half of 2019. In Europe there are only about 64 major transplant clinics in the EU4 countries (Germany, UK, Italy and France), so we can clearly commercialise ATIR101 ourselves.
For a regulatory filing in the US we will need to submit data from our ongoing phase III study. In the US about 27 transplant clinics do about 50% of all transplants – so it’s really concentrated – and you don’t need a large sales organisation. We’re setting up our own manufacturing facility, in addition to the CMO we’re using, and we’re building up our own commercial organisation. π
