ALS Medication Development Hits Roadblock but Holds Promise: Insights from Treeway CEO

An interview with Inez de Greef, CEO Treeway
Translated from Dutch, original article from the VIG

Developing a new medication is challenging, especially for a rare disease like ALS. It becomes more difficult to find enough patients for clinical trials to test the effectiveness and safety of a potential new drug. Also, demonstrating that the drug works in practice, Real World Evidence, is then more challenging. Nevertheless, Inez de Greef took the plunge.
 

Biotech company Treeway, where she is CEO, developed a medication for the rare nerve/muscle disease ALS (amyotrophic lateral sclerosis). However, the drug will not reach the market: the development process recently stalled in the very last phase of clinical trials. ‘The research results showed, contrary to all expectations, insufficient effectiveness,’ De Greef explains. ‘Very disappointing for everyone who was hopeful for a new ALS drug, initially for patients and their loved ones.’

De Greef studied medical biology and subsequently obtained a PhD in pharmacology. Her career began at a company developing HIV medications. ‘Inventing something new for and with patients; that's what drove us to develop one of the first cocktail therapies against HIV at the time. I found it important to be close to the patient. Ultimately, they are the ones for whom you do everything, no matter what position you hold within a biotech or pharmaceutical company.’ Through cocktail therapies, HIV eventually became a chronic disease.

Clear request

A few years later, De Greef, along with business partner Ronald van der Geest, founded a consultancy company. The company offers the full range of expertise needed in drug development, from discovery to market entry. This is how she gained recognition in the field of drug development. ‘At one point, I was called by two ALS patients, Bernard Muller and Robbert-Jan Stuit. They had heard about me and asked if I would help them develop a medication for ALS. I was familiar with neurodegenerative diseases, due to my interest in neurology. But ALS was certainly not my expertise. I immediately said yes, because various things that I find important came together: developing something new, a clear request from patients, and collaborating with a team of experts and stakeholders.’

Developing a biotech company

De Greef was appointed CEO of Treeway. She began developing Treeway into a biotech company. ‘Developing a medication carries a high risk and requires a substantial budget. Not only for developing a new drug, but also for bringing it to market. In an academic setting, it is generally more difficult to take a big risk with a significant investment. I wanted to be able to make quick progress and felt that the biotech company model was best suited for that.’ Collaboration was crucial for taking these steps. ‘We continuously did this with Treeway; with academics, with the ALS center, with patient organizations. Each party has its own expertise, which we can complement.’

Step by step From the outset, De Greef realized that developing a medication for ALS was not easy. ‘All studies that had been done until then had all failed at their endpoints. I wanted to be realistic at that moment and started from the idea: if we first start developing a drug that slows down ALS, then we can already help patients now. With the knowledge and experience we gain during that process, we can take the next step towards halting the progression. And finally, take the step towards a drug that cures ALS.’

Unknown cause

What makes developing a drug against ALS even more challenging is that in ninety percent of patients, the cause is unknown. ‘In only ten percent of cases is the cause a mutation. And within that ten percent, there are also different genetic mutations,’ De Greef explains. ‘The biology of ALS is complex; different disease processes occur in the brain. The signals that neurons send to the muscles are disrupted or reduced, ultimately causing the muscles to weaken. Because of these different disease processes, it is more difficult to identify a specific target for the drug under development. This unpredictability reduces the chance of success and thus increases the risk profile.’

Insufficiently effective

Treeway discovered an active substance that could potentially slow down the ALS disease process. ‘Together with our partner Ferrer, an international pharmaceutical company, we entered phase III of clinical trials. Phase III is the final phase of clinical research before evaluation by the EMA (European Medicines Agency). After that evaluation, the EMA provides a positive or negative opinion on market entry. ‘Based on previous studies and scientific literature, we expected to achieve the endpoints. But unfortunately, the results in January showed that our drug was not sufficiently effective.’

Biomarkers and endpoints

Although the disappointing results were a major letdown, De Greef does not see the termination of their study as a failure. ‘It has been one of the largest studies in Europe. We included existing endpoints and biomarkers in our study.’ Biomarkers are measurable indicators in the body that provide information about the condition and how it behaves. They are measured to investigate a biological process, a disease-causing process, or the response to a medication. ‘Our study provided many insights into both the mechanism of action of our drug and the disease process in ALS. This is of great value for the development of future medications. Not only for ALS, but also for other neurodegenerative diseases such as Alzheimer's or Parkinson's.

Future perspective

Translating insights from one condition to another or translating results from the laboratory to the patient, translational drug development, will be increasingly seen in the future,’ De Greef predicts. She sees this as a positive development. ‘It makes the development of new medications more efficient and less costly. You can predict in an earlier stage whether the medication will be effective and therefore also decide earlier whether to advance the study to the next phase.’ De Greef also finds the development in the field of personalized treatments (personalized medicine) and cell and gene therapies promising. ‘The more personalized and targeted you can make a therapy, the more effective it can be.’

Investment fund

Another reason to be hopeful is that Treeway has always aimed to give other startups the opportunity to discover and develop something new. ‘From the perspective of the patient, our philosophy was: the more parties working on something, the greater the chance of discovering something. We wanted to facilitate that. Together with another ALS patient, Garmt van Soest, we took the initiative for the ALS Investment Fund. Garmt passionately worked to get this fund off the ground. Once it was established, Treeway withdrew from the fund. There is no conflict of interest.’

Out of the world

The fund contributes to dozens of studies into the cause and treatment of ALS. ‘By now, there are quite a few potential new medications in the pipeline. Because of this, I am much more positive about the future of ALS patients than ten years ago. When we started, there was actually nothing. Promising steps are being taken now. Think of Biogen's medication, which recently received a positive opinion from the EMA for market approval. Because such promising steps are now being taken, there is also more interest in investing in ALS than before.’ Treeway also continues to strive for a medication for ALS. ‘We are now exploring what we can do with the knowledge and experience we have gained. Our mission is and remains: to eliminate ALS from the world.’"