While the ALS clinical trial pipeline is in fact deep, there is still room for more. Will one of the phase 3 trials enrolling today lead to positive results? Are open label arms for phase 2 trials becoming the new norm? When will the first trials on C9orf72 start?
Today, there are more than 50 clinical trials enrolling people with ALS in the world. Among these are several trials aimed at specific genetic forms of ALS, natural history studies to try and identify subtypes of disease and two different pivotal phase 3 efficacy minded trials on drugs. Included in the mix of drug trials are both placebo-controlled studies as well as open label trials, in which all participants get access to the experimental medication.
Right now, there are more opportunities to participate in different clinical trial approaches than ever before. Below a handful of noteworthy examples are discussed because of their advanced stages in clinical trials or their pioneering approach to studying ALS.
Two Phase 3 Drugs in Trial
For the first time in a long time, two different phase 3 trials are occurring in people with ALS simultaneously; and both go after ALS in very different ways. The phase 3 trial of NurOwn being done by Brainstorm Cell Therapeutics is now 40% enrolled and aims to understand if multiple infusions of enhanced cells created from a patient’s own stem cells can reduce inflammation and provide neurotrophic support, leading to a slowing of disease progression.
More recently, a phase 3 trial which has opened for enrollment in the US and Europe, is investigating whether Levosimendan (ODM-109), a pill developed by Orion Pharma, can enhance the way a patient’s muscles react to signals from motor neurons. The aim is to “trick” the muscle into believe it is receiving more signal than it is from the motor neurons, potentially enabling the patient to continue to move their muscles longer, even when connectivity is lost as the disease progresses. The study is enrolling 400 people across about 30 sites in five countries.
See EDIT below for update.
Familial ALS Drug Trials
In 1998, SOD1 was the first gene identified to be associated with ALS and since then, much of the focus of gene therapy based clinical trials have targeted SOD1. Today, there is renewed hope thanks to the advancement of a novel antisense oligonucleotide approach from Ionis Pharma in partnership with Biogen. That approach is starting to be tested in a long term evaluation study in people with SOD1 mutations and participants are optimistic. There is no placebo arm in the long term study. Similarly hope is coming from an early stage clinical trial of a drug called Copper ATSM being done in Australia. That compound was pre-clinically validated as a clinical candidate in research done at ALS TDI and elsewhere.
However, SOD1 is only one of nearly 40 known genes known to be associated with ALS. Recently, researchers at the University of Kentucky began enrolling 10 ALS patients with FUS gene mutations in a study of the corticosteroid Betamethasone. This is the first drug trial to specifically target those with FUS mutations. Also, there are several companies working to become the first to start trials of therapeutic approaches for the most common ALS gene mutation; C9orf72. These include Biogen/Ionis, Pfizer/Sangamo and Wave Life Sciences. Wave has announced plans to begin enrolling their C9orf72 antisense trial in Q4 of 2018.
Open Label Trials
Many people with ALS cite the potential to receive a placebo in a trial as the greatest barrier to their decision to enroll or not. There are several options for patients to participate in open label trials, including the FUS and SOD1 trials named above. Others include a stem cell trial from Kadimastern in Israel, one from Flex Pharma, another by Grifols Therapeutics on Albutein being done by in New Hampshire, and another stem cell trial being done at the Mayo Clinic in Rochester, Minnesota, among others.
In addition, it is becoming more common for trial sponsors to offer patients access to experimental medications following the completion of the trial through open label extension arms of those studies. This follows the leadership from Cytokinetics in providing access to their experimental medication, tirasemtiv, to those that completed that trial who wanted to stay on it, even though the study itself missed its endpoints. Two such examples of trials that offer the option to move to an open label arm following participation in the study are the phase 2 trial of AMX0035 from Amylyx Pharmaceuticals and the phase 2 trial of H.P. Acthar Gel from Mallinkrodt.
Precision Medicine Program
Right now, more than 500 people from 20 different countries are enrolled in the Precision Medicine Program from ALS TDI. However, hundreds more are needed as early results need crucial validation. ALS TDI scientists reported in December 2017 that together with scientists at Google, they had developed tools and algorithms that may reduce the time and size of trials by as much as 50% but also reduce the burden on patients by tracking their disease progression entirely from home. These new potential clinical trial endpoints need validation before being applied broadly.
Enrolling in the PMP now gives patients access to some of those tools right away while providing data needed to validate the initial results reported. Prescreening for enrollment starts online here.
While the ALS clinical trial pipeline is in fact deep, there is still room for more. It is also important to note that many people in the ALS community want to see major changes in the way that trials of potential treatments are done in people with ALS. Thousands of comments were recently submitted to the FDA as part of their development of the first Industry Guidance on Clinical Trials in ALS.
For a complete listing of clinical trials, visit https://www.als.net/als-research/als-clinical-trials/
EDIT (8/14.18): At the time of publication of this article, there were only two phase 3 clinical trials enrolling people with ALS. However, the first patient was doses in a phase 3 clinical trial of the drug arimolcomol today, which signals that that trial is recruiting participants even though there are no open enrollment sites listed at this time. Regardless, Orphanzyme's phase 3 trial starting marks the first time in history there have been three simultaneous phase 3 trials enrolling people with ALS at the same time. The arimolcomol study will include 30 sites in the US, Canada and the EU and enroll more than 270 people with results expected in 2021 according to a press release from the company.