Clene Banks on Novel Gold Nanotherapeutic for ALS and Beyond

Rob Etherington

In late January 2020, the FDA approved the investigational new drug (IND) application for the HEALEY ALS (amyotrophic lateral sclerosis) platform trial, ultimately giving the green light to evaluate zilucoplan, verdiperstat, and nanocrystalline gold in patients with ALS.

The groundbreaking trial is the first to evaluate multiple potential ALS treatments at once. Clene Nanomedicine’s CNM-Au8, or nanocrystalline gold, was among 1 of the 3 selected investigational therapies from a pool of approximately 30 applications chosen for the first round of the trial after it had shown positive results in mouse models.

In an interview with NeurologyLive, Rob Etherington, chief executive officer and president of Clene Nanomedicine, gave an in-depth look into the HEALEY ALS trial, how it will be executed, and the impact that the platform trial may have on the ALS community.

NeurologyLive: What are your overall thoughts on the HEALEY-ALS platform study, and what advantage does this study present over other single drug trials that are currently ongoing in the ALS space?

Rob Etherington: Mass General and the HEALEY program are advancing the neurodegenerative state considerably [with this platform trial]. Approximately 30 different companies worldwide applied for this program, and Healy has chosen drug assets from 3 different companies to start the project. After extensive scientific review, they selected the 3 that they think are most promising to help in the ALS community, and will asess them head to head with shared placebo. There's a master protocol, and each one of these 3 assets follows the same inclusion criteria. Each patient is then effectively masked as much as possible and then they share each other's placebo. Of the 160 patients per treatment arm, 120 are on active drug and 40 are on placebo which is important for the patients, as they have a lesser chance of being on placebo and a higher chance of being on active drug. As for the companies involved, they have the opportunity to have an accelerated path to approval.

The FDA always reserves the final right to make their decisions at the end of the program, but the way that this has been designed, if one of these drugs is successful in reaching the primary end point, then there will be tremendous pressure to get the drug approved into market. It's possible that we could see an acceleration of ALS-approved drugs. I mention that in the plural, because it's possible that 1 or more of these assets actually show benefit and 1 or more of these assets could be approved for this horrible disease that has had very little real progress over the past several decades.

What positive signs have you observed prior to this study that has suggested that this drug would be a good candidate?

We've been focused for the last 5 or 6 years on remyelination and neuroprotection. We started working in ALS about 18 months ago, so our ALS road is relatively recent. We did a SOD1 mouse model with mice that all have and develop ALS. WIth CNM-Au8, we found both an improvement in health span and an improvement in lifespan. There were a series of assessments that suggested the mice were actually performing better and able to do better against mice that were on placebo in terms of activities of daily living, Additionally, we saw a mortality advantage versus placebo.

After this data was shown to the ALS scientific community, they suggested that we should do an induced pluripotent stem cell model using an ALS human tissue donor and cell lines. We ended up building ALS stem cells effectively and saw a benefit in this model compared with placebo. That data taken together was then presented to the HEALEY team, a scientific advisory committee that evaluated all the assets from around the world. That led us to be one of the first drugs chosen for this program. We'd already solved for many of the safety and toxicity issues the agency is often focused on through our program for Parkinson disease (PD) and multiple sclerosis (MS) phase 2 clinical work, which had been approved before the HEALEY trial. We learned through those programs that the drug had a very appropriate safety profile, so the previous work enabled us to be a very able candidate for this program.

READ MORE: How an Innovative Trial Design May Change the ALS Treatment Landscape

What types of outcome measures are you specifically looking and hoping to accomplish in this upcoming trial?

We have 3 ALS clinical programs that are underway right now. One is the HEALEY program, and the other is headed by Merit Cudkowicz, MD, MSc, the Julieanne Dorn Professor of Neurology at Harvard Medical School and chief of neurology at Mass General, who is also the director of the HEALEY Center. She suggested and we agreed that we should ask for early access approval from the FDA. In this trial, she placed 20 patients on our drug through an early access program that was enabled by the 21st Century Cures Act of Congress that encourages the FDA to approve high medical need diseases for drugs that have already demonstrated some safety. Clene is already being taken by 20 patients in that early access program since commencing in the fourth quarter of 2019, so we've had patients on our drug for a number of months. In addition to that, Clene applied and was approved for a large grant from Fight MND a foundation based in Australia for diseases like ALS and including ALS. With that, we started the Rescue ALS program, which contains 42 patients that have ALS, in a placebo-controlled, double-blind, trial that’s been underway since last month. As for the HEALEY trial, Clene and the other 2 drugs included in the study are all on the same master protocol and will evaluate change in ALS functional scores as a primary end point. This primary end point is essentially a composite score recognized by the FDA and chosen by the HEALEY program. All 3 drugs will be competing head to head with that composite score. By using that score, investigators are getting a basic assessment of how patients with ALS are doing.

Do you anticipate making any changes in terms of dosing regimens in order to possibly tease out the drug’s efficacy?

We originally proposed that patients take up to 30 mg CNM-Au8 or placebo, which is our mid dose; however, the [FDA] asked that we include 2 doses: a 30 mg mid dose and high dose of 60 mg. We did agree with the FDA’s recommendation to do a bit of a dose ranging and then push the dose further, but the intent of this program is to take the drug to the market if either one or both doses meet the primary end point.

How can this platform trial potentially impact future clinical development in the ALS space?

The idea of a platform study with head to head drugs sharing placebo has been used successfully in the oncology space for high medical need, such as cancer treatments. We are thrilled that the neurodegenerative space now gets to avail itself of the same benefit. These such studies advance drug development. We are especially grateful for John Healey and AMG, who gave the money to Harvard to enable this program to proceed. Usual traditional drug development occurs with 1 pharmaceutical company with 1 asset against 1 placebo. Additionally, they all run in parallel with different scientific tracks and different scientific advisory groups. In this case, there is 1 aligned team, 1 group of science advisors, 50-plus centers that are all part of the Northeast ALS Consortium (NEALS) across the United States. This allows the patients to have access to 3 of the most promising drugs as determined not by the pharmaceutical companies, but by an esteemed group of ALS experts.

Is there anything else that people should know about Clene’s nanocrystalline gold?

Our asset is very unique--tt's the world's first nanotherapeutic that patients will drink every morning. It has, so far, had a very clean side effect profile as we are simultaneously studying this drug in clinical trials of MS and PD. We're indeed hopeful that we may see a neuroprotective disease modifying agent with our assets, and we're looking forward to the results in about 18 months to 2 years.

Transcript edited for clarity.