By Deborah Borfitz

October 17, 2019 | In recent years, master protocol trials that perpetually evaluate several therapies at a time for a single disease type—aka platform trials—have become a staple of oncology research. By some estimates, this next-generation clinical trial design cuts the time to find an effective treatment in half and decreases costs by a third or more relative to the traditional two-arm strategy, according to Merit Cudkowicz, director, and Sabrina Paganoni, investigator, at the Sean M. Healey & AMG Center for ALS (amyotrophic lateral sclerosis) at Massachusetts General Hospital.

The Healey Center is about to launch the world’s first platform trial to lower the barriers to testing promising compounds and improve access to trials for people living with a life-limiting ALS diagnosis.

As a first step, Healey Center researchers spent several months learning from investigators at other academic institutions successfully running platform trials in oncology, Paganoni says. The sites visited included Washington University that is leading the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial testing multiple drugs for Alzheimer’s disease.

The timing couldn’t be better, says Paganoni. Several ALS drugs have entered the pipeline over the past five years and almost 140 companies are working on ALS worldwide. “We know there are at least 40 compounds ready to go into trials in people with ALS.”

For patients stricken with ALS, “time is of the essence,” she notes. Life expectancy of a person with ALS averages two to five years from the time of diagnosis. “We want to cut the time to find an effective treatment, decrease the cost, and give patients more options.”

Steps to Success

The HEALEY ALS Platform Trial is one of the signature programs of the Healey Center, which was founded less than a year ago to rethink how ALS research gets done and accelerate the path to treatment, Paganoni says. Central to that mission is facilitating collaboration between domain experts and providing the trial infrastructure needed by smaller drug developers.

After issuing a call for the best therapeutic ideas for the platform trial, researchers received almost 30 applicants from 10 countries, she continues. The Therapy Evaluation Committee that included several scientists from the Healey Center Science Advisory Committee, and the Scientific Advisory Board of the Northeast ALS (NEALS) consortium provided recommendations about the initial five drugs to be tested.

The selection criteria included scientific merit and readiness to enter clinical trials, says Paganoni. The experimental treatments include zilucoplan, a small macrocyclic peptide inhibitor of complement component 5 [C5], developed by Ra Pharmaceuticals, Inc.; Verdiperstat, an oral myeloperoxidase inhibitor, developed by Biohaven Pharmaceutical Holding Company Ltd.; Bioenergetic Nanocatalysis (CNM-Au8, nanocrystalline gold) developed by Clene Nanomedicine, Inc.; Pridopidine, a highly selective S1R agonist, developed by Prilenia Therapeutics; and IC14 immunotherapy, developed by Implicit Bioscience Ltd.

All the compounds have completed pre-clinical and early clinical studies, says Paganoni. As reported by Prilenia, the safety and efficacy of Pridopidine is now being separately evaluated in a phase 2 Parkinson’s Disease trial. Zilucoplan is also being evaluated in a phase 3 trial for myasthenia gravis, and Verdiperstat is in a phase 3 trial for multiple system atrophy, Paganoni adds.

The Center will launch the platform trial with three therapies first, with plans to add two more shortly afterwards. “Our expectation is that we will continue to find new promising treatments that are ready or about to be ready to put into trials,” Paganoni says. That means the HEALEY ALS Platform Trial will continue to grow and potentially quite rapidly—for now, in the U.S., but with the potential to expand globally in the future.

At launch, the trial will involve 54 of the larger NEALS member sites that geographically cover most of the country, Paganoni says. Every drug tested will enroll 160 participants.

Protocol Design

The trial design leveraged input from ALS experts, including patients and clinicians, and is largely set—subject to expected feedback from the Food and Drug Administration (FDA) on a final round of edits at a meeting in November, says Paganoni. The trial is slated to get underway in 2020.

Academic researchers with the NEALS consortium together with Berry Consultants, the leading statistical specialists in adaptive designs and platforms trials, helped develop the master protocol, she notes.

A data monitoring committee will be doing interim analysis and rules are in place to stop the trial early for success (drug effectiveness) or failure (drug ineffectiveness), which is only one of several efficiencies of an adaptive platform trial, Paganoni says. The main advantage for trial participants is that they will have greater access to the active treatment versus the typical 50-50 chance of being randomized to the placebo arm. “For every four people who enter the platform trial, three will have access to the active drug and only one will be assigned to the placebo.”

Additionally, participants who complete the trial will have the option to either go on an open-label extension and know for certain they are getting the active treatment or go back and be rescreened into the platform trial to try a different treatment, Paganoni says. “We want to keep the trial open long term until we find a cure for all people with ALS. That’s our goal.”

One of the challenges with ALS trials is that they take a relatively long time and large number of patients because treatment effect is measured based on activities of daily living, says Paganoni. But new biomarkers, including blood tests and measures of muscle strength, have recently been developed that could potentially provide a faster, more economical way to see if a drug is or isn’t working.

Some of the candidate biomarkers will be tested in the platform trial and others will possibly be discovered, she says. For example, researchers are eager to learn if neurofilaments in the blood that are indicative of neurological damage can be reduced by any of the platform drugs. If so, and that correlates with other results, the finding would support use of the biomarker in clinical trials.

Fostering Collaboration

Government agencies have been at the forefront of master protocol trials, but much of work being done by TransCelerate BioPharma will facilitate the implementation and operation of master protocol trials by its member companies, says CEO Dalvir Gill. Membership comprises 20 global drug developers, including all the top ten pharma companies.

Platform trials aren’t the only type of master protocol trials, Gill says. Others include umbrella trials that are typically used for a single disease and are finite in length, and basket trials that involve testing one targeted drug or biomarker for multiple diseases or cancer types.

Most of the activity has been centered on cancer, he says, including the groundbreaking I-SPY 2 platform trial for breast cancer and Lung-MAP umbrella trial for advanced non-small cell lung cancers. The I-SPY 2 trial has resulted in accelerated approval of three agents, and several TransCelerate members are sponsors. Lung-MAP is an unprecedented public-private partnership that launched in 2014 and significantly expanded in 2018.

Design work more recently began on a muscular dystrophy platform trial, first discussed in 2016.

Gill says that he expects master trial protocols to become more prevalent, with TransCelerate helping to foster collaboration among companies. Even today, he notes, members recognize each other’s good clinical practice training. TransCelerate also has cross-company initiatives to enhance the professionalism of data monitoring committee members and develop a Common Protocol Template with machine-readable content that can automatically populate statistical analysis plans.

In the “world of the future” Gill envisions, if four companies have a drug with the same target, they will do one trial together rather than four separate studies generating four sets of results—and more quickly figure out which ones will get accepted by the FDA and payers and are better for patients.

Companies may decide to move in that direction once the FDA finalizes newly issued draft guidance on complex innovative trial designs, which include master protocols. A final version of the guidance is expected in 2020.

Pioneers in the UK

Master trial protocols are being conducted primarily in the U.S. and the U.K., says Gill, noting the greater logistical challenges in Europe where multiple countries report to a single regulatory agency. The U.K. is particularly amenable to master protocol trials because it has a single, connected healthcare service. “A patient can go anywhere in the UK and access their records. That’s harder to do here.”

These types of study designs were conceived in the U.K. where academic groups stake their reputation on them, says Matt Cooper, P.D., director of business operations, research delivery, at the National Institute for Health Research (NIHR) Clinical Research Network Coordinating Centre. In the FOCUS4 trial for patients with colorectal cancer, for example, patients have a window of opportunity during their first treatment phase to be screened against a panel of biomarkers that determine the treatment arm they’re randomized to.

The National Lung Matrix Trial, funded by Cancer Research UK, works much the same way for patients with non-small cell lung cancer, says Cooper. AstraZeneca and Pfizer were involved from the beginning.

“It’s quite a good way for companies to collaborate in a non-competitive manner because each of the arms is kept separate,” Cooper continues. The added advantage in the U.K. is that the NIHR can facilitate setup of a master protocol trial because it has visibility to studies underway nationally, including those screening patients for the same disease biomarker.

One master protocol trial for prostate cancer, STAMPEDE, has been ongoing in the U.K. and Switzerland since 2005, says Cooper. Data coming out of that one study has twice resulted in global clinical practice changes.