Need to Know:

  • Regulators want ALS survival data, but it can take a long time to collect. They recognise the importance of functional endpoints and quality-of-life measures as an early efficacy signal.
  • The ALSFRS-R is a widely used functional endpoint, but regulators are concerned it can generate incomplete data if patients drop out. To alleviate this issue, the FDA prefers an endpoint that jointly ranks function and survival, such as CAFS.
  • ALS trials should attempt to stratify patients based on severity of disease progression for clean data. Ongoing work towards disease state biomarkers could aid future trials.
  • The EMA has more stringent criteria for approval, although this does not preclude the possibility of an earlier filing and approval with the FDA.
  • European payers have an even higher efficacy data threshold than either US or European regulatory authorities, but such payers are receptive to linking payments to future trial results.

When Harvard University met with the FDA to discuss a platform clinical trial for amyotrophic lateral sclerosis (ALS), each party had a different primary endpoint in mind.

Clene Nanomedicine CMO Robert Glanzman, who was at a meeting with the FDA and Harvard, says the agency wanted a primary endpoint of Combined Assessment of Function and Survival (CAFS). CAFS ranks patients’ clinical outcomes based on survival, as well as the ALS Functional Rating Score – Revised (ALSFRS-R). On its own, ALSFRS-R is a widely used, validated primary endpoint in ALS clinical trials.

“The FDA likes CAFS because there’s no missing data,” Glanzman explains. “Everyone, including patients who drop out of the study, contribute to the ranked score.”

However, after a long discussion, the FDA agreed to use Harvard’s preferred endpoint, ALSFRS-R, which is more sensitive to changes in ALS disease progression. The Phase II/III HEALEY study (NCT04297683) is now underway, with a primary endpoint of change in ALSFRS-R after 24 weeks and survival as one of three secondary measures.

Clene’s lead candidate CNMAU-8 is in one arm of HEALEY (NCT04414345), with data expected in mid-2022. While Glanzman sees merit in both primary endpoint options, he will advocate for changing HEALEY’s endpoint to CAFS with Harvard and the FDA while data is still blinded. Given that CNMAU-8’s safety profile appears clean, he says there is less risk associated with using the FDA’s preferred endpoint of CAFS.

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The debate over HEALEY’s primary endpoint reflects many of the broader challenges drug developers face as they seek to develop ALS treatments. ALS is a rare, progressive neurodegenerative disease with an average life expectancy of four years after diagnosis. Although the ALS drug development landscape has historically been sparse, several drug trial readouts will headline a busy 2022.

All stakeholders want endpoints that are sensitive to subtle disease changes but also correlate with improved quality of life conditions. On top of this, selecting effective biomarkers, stratifying patients according to disease severity, and satisfying regulators in both the US and Europe present further challenges. As Richard Sear, business director at Dolon, a UK-based market access consultancy specialising in rare diseases, notes: “It’s really difficult to design an ALS study that’s going address all these needs.”

ALS clinical trial endpoint balance ideal

Survival was thought to be the only relevant endpoint in ALS 30 years ago, notes Chair of the Barrow Neurological Institute Dr Jeremy Shefner. However, a survival trial requires hundreds of patients followed over a long period of time, and that is not an efficient way to do drug development, he adds.

ALSFRS-R is one commonly used functional primary endpoint, but it can lead to missing data that the FDA struggles to interpret, Glanzman says. In contrast, as a joint analysis of function and survival, CAFS provides a ranked score to all patients, including those who drop out of trials, he adds.

In a 2019 guidance document, the FDA summarised its stance on ALS trial endpoints: “If patient function is intended to be assessed by the primary outcome, mortality should be integrated into the primary outcome by an analysis method that combines survival and function into a single overall measure.”

With Amylyx Pharmauticals’ AMX0035, these regulatory concerns with ALSFRS-R bore out. In the 135-patient Phase II CENTAUR trial (NCT03127514), AMX0035 met its primary endpoint of change in ALSFRS-R after six months. However, AMX0035 was initially rejected by the FDA largely because the agency was unsure how to interpret the approximately 20% of patients who dropped out of its study, Glanzman explains. The FDA reversed its initial rejection and is now reviewing AMX0035’s approval package with a PDUFA date set for 29 June.

To improve their chances at receiving approval from the FDA, ALS trials should have a six-month, placebo-controlled portion with a functional endpoint, followed by an open-label period where further survival data is collected, Glanzman notes. This design can balance getting short-term, sensitive functionality data with longer-term survival data that regulators desire.

ALS quality of life key in clinical trial

To successfully convince regulators and payers of an ALS drug’s efficacy, drug developers should include a variety of endpoints measuring ALS functionality and quality of life, Sear says. “There’s not just one ALS endpoint that is going to please regulators and convince payers.”

Outside of ALSFRS-R, there are important pulmonary measures and quantitative strength assessments for ALS, Shefner adds. The ALS field has also placed a focus on quality-of-life measures, particularly the 40-question ALS Assessment Questionnaire (ALSAQ 40), he notes. ALSAQ 40 is a patient assessment covering five quality-of-life categories: mobility, daily living, eating and drinking, communication, and emotional reaction.

Companies must persuade regulators that ALS functional endpoints correlate with prolonging patients’ lives during favorable quality-of-life conditions, says former European regulator Lincoln Tsang, currently the head of European Life Sciences Practice at Ropes & Gray. Prolonging survival in earlier ALS disease stages, when patients have greater ability to function, is much more valuable than prolonging survival in the later stages of ALS, Sear explains.

Biomarkers could aid patient selection

ALS as a disease is highly heterogeneous, both in terms of how it presents and how fast it progresses, Sear says. As a result, trials should aim to narrow inclusion criteria to patients with a relatively homogenous rate of progression, Shefner adds.

Clinicians often want trials stratified by slow and fast progressing patients, but this can be exceedingly difficult due to variations in the genotypes that underpin the disease, Sear explains. ALS can begin presenting symptoms via impacting either limb or bulbar function, and a large majority of cases are not directly tied to any traceable family history.

As a result, there is a significant push on developing biomarkers of disease state in ALS, which could help patient selection in the future, Shefner adds. For example, recent data suggests that neurofilament light chain (NfL) could be associated with more rapidly progressing ALS, he says. For now, there are currently no validated biomarkers in clinical trials aimed at approvals.

Looking ahead, target engagement biomarkers could play an important role in early stage ALS trials. They could both provide important outcome measure information and aid in patient selection for specific drugs whose targets are understood.

ALS regulatory standards vary

ALS is not a regionally confined disease, and it affects populations across all parts of the globe. According to GlobalData’s clinical trial database, there are currently 125 active ALS trials across Asia, Europe, North and South America. This includes 59 trials in North America and 47 trials in Europe.

Yet the two largest drug development markets, the US and Europe, can have vastly different standards for regulatory approval. “There’s a gap between the EMA and the FDA, with the EMA often slightly more restrictive and demanding,” Sear notes.

European regulators will not accept data shorter than one year, while the FDA will allow a six-month trial followed by an open-label extension, Glanzman notes. The EMA also expects an active comparator arm, while the FDA is open to placebo-controlled trials, Tsang adds. The EMA uses the comparator not only to help assess a new treatment’s efficacy, but also to determine the trial’s assay sensitivity, he explains.

In 2017, these varied expectations impacted Mitsubishi Tanabe Pharma's plans for its ALS drug Radicava (edaravone). Radicava received FDA approval for ALS after meeting its primary endpoint of ALSFRS-R in a 24-week, placebo-controlled, Phase III study (NCT01492686). However, the company withdrew its marketing application in Europe after the EMA cited concerns about the study’s short length and efficacy in measures beyond ALSFRS-R.

Companies could run separate US and European trials to satisfy differing regulatory demands. However, if a trial intended to satisfy stricter European requirements goes wrong, this could negatively affect the drug company’s US application, Sear notes. On top of HEALEY, which is recruiting in the US, Clene plans to run a separate European trial of CNMAU-8 in the future, Glanzman says.

European payers stricter on coverage

If an ALS trial shows an overall survival improvement of more than three months against an active comparator, the drug developer is in a very good place to negotiate with any payer, Sear says. Because ALS progression is highly heterogeneous and trials powered for survival require long time periods and an exceedingly high number of patients, payers understand this bar is tough to meet, he adds.

Many ALS trials are powered to show a 20% improvement in functional endpoints like ALSFRS-R, which could be enough to satisfy regulators, Sear says. However, ALS drug developers should expect payers to ask for data beyond what they plan to submit for regulatory approval, Tsang adds.

For functional endpoints like ALSFRS-R, payers would likely require at least a 30% improvement for coverage, particularly when data on survival is limited, Sear adds. European payers will also seek evidence suggesting survival data could become statistically significant with time and correlate with data from functional endpoints, he says.

Due to unmet needs and the challenge of collecting survival data, payers are open to negotiating deals. It is common for European payers to ink deals with developers that link future payments to a long-term follow up that confirm survival, Sear notes.

Long-term vision reaps rewards

While designing an ALS clinical trial can be challenging, strategic trial design can pay long-term dividends. An ideal set of endpoints, strategically collected throughout the trial's duration, would include functional assessments, survival data and quality-of-life measures to solidify a treatment’s real-world value.

Trials should aim to stratify ALS patients according to rate of disease progression. Developers should keep up-to-date on ongoing research into biomarkers that could help zero in on ideal subpopulations for study. Given the range of data expectations from regulators and payers, drug companies should involve all stakeholders in the trial design process as early as possible.

Globally, ALS affects an estimated two out of every 100,000 people, and its high unmet need looms large. A long-term strategy to get the drugs from clinical trials to market could reap long-term rewards.

ALS milestone calendar

CompanyDrug NameClinical Trial2022 Milestone
Amylyx PharmaceuticalsAMX0035Phase II CENTAUR trialPDUFA date of 29 June
Biohaven PharmaceuticalsverdiperstatPhase II/III HEALEY ALS trialData in mid-2022
Clene NanomedicineCNMAU-8Phase II/III HEALEY ALS trialData in 1H22
Prilenia TherapeuticspridopidinePhase II/III HEALEY ALS trialData in 3Q22
Wave Life Sciences WVE-004Phase I/II trialData in 2022
Eledon PharmaceuticalsAT-1501Phase IIa trialData in 2022