Neuraltus Pharmaceuticals Announces Phase 2 Clinical Results for NP001 in Patients with Amyotrophic Lateral Sclerosis (ALS)
- 136 PALS were included.
- There were three groups; placebo, low-dose (1 mg/kg) and high-dose (2 mg/kg)
- The study lasted 6 months for all participants.
- NP001 is a small molecule that is reported to regulate macrophage activity.
- NP001/placebo was delivered intravenously in all patients in the trial.
What does the press release say?
- The drug NP001 was found to be safe and tolerated by ALS patients.
- NP001, failed to meet statistical significance in any pre-defined endpoint measure in the clinical trial. However, the company reports seeing “positive efficacy trends”.
- Neuraltus announced today that they will launch a Phase III clinical trial of NP001 in ALS patient in the middle of 2013. No additional details regard size, location or participation data was made available in the release.
- A reduction of 13-19% in “multiple parameters of clinical benefit” was reported in the press release, but the company doesn’t identify what those parameters were. The company does acknowledge that this reduction was statistically insignificant in the trial.
- There have been reports on Forums that the clinical benefit measures used included FVC, strength, range of motion, etc, which would make sense as they are part of the typical clinical measures taken when a PALS visits a clinic.
- The press release reports that 27% of those in the study which were in the high-dose group (2mg/kg) experiences the greatest benefit that the company reports as “having no progression of their disease during the six-month dosing period”. However, again, this finding missed statistical significance.
- Why did the high-dose group have an effect and not the low-dose group?
- Understanding how/how much to dose drugs in people is a key part of the clinical trial process. Typically this requires that multiple doses be tried in order to find the optimal dosing stratagem, especially for novel drugs such as NP001. It is not surprising that one dose had a different effect from the other in this trial. In fact, it is encouraging as it may be leading this company to the optimal dose for this drug that could be used in the Phase III clinical tria
- Why did some people respond and others didn’t?
- This is a clear example of the heterogeneity of this disease. Every case of ALS is different in site of onset and progression rate. It is not surprising that some patients responded while others didn’t to NP001 at either dose. It has long been thoughts and now generally accepted that it will take a number of therapeutics to cover the vast array of ALS cases that exist. Similar to multiple sclerosis, where there are nine approved compounds for that disease but it is common that a patient will respond to only one or two of them. This is likely to be the similar case for ALS and the results from this trial highlights that likelihood. Understanding which patients are likely to respond to each available treatment that emerges for ALS will be a key endeavor and we encourage all those operating clinical trials to think about potential biomarkers that can be used to help identify the most likely treatment responders for each.
- Upon the completion of the study and analysis of results, some of which are reported in this memo, Neuraltus expanded its control group to include an unspecified and uncharacterized number of “historic placebo controls” as part of an ad hoc analysis. Only then did the results found reach statistical significance. Neuraltus states that its ad hoc analysis was subject to bias and the results from it should be viewed with sincere cautious optimism.
What does TDI think about the NP001 results reported in this press release?
The ALS Therapy Development Institute is encouraged by this early report of a trend toward efficacy of NP001 in ALS patients. However, this is a press release, and TDI encourages Neuraltus to make its clinical trial data available to public review as soon as possible – and certainly before launching its Phase III clinical trial. Only when TDI and others have access to the full data from this Phase II trial can we make any additionalcomments then these. However, at this time it is clear from the press release that there may have been a trend toward benefit which seems to justify moving NP001 into a Phase III clinical trial in ALS patients. The study’s lead, Robert Miller, of CPMC, is expected to make a presentation during the ALS/MND International Research Symposium in Chicago this December 5-8. TDI is a sponsor of this symposium, providing wireless internet access to all in attendance in order to report any data from presentations like that back quickly with the entire ALS community.
Clinical trial design as well as interpretation is an extremely challenging yet important thing in the field of ALS drug development. There have been a number of innovations and explorations in clinical trials in recent years, including the use of adaptive design trials, joint rank analysis and others. Similarly there has been an ongoing and for many anunresolved debate about the appropriate use of historical controls to replace some or all of a placebo group or upon the analysis of clinical trials. The issue with using historic controls in clinical trials remains highly controversial, especially as a necessity to reach statistical significance for endpoints. The issue of having sufficient numbers in a clinical trial played heavily in TDI’s decision to make its Phase IIB clinical trial be on a single dose of Gilenya® and include nearly 250 PALS and to track them over a year. Gilenya®, an FDA-approved compound for the treatment of relapsing/remitting multiple sclerosis, has also been shown to reduce the activation of macrophages and effect other immune cells.
About statistical significance:
What is statistical significance?
- The term statistical significance is used to describe a threshold that the results from an experiment are the result of a pattern, not simply chance (random error, noise in the system, etc). There are many different ways to describe, determine or interpret statistical significance. Similar to different measures, such as “margin of error”, statistical significance is a tool used to help people interpret large data sets and compare them to each other by accounting for a similar set of variables. Specifically, in science and medicine it is common for researchers to strive for at least a 95% confidence value that their findings are not a false positive, caused by random error or noise in the system. This is usually denoted as a “p value” and expressed in medical and scientific literature as p=0.05 (for 95% confidence) and up and down from there depending on the results. Measures that miss this threshold are said to have missed statistical significance. Clinical trials identify the threshold they will use in advance of launching the trial and it is considered, among other outcomes, in the decision as to whether or not the trial should move forward.
If NP001 missed “statistical significance” why is it moving forward into a Phase III?
- There can be no doubt that this trial and its result is significant to the ALS community. However, this trial was powered and designed to primarily address whether or not NP001 was safe and tolerable in ALS patients, not efficacy from a purely statistical perspective. It is not uncommon for trials to move forward when there is a trend toward significance only.
What does TDI think about statistical significance and what does it mean to patients today?
- While some may believe the 95% threshold is controversial, TDI believes, as it did with the SOD1 mouse model (Scott, et al), that researchers should create the best opportunities whenever possible to get the greatest confidence in clinical results from trials in which patients are taking a huge chance on highly experimental interventions and drugs. We believe that clinical trials should and can be designed so that they are best positioned to reach statistical significance upon completion.
- Patients gain confidence from a trial that is well powered for this measure in not only making the decision on whether or not to take a drug but in better understanding the potential side-effects from that decision. Similarly, these measures are some of those, together with other input from patients, that are used by the regulatory agencies when making approval decisions as well as neurologists when making treatment recommendations to their patients.
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