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The FDA’s two leaps at once: on fast approval pathways and neurofilament light



Summary

Neurofilament Light (NfL) is potentially the most important biomarker in neurodegenerative diseases.

The FDA’s AdCom validated that importance in the framework of the negative vote for Amylyx’s Albriova for ALS.

I am recently seeing exceptional FDA review and approval pathways being explored by players in the neurodegenerative space.

From what I am seeing, the FDA may finally be taking giant steps in the review process of neurodegenerative diseases.


Introduction: the (alleged) contrast between the FDA’s treatment of neurodegenerative and other diseases

It has been mentioned several times at this point that the FDA should do in neurodegenerative diseases what it has been doing in oncology for years. That is, allowing faster approval pathways, such as Accelerated Approval based on surrogate endpoints such as biomarkers, to drug candidates that show favorable trending of such biomarkers considered relevant for disease progression or disease reversal. There are a number of possible faster approval pathways the FDA offers, such as Fast Track Designation or Breakthrough Therapy Designation.

I wonder whether we are not seeing early signs of use of such pathways already.

And I will set out below where I see the respective players in the neurodegenerative space lining up on their Neurofilament Light reporting.


Neurofilament Light

For a background on Neurofilament Light as a biomarker, I refer to my earlier blog post of March 8, 2022. It tried to summarize the abundant literature on the matter, the all the more regular appearance of it as a secondary endpoint in trial. Neurofilament Light is essentially a putative marker of neurodegeneration, but also a marker of neuroregeneration that could be used to diversify between disease-modifying and disease-non-modifying treatments. Measuring the tiniest neuronal filaments that can be detected in the bloodstream, NfL is higher in patients with neurodegenerative diseases and even those with sports concussion compared to healthy patients. Still recently, I found a paper mentioning that elevated plasma neurofilament light predicts a faster rate of cognitive decline over 5 years in participants with objectively-defined subtle cognitive decline and MCI. It’s an example. Google it for any neurodegenerative disease, and you will find an abundance of articles.

For me, Neurofilament Light reductions derisk possible investments considerably, or the lack of reporting or lack of effect compared to placebo makes investments riskier. Absolute numbers matter a bit, but I believe the FDA will mostly look at how data are trending.

NfL reportings
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How things looked before 2022

Let’s first go back to how things looked six years ago. When scientists met with FDA on frontotemporal dementia, the following was said:

Q: Could accelerated approval based on a biomarker related to the disease mechanism be applied under subpart H? For example, one genetic cause of FTLD is haploinsufficiency of the progranulin gene, which causes low progranulin protein levels in brain. Could approval be pursued on the basis of restoration of CNS progranulin levels combined with a reduction for a fluid biomarker of disease activity, e.g., neurofilament light chain?
A: It is very tempting to jump in on this. At this point we do not understand the pathophysiology of progranulin and NFL well enough to base approval on them. Biomarkers will be incredibly valuable here, it’s just that we need to learn more first. Consider amyloid as a cautionary tale. There was interest in using amyloid as a surrogate for approval. It seemed so logical at the time. But we needed to learn more and based on what we know now, the relationship between amyloid and clinical benefit is not clear.“

Clearly, Neurofilament Light was on the discussion table, but more work needed to be done to retain it as an essential biomarker for disease modification.

Then in 2019, Novartis’ Mayzent was approved for relapsing forms of MS. Mayzent prevents immune cells from migrating to the brain and spinal cord, thereby reducing the inflammatory process that promotes MS development and progression. Immune cells are glial cells, as I’ve covered before. Mayzent was also seen to significantly reduce blood levels of neurofilament light chain — a biomarker of nerve cell damage — meaning the therapy can effectively protect nerve cells. What did ‘significant’ mean here? A 5.7 reduction over 21 months compared to a 9.2 increase of the placebo group.


The FDA’s AdCom including Billy Dunn now openly favoring Neurofilament Light

I believe the FDA’s AdCom has now confirmed its validity as a helping light in the darkness of neurodegenerative disease repair.

As one may know, the FDA’s Advisory Committee voted negatively 6/4 against the approval of Amylyx’s Albriova for ALS. The March 30, 2022, 300+ pages long transcripts of the discussions surrounding that vote are publicly available, and show how important the FDA advisors and its Director of the Department of Neuroscience Billy Dunn considered this biomarker.


How questions and statements surrounding NfL came out during that sessions was well covered by Nina Lanyon as follows:

In a question posed to FDA officials, panel member Caleb Alexander — one of only two individuals on Wednesday’s committee who also took part in Biogen’s contentious hearing — asked about the utility of a biomarker known as neurofilament, which has seen increased interest from researchers in recent years to potentially track the course of neurodegenerative diseases. Alexander inquired how AMX0035 affected neurofilament levels in patients’ blood and how it stood up to the two older ALS drugs’ impact on the biomarker.
This proved one of the more significant developments of the hearing before the lunch break, given that the FDA’s voting question contained a stipulation asking panelists to consider what other information might be needed to establish the drug’s effectiveness, if they believe the Phase II study is not enough. The theory goes for most neurodegenerative diseases that if a drug is working, then neurofilament levels — a byproduct of neuronal cell death — would be lower.
The FDA’s Director of Division of Neurology 1 Teresa Buracchio responded that while neurofilament research remains promising, the agency still considers it an “exploratory” measure. Making his first remarks of the day, FDA neuroscience chief Billy Dunn concurred with Buracchio and said while neurofilament is not appropriate to use as a standalone measure, a drug’s impact on the biomarker helps to better contextualize the data.
Dunn then emphasized that AMX0035 showed no impact on lowering patients’ neurofilament levels in its Phase II study.
It’s something we found to be part of the overall character of data that we see that does not support robust data for the primary measurements,” Dunn said. “In the interest of having an effective medication available for ALS patients, all of us would have preferred to have seen a benefit … that we didn’t is a concern.”

Billy Dunn’s passage is even stronger when reading it in the transcripts. It is clear that the FDA’s AdCom considers this biomarker particularly helpful, not as a standalone measure to go for approval, but to help approval in light of good data, and to perhaps reject a request for approval.


Recent lessons from Eli Lilly’s approach with donanemab

Let it be clear: even though many want to throw them in the basket, amyloid olygomers and hyperphosphorylated tau tangles are still primary biomarkers for AD. Reducing them should reduce the overinflammatory response by glial cells, but the side effects of doing so are probably too problematic, and the effect so far seems to be fairly moderate. I think the approval of Aduhelm by the FDA may have been more a biomarker- than efficacy-based approval. And donanemab reduces both, but insofar as I know, has not reported on Neurofilament Light yet.

Things have been moving recently around Eli Lilly’s donanemab, another anti-amyloid antibody. Jim Cramer’s highly in favor of its approval, which makes me doubt whether he even looked at what it does. That said:

- on June 24, 2021, Eli Lilly received Breakthrough Therapy Designation for donanemab;

- Eli Lilly’s Phase 3 trial for donanemab is ongoing;

- in June 2021 and again in April 2022, Eli Lilly has announced that it would go for Accelerated Approval for donanemab;

- on August 4, 2022, Eli Lilly has officially chosen the Accelerated Approval pathway:

“That means that Lilly has a shot at getting an advanced approval based on biomarker evidence, rather than clear clinical efficacy data. It’s a pathway that has become a flashpoint of debate in the Alzheimer’s community since the FDA approved Biogen and Eisai’s Aduhelm that way, only to grant the companies nine years to conduct a confirmatory study to show the therapy had an actual clinical effect. Aduhelm has since been backed off the market after a lackluster launch and numerous problems.”

That now has a six-month assessment clock ticking.

In short, Eli Lilly is leading the way here. And we know how big pharma lobbies and is in constant conversation with regulators. If this pathway is now, finally, being walked on, then that may mean regulators and precedents may have hinted that it is a valid one to use for neurodegenerative diseases.


More activity in the neurodegenerative space based on biomarkers

I will add here that Biogen has recently introduced a biologics license application for Tofersen which it co-developed with Ionis Pharmaceuticals, and BrainStorm Cell Therapeutics has just this month announced that it will introduce the same for BIV001, both in ALS.

In its latest August 15, 2022, quarterly Presentation conference call discussing its announced upcoming BLA filing, BrainStorm Cell Therapeutics has expressly mentioned that it has been and will be in talks with regulators.

As we've mentioned, we're continuing a very active dialogue with leading MS experts, the Global MS advocacy community, and with regulators, all of which will inform and shape our plans to advance NurOwn in this underserved disease.
We believe that the clinical and biomarker results we have generated with NurOwn in the Phase 2 trial provide strong rationale for its potential to address the unmet clinical needs of progressive MS patients. We plan to present additional biomarker data from this trial later this year at the ECTRIMS Conference in Amsterdam, and along with the published manuscript, look forward to additional feedback from MS experts and regulators, which will eventually inform our plans to advance NurOwn in this disease.

I expect nothing less from Biogen, to the contrary even. The whole Aduhelm overhang, with an FDA internal investigation pending, in fact relates to Biogen talking to regulators.

The FDA has granted Biogen’s Tofersen Priority Review in July 2022, and Biogen has filed for Accelerated Approval for Tofersen as reported on August 5, 2022.

Both Biogen’s Tofersen and BrainStorm Cell’s BIV001 have favorable results on Neurofilament Light. Both missed a primary endpoint in a Phase 3 trial, but Brainstorm recently corrected results showing statistical significance in less evolved subgroups.

INmune Bio’s CEO had stated on November 4, 2021:

We watch with interest the rush of companies seeking approval for anti-amyloid therapies based on Phase 2 trials using the FDA accelerated approval mechanisms commonly used to gain conditional approval in oncology. It is too early to know exactly how this will play out for XPro, but we are preparing for accelerated approval after successful completion of our Phase 2 programs. Two elements are necessary for success, clinically relevant efficacy data and an ample safety database. We believe the potential weakness of a single trial strategy is not enough safety data, adding a second Phase 2 has the potential to expand both the efficacy and the safety databases.

Whereas the FDA’s decision on whether or not to approve Amylyx’s Albriova is scheduled for September 29, 2022, FDA’s decision on Biogen’s Tofersen is due for January 25, 2023. Exciting times lie ahead for the neurodegenerative space.


Conclusion

I am seeing two major leaps forward in an always more exciting neurodegenerative environment.


Look for reductions in Neurofilament Light. If reductions in cancer lesions are essential to oncology study results, then why would NfL reduction not be essential to neurodegenerative diseases, at least as a helping light? I have given my take on the matter in March 2022, and a bit later, saw confirmation coming from the FDA.

Amyloid oligomers and tau tangles may have biomarker value as well in Alzheimer’s disease, but neurofilament light is now additionally being considered as a guiding biomarker in the current assessment of disease-modifying drugs, across neurodegenerative diseases. That is one major leap forward. I have given an overview of reportings I found on that biomarker in different neurodegenerative diseases.

The Accelerated Approval pathway is best fit for an approval based on biomarker evidence.

I assume that Biogen’s recent BLA filing and BrainStorm Cell Therapeutics’ recent BLA announcement in ALS will be based on their good reportings of neurofilament light.


FDA is picking up the pace. What I am seeing now in the space shows speed and action coming from both the FDA and several players in the neurodegenerative space.

The Accelerated Approval pathway is now being used both by Biogen in ALS and Eli Lilly in Alzheimer’s disease, within a particularly short timeframe. The FDA has been granting Breakthrough Therapy Designation to Eli Lilly and Priority Review to Biogen’s Tofersen. I will assume this would not have been the case if there would not have been talks with the FDA.

These steps are perhaps already leading the way to other companies in the space, and their outcomes may have value of precedent.

Exciting times are ahead of us.


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