Clene Inc. Common Stock H.C. Wainwright 28th Annual Global Investment Conference

Rob, over to you. Thank you, Lander, and thanks to H.C.

Wainwright for inviting Clene to speak today at this meeting. Clene is indeed a unique company. We have a series of forward-looking statements here that speak to things that I'm about to speak to, and I'll refer to some of this forward looking during the course of this presentation. We are entirely, effectively now, focused on ALS, and as everybody in this room and on this viewing audience knows, ALS is a remarkably devastating disease. This notion of 100 being diagnosed every week is a tragedy because we also see 100 people dying every week, and data this week, in fact, shows that this number is an undercount. It is possible that this number could be well 60% north of 100 weekly passing away.

Survival is an extraordinarily important thing in this area, and unfortunately, diagnosis remains very much compromised throughout America. I am familiar and definitely rest of world. I am familiar with friends of mine that have had diagnosis and symptom onset, rather, a year ahead of when they actually got to diagnosis. That year, in a disease like ALS, where mortality is 2 to 4 years before they pass, is way too much missing. By consequence, there remains no cure. Everybody agrees that there is complete burden. So what Clene's doing is a proprietary gold nanocrystal suspension that people drink to enhance cellular energy and to protect neuron function. The consequence, and that's a very relevant, extraordinarily important consequence, restore mitochondrial function. Now, how could this actually happen? Why could drinking a nanotherapeutic suspension drive function?

Your brain and mine is only about 3% to 5% of our body weight, but it occupies and really needs 25% of the energy that you and I generate day in, day out, night and day. What our asset is doing as part of this massive energy-dependent process for our central nervous system, the way that you and I move and walk and talk and eat and chew and breathe, is driving not just the energy that our mitochondria requires through ATP or NAD+, but also reducing reactive oxygen species, and in the process, supporting neuron health. I like to think about it, and I've said this metaphor before, a little bit like a car. There needs to be gas in the engine.

The engine needs to do its bit. The output of such gas in a combustible engine is a catalytic converter that is washing and protecting the exhaust. It is not that dissimilar at a cellular level to what is occurring. There must be energy in the engine, the neuron, to drive function. As part of this energetic process, the reactive oxygen species reduced. Our asset, crossing the blood-brain barrier, is able to affect these things. We have anchored our upcoming New Drug Application on neurofilament light. Let me talk about that for a second. Neurofilament light is a cytoskeletal protein remainder of a debris field, if you will, after the disease ALS and other neurodegenerative diseases attacks the neuron. By consequence, I can measure it in the blood. I can measure it in the CSF.

ALS neurofilament matter immensely because if I was to ascertain my neurofilament levels today and see that they were rising and I had no present symptom onset, then I need to stand down, batten the hatches, and be prepared for compromise with my motor neuron function. That would be the case in many neurodegenerative diseases, but there is regulatory precedence in ALS because the agency has anchored neurofilament in the case of another example to give accelerated approval to another asset in SOD1 ALS. That is to say, individuals, very small subset, that are missing the SOD1 gene, a homogeneity ALS condition of missing SOD1 gene ALS individuals numbering in the hundreds in this country. The agency gave this asset and the company that sponsors it an accelerated approval process.

Clene is, in fact, leveraging this thesis because we remain a heterogeneous phase II double-blind placebo-controlled studies, the only company thus far to have a double-blind placebo-controlled benefit on neurofilament that was statistically significant. It was modest, one could argue. However, I want to clarify modest, because the improvement of the reduction or the stability matters immensely in ALS. Extensive data, and here is one example, shows that neurofilament trajectory increase or stability is categorically applicable to mortality risk. Even modest changes drive survival. In consequence, after now a number of meetings in the last 2 years with the FDA, totaling 5 type C meetings, we have actually built an NDA in partnership with agency direction, really fundamentally around 3 programs.

One is the HEALEY phase II double-blind placebo program, 2 is our phase II RESCUE program, and 3 is the $45 million that we got from the Accelerating Access to Critical Therapies for ALS Act, $100 million per year that Congress authorized for ALS research and expanded access. That $100 million over 5 years, $500 million, is 10% of which nearly, $45 million, was given to Clene for expanded use. In other words, compassionate use or the opportunity for us to put hundreds of individuals on drug for which we collected their neurofilament light data. In the spirit of that, from the double-blind HEALEY program, we saw pre-specified statistically significant 10% improvement in neurofilament, a reduction versus placebo. Similarly, the secondary endpoint pre-specified during the 6-month randomized period was a 94% risk reduction in survival.

These two data points from the HEALEY program really anchored the path that we are presently on. A neurofilament benefit seen in the double-blind placebo program, a survival benefit as the secondary seen in the double-blind program. Just to be clear, we missed the primary ALSFRS, which unfortunately for the sake of ALS people worldwide, everybody keeps missing. There was another phase II program this morning that read out negative in ALSFRS. If you were to plug the question into your ChatGPT, AI is the topic now all the time it seems, how many patients or rather drugs have failed in ALS? You would get tens of thousands, I mean, tens of dozens rather. I think the number is 80 to 100 assets that have failed on ALSFRS in the last number of decades, including Clene.

What we did achieve is the secondary survival, the exploratory of clinical worsening, and neurofilament light. The agency, wanting to understand the clinical relevance of a neurofilament change, asked us to replicate that in the National Institutes of Health-sponsored study I referenced earlier. Despite a completely different patient subset, the HEALEY phase II were about 6 to 12 months diagnosed, earlier rather ALS diagnosis. The EAP were patients that could not get into any clinical program. They were appreciably worse on their ALS. They were, in some cases, 4 or 5 years diagnosed, and that is saying something in a disease that is uniformly fatal in 2 to 4 years. They were long in the tooth with their ALS, sadly. Again, such that they could not get into any clinical program because they did not meet inclusion and exclusion criteria.

They nonetheless saw this different patient group on CNM-Au8 about the same 10% reduction in neurofilament light change over the pre-specified SAP that we submitted to the agency, and that is a 9-month period versus 6. We see two concordant arguments on neurofilament. The agency really came back to Clene and asked three questions. One, does Au8-treated participants have a neurofilament response that correlates with a clinical response? Two, is that neurofilament response versus randomized controls demonstrative of clinical benefit? Three, can you independently replicate in an independent study, in this case RESCUE-ALS, the same benefit? There is a whole fourth piece that is, can you prove this in a causal-based randomization analysis as well? In the spirit of that, we have used HEALEY to address point one and two, questions one and two, and we have used the RESCUE-ALS study to answer question three.

Now, about question two, this becomes a very interesting situation that is unique to Clene. When HEALEY was organized, HEALEY randomized 480 subjects into regimen A, B, and C at the same time. Same master protocol. Same inclusion and exclusion criteria. Well, similar, to be precise. There were some drug-specific things on each regimen. For instance, our patients could not have a gold allergy. That is an example of similar. Same eligibility criteria, same clinical sites treated, same follow-up, same duration. So we have a very long set, now nearly 4 years' worth of data. Gratefully, regimen A and B, as the agency has asked us to see if they would be willing to share, have done so, and all of that is put into our regulatory filings.

What it means is we have 480 subjects that were 160 per arm, there is 320 placebos effectively as concurrent controls because both regimen A and B was completely negative. Unfortunately, in HEALEY, there was no primary, secondary exploratory benefit. Both programs have stopped all clinical development for those 2 assets, yet we have them for an assessment period in our case. This is very relevant because the FDA does not like natural history controls. They have said this in multiple programs, other places. They wanted to see a concurrent control, and that is what we have sent them. In the spirit of that, we have seen in the HEALEY case that the survival in neurofilament responsive individuals was a 52% reduction, with RESCUE showing a 76% reduction in survival.