VDP-131 [Assessment] Maxwell Biosciences

[Paolo]

One-liner

Maxwell Biosciences is a multi-asset longevity biotech company developing a powerful nasal spray (on track for FDA clinical trials in 2024) to clear pathogens and inflammation, with the long-term goal of restoring immunity, extending brain healthspan, and returning memory and personality.

Longevity Dealflow WG Team

• Senior reviewers: senior review launched on November 26th

• Shepherd: Paolo Binetti

• Squad members: Abhijit Kale, Ryan Spangler, Winnie Qiu

• Sourced by: Paolo Binetti via lifespan.io Longevity Investor Network

Project PI

• J. Scotch McClure, founder & CEO

Summary

Maxwell is a multi-asset biotech company pioneering a new class of small molecule drugs based on biomimicry of the innate human immune system. Maxwell’s lead compound mimics the pathogen-agnostic core immune peptide, Human Cathelicidin Antimicrobial Peptide (LL-37), that has shown promise in the lab and in animal studies against a wide range of pathogens that can trigger chronic disease. These pathogens remain in the system, building inflammation and immune dysregulation over time. Our compounds’ structural stability and novel mechanism(s) of action have the potential to disrupt current standard of care for chronic diseases caused by viral, bacterial, and fungal infections, as well as post-infection inflammatory conditions correlated by the existing scientific literature with hallmarks of aging.

Maxwell’s novel drug platform was discovered using an artificial intelligence analysis of the proteomics of vulnerability in aging. Our technological breakthrough was facilitated by a grant from the US Defense Advanced Research Projects Agency (DARPA) given to develop a Synthetic Immune System.

What our artificial intelligence analysis revealed was a wide variety of potential factors in blood that could be correlated with youth and health, but specifically pointed out the multi-system value of LL-37. Our analysis pointed to LL-37 as the perfect super drug able to help with rejuvenating signs of aging, and healing all kinds of diseases, especially chronic disease and life-threatening infections. There was one major problem: LL-37 disappears quickly - cut apart or “cleaved” by protease enzymes produced by microbes, viruses, and your own body.

What our scientific researchers realized was their efforts with DARPA and in subsequent research to mimic LL-37 had solved the stability and delivery problems of peptide drugs, creating a First-In-Class novel drug delivery platform, “Claromer”. They had created small molecule mimics of LL-37 with a nitrogen-centric structure, designed to be highly biostable and highly predictable drug candidates.

Our lead candidate (MXB-22,510) has been shown to be safe in animals and able to tackle viruses, all tested bacteria and all tested fungi—including many drug-resistant strains and biofilm formations. Maxwell’s platform may provide the treatment necessary to eradicate the infectious agents that are responsible for many diseases of the aged, including Alzheimer’s disease, Parkinson’s Disease, rheumatoid arthritis, multiple sclerosis, Epstien-Barr virus, and many others with origins connected to pathogens.

The company plans to invest significant funds into its upcoming 2024 FDA clinical trials, as well as in R&D to expand its indications in the longevity field. The technology has remarkable potential in a wide range of therapeutic settings. Maxwell strategically sees a pathway to speed the development of age-related and longevity applications by first proving its infectious disease pipeline, which provides advantages for speedier clinical trials.

Our technology is backed by over $40M in government grants & private investments. The R&D team is being led by former pharmaceutical executives, who successfully commercialized over 80 drug products such as Adderall XR, Carbatrol, Equetro and Claritin. There is now preclinical scientific evidence that Maxwell’s antimicrobial drug technology works safely without developing resistance - a $72B+ revenue opportunity.

Problem

Chronic Rhinosinusitis is Maxwell’s strategic lead program. Chronic Rhinosinusitis (CRS) is a disease of the nasal cavity and paranasal sinuses and is characterized by patient complaints of inflammation that lasts 12 weeks or longer and does not resolve with antibiotic treatment. According to the CDC, CRS is suffered by around 11% of the population. The infection is triggered by a virus generally, and then driven into chronic status by combinations of opportunistic fungal and bacterial infections.

FDA considers chronic sinus infections an unmet medical need because there are no therapies approved that target the root cause of sinus infections: a mixture of bacteria, viruses and fungi. Maxwell’s First-in-Class CLAROMER® brand drug delivery platform is able to selectively target all kinds of pathogens without the use of antibodies by recognizing exposed phosphatidylserine.

Increasingly, researchers are investigating how chronic sinus infections caused by polymicrobial infections may cause a cascade of issues that impact healthspan. For instance, Frontiers in Aging Neuroscience published research showing that chronic sinus infections constitute an underappreciated player in the aging narrative. Studies have suggested a potential link between chronic sinusitis and reduced volume in certain brain regions. There are even studies showing a high correlation between sinus infections and Alzheimer’s / dementia. With the context of increasing focus on polymicrobial infection’s relationship to aging, it becomes clear that the siege of chronic sinusitis is not just a battle for our sinuses, but potentially also a battle for our minds.

Solution

Maxwell’s CLAROMERS® have demonstrated membrane disruption across a broad-spectrum of pathogens —including confirmed pan-coronavirus and pan-influenza efficacy—and effectiveness against all tested bacterial and fungal pathogens, indicating “One drug for MANY bugs” efficacy. As shown above, our lead candidate demonstrates pathogen-agnostic activity against a broad spectrum of bacteria, viruses and fungi. We have preclinical safety data for our lead candidate MXB-22,510 demonstrating its safety in both in vitro and in vivo assays that are mandatory prior to testing in humans.

In addition, CLAROMERS®, including our lead candidate MXB-22,510, have also shown the ability to prevent the development of drug resistance, which has become an increasing problem with current antibiotics.

We aim to partner with governments to stockpile against future pandemics, service military personnel (e.g. wound care anti-infectives), and address other infectious disease concerns (e.g. Ebola, WHO [World Health Organization] ESKAPE Pathogens).

MXB-22,510 is moving into human trials next year, and could delay, prevent or even reverse the degradation of innate immune function, allowing the body to focus energy on rejuvenation. MXB-22,510 could eventually augment our defense mechanisms or even help reverse the damage caused, extending our healthspan.

Opportunity

The typical standard of care by a general physician for Chronic Rhinosinusitis (CRS) is to first prescribe corticosteroids and saline nasal irrigation systems and then refer to an otolaryngologist if symptoms do not resolve in 4 weeks. If the patient goes to see the otolaryngologist, they are typically prescribed antibiotics and more corticosteroids. In more than half of all patients treated for CRS, symptoms persist, leaving patients with the option of painful surgery or risky biologics.

The estimates on the prevalence of CRS in patients ranges from 14 - 28 million in the United States. A fraction of these patients seek treatment with an estimated 7.3 million people seeking medical care annually. The estimated cost for a single patient in a year with CRS is $5500. This results in a US market of over $40 billion annually. This is a massive population of people that need help to be treated and a significant economic burden for payers.

Quick Stats

• Unmet medical need: High

• Addressable market: $40 billion annual US market for CRS patients; Global market is more than >$80 billion annually

• Target revenue: $6 billion US; Global market >$12 billion

• Chronically recurring due to reinfection from environmental pathogens

• Polymicrobial fungal, bacterial, viral biofilm ecosystem uniquely well targeted by broad spectrum CLAROMERS®

Relevance to Longevity

Researchers have noted the significant impact of immunosenescence (the complex processes involved with the aging of the immune system) upon biological aging and age-related diseases. One major driving factor of immunosenescence is a phenomenon typically described in scientific literature as “inflammaging” – defined as a low-grade inflammatory state triggered by continuous antigenic stimulation. The duress of combating pathogens over a lifetime accumulates, accelerating the aging process of our immune system.

To address this need in longevity, Maxwell is developing a powerful nasal spray to clear pathogens and inflammation. Our compounds are able to cross the blood / brain barrier, so we hypothesize that our nasal spray may likely also impact existing immune dysregulation or chronic inflammation in the brain and upper respiratory system.

Maxwell’s scientific cofounder, Dr. Annelise Barron, has won multiple awards, including the NIH Pioneer Award in 2020, for her research into the molecular biophysics and mechanisms of LL-37 and its involvement in Alzheimer’s dementia (via LL-37 dysregulation and degradation by pathogen virulence factors). Alzheimer’s dementia can be caused by (or at least, accompanied by) polymicrobial cerebral infections. Barron’s lab is at work creating Maxwell’s biostable mimics of LL-37 as therapeutics that can combat antibiotic-resistant infections, especially cerebral infections, ear infections, and sinus / lung infections.

Mimicry of the Immune System - A Giant Leap Forward
Maxwell’s team applied their understanding of the human immune system and breakthrough biotechnology to create the CLAROMER® drug platform. One day soon, perhaps mimicry of the immune system will be counted as one of humanity’s greatest advancements in healthy lifespan.

IP Roadmap

Maxwell’s Patent Estate and intellectual property is fully owned, with full control of the CLAROMER® Platform, a tissue-safe extremely broad spectrum anti-infective with potential world-first efficacy against many viruses, fungistatic efficacy against a broad spectrum of deadly fungi (including mold and yeast), bacteria, and currently untreatable biofilms. Maxwell’s IP portfolio has 6 granted patents and 9 more in prosecution that include composition of matter and both linear and cyclic biomimetic oligomers.

In addition, Maxwell continues to develop IP around novel compounds/structures, new methods of use, and animal/livestock health.

Plan and Budget

The budget over the next 2 years is focused on:

• FDA human trials

• Revenue acceleration

• Broadening R&D efforts

• Deep learning

• Drug manufacturing

Financing and VitaDAO Funding Terms

Maxwell was incorporated in 2016 as a Delaware C corporation and has raised over $15M. Notable investors include Keiretsu Forum, DecentraNet, David Shaw (former Venrock partner), Accelerator Venture Partners and Cause First Ventures.

The company is actively seeking funding to continue to develop our compounds. We recognize the value that VitaDAO members bring, both in terms of financial support and expertise. We are offering an opportunity for VitaDAO members to provide funding under the current Convertible Note (raising up to $20M with a $94M cap, 20% discount to the next round and 10% interest coupon), ensuring a mutually beneficial partnership. Maxwell’s seed round closed in 2021 with a valuation of $61M. We have both hard and verbal commitments for a significant portion of this Convertible Note and anticipate closing it soon. This closure will also be based on the outcome/time frame resulting from current discussions with investors.

We have a number of followers identified for the Series A and are working through several options for a lead investor.

Leadership Team

J. Scotch McClure, MBA - CEO & Co-founder
Mr. McClure is an engineer and MBA with over 20 years of experience as a CEO, and 10 years of experience as a corporate board director. He is a multi-patent inventor including anti-viral applications of Maxwell’s platform, and human gene expression technology.

Annelise Barron, PhD - Scientific Co-Founder, Co-Inventor & Board of Directors
Dr. Barron is a Professor of Bioengineering at Stanford University. She is an Associate Editor for Frontiers in Aging Neuroscience and recently received a highly competitive NIH Director’s Pioneer Award. In 1999, Dr. Barron invented the first of Maxwell’s anti-infective drugs.

Kent Kirshenbaum, PhD - Chief Scientific Officer
Professor of Chemistry at New York University. As a co-inventor of the drug class, he is able to answer questions regarding the fundamental chemical science behind the discovery of the drug class and support ongoing scientific research collaborations with academic institutions around the world.

Edward Rudnic, Ph.D. - COO
Dr. Rudnic is the former head of US R&D for Shire Pharmaceuticals where he led projects that drove over $30 billion in revenue for Shire. He has also been either the lead inventor or a co-inventor of 58 issued U.S. patents and numerous related international patents.

Tony Verco, MD, MBA - Chief Medical Officer
Tony is an anesthesiologist with over 23 years experience in the pharmaceutical industry. He has worked in both the contract clinical research sector as well as small and large pharmaceutical companies, with experience spanning research in toxicology, pharmacology, drug safety, regulatory, commercial, and product development strategy.

Highlights

• Our tests in vitro and in vivo indicate that our compounds can clear pathogens and inflammation

• Our compounds appear to reduce “inflammaging” – defined as a low-grade inflammatory state triggered by continuous antigenic stimulation.

• We have a new class of breakthrough drugs to potentially address refractory diseases with novel mechanisms of action

• Our team has extensive experience bringing new drugs to market. Our COO and key leadership team successfully commercialized over 80 drug products, including several multibillion blockbusters like Adderall XR, Carbatrol & Claritin.

• Signed agreement with the U.S. Army Medical Research Institute for Infectious Disease to conduct studies on our behalf for a number of dangerous pathogens - helping us to continue to develop our overall platform

• Maxwell owns all IP associated with this novel class of drugs

• Demonstrated preclinical safety and selectivity, including studies where CLAROMERS® have been tested in animals at over 100x times the therapeutic dose without toxicity

Risks

• First-in-class, novel mechanism of action compound poses potential clinical risks. While we are conducting significant safety and efficacy testing before entering humans, the inherent complexity of the human body means we can’t know for certain how our compounds will interact until we enter human clinical trials.

• Standard development risk factors and regulatory authority requirements associated with drug development

• As we gain additional traction with the U.S. Government, including the Department of Defense, there are additional compliance and regulatory requirements that we must meet on the business side.

• The biotech startup environment is currently experiencing a tough few years for capital raising. While we have been successful so far in raising the capital necessary to continue to develop our compounds, there is no guarantee for the future.

References

Alonso R, et al (2018). “Infection of Fungi and Bacteria in Brain Tissue From Elderly Persons and Patients With Alzheimer’s Disease.” Front. Aging Neurosci.

Barbé-Tuana F, et al (2020). “The Interplay between Immunosenescence and Age-related Diseases.” Semin Immunopathol.

Chongsiriwatana, et al (2017). “Intracellular Biomass Flocculation as a Key Mechanism of Rapid Bacterial Killing by Cationic, Amphipathic Antimicrobial Peptides and Peptoids.” Scientific Reports.

Cunha, L. L., et al (2020). “Remodeling of the Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response.” Frontiers in immunology.

Conboy, M. J., et al (2013). “Heterochronic Parabiosis: Historical Perspective and Methodological Considerations for Studies of Aging and Longevity.” Aging cell.

Feehan, J., et al (2021). “The twilight of the immune system: The impact of immunosenescence in aging.” Maturitas.

Fülöp, T., et al (2016). “The Role of Immunosenescence in the Development of Age-Related Diseases.” Revista de investigacion clinica.

Harrass S, et al (2021). “Chronic Rhinosinusitis and Alzheimer’s Disease-A Possible Role for the Nasal Microbiome in Causing Neurodegeneration in the Elderly”. Int J Mol Sci.

Lathe, R. et al (2023). “Programmed Ageing: Decline of Stem Cell Renewal, Immunosenescence, and Alzheimer’s disease.” Biol Rev.

Rodrigues, L. P., et al (2021). “Hallmarks of aging and immunosenescence: Connecting the dots.” Cytokine & growth factor reviews.

Sansoni, P., et al (2008). “The immune system in extreme longevity.” Experimental gerontology.

Tate, Patrick M, et al (2023). “Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity.” ACS Infectious Diseases.

• Agree
• Revisions Requested (Detail in Comments)
• Disagree

[bowtiedshrike]

Looks like there are some arguing LL37 exacerbates Alzheimer’s: Human antimicrobial peptide LL-37 contributes to Alzheimer’s disease progression | Molecular Psychiatry

From what I recall of antimicrobial peptides, I thought there were some big differences between human and mouse, and various toxicity issues with using them.

For bacterial lipids, how much is PS, and how much of that PS is surface exposed? Thought fungi at least kept the PS inside. So the MoA is not clear if it’s supposed to be PS-binding.

[Maxie]

Hi,
Thank you for the question! I will answer the first part of your question here. Once our team has responded to the PS portion of the question I will reply with that answer separately.

Peptides are often immunomodulatory and can cause inflammation which is associated with dementia. Additionally, antimicrobial peptides are highly concentration dependent. So, too little or too much of an antimicrobial peptide can either allow a disease like dementia to progress or can make it worse by creating inflammation.

However, our compounds are not peptides and have not shown ANY toxicity or inflammation at all even at extremely high doses, over 300X higher than the therapeutic concentration.

In the case of LL-37 and that study, specifically, the analysis is focused on correlation not causation. LL-37 is found in the brain and all organs of all humans including Alzheimer’s patients because it is the main antimicrobial peptide of the body. Alzheimer’s is also associated with infections in the brain and LL-37 is expressed in greater amounts by the local tissues when an active infection is in place.

[matthew.oconnor]

What stage of GLP/GMP are you at?

[Maxie]

Hi,
Here are the answers for second part of this question around PS:

This question is best evaluated by considering antiviral, antibacterial and antifungal mechanisms of action.

Antiviral

Within the context of the antiviral mechanism of action, we have established that negatively charged phospholipids in the viral envelope are important determinants in conferring susceptibility to disruption by our Claromer compounds. The presence of the negatively charged phospholipid phosphatidylserine is particularly important. Viruses can obtain this lipid as they bud from host eukaryotic cells.

see PM Tate et al., Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity. ACS Infect Dis. 2023 Aug 11;9(8):1508-1522

Antibacterial

With regard to antibacterial mechanisms of action, the situation is much more complex. This is for two reasons – bacterial membranes are very different from one another, and our compounds display a combined mechanism of action that includes activity both at the cell membrane and also intracellularly (ie., association with nucleic acids, ribosomes and altered cytoplasmic fluidity).

It is not easy to describe accurately the composition of bacterial membranes as a general class. However, one characteristic is evident – bacterial membranes tend to have a greatly enhanced content of negatively charged lipids than mammalian membranes – we believe this overall feature establishes the selective susceptibility of bacteria to our compounds. In contrast, mammalian membranes have a greater content of neutral lipids.

But the particular details are complex:

“… it is clear now that there is no such thing as a typical bacterial membrane lipid composition. Different bacterial species display different membrane compositions and even the membrane composition of cells belonging to a single species is not constant, but depends on the environmental conditions to which the cells are exposed.”

see Sohlenkamp & Geiger, Bacterial membrane lipids: diversity in structures and pathways, FEMS Microbiology Reviews, Volume 40, Issue 1, January 2016, Pages 133–159

Maxwell is currently sponsoring studies to evaluate how Claromers interact with membranes incorporating different lipids – including other negatively charged phospholipids that are typically present on bacterial membranes, such as phosphatidylglycerol and cardiolipin.

Some bacteria may have the capacity to preferentially position some lipid components within their inner membrane leaflet. However, this is generally likely to be less prevalent than for mammalian cell membranes, which actively sequester lipids like phosphatidylserine to the inner leaflet using the dedicated flippase enzyme machinery.

Again, the take-home message is that bacterial cell membranes present extensive negative charge features, which establishes electrostatic association with our positively charged Claromers.

Antifungal

The picture with fungal membranes is really fascinating.

Our studies of antifungal mechanisms of action are just initiating. Again, it seems that Claromers can exert activity at the fungal membrane, but also intracellularly:

See Uchida et al, Soft X-ray tomography of phenotypic switching and the cellular response to antifungal peptoids in Candida albicans. Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19375-80.

Phosphatidylserine synthesis is typically required for fungi and PS is a virulence factor for many fungal pathogens. Fungi do have flippase activity and generally are capable of sequestering PS within the inner leaflet. However, unusual organelles can form within fungi, particularly as they undergo hyphal growth. There is a structure called the Spitzenkörper that is enriched in PS, and can be visualized at the apex of fungal cells in hyphal growth.

see: Schultzhaus Z, Yan H, Shaw BD. Aspergillus nidulans flippase DnfA is cargo of the endocytic collar and plays complementary roles in growth and phosphatidylserine asymmetry with another flippase, DnfB. Mol Microbiol. 2015 Jul;97(1):18-32.

also see associated commentary: Peñalva MA. A lipid-managing program maintains a stout Spitzenkörper. Mol Microbiol. 2015 Jul;97(1):1-6.

Needless to say, there is lots more to discover, and we are conducting additional mechanism of actions studies currently that will reveal additional details.

[Maxie]

Hi Matthew,

Thank you for the question!
We are in the process of planning our initial GLP toxicology and pharmacology studies to support opening our Investigational New Drug (IND) application with the FDA. These studies will be conducted over the next 12 months. From a GMP perspective, we will manufacture our first GMP drug substance and drug product batches to be administered in our first-in-human (FIH) studies. These FIH studies will be conducted once the GLP studies are complete and our IND has been opened with the FDA.

[aschwartzphd]

1)They have a lot of data, but my biggest concern is they all seem to be compared to placebo. No comparison to any FDA approved drugs. For example, their in vivo COVID experiment wasn’t compared to anything (Abs, Steriods, etc.), not even PLAXVID. They should at the very least compared to LL-37–why not just use LL37?. Some of their in vitro work compares to LL-37 and it’s somewhat comparable in efficacy. These diseases are insanely complex, and as history tells us, the likelihood of LL-37 alone being efficacious is slim (e.g., sepsis)

2)They said they had a PREIND meeting with the FDA in March—what was the response?

3)Their lead indication is CRS, which there is an unmet need. They said they have efficacy data but it was not presented? Was it compared to standard antibiotic treatment?

4. There’s no real market for Ebola-not that any for profit fund would really invest in. Gates foundation would be interested. Covid market is saturated.

5. Panorama Research Inc, University of Edinburgh, University of Nebraska Medical Center, National Cancer Institute all have/had LL-37 peptides/drugs. How is Maxwell better? If these existing agents failed, why? Why would Maxwell succeed? Promore Pharma has an IL-37 drug.

6. IP estate seems strong, through 2040, but some expire in 2030, if the compositions are in 2030 that’s concerning.

7. They propose a nasal formulation, but it does not appear thatʼs been
   developed. Timeline is aggressive and unrealistic. IND acceptance and safety are not value inflection points for this.

8. Proposed use of funds should be 90% for CRS, it currently seems scattered without focus.

My biggest issue is the lack of any clinically meaningful controls in addition to LL-37, side by side in every experiment–especially mouse studies. Placebo doesn’t cut it here and it should be a big red flag. No data in their lead indication??

[Maxie]

Hi,

Thank you for the feedback. We do have a significant amount of comparative data that we generally share in a deep dive. Please let us know if you have additional questions we can help answer. Here are the responses to your questions:

1. They have a lot of data, but my biggest concern is they all seem to be compared to placebo. No comparison to any FDA approved drugs. For example, their in vivo COVID experiment wasn’t compared to anything (Abs, Steriods, etc.), not even PLAXVID. They should at the very least compared to LL-37–why not just use LL37?. Some of their in vitro work compares to LL-37 and it’s somewhat comparable in efficacy. These diseases are insanely complex, and as history tells us, the likelihood of LL-37 alone being efficacious is slim (e.g., sepsis)

Response: Numerous studies have now established the normal human microbial commensals, the microbiota, as an important contributor to essential mammalian functions such as metabolism and immunomodulation. The host-microbiota interface such as the gut intestinal mucosa and nasal mucosa is particularly important in chronic mucosal inflammatory conditions where the microbiota interact directly with the host. By their very nature, they are clearly multifactorial in nature, have heterogeneous clinical presentations and vary in treatment response. With specific focus on CRS, it has been well established that the nasal microbiome between healthy individuals and CRS patients is dynamic and has wide geographic diversity with a reduction in bacterial load and diversity. Since microbial composition plays a key role in the protection against pathogen overgrowth (through quorum sensing) and virulence gene expression, perturbations to the nasal commensal diversity must be a contributing factor to the infectious and inflammatory disease etiology associated with CRS. The treatment of CRS includes the use of antibiotics (macrolides and non-macrolides) with an efficacy rate of about 40%. Significant factors that likely contribute to the failure of antibiotic therapy includes 1) intrinsic resistance to antibiotic therapy, and 2) incorrect empirical choice of antibiotic due to lack of ability to identify the offending pathogen or pathogens. Other components of standard-of-care treatment include intranasal administration of corticosteroids using nasal sprays, as well as the use of saline washes. The efficacy of corticosteroids administered using nasal sprays has been firmly established - see further details in the response to Question 7 below.

Maxwell’s lead compound (MXB-22,510) has been confirmed to possess a wide breadth of efficacy at clinically relevant concentrations against all bacteria selected for testing and commonly associated with CRS, including Staphylococcus aureus, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Klebsiella pneumoniae, Citrobacter freundii, Streptococcus pyogenes, and Streptococcus pneumoniae. Studies performed to assess the relative efficacy of Maxwell’s Claromer compounds against these pathogens have included standard-of-care active controls such as 1) vancomycin against MRSA, MSSA, S. pneumoniae, and S. pyogenes, and 2) meropenem against Klebsiella pneumoniae, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Citrobacter freundii. Of notable importance is the efficacy of the Claromer compounds against biofilms of these pathogens, both the formation and disruption thereof.

Further confirmation of the breadth of effect of the Claromer compounds has been obtained by demonstration of effectiveness against the most important global fungal pathogens considered of critical importance by the World Health Organization i.e. Candida albicans, Candida auris, and Aspergillus fumigatus. In particular, all Claromer compounds tested against C. albicans showed superior efficacy compared to fluconazole; C. albicans has the highest prevalence of all pathogenic fungal species varying between about 40% and 80% globally, with resistance to fluconazole ranging from 44% to 100% depending on geographical location. Further, Maxwell’s demonstration of effectiveness against resistant fungal pathogens will provide clinicians with the opportunity to avoid the use of severely toxic standard-of-care therapeutics such as amphotericin B.

In addition to the above, preliminary safety information indicates a favorable benefit-risk profile. MXB-22,510, in addition to other Claromers, has not demonstrated cytotoxicity in vitro, and no systemic side-effects when administered intranasally to rats at the maximum feasible concentration, many thousand fold above the expected therapeutic dose. Further, the therapeutic margin with respect to local toxicity at sites of administration is also expected to be wide, favoring a flexible dosing regimen when entering the market.

With reference to the question about the use of LL-37 as an active comparator, please see further comments below under Question 5.

2)They said they had a PREIND meeting with the FDA in March—what was the response?

Response: Maxwell received a Written Response Only for the Type-B PIND Meeting on March 17, 2023. (Please note, the FDA is very busy and denies a large number of PIND requests) Based on the fact that they granted us a meeting, this signifies the importance of our compounds and the proposed indication: CRS. FDA went above and beyond normal efforts to give Maxwell helpful guidance. The Briefing package and information request response was professional and thorough. FDA’s comments were specific as well as broad reaching, and addressed all 8 posed PIND questions focused on both non-clinical and clinical areas. FDA’s specific responses were largely in agreement with Maxwell’s proposed non-clinical plan. They agreed to species selection and duration of study for the non-clinical studies, and suggested additional safety factors to monitor, including in the CNS and respiratory areas. FDA Included additional comments relevant to expanding the later stages of the proposed development program that could augment the product label.

Maxwell was invited to submit a second PIND package, which is largely unheard of in the industry. This is extremely positive. We will be incorporating all of their guidance into our overall program to ensure IND review is successful and that we receive a “Study May Proceed” Letter subsequent to our IND submission, targeted for 2H2024. Based on their responses, we believe we have the attention of the FDA, and believe they are very interested in our compounds and development program.

3)Their lead indication is CRS, which there is an unmet need. They said they have efficacy data but it was not presented? Was it compared to standard antibiotic treatment?

Response: See answer to question #1.

4)There’s no real market for Ebola-not that any for profit fund would really invest in. Gates foundation would be interested. Covid market is saturated.

Response: The United States government has awarded a number of contracts to companies that have solutions for Ebola and other dangerous pathogens. The contracts include both development funding as well as funding to stockpile treatments. Contracts have been awarded from $214M to $837M for treatments that still have high fatality rates with several strains of Ebola, with no approved treatments yet. The United States Army just awarded Maxwell a Cooperative Research and Development agreement based on testing originally done by NIAID to evaluate our compounds against Ebola to potentially replace the current standard of care drug treatments. Given the broad effectiveness of our compounds, the U.S. Army is testing our compounds on a broad range of diseases, beyond just Ebola.

5)Panorama Research Inc, University of Edinburgh, University of Nebraska Medical Center, National Cancer Institute all have/had LL-37 peptides/drugs. How is Maxwell better? If these existing agents failed, why? Why would Maxwell succeed? Promore Pharma has an IL-37 drug.

Response: A variety of Antimicrobial Peptides (AMPs) from different sources have been evaluated as therapeutics, largely without success. In large part, these efforts have failed precisely because these drug candidates were peptides.

It’s of fundamental importance to note that our Claromer molecules are not peptides. Claromers are small molecule oligomers that mimic the antimicrobial functions of the AMPs. Claromers are structurally distinct and do not exhibit many of the more problematic activities of AMPs. And we overcome many of the pharmacological limitations of peptide drugs as a general class.

Tailored activity:

Claromers are broadly antimicrobial. Their antibacterial, antifungal, and antiviral properties have been thoroughly studied, leading to a robust set of peer-reviewed reports. In this sense, they mimic the essential desirable functions of AMPs as anti-infective agents. However, AMPs generally (and LL-37 in particular) have additional bioactivities that may be undesirable in a therapeutic context, including immunomodulatory effects. LL-37 can be neuroinflammatory and neurotoxic, and it has also been associated as a T-cell autoantigen that can trigger autoimmune disorders such as Psoriasis. For this reason, many efforts to develop AMPs have focused on topical administration to avoid systemic toxicities.

We have conducted a range of pre-clinical safety studies to address these concerns. We have observed no undesirable immunomodulatory activity, and Claromers do not evoke the release of immunostimulatory cytokines. In addition, we have observed no significant neurotoxic effects. We have obtained very favorable Maximum Tolerated Dose results that demonstrate that Claromers are well tolerated, even when administered systemically. Thus, Claromers are exhibiting tailored desirable antimicrobial properties.

Improved pharmacological properties:

Peptides have severe limitations as drug molecules. They can be rapidly degraded by proteases in vivo. However, these mechanisms of inactivation do not pertain to Claromers. Again, Claromers are not peptides. They are fully synthetic small molecules, and are essentially impervious to proteolytic degradation. Thus, they can overcome many of the limitations of AMPs, such as a short half-life in circulation and difficulties in adequate systemic dosing.

Claromers have other dramatic advantages over LL-37. As small molecules, they are much easier and cheaper to manufacture. And as non-biologics, Claromers have superior thermal stability and may not require a cold chain for distribution.

[Promore Pharma appears to be in liquidation currently, casting significant doubt on whether LL-37 will be introduced for clinical use.]

6)IP estate seems strong, through 2040, but some expire in 2030, if the compositions are in 2030 that’s concerning.

Response: The Claromer platform of anti-infectives Maxwell is developing will likely qualify for the GAIN Act and the Pasteur Act which provide additional protection beyond patent protection. The GAIN Act is an incentive program that provides a mechanism for FDA to grant additional exclusivity (up to 5 years) beyond the standard 7 years for certain drugs, namely new chemical entity antibacterial and antifungal drugs intended to treat serious or life-threatening infections, especially those that are increasing in resistance. The Pasteur Act would establish an innovative payment contract where the federal government invests in highly novel antibiotics and antifungals through installment payments in exchange for free access to developers’ drugs in government programs once available. We have been advised by counsel that if our Claromer products are successful, we would qualify for these programs.

In addition, Maxwell is continually working to expand the Maxwell Patent Estate with new composition of matter (new chemical entity) patents as well as novel product/use patents to cover the Claromer platform and product portfolio, both currently in development.

7)They propose a nasal formulation, but it does not appear thatʼs been
developed. Timeline is aggressive and unrealistic. IND acceptance and safety are not value inflection points for this.

Response: The FDA has agreed that we will submit results from 7-day rat and 28-day dog toxicology studies as part of our initial IND filing. The intranasal formulation will be developed for First-in-Human studies while these toxicology studies are being conducted. The timeline to author and submit the initial IND filing is 12-15 months, which is gated by the toxicology studies, drug substance raw material lead time and drug substance manufacture and release.

IND acceptance and safety are major value inflection points. IND acceptance is not a foregone conclusion for drug development and each step that reduces risk increases value. In our case, as a first in class compound, the safety data results can prove our overall platform is safe, thus derisking the entire platform and not just this single compound.

8)Proposed use of funds should be 90% for CRS, it currently seems scattered without focus.

Response: We have a two part development strategy: commercial and government. The government strategy largely funds itself over time so while we devote some resources to this effort, most of these resources will ultimately be funded by the U.S. government. Our commercial strategy is focused on the development of CRS, so the bulk of our funding will be allocated to CRS in order to move it into human trials and then through human safety and efficacy trials.

[timrpeterson]

This sounds like a great idea, but i voted “Disagree” because I echo @tylergolato 's plea that we stick to VitaDAO’s mission of funding early stage projects. At the early stage of commercialization is where we can make the biggest impact both by providing funds where none exist but also in owning a larger stake. Owing a larger stake is critical for VitaDAO having a strong incentive to help the project succeed. A company at this stage of Maxwell is already off and running. VitaDAO’s small contribution won’t have the same impact. Just trying to set the culture of giving an explanation when the vote is “No”.

[Paolo]

@timrpeterson, thank you for your transparency.
So, I would like to share why I brought this project to VitaDAO and why so many others might be backing it in spite of the relatively late stage. My view is that in order to make an impact we should fund not only 20 early stage projects, but hundreds, like the Cystic Fibrosis Foundation did before hitting a breakthrough therapy from a single startup (and even more, because aging is multifactorial). This requires us to scale and be around for a long time, which in turns requires us to be self-sustainable. The interest of having some shorter-time-to-market ventures in our portfolio is to cash in early and fund more early stage ventures without needing to raise. Now, quick cash in could also be possible for early-stage deals via the IP-NFT / IPT route: this is actually a transformative innovation we introduced, but it is still in its infancy. Thus, while building on it, I think it is important to hedge with other approaches.

[timrpeterson]

Thanks @Paolo. I agree we need quick wins, but we’ve funded many of those to date. Is it fair to Maxwell to say “okay, now we’ve funded enough quick wins.”? I dunno. It’s just my opinion. Everyone should decide for themselves.

I do appreciate how much work went into this and think the idea is very cool. FWIW if any investor wanted my opinion on the company I would be highly complimentary. My vote is just to start to biasing VitaDAO back towards earlier stage stuff.

[aschwartzphd]

Again–Where are the CRS data? Comparison to SOC? This is a HUGE (Font size 10000) flaw that the company can’t even show data from their lead indication. It’s probably why they can’t get VC funding. There is NO nasal formulation developed no any indication whatsoever it works. I don’t think I’ve ever seen a pitch deck with no data for their lead indication. No IL37 comparisons. Why not use another indication with data? Again, these are fundamental flaws that keep arising with Vita projects that need to be considered before everyone"just agrees" to fund something because it sounds great. Also, no longevity data and that’s one long shot.