INKMUNE AS A NEW APPROACH IN NK-TARGETING IMMUNO-ONCOLOGY

Summary:

• INKmune is an NK-targeting immuno-oncology drug allowing treatment in a wide range of NK-related cancers;

• INKmune’s production cost is about one tenth of the production cost of other immuno-oncology drugs;

• With XPro expected to yield excellent results across neurodegenerative diseases and depression, I expect the still thinly traded INMB to become a biotech powerhouse in years to come.

Introduction

INMB is a dichotomous biotech company, with focus both on immuno-oncology and neurodegenerative diseases. The company has a lot going on, is the least one can say, yet only sports about a $ 180 million market cap at the time of writing and an enterprise value of $ 129 million.

The focus of this article will be on its paradigm-shifting immuno-oncology drug INKmune.

INKmune is an immuno-oncology drug, meaning it harnesses the body’s immune system against cancer. The main focus of immuno-oncology drug therapies is on T-cells and natural killer (NK) cells, both lymphocytes, T-cells being part of the adaptive immune system, and NK-cells being part of the innate immune system. The oncology field has been very active in this field over the past years, with many biotech companies active in it, constant developments, and among others CAR-T (chimeric antigen receptor – T-cell) drug approvals such as Yescarta and Kymriah and surely many others in the pipeline. However, these therapies, which also comprise T-cell receptor therapy and tumor-infiltrating lymphocyte therapy, are considered highly promising, yet come with considerable limitations and side effects, including sometimes major toxicities in most cases. On CAR-T cells, which is the area of highest focus, the CEO of French immunotherapy developer Cellectis stated clearly:

I’m just trying to be realistic, CAR-T is not the miracle cure for cancer.

The field’s focus is shifting or at least diversifying to NK cells. Different to T-cell based therapies such as CAR-T’s (chimeric antigen receptor), NK cell therapies’ biggest benefits may be the lack of toxicities due to cytokine release syndrome, graft-versus-host disease and neurologic issues, problems often mentioned in T-cell based therapies.

I expect both therapy fields to be viable in the longer run, as each cancer is different, evoking a different immune response, and as a function of that, treatment by a T-cell therapy may in certain cases be more effective than an NK-cell-based therapy, and vice versa. Yet, there are quite some biotech companies active in the field, with biggest focus on Fate Therapeutics and Century Therapeutics, and I expect many drug candidates to bite in the dust upon commercialization, if already they would get as far as market approval.

Accessibility of good therapies is quoted as one of the major challenges in oncology, as most of these drugs are unaffordable for the average person, and certainly for the less wealthy part of the population. Approved immunotherapies have a cost starting at $ 100,000 and as they are often used in combination and with follow-up, a total price tag of $ 850,000 is not unheard of. For example, pembrolizumab (Keytruda) was found not to be cost-effective in advanced hepatocellular carcinoma at the reference willingness-to-pay threshold $ 150,000 per quality-adjusted life-year. This also brings the issue of health care sustainability, making it a systemic issue. Looking at Hispanic or other less-favored communities or even beyond the Western world, immunotherapy at present for the happy few, and accessibility is a huge concern as cancer is on the rise, having been the second leading cause of death in the US for several years including 2020 until that spot claimed in 2021 – and expectedly only for that year - by Covid-19.

INKmune, coming out of the stable of a very renowned name in oncology, is a pseudokine™. It is unlike anything I have seen, and I believe it is unique, paradigm-shifting, and unlikely to have any serious peer in the years to come.

INKmune is a pseudokine

INMB has registered the word ‘pseudokine’ as a trademark, stressing its long-term ambitions and unique profile, and recently included a summary of what a pseudokine is. I have extracted the essential part of that summary below:

“Traditionally, cancer killing cytokine strategies focus on one cytokine at time (e,g., IL2 or IL15) due to the high risk of initiating cytokine release syndrome. To get better cancer killing cells, use of more than one cytokine is needed but giving one or more cytokines to a patient is likely to have toxicities that limit the use of this treatment strategy.

To circumvent the toxicities of multiple cytokines, immune cells can be removed from the patient, treated with multiple cytokines to “rev up” their cancer killing abilities and then be given back to the patients. This strategy is sometimes effective but is expensive and logistically complex. INKmune converts resting NK cells to cancer killing memory like NK (mlNK) cells. Conversion of a resting NK cell to a mlNK cell takes at least 3 cytokines (IL12, IL15 and IL18). This type of mlNK cell is called a CIML (cytokine induced memory like NK cell). CIML can only be produced from immune cells outside of the patient in a complicated ex vivo manufacturing process and a need to sustain the CIML in the patient with addition of systemic, low dose IL2. INKmune produces tumor induced mlNK cells (TIML). With INKmune, TIML are produced by converting the patient’s own resting NK cells to mlNK cells in the patient (no ex vivo manufacturing). The patient gets an infusion of INKmune, and the resting NK cells become mlNK. This is why we call INKmune a pseudokine – it acts like multiple cytokines but is not a cytokine. It is a single agent given to the patient to produce a cancer killing NK cell.

There may be advantages in the cancer killing power (avidity) and persistence of TIML compared to CIML. There are clear logistical advantages and possibly safety advantages to INKmune, the pseudokine compared to any cytokine-based strategy."

What is INKmune?

Immuno-oncology drug candidates focus on modulating the body’s own immune system. This can be proceeded to in various manners, and often a distinction between autologous and allogeneic therapies is made. With autologous therapies, the patient’s own immune cells are extracted, engineered outside the patient (ex vivo), and then reinserted into the patient. The allogeneic way uses a donor’s cells, engineers them, and inserts them into the patient. The autologous way is obviously more complex, and the field’s future focus will likely be more on allogeneic therapies.

In INMB’s words, as a pseudokine, INKmune is a replication-incompetent human tumor cell line into the patient, which conjugates to resting NK cells and delivers multiple, essential priming signals to these NK cells, which allow them to trigger and kill (lyse) upon the encounter of a tumor cell. In layman’s words, INKmune mimics a cancer cell which resting NK cells recognize, activating (priming) them, and subsequently allowing them to kill actual cancer cells, which up to that point had evaded the immune system due to tumor immune-evasion.

Contrary to techniques where the use of cytokines leads to cytokine-primed natural killer cells (CpNK), INKmune leads to tumor-primed natural killer cells (TpNK).

This approach, whereby nature does most of the job in priming NK cells instead of always more complex human engineering of immune cells, is unique in my eyes, actually more logical than the other techniques mentioned above, and one that makes perfect sense. It is the immune-evasion hallmark of cancer that leads to its proliferation. If the immune system would have been able to recognize the cancer cells in the first place, it would be able to kill them and there would not have been cancer. Cancer comes to exist as the body’s own immune system fails to recognize the concerned cancer cell.

“The main “job” of a cancer cell is to survive and grow. Unfortunately, the “successful” cancer cell ultimately kills the host. The first priority for survival is to evade NK cell killing. The vast majority, >98%, of cancer cells do this by downregulating expression of priming ligands. When an NK cell interrogates a cancer cell lacking sufficient priming signals, the NK cell is unable to trigger lysis. This allows the cancer to evade NK cell killing to grow, and, we believe, is one of the causes of cancer relapse.

Cancer killing therapy in that sense essentially becomes an effort to shift the balance from NK celles being inactivated to ‘primed’ to ‘killing’. The video on INMB’s website shows how it works."

“The INKmune:NK interaction ligates multiple activating and co-stimulatory molecules on the NK cell and enhances its avidity of binding to tumor cells; notably those resistant to normal NK-mediated lysis. Tumor-primed NK (TpNK) cells can lyse a wide variety of NK-resistant tumors including leukemias, lymphomas, myeloma, ovarian cancer, breast cancer.

INMB does not engineer human cells to be maximally effective in the patient’s body, which technique is lately becoming all the more complex and costly.

As I see it, a pseudokine is the next step in a rapidly evolving immuno-oncology landscape. The idea of identifying the best-equipped tumor cell line that can allow NK cells to trigger and lyse (kill) otherwise immune-evading tumor cells, is simple and makes sense. The more complex and cost-ineffective an idea is, the less its lifetime will be. I therefore see INKmune as a promising way forward in immuno-oncology, and a new chapter in immuno-oncology handbooks; I expect partnerships and licensing deals to come along as time progresses.

Preceding INKmune is more than a decade of research and previous trials, both by Prof. Lowdell, head of immunology at University College of London and leading the INKmune program, and RJ Tesi, INMB’s CEO. Both have met when RJ Tesi was still the CEO of Coronado Biosciences, currently known as Fortress Biotech, a holding company with several subsidiaries.

INKmune is the first drug to create memory-like NK cells in vivo

On August 25, 2021, INKmune has been reported to create memory-like NK cells in vivo, and this is actually a very important fact, and was as such a sufficient reason to take an investment position in my eyes (even though I was an investor prior to that). INMB added to that:

Over the last years, memory-like NK cells had been generated outside of the human body, and the best way to do so appeared by adding three cytokines ex vivo: IL-12, IL-15 and IL-18. If they are produced by cytokines, one refers to them as cytokine-induced memory-like NK cells (CIML). Unfortunately, cytokines cannot be added in vivo, and so when the effect of therapy is exhausted, one would need to administer further CIML.

Until the advent of INKmune, the creation of memory-like NK cells had never before been achieved in vivo:

The company believes that this is the first ever successful generation of mlNK cells in patients.

For a broader understanding, NK cells are part of the innate immune system, and were until recently not considered to have the capacity of memory-like response, which was considered to be the privilege of the adaptive immune system.

“Memory NK responses were initially reported over a decade ago in studies involving mouse models of cytomegalovirus infection and delayed-type hypersensitivity reactions to chemical haptens and viral antigens. Since then, a growing body of literature suggests that memory or memory-like NK cell responses may occur in a broader range of immunological settings, including in response to various viral and bacterial infections, and some immunization protocols."

Source: link

These memory-like NK cells are, in a way, the crossover between the innate and the adaptive immunity. When NK cells remember what to kill, then immune evasion by tumor cells, a hallmark of cancer, becomes all the more difficult.

Persistence and avidity are key

Basically, as an NK cell therapy developer, you would want your NK cells to exhibit memory-like function. Memory-like NK cells persist longer and kill better: “TIML-NK cells exhibit superior, tumor-specific in vitro functionality”. When cytokine-induced memory-like NK cells have been generated in vitro, a persistence of about three weeks had been reported, which was already considered remarkable. In 2019, with added cytokine support, it had been reported that memory-like NK cells were sustained for more than 2 months, constituting 20-50% of total NK cell count at day 60. In vitro, one can add any cytokine such as IL-15 to keep these NK cells alive as much as one wants, but this does not work in vivo. Once they are inside the patient, adding cytokine support may be problematic as it may lead to toxicity and neurologic issues.

INKmune’s tumor-primed NK cells have longer persistence without added cytokine support, either ex vivo or in vivo. In the chart below, I have combined the information from two press releases of INMB:

Percentage of activated NK cells

“More than 80% of the activated NK cells expressed markers associated with a memory-like NK cell (CD57++, NKG2D+, NKG2A-ve, NKp46-ve). In vitro, the INKmune™ activated NK cells were better at killing cancer cells than the patient’s own NK cells prior to treatment, with an 82% increase in lysis of K562 leukemia cells and a 47% increase in lysis of NK-resistant RAJI lymphoma cell tumor cells as early as day eight. Despite this high level of activated NK cells and tumor killing, the patient showed no symptoms of Cytokine Release Syndrome (CRS).

Day 119 was the last day measured. That is at least 17 weeks of persistence, or 4 months, without cytokine support. And looking at the percentages, this persistence probably lasted even longer. Considering the half-life of NK cells is relatively short, the persistence of these INKmune-induced NK cells over the course of at least 17 weeks would suggest to me that either upon cell division the memory-like characteristics are passed on, and/or that the interaction between NK cells renders the memory-like function persistent.

The INKmune-induced memory-like NK cells therefore far outperform memory-like NK cells generated ex vivo not only in persistence (+100% comparing the trial reported in 2009), but also in numbers.

Prof. Lowdell recently elaborated on the sustained NK response in an interview:

“INKmune is different because obviously it is this pseudokine. It’s a suspension of cells, and they don't have to survive in the patient very long because they activate the patient's own NK cells. So you haven't got this persistence problem that you have with allogeneic NK therapies that are being rejected. These cells come in and they activate the patient's own NK cells, and because it's so cost-effective, in the clinical trials we're giving just three doses on day one, one on day eight, and one on day fifteen, and in the patients treated, we've detected activated NK cells for many months after. In the clinical trial, we're only allowed to follow 119 days, and still at 119 days, our first trial subject had activated NK cells, which were memory-like NK cells able to kill cancer cells right until day 119 when we stopped formal follow-up. So, this response seems to be sustained.

Additionally, tumor-primed NK cells (TpNK) also show better avidity than other NK cells as shown here:

In short, the memory-like NK cells generated by INKmune have supreme persistence and avidity to kill tumor cells. A deeper dive into INKmune can be found here.

INKmune’s low manufacturing cost

Additionally, INKmune’s manufacturing cost is about one tenth of current immuno-oncology therapy candidates, which bodes really well for accessibility and health care sustainability. Correctly priced, the drug could allow both good profits for pharmaceutical companies as well as access to a much larger clientele than what the current drug candidates can be aiming for, without even compromising in effectiveness, rather to the contrary.

Prof. Lowdell of INMB put it this way:

“Now, INKmune is very different, it's an immortalized cell line. It grows in large vats, we can make very large amounts of INKmune very cost-effectively, so when it is successful, when it is on the market, and I can say when because I believe in it, that is a very affordable drug to deliver and it's very easily delivered because it's shipped at -80 just like like many other drugs, and it can be stored in hospital pharmacies much more easily than a CAR-T cell or other NK cell therapy. […][…]

But because it's an inexpensive and easy drug to deliver, there's no reason why like most chemotherapies you can't repeatedly treat a patient. And you think about Gleevec, the most successful therapy in the treatment of chronic mild leukemia ever. No one expects Gleevec to cure a patient. Patients are repeatedly treated with Gleevec, and we could think about INKmune in the same way. It doesn't have to be a treatment that in a single dose like a CAR-T, cures you. It can be a maintenance therapy because it's so low risk, and it's so well tolerated that in an elderly patient population that couldn't be treated with something that was more aggressive, appears to be safe and could be given multiple treatment.

INKmune could be effective as a standalone therapy

The holy grail in these therapies is standalone therapy. Most of the other immuno-oncology drug candidates are still in trials mainly in combination with already existing medication or therapy, which mostly consists of chemotherapy, radiation, surgery in the case of solid tumors or a stem cell transplant in the case of hematological tumors. Among others due to the acidic and dense nature of the tumor micro-environment in solid tumors, immuno-oncology drugs have so far not yielded as impressive results in solid tumors as they have in hematological malignancies.

Future will tell, but with this level of efficacy and the results shown in two terminally ill patients, I believe INKmune can be approved as a standalone therapy.

Shipping

Contrary to other cell therapies which need to be storted at -180°C, INKmune™ is stable at -80°C, can be shipped on dry ice and is delivered by a simple IV infusion without conditioning therapy or need for systemic cytokines. That’s a big difference. A temperature of -80° C is standard for pharmacies and hospitals; it is also the temperature used for storage of the MRNA Covid vaccines.

INMB’s second platform: Xpro in neurodegenerative diseases

As mentioned above, INmune Bio is a dichotomous company, essentially sporting two platforms. I had originally been an investor for XPro, which to me is the most promising drug in Alzheimer’s disease that I have come across, having shown massive improvement in relevant AD-related biomarkers of neuroinflammation and neurodegeneration.

INMB has also made it clear in its last conference call that it will be going for accelerated approval here, which may lead to it being approved after its Phase 2 trials ending in 2023 both in MCI and AD.

“Why start an MCI trial now? The answer is simple. 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. […]

We will aggressively pursue accelerated approval strategies for our Alzheimer’s disease program. We do not know if we will be eligible for or successful in those efforts, but to ignore them would not be fair to patients or our shareholders.

Source: quarterly results conference of Nov. 3, 2021

There is also so much under the radar with this company that I believe it is a strong hold for a long term future, both in immuno-oncology as treatable diseases and trials unravel, as in neurodegenerative diseases.

“We have a corporate in our corporate deck is a slide we call the iceberg slide. The iceberg slide is a slide that that basically shows an iceberg, because the tip of the iceberg, the stuff above the water line, is what you know about. It's Alzheimer's disease, TRD and ALS, but below the water line is a long list of diseases that all have neural formation as part of their pathophysiology that we have animal dat on. Things like MS, Parkinson's disease, TBI, PTSD, and there are more. Based on how well the animal data translate to man, we expect all those diseases to come above the water line over the next three or four years. Okay, it'll take a little bit of time because obviously we don't have unlimited resources, but the big advantage of XPro over a drug like Biogen's drug which targets amyloid, if you target amyloid once you go beyond Alzheimer's disease, there's nothing to treat. When you treat neuroinflammation, Alzheimer's is just the start. And so we're at the beginning of a very interesting journey. That journey will make a difference to patients. It'll make a difference to clinical teams. It'll make a difference to investors who invested in INmune Bio, and we're pretty excited about it.

What’s next for investors?

INMB being so drastically undervalued, I expect the market to pick up on the potential of both platforms of INMB with time. Both of INMB’s platforms are perfect buyout targets, and I do not exclude big pharma comes sniffing, with immuno-oncology dominating big pharma’s agenda, biotech valuations having come down, and INKmune being a fully new approach which could allow a very profitable and unique business case. Proper preclinical trials have taken place, and this is a drug that has been in development for the past 10 years by Prof. Lowdell at UCL, so to speak. Buyout can occur at any time. As a reminder, the Trillium Therapeutics buyout by Pfizer has also occurred when human trials were still in early stages.

INMB should at any moment now announce Phase 2 trial starts in its trial for Alzheimer’s disease, mild cognitive impairment, treatment resistant depression (TRD) and ovarian cancer. The start of these trials often leads to higher valuations.

The ovarian cancer trial is a trial in a solid tumor, which immunotherapies have not had so much success in so far. Prof. Lowdell expects INKmune to be successful in that area too, in light of his preclinical trials in ovarian cancer, a video of which is shown here.

INMB has mentioned a lot is going down under the hood investors aren’t so much aware of, so I include a caveat for some of these. The present article does not cover INB-03, which is XPro for oncology.

Insider ownership inspires confidence

The total amount of shares outstanding is 17.84 million, 26% percent of which is held by insiders. Insiders had a rule 10b51 trading plan in place, the annulment of which has been announced on January 27, 2022.

Xencor, the exclusive licensor for XPro, owns 1,885,533 shares, owning somewhat 10,6% of INMB.

Institutional ownership stands at 14,66% percent, with some additions having been filed recently.

The float is about 11 million shares.

Short interest is just under 10%.

Finances

INMB has about $80 million in cash in hand. Its current cash should last it until some time in 2023, normally until after the MCI and AD trials, as management had mentioned. INMB is mostly reasonable when it comes to dilution. It’s difficult to predict, however, how costs in future will play out, now that quite some trials are soon to begin, which will inevitably raise costs. I expect no further dilution before mid 2023.

Risks

Investment in biotech companies is always high-risk. Drugs may fail, or may be perceived to fail, sending the share price down often more than reasonably attributable to that failure alone. Sometimes good results are even perceived as failures. Recently, INMB discontinued its XPro program in hospitalized Covid patients, not starting a Phase 3 trial, due to the competitive landscape, quickly-changing Covid-situation, and the risk of burning through its cash on a Phase 3 trial in Covid alone. INMB is very cost-conscious, and the essence of its existence is in immuno-oncology and neurodegenerative diseases. The discontinuation was a good choice in my eyes, yet sent the share price spiraling down. On top of that, recent ongoing inflation woes had the price reach even muddier waters. None of these reasons affect the thesis of INMB’s reasons of existence, and as such they neither affect my thesis.

Conclusion

INKmune works, its mechanism of action is revolutionary, simple, it is cheap to manufacture and easily transportable. I believe the combinations of these factors is not found elsewhere in immuno-oncology therapy candidates. As accessibility and financial sustainability of the healthcare system are prone to become an issue in years to come, I believe INKmane has high promise over the coming years.

I expect INMB to continuously bring outperforming results with this drug candidate, as it will with XPro in neurodegenerative diseases. Even though investors lag behind, INMB is clearly the fruit of year-long research and a clear goal to be successful.

Seeing these results in both platforms of the company, I believe management had never designed this company to be average. The preclinical studies in both platforms were ample, have been published for investors to assess, and are so far translated perfectly - beyond expectations in fact - into humans. Management, with sufficient expertise behind its belt, obviously had a well-designed plan for this company from the get-go, and I am happy to take a seat to enjoy the ride.

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End note. The above is the content of an article on INMB which has today been rejected for publication by an investor website for plagiarism and quotation concerns, which are unwarranted in my opinion.

To adapt the content for this website, some information that had already been used in previous blogs of my hand which have been posted on this website have been left out to avoid doubling information for the readership of this blog. Some information on patients in treatment has deliberately been left out, as I am as curious as other investors as to what has been happening since November 2021, as time is on my hands as will remain so for the years to come.

This post will be followed up by a shorter post on the chances of long term success of INKmune in light of preclinical tests and trials with NK cells and cytokine-induced memory-like NK cells (CIML), as there is useful information out there that can serve as guidance and as I believe INKmune may outperform CIML, and a further blog summarizing my recent thoughts on what INMB is doing in TRD.