Accum™ technology in early cancer trials and beyond

The following transcript is automatically generated

00:00:07 Will Mountford

Hello. I’m Will. Welcome to researchpod.

 

00:00:10 Will Mountford

In terms of drug development and widening treatment horizons, we are living in a time of unparalleled growth. Many of these drugs are targeted towards molecular differences in cells, minuscule mutations that set disease types apart. But even if you know the genetic makeup of a tumor through and through, getting medicines to and then into the tumour is a wholly different challenge.

 

00:00:31 Will Mountford

Doctor Moutih Rafei at Defence Therapeutics, speaks to us today about a novel drug technology that gets more treatment to the cells that need it and what that might mean for the future of designing, trialing and marketing medicines.

 

00:00:47 Will Mountford

Doctor Rafei. Hello.

 

00:00:49 Dr Moutih Rafei

Hi. Nice meeting you.

 

00:00:50 Will Mountford

Could you tell us a bit about defence therapeutics and your journey through academics through business as well, and what brings us here today?

 

00:00:59 Dr Moutih Rafei

So I joined Defence in 2019 and was initially the VP Research and Development and nowadays I’m acting as the Chief Scientific Officer of the company and my mandate is to really build the pipeline of the company based on the platform. So today we have many verticals being developed or many different products.

 

00:01:19 Dr Moutih Rafei

Targeting different indications in cancer as well as infectious diseases.

 

00:01:23 Dr Moutih Rafei

So I’m an immunologist by training and I have a lot of interest in anything related to translational immunology, so translational immunology means developing products that are able to basically activate the immune system, so we can target cancer or any kind of ailments that are kind of hard to treat for patients, therefore.

 

00:01:43 Dr Moutih Rafei

What I really like about the work I’m conducting at Defence is the fact that they have this product or this platform.

 

00:01:51 Dr Moutih Rafei

That really answers very important unmet medical needs, which is really making any product get efficiently in the cell. For example, the Pharmaceutical industry has been struggling for a while now with the RNA I drugs, which are basically small pieces of RNA that get into the cell.

 

00:02:11 Dr Moutih Rafei

And their objective is to really block translation of mRNA. The problem is they have to deliver a huge amount of this product, so that 1% of it can make it to the.

 

00:02:23 Dr Moutih Rafei

Therefore, our technology could basically come up as a savior for this product as well as other products including antibody drug conjugates, vaccination or anything including mRNA vaccines that anyone would like to insert into a cell. The fence Therapeutics is a Canadian biotechnology company that was found in 2017.

 

00:02:44 Dr Moutih Rafei

Based on the Accum technology.

 

00:02:46 Dr Moutih Rafei

So the acute technology is basically just a platform that enhances the accumulation of any biomedicine in a cell. It could be M RNA DNA. Any genetic material could be an antibody, a protein antigen, anything you would like to insert within a cell and really works through.

 

00:03:07 Dr Moutih Rafei

Breaking down the endosomal components, while the endosomal membranes allowing the product to be released in the cytosol. In fact, we’ve been traveling to many countries participating in different conferences.

 

00:03:19 Dr Moutih Rafei

We usually go to the International Society of Cell Therapy to talk about our cell vaccination projects, which was held in France this year. We’ve been to London, UK to be able to meet different investors, family offices and talk about our technologies. We’ve been to Switzerland festival of biologics to be able.

 

00:03:38 Dr Moutih Rafei

To present all our ADC program, other programs that are basically ongoing in the company, we’re actually going back to Switzerland in January next year to be able to present the new program, the new clinical program we’re going towards. We’re also heavily involved in the immuno Oncology 360 meeting which is a yearly meeting.

 

00:03:58 Dr Moutih Rafei

Held in New York, USA every February. So we’re always participating in those international meetings to really put defence therapeutics on the map, especially that right now we’re achieving very important inflection points related to our clinical programs, which should be starting off in 2020.

 

00:04:17 Will Mountford

Well, to talk about antibody drug conjugates in broad strokes leading up to the invention and development of acne technology, could you give me some of the back story here of what has been the last you know, 10-15 years of development and some success stories?

 

00:04:32 Dr Moutih Rafei

Sure. So antibody drug conjugates are basically antibodies on which you would attach a payload. So these are toxic molecules chemotherapeutics. And the objective really is to be able to bring those chemotherapeutic agents directly onto cancer cells, so.

 

00:04:49 Dr Moutih Rafei

The antibody drug conjugate field has been mainly focused so far on breast cancer, especially because a lot of these antibodies will target her too, which is a Herceptin which is expressed on breast cancer cells. So the problem with this technology is that even though these antibodies are good at bringing the pillow to the cell.

 

00:05:10 Dr Moutih Rafei

Most of these patients are suffering from pretty large set of side effects. They have to be on a very long regimen that can go up to six cycles. So that’s you know months and months and months of treatments.

 

00:05:25 Dr Moutih Rafei

On top of that, these antibodies are not efficient because of the fact that these antibodies get entrapped into the endosome and the payload could not be released efficiently into the cytosol. So we have some issues with respect to the therapeutic potency of these ADC’s, their ability to really accumulate and target cells. So what the Accum is able to provide in this context.

 

00:05:46 Dr Moutih Rafei

Is the ability to really bring in the molecule very efficiently within the cell, and if that is basically the objective, then you can imagine not only having great impact on manufacturing because now the patient will have.

 

00:06:01 Dr Moutih Rafei

To receive a very, very low dose compared to the original regimen. But now these patients will be eventually able to get the treatment on a shorter scale, a shorter timeline and that will have a great impact on minimizing any sort of cytotoxicity or toxicity and used by.

 

00:06:17 Dr Moutih Rafei

These ADC’s.

 

00:06:18 Dr Moutih Rafei

That are being given to these cancer patients.

 

00:06:21 Dr Moutih Rafei

Now with respect to developments, I know everybody’s focused on breast cancer, but Defence right now is not only working on applying the acumen technology on commercially available or FDA approved Adcs to really enhance their therapeutic potency, but we are also developing our own in-house antibody drug conjugates.

 

00:06:38 Dr Moutih Rafei

So we have two targets that we’re working on right now. So we can have new Adcs on the market able to not only target breast cancer, but target a variety of other cancer indications. We’ve also established A partnership with the European biotech to be able to use their ADC, enhance the ADC they have because they’ve got amazing data, but the doses they have to deliver are quite.

 

00:07:01 Dr Moutih Rafei

So we’re really trying to minimize our doses by 5060 or even 70% to be able to reach the target effect we’re looking for. So there are a lot of developments currently for the ADC program in Defence and we’re pretty excited because that really shows you the versatility of our technology and how we can apply it to not only one or two products, but really develop you know.

 

00:07:22 Dr Moutih Rafei

Over hundreds of different ADC related products.

 

00:07:31 Will Mountford

I’ll ask you about some of those branching ideas for different applications in a second, but you mentioned some percentages there, and I think it’s worth following up on those numbers to say that taking those numbers into a human context, to say that you are able to deliver the same.

 

00:07:44 Will Mountford

Potency with the medicine at a lower frequency of doses, so less time that a patient has to spend in the clinic.

 

00:07:50 Will Mountford

Lower doses given at any one time. What’s the human experience of being on the receiving end of?

 

00:07:56 Dr Moutih Rafei

Yeah. So let’s assume you’re doing an experiment in vitro on cancer cells. If you’re at, let’s say, a specific dose on these cells, you’ll be able to derive what we call an IC50 dose, which is the dose that will inhibit or kill by 50% the number of cancer cells we have in culture. Now what happens in this case?

 

00:08:16 Dr Moutih Rafei

Is when we’ve done some studies where we bio conjugated the Accum on TDM one for example, which is currently used for breast cancer.

 

00:08:24 Dr Moutih Rafei

We were able to enhance the potency by 20 to 100 folds, meaning that we can decrease the amount of the antibody added by 20 fifty 7000 folds and reached the same therapeutic efficacy we were able to get with higher doses. Now what that means or.

 

00:08:44 Dr Moutih Rafei

How it translates into a patient is that if let’s say you have a patient that is receiving, I’m just giving a number like this 5 milligram per kilo of the anti.

00:08:53 Dr Moutih Rafei

Then this will be given, let’s say once a week over a period of 12 weeks. Well, now we no longer need to deliver 5 milligram per kilo. We can lower the dose to 1 milligram per kilo for example, or .5 milligram per kilo. And instead of giving it to a patient over 12 weeks or six weeks, we can decrease that period.

00:09:13 Dr Moutih Rafei

By 50%. So the patient will have to take it.

00:09:16 Dr Moutih Rafei

Over two or three weeks and they will.

00:09:18 Dr Moutih Rafei

The same potency or therapeutic effect as they used to get in the past, so you can imagine this case that this will have a great impact in terms of manufacturing because we no longer need to manufacture a very large number of the drug and also it will minimize tremendously the side effects that the patients will have to go through because instead of.

00:09:39 Dr Moutih Rafei

Getting large doses over a long period of time and having to suffer from all the.

00:09:44 Dr Moutih Rafei

Different side effects. Now we’re really minimizing the exposure to the drug and we’ll lower in tremendously the dose, meaning that the patient is no longer going to be facing these kinds of toxicity effects.

00:09:56 Will Mountford

Having a shorter course of more not targeted but more smartly applied medicine and having the less side effects go with it. I can imagine not being a huge benefit for the patients, but in terms of a healthcare system as well, you mentioned the manufacturing cost, but also what that means for the purchasing price for the.

00:10:15 Will Mountford

Budgeting of any national healthcare system I can imagine that’s going to have a lot of.

00:10:19 Dr Moutih Rafei

Impact there as well? Well definitely because now you’ll have to pay less of the product of the drug, meaning you’ll have to spend less money. Patients don’t have to go very often to the clinics or the hospital centers, which means they will have a great impact on the healthcare.

00:10:36 Dr Moutih Rafei

Of course, we’re always thinking about this when we develop products because the idea is to have something that is long lasting, efficient and for which you can use smaller doses. So by doing that, you’ll be able to hit three birds with one stone. So making sure that you inject smaller doses. So it’s going to be cheaper. You’re making sure that you have.

00:10:57 Dr Moutih Rafei

The best hope for outcome clinical outcome down the line and also making sure that the patient doesn’t have to suffer through the same side effects he’s been encountering.

00:11:05 Dr Moutih Rafei

With these payloads that are quite toxic because these are chemotherapeutic drugs, even though they’re guided by the antibodies, they’re still, you know, toxins that can cause a lot of damages.

00:11:14 Dr Moutih Rafei

To the patient.

00:11:15 Will Mountford

Follow up on what you mentioned about other uses, other indications for this kind of branching technology. There was something in your research that stood out to me in terms of the development of vaccination and tumor immunity, and we’ve all had some of a crash course globally in the development of vaccines, but that’s kind of an atypical example to a vaccine develop.

00:11:35 Will Mountford

So just to retreat, some of the usual steps in terms of how vaccines are developed, how oncologic drugs are developed could go over some of the different styles of vaccines. Some of the steps into making all of this and then where acumen takes it into that next step forwards.

00:11:49 Dr Moutih Rafei

Yeah. So when we talk about vaccines and we’ve been all vaccinated lately with the pandemic, the COVID pandemic. So everybody’s aware of what vaccines.

00:11:57 Dr Moutih Rafei

Are vaccines are basically means of activating the immune system or targeting the immune system or educating the immune system to target an antigen or protein derived from a specific Organism?

00:12:10 Dr Moutih Rafei

Now what’s important to realize is that when we’re talking about infectious diseases and cancer, there is a tremendous difference out there. Even though the concept is the same. You have to remember that a viral or a bacterial derive protein is considered non self, meaning they’re not part of our body. So the immune system is heavily trained.

00:12:30 Dr Moutih Rafei

To be able to activate or respond to these antigens or proteins, what we’re talking about cancer on the other hand, it’s a bit more challenging because we’re dealing with the so-called self.

00:12:41 Dr Moutih Rafei

So in the 90s, a lot of the cancer immunotherapeutics or vaccination protocols were programmed or designed to target tumor associated antigens. So these are normal proteins that are found in our healthy cells. But they’ve been observed to be highly expressed on the surface of cancer cells. So even though they’re highly expressed, it doesn’t mean they’re immune reactive.

00:13:03 Dr Moutih Rafei

That doesn’t mean they can actually activate the immune system, because the immune system.

00:13:07 Dr Moutih Rafei

Has been tolerant during its development towards these tumor associated antigens. So this is where the whole field of proteomics transcriptomics came into play, because the idea there is to be able to identify tumor specific antigens. So antigens or proteins that are only expressed on the cancer you’re targeting.

00:13:28 Dr Moutih Rafei

The problem with this approach is twofold. First, you have to really create this kind of an approach for every single patient, because these patients are specific, so everyone has its own cancer cells, its own tumor antigens. So you’ll never be able to share or find a patient that has an antigen that is shared with another patient.

00:13:49 Dr Moutih Rafei

That’s really specific. And second of all, this approach will take between 6 to 12 months to be able to actually bring in a list of tumor specific antigens on your antigens that you’ll be able to express and eventually use as a vaccine.

00:14:05 Dr Moutih Rafei

So how did we resolve this problem? We decided to basically first of all use a completely different approach. So we have a variant of the acumen that we have basically developed that is able to reprogram a type of stem cell into becoming an antigen presenting cell.

00:14:24 Dr Moutih Rafei

So this is really innovative. This is novel, not a lot of people are aware of this tech.

00:14:28 Dr Moutih Rafei

Allergy what we do in this case is we take the A1 molecule and we mix it, in this case with the tumor lysate coming from that patient. So what that means is that I have to take a biopsy of the tumor in that specific patient, which is basically a mix of the good and the bad. The good being the new antigens or the tumor.

00:14:49 Dr Moutih Rafei

Specific antigens. The bad being the tumor associated antigens or the self antigens and then by mixing it with the A1, we pulse those stem cells to reprogram them into antigen presenting cells. So what happens in this case without knowing what is the antigen we’re targeting?

00:15:06 Dr Moutih Rafei

Those stem cells are able eventually to present both the tumor specific and the associated antigens at the same time, and because the immune system would react to the tumor specific antigen, that’s how we can develop a personalized immune reactivity against the tumor from that patient. So in other words, even though.

00:15:27 Dr Moutih Rafei

This is a universal off the shelf allogeneic cell based vaccine. It always relies on tumor samples from the patient to make sure that we develop the immune response specific to his own antigens. So this is the approach that Defence has been developing over the last three years.

00:15:44 Dr Moutih Rafei

There’s, but that is not the only approach, so this is a cell based vaccine reprogrammed with the A1 molecule. But we have also mRNA vaccination trials or studies that are ongoing right now to be able to demonstrate that we can mount a new response.

00:15:59 Dr Moutih Rafei

Not necessarily against cancer only, but also targeting infectious diseases.

00:16:03 Will Mountford

And another branch of oncology that’s attracted a lot of attention and development over the last few years besides targeted therapy has been immunomodulation and immuno oncologic. So is there any opportunities for combining these two styles of approach, anything that would work with akin to augment or enhance its delivery of that pain?

00:16:23 Dr Moutih Rafei

That’s a very interesting question. In fact, the answer is yes. In fact, what we have done, we have also developed a variant of the acute we called the acute docs, and in fact the Ind submission has been done last week. So if everything goes well, we should be getting the approval from the FDA to move on to a phase one trial early next year and.

00:16:42 Dr Moutih Rafei

Acute tox is basically a molecule that you can inject directly into the tumor and what it will do, it will induce cell death. It will kill the cancer. But the way it kills the cancer is very interesting because it does so from inside out.

00:16:57 Dr Moutih Rafei

So it goes inside the cell. It disrupts endosomal transport, the transport mechanism, the endosomal membranes, it causes genotoxic effect on the DNA or it causes DNA damages. It blocks the DNA repair mechanisms and it also creates a form of cell death called immunogenic cell death. So what that means is that it will make the cell.

00:17:17 Dr Moutih Rafei

Leaky. It will start, you know, producing some inflammatory molecules that will bring in the immune cells, including antigen presenting cells where they’re they can basically uptake the antigens being released from that cancer and mount an immune response to be able to go and reach an anesthetic nodules.

00:17:36 Dr Moutih Rafei

The tumors. And So what we’ve realized with this therapy is that not only it works very efficiently as a monotherapy. So by just injecting the acute docs. But we’ve also observed amazing synergistic effect with the famous immune checkpoint inhibitors. Immune checkpoint inhibitors are being used nowadays in the clinic or Melanoma, non Hodgkin’s lymphoma and other indications.

00:17:57 Dr Moutih Rafei

Some of the most popular ones are NTPD 1, NTPL 1 antibodies, ctla 4. They’re CD 47. These are all immune checkpoints that we have tested in our lab and we’ve demonstrated.

00:18:09 Dr Moutih Rafei

That the acute tox technology works pretty well and in synergy with these immune checkpoints. In fact, when we conducted studies, for example on Melanoma, breast cancer as well as solid T cell lymphoma, we’ve shown that our molecule works very efficiently with the anti CD47 with NTMA 4 with NTPD 1.

00:18:29 Dr Moutih Rafei

And we were able to get between 70 and 100% survival in these animals. Some of them had their tumors shrinking, others were kind of stabilized. So we’re seeing a very potent effects with these combinations. And right now, what we’re working towards is to have a phase one trial at City of Hope in the US.

00:18:47 Dr Moutih Rafei

Next year, where Acetoxy is going to be delivered with Abdullah, which is a BMS product containing both anti lag three and anti PD one in the context of solid Melanoma. If that works we’ll be able then to move on to a wider range of indications to be able to treat.

00:19:06 Will Mountford

Now it’s worth noting that we’ve talked a lot about success stories and some of the prospective applications here, but anytime something is being introduced to a biologic system, there’s going to be some adverse events associated with it, no matter how inert that molecule might be. So it’s worth taking the time to mention now is there any

00:19:24 Will Mountford

Dose dependent response to Accutox or to the Accum technology that has to be weighed against the benefits as at any you know, downside to everything that’s been very promising so far?

00:19:34 Dr Moutih Rafei

Yes. In fact, we have conducted a GLP study, so GLP studies were conducted on both dogs and rats because we have to test our molecules on two different species.

00:19:45 Dr Moutih Rafei

And we went up to a dose of 100 milligram per kilo.

00:19:49 Dr Moutih Rafei

In fact, we didn’t observe any death happening in these animals. The only thing we observed with doses approaching 40 or 50 milligram per kilo were redness and inflammation and the cytomel injection. So that’s normal. Now what we have to keep in mind is that acute docs could not be delivered intravenously because we think it’s going to cause a lot more side effects.

00:20:10 Dr Moutih Rafei

This is why currently we’re delivering it locally intratumoral. So we’re having, let’s say, a solid tumor on the arm of the patient. And then with specific needles, these drugs are delivered directly inside the tumor.

00:20:24 Dr Moutih Rafei

What’s really good about this approach is that this is a small molecule, so it’s not going to diffuse very fast and very long away from the tumor, and by doing so, we’re making sure that also the half life is very short. So even though if you have some diffusion going on, this is not a molecule that will be circulating around for 6, 8, 12 hours, it’s going to be like.

00:20:44 Dr Moutih Rafei

Less than an hour and the molecules cleared out.

00:20:46 Dr Moutih Rafei

Now eventually what we are looking to do develop is an antibody drug conjugate where this acute tox is going to be the payload. So instead of using, let’s say, a commercially available chemotherapeutic agent, we will be attaching the acute tox on our antibodies and the antibodies will bring them systemically.

00:21:06 Dr Moutih Rafei

Where the tumor is located. So that’s how we minimize really the side effects, but in our hands, in our studies both preclinical and GLP, what we were able to demonstrate is that the molecule works pretty well at a dose of 16 milligram.

00:21:21 Dr Moutih Rafei

per kilo and side effects such as inflammation, redness, and some you know at the side of injection were only noticed when we reach doses of 40 and 50 milligram per kilos or way higher than the therapeutic dose.

00:21:36 Will Mountford

But you mentioned some of the trials for development and expansion, the city of Hope trial coming up for next year. Are there any other current trials that it’s worth highlighting and noted from the paper that there’s a range of different tumors that this is being looked at for solid ovarian and pancreatic cancers?

00:21:52 Dr Moutih Rafei

Yes indeed, we have two phase one trials that will be starting.

00:21:56 Dr Moutih Rafei

Early next year, so the first one I mentioned was Accutox and that’s in the US at City of Hope in LA and that’s going to be an injectable anti cancer molecule, which is the acute toxin combination with Abdullah. The second trial is related to the ARM vaccine. So this is the A1 reprogrammed mesenchymal stromal cell. So this is the molecule that I told you could reprogram.

00:22:17 Dr Moutih Rafei

A type of stem cell and the cell based vaccine. We’re having a meeting with Health Canada in January of 2024 to be able to have the phase one clearance in order to really target Melanoma.

00:22:30 Dr Moutih Rafei

Now, having said that, we have currently work ongoing both in our lab as well as with CRO’s to target both pancreatic cancer as well as ovarian cancer. And the reason why we focus on these two different cancer types is because they’re really hard to treat and they’re basically killer cancers killing cancers. You know they kill within six months.

00:22:51 Dr Moutih Rafei

If they reach to stage 3 or stage 4, and for which there is absolutely no therapy available on the market, the only thing we can do is the standard of care, which is basically just trying to attempting to remove the tumor by surgery or giving chemotherapy or radiotherapy. But these therapies or standard of care do not work unless the cancer is diagnosed pretty early.

00:23:12 Dr Moutih Rafei

Which is not happening very often. So idea here is that the ARM vaccine, which could be easily adaptable to any kind of cancer, we will be looking forward to using not only in Melanoma but also targeting ovarian cancer in the States and potentially pancreatic cancer as well.

00:23:28 Dr Moutih Rafei

These are the two most advanced programs we have right now, but there are other programs we’re working heavily on, such as a protein vaccine targeting head and neck cancer, but that’s probably going to be our third phase one trial, which will be attempting to move forward by the end of next year.

00:23:44 Will Mountford

Are there any other milestones that it’s worth highlighting or collaborations?

00:23:48 Dr Moutih Rafei

Yes. In fact, Defence has established various partnerships. We’ve got a partnership with Orano in France, which is a gigantic company involved in nuclear medicine.

00:23:59 Dr Moutih Rafei

We’ve got a contract with Onco Matrix, a European based company working on antibody drug conjugates. We’re currently negotiating a partnership with a giant Asian Pharmaceutical Company and we have other programs ongoing currently in Europe where we’re trying to really approach large companies like Bio Entech as well as other pharmaceutical giants like Sanofi.

00:24:20 Dr Moutih Rafei

As well as Merck to be able to Co develop any products, including antibodies or conjugates or vaccines with these companies. So we’re pretty active in that.

00:24:29 Will Mountford

Who should be listening to this interview and what should they know at the end of?

00:24:33 Dr Moutih Rafei

This call well, what is important to deliver as a message here is that Defence therapeutics is hopefully going to be the next Genentech. That’s our aim at the end of the day. I know Genentech eventually got purchased or got fused with another giant, but the idea here is to really develop a company.

00:24:50 Dr Moutih Rafei

That we’ll be able to develop different products, different verticals, different objectives and we could reach that because we’re using a highly versatile platform. Now we’re hoping eventually to attract the attention of investors because we’re currently.

00:25:05 Dr Moutih Rafei

And funding rates for our programs that are very interested bankers and institutions that are in negotiation with us right now to put in between 10 and 15,000,000 to run out to phase one trials. But we’re also hoping to be able to reach big pharmaceutical companies that have, let’s say, antibodies or congregates that they want to.

00:25:24 Dr Moutih Rafei

Enhanced in terms of the therapeutic potency, any other ADC’s that is currently in preclinical development, we’re hoping eventually to be able to work with via Antech or Moderna because we believe that the acute technology could be.

00:25:37 Dr Moutih Rafei

Highly potent at enhancing the mRNA delivery into muscle cells to be able to really enhance by 10, 20 or even 50 fold, the immunogenicity of their vaccine. So at the moment we’re active in terms of partnership, we’re also interested in recycling any ADC that has failed phase two trial because of.

00:25:59 Dr Moutih Rafei

Dosing effect or therapeutic effect.

00:26:01 Dr Moutih Rafei

We’re interested in licensing agreements we’re interested in.

00:26:04 Dr Moutih Rafei

So really anyone who’s interested in working with us or knowing more is more than welcome to approach us and talk to us. We have a website, thefencetherapeutics.com, or they can reach out to me directly or our President, Mr. Sébastien Plouffe. It’s very simple. I mean, if we go to Google and you just type in Defence with a C, you’ll be able to find.

00:26:25 Dr Moutih Rafei

A lot of press releases, access to our slide decks, access to our website where we have all the information available there.

00:26:31 Will Mountford

Once again, Doctor Rafei, thank you so much for your time today and I look forward to seeing what comes from Defence therapeutic next.