Matinas Review and (moderately) Deep Dive
Noah asked me to expand on Matinas, so I thought I’d do it as a full review. This is a company that has amazing potential if it gets its act together. Part of what I’ve included is taken direct from the website. Here’s Noah’s question:
Matinas stock crashed after they released the results of a stage 2 study despite achieving the primary goal. You mentioned that their study design was not smart. Where do you think they went wrong and how will they will be able to fix it? Do you think they have a viable platform? Thank you.
Growing antimicrobial resistance is a global, public health threat. Drug resistant infections, often called “superbugs” will kill millions of people yearly worldwide unless action is taken. The combination of these multidrug resistant infections, coupled with the toxicity of many available drugs, has rendered many current therapies obsolete.
Matinas BioPharma, founded in 2012, and IPO’ed in 2014, and listed on the NYSE,is a clinical-stage biopharma that aims to transform the way potent medicines are administered in order to provide physicians and patients with more tolerable, safer, more effective and more powerful options in the battle against these superbugs. Using its proprietary, lipid-crystal, nanoparticle delivery technology, it is able to provide three critical and unique benefits:
(1) oral administration of medicines which today are only able to be delivered intravenously,
(2) multi-organ protection from otherwise highly toxic compounds in a stable, solid particle,
(3) targeted delivery directly to sites of infection or inflammation, with the potential to achieve rapid tissue penetration, days ahead of what is available with injected drugs.
[So, very simply, what Matinas does is take a toxic medicine which can only be given intravenously, puts it inside nano sized particles with a hard shells, which then can be given orally, are absorbed into the bloodstream, where they are mistaken for bacteria or viruses by the macrophages, so the macrophages engulf them (eat them), whereupon the medication is released and taken direct to the infection site by the macrophages. Read on. It will be explained much more elegantly.]
This disruptive, game-changing technology seals the treatment drug in a soy-based lipid bilayer sheet, which rolls into a spiral structure called a cochleate with no internal aqueous space. The end product is a stable (can be boiled in detergent), solid nanoparticle. Once swallowed, the cochleate passes naturally through the walls of the intestinal tract. After it is absorbed into the body, scavenger immune cells that ingest foreign particles, such as macrophages, engulf the cochleate. Once engulfed by the macrophage, the cochleate enters its cytoplasm, an environment of low-calcium concentration inside the cell. The cochleates have been designed to unroll in intracellular low-calcium environments and purposefully release the drug on the inside of the macrophage, protecting the body from the toxic drug. In infected individuals, macrophages then follow a signal-molecule trail through the lymphatic vessels directly to the site of infection and deliver the drug precisely where it is needed. [WOW!!!]
The lead drug candidates are being developed in collaboration with NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which has been an integral part of all preclinical and clinical work conducted to date and provides independent scientific validation of the potential for this platform.
On top of the improved clinical profile made possible by this technology, successfully moving from IV-administration of drugs to orally available medications, on top of improved safety and efficacy, there are enormous savings to be achieved through reduced hospital stays and the reduction or elimination of the need for frequent blood tests. The improvement in the quality of life for patients, many of whom are immuno-compromised and require long term care, by providing the availability of oral drug therapy in the comfort of one’s home is another reason why Matinas can have a transformational impact on the future of drug delivery for numerous medicines.
Beyond these lead clinical programs, work is being conducted with anti-virals, anti-inflammatories (no lesions in preclinical animal studies), and vaccines (significant improvement on traditional flu vaccines), and Matinas has the potential eradication of diseases like HIV, tuberculosis and other infectious diseases in its sights. Unlike many binary biotech product plays, there seems to be no shortage of “what’s next” when considering downstream applications and products utilizing Matinas’ proprietary cochleate technology.
Cochleate Technology
Solutions such as pills and injections typically rely on a diffusion-like process that essentially soaks our bodies in medicine with the hope it gets to every anatomical corner where it may be needed. For numerous medications, in particular for those with mild side effects, this approach works to reasonable satisfaction.
Unfortunately, not all drugs are soluble enough to easily penetrate all desired tissues, and many medications have serious side-effects. Medications with high toxicity can cause numerous painful and often damaging side effects such as nephrotoxicity (kidney toxicity), hepatotoxicity (liver toxicity), headaches, vomiting, and severe chest pains, amongst others. However, doctors continue to use these drugs because they are effective in treating diseases. Many highly effective medications with significant side effects include anti-bacterial, anti-fungal, anti-viral or anti-inflammatory drugs.
Our lipid-crystal nano-particle cochleate formulation technology offers a drug delivery solution with three differentiating and disruptive features:
1. Multi-organ Protection: The key innovation of our cochleate technology is our ability to package medication inside lipid-crystal particles. Because of their crystal nature, these particles are truly solid and hold on tightly to their medication pay-load.
2. Targeted Delivery: The size of our lipid-crystal cochleate particles is typically in the range of 50-500 nm. This is very small and by comparison close to the size of a large virus or a small bacteria. Our body produces several cell-types like macrophages that are designed to remove viruses and bacteria from our system. They are part of our immune system and “swallow” the bacteria and viruses they encounter in order to protect us from infections. Because of the size of our cochleate particles and their surface structure, macrophages tend to absorb them very well. These macrophages may contain already the microbes we would like to eradicate or may be on their way to a site of infection or inflammation in our body, taking their pay-load along.
Cochleate Formulations: “Encochleation” was invented by Dr. Mannino, our Chief Technology Officer when he was Prof of Medicine at Rutgers, and was further perfected by Dr. Mannino along with some of our key-scientists.
Cochleates have a multilayer crystalline, spiral structure with no internal aqueous space. The structure is formed when a series of solid lipid sheets roll up and capture drug molecules in between the sheet, a process referred to as “encochleation.” The result is a lipid-crystal encochleated drug made up of nano-sized particles.
Once the cochleate, with the drug inside, is administered, it is engulfed by target cells in the body, such as macrophages , and taken directly to the site of infection or inflammation. The lower calcium levels inside the macrophage compared to the high level of calcium outside the macrophage, triggers the cochleate to open, thus releasing the drug inside the cell. Because the drug is locked up in the solid cochleate particle or in the target cells, the rest of the body is protected from the toxicity of the desired medication.
3. Oral Drug Delivery: The unique cochleate crystal-structure protects the drug from degradation when it passes through the GI tract and its lipid surface features allow the particle to be absorbed into the blood stream.
Many drugs that are currently on the market are only effective in treating diseases when given intravenously (IV). For example, many anti-infective drugs must be administered intravenously in order to be effective. However, IV administration presents several challenges to care, such as risk of infection, patient discomfort from injections, and higher cost of care than oral administration (IV delivery must be performed by a doctor or nurse, often within a very expensive hospital setting).
The anti-fungal medication Amphotericin B is a good example to demonstrate the unique features of the cochleate technology. Currently available formulations of amphotericin B cannot be absorbed through the GI tract and therefore must be given intravenously. By encochleating amphotericin B, in a mouse candidiasis study we demonstrated comparable survival with oral administration of a quarter of the IV dose. The very mild side effect toxicity profile with the encochleated treatment group is consistent with lower dose and drug shielding properties of the cochleate technology. With this technology, we are able to deliver amphotericin B, orally, to the target cell, with reduced toxicity.
Apr 2017 – Dec Quarter and Year end results
MAT2501 - Recently announced positive topline data from initial study in Phase 1
MAT2203 - Will report interim Phase 2 data of and topline data of vulvovaginal candida study in June 2017
Recent corporate highlights
• Commenced trading on the NYSE MKT;
• Successfully completed warrant tender offer with gross proceeds of $13.5 million from exercise of warrants;
• Opened a Good Laboratory Practice lab space and Good Manufacturing Practice commercial scale manufacturing facility; and
• Received contract award from Cystic Fibrosis Foundation to study MAT2501 for the treatment of NTM-infection in pre-clinical models of CF.
Anti-infective program achievements
MAT2203: orally-administered, encochleated amphotericin B, a broad spectrum fungicidal agent, currently in Phase 2 clinical studies for the treatment of refractory mucocutaneous candidiasis and vulvovaginal candidiasis (VVC)
Commenced patient dosing in NIH-sponsored Phase 2a study for the treatment of mucocutaneous candidiasis infections ;
Initiated enrollment and commenced patient dosing in Phase 2 study for the treatment of vulvo-vaginal candidiasis; and
Initiated open-label extension to Phase 2a Study of MAT2203 in chronic mucocutaneous candidiasis.
The FDA has designated MAT2203 as a QIDP with Fast Track status for the treatment of invasive candidiasis, aspergillus, and prevention of invasive fungal infections in patients on immunosuppressive therapy.
MAT2203 is also being explored for treatment of additional infections including cryptococcal meningo-encephalitis, and is being developed to be eligible for Orphan Drug designations in various indications.
(QDIP means Qualified Infectious Disease Product and gets faster consideration and a five year patent extension)
MAT2501: orally-administered, encochleated amikacin, a broad spectrum antibiotic agent, with a lead chronic indication for treatment of non-tuberculous mycobacterium (NTM) infections
Reported positive topline data from the Phase 1 single-ascending dose study of MAT2501 in healthy volunteers; and
Reported positive preclinical efficacy results of MAT2501 in an in vitro model of Mycobacterium abscessus infection.
The FDA has designated MAT2501 as a QIDP and an Orphan Drug for the treatment of NTM infections. We intend to initially develop MAT2501 for the treatment of NTM infections and will also explore it for the treatment of a variety of multi-drug resistant, gram negative bacterial infections. If approved, Matinas believes MAT2501 would become the first orally bioavailable aminoglycoside and represent a significant improvement over existing therapies from a treatment and health economic perspective.
Expected near-term milestones
Commence tolerability/PK study of MAT2203 in patients with a hematologic malignancy in Q2 2017, to position this lead product candidate for a pivotal study in this population;
Report interim results from the open label, NIH-sponsored Phase 2a clinical study of MAT2203 in immunocompromised patients in June.
Report topline results from the ongoing Phase 2 study of MAT2203 in VVC in June 2017; and
Commence multiple ascending dose PK/tolerability study of MAT2501 in healthy volunteers.
Summary of financial results for 2016
For the year ended December, 2016, we reported a net loss of approximately $7.6 million, compared to a loss of $9.1 million, the year before.
The net loss is attributable to the ongoing R&D activities related to our MAT2203 antifungal and MAT2501 antibacterial product candidates as well as the costs associated with operating as a public company. We ended the year with cash and cash equivalents of approximately $4.1 million.
Based on our current projections and with the approximate $12.7 million raised with the close of our warrant tender offer on January 13, 2017, we believe that cash on hand is sufficient to fund operations through the second quarter of 2018.
Apr 2017 – Report of study - Plasmid-cochleate shows promise for commercially viable effective oral and systemic vaccines
This preclinical study evaluated the oral or IM administration of encochleated plasmid pCMV HIV-1 containing 3.5µg or 17µg of DNA, given to mice.
Oral administration of two doses yielded strong responses analogous to IM injection, but oral naked DNA (unencochleated), was inactive, even in higher doses.
Low doses of oral encochleated DNA induced antigen specific splenocytes ten times above background, similar to injected. Unencochleated, nothing happened.
These studies affirmed that co-administration of cytokines can enhance the immunogenicity of a DNA-based vaccine. Naked DNA was inactive.
May 2017 – Mar quarter results
Announced positive data from initial study in Phase 1 program for MAT2501.
We also reviewed the progress of our lead anti-infective products in development,
MAT 2203, an orally administered, encochleated formulation of amphotericin B (a broad spectrum fungicidal agent), and
MAT2501 an orally administered, encochleated formulation of the broad spectrum aminoglycoside antibiotic, amikacin, to treat gram-negative bacterial infections and other intercellular bacterial infections.
We remain focused on the progression of our MAT2203 and MAT2501 clinical programs, and look forward to announcing interim results and topline data in June, which we believe have the potential to provide important validation of our cochleate platform technology broadly.”
Corporate Highlights
Completed warrant tender offer with gross proceeds of $13.5 million from exercise of warrants;
Opened a Good Laboratory Practice (GLP) lab space/Good Manufacturing Practice (GMP) commercial scale manufacturing facility.
MAT2203: Initiated open-label extension to Phase 2a Study of MAT2203 in chronic mucocutaneous candidiasis.
MAT2501: Reported positive topline data from the Phase 1 single-ascending dose study of MAT2501 in healthy volunteers; and
Reported positive preclinical efficacy results of MAT2501 in an in vitro Model of Mycobacterium abscessus infection.
Expected Near-Term Milestones
NIH to report interim results from the open-label, NIH-sponsored Phase 2a clinical study of MAT2203 in immunocompromised patients in June.
Report results from the ongoing Phase 2 study of MAT2203 in June;
Commence tolerability study of MAT2203 in patients with a hematologic malignancy in Q3 2017 to position this lead product candidate for a pivotal study in this population; and
Commence multiple ascending dose tolerability study of MAT2501 in healthy volunteers.
Financial Results
Based on current projections, we believe that cash on hand is sufficient to fund operations into June 2018.
June 2017 – Preliminary results – Very Positive !!! These are patients with no other effective treatment available.
The NIH presented interim data from two patients enrolled in the collaborative Phase 2a study of MAT2203 for the treatment of chronic refractory mucocutaneous candidiasis (“CMC”) infection. Two out of the two patients with long-standing azole resistant mucocutaneous candidiasis met the primary endpoint of the study, achieving = 50% clinical response. MAT2203 was well tolerated with majority of adverse events observed being mild in severity and unrelated to study drug.
We are incredibly pleased with the interim safety and efficacy results of this Phase 2a study of MAT2203. While we understand the results are representative of just two patients, these patients are difficult to treat because of their severe underlying immunocompromising condition. With the statistical success hurdle that was prospectively set at a 20% patient-response, seeing a clinical response in two out of two patients brings us very close to the 3 out of 16 responders required for the study to meet its primary endpoint.
“We believe that we have made a significant step toward establishing proof-of-concept for treating fungal infections in immunocompromised patients, and importantly have begun to demonstrate in a clinical setting the depth and breadth of our cochleate technology to deliver amphotericin B orally as a chronic treatment. We believe these initial results may be predictive of the full study outcome.”
The interim data presented showed that the first two patients in this study, both with Job’s Syndrome and long-standing azole resistant mucocutaneous candidiasis for more than 20 years, achieved = 50% clinical response after 14 days of treatment at an efficacious orally administered dosage of MAT2203, thus meeting the primary endpoint. Job’s Syndrome is a hereditary condition rendering the patients severely immunocompromised and exposes them to chronic infections, often involving the oral, esophageal and vaginal mucosas and nails. Both patients suffered from chronic azole resistant oral thrush as their primary infection and had an inadequate response to current oral antifungal therapy. The clinical severity score for oral thrush decreased by 57% for patient 01 and by 85% for patient 02, with corresponding reduction in fungal culture counts. Both patients reported meaningful quality-of-life improvements.
MAT2203 was generally well tolerated and there were no signs of nephrotoxicity, hypokalemia or hepatoxicity. Indicators of kidney and liver toxicity remained within normal limits throughout a 6-8 week treatment period.
As expected, oral thrush promptly returned after stopping treatment with MAT2203. Therefore, Matinas’ preliminary clinical data indicate that MAT2203 is promising as an oral systemically-absorbed broad-based antifungal without the toxicity of parenteral amphotericin B.
Both of the patients have requested to enroll in an open-label extension study.
The Phase 2a study is being conducted at the NIH in Bethesda. The ongoing open-label, dose-titration study is designed to assess the efficacy, safety, tolerability and pharmacokinetics of MAT2203 in hereditary immunodeficient patients with a recurrent or chronic mucocutaneous candidiasis infection (esophageal, oropharyngeal, vaginal) who are refractory or intolerant to standard non-intravenous therapies. The study will enroll up to 16 patients, and study endpoint in the statistical analysis plan is defined as a response in three or more patients. In March we announced that the Institutional Review Board granted approval for a 6-month open-label safety extension of the Phase 2a study.
FDA has designated MAT2203 as a Qualified Infectious Disease Product (QIDP) with Fast Track status for the treatment of invasive candidiasis, aspergillus, and prophylaxis of invasive fungal infections in patients of immunosuppressive therapy. MAT2203 is also being explored for treatment of additional infections including cryptococcal meningoencephalitis, and is being developed to be eligible for Orphan Drug designations in various indications.
Jun 2017 - Their lead product candidate fails to match standard-of-care treatment in yeast infection study;
A proof-of-concept Phase 2 clinical trial assessing Matinas’s lead product candidate, MAT2203, for the treatment of women with moderate-to-severe vulvovaginal candidiasis (VVC) met its primary endpoint of safety, but failed to match standard-of-care fluconazole in effectiveness.
Despite the setback, the company plans to continue developing the candidate for the indication, at a higher dose and longer duration of treatment. Additional guidance will be released next quarter.
(Saul here) MY DISCUSSION
Okay, If you followed me this far you know that there was no reason for them to do this study. They did show it was safe. But they already knew it was safe!
There was already an easy to use, long established treatment, fluconazole, that works for the common problem of vulvovaginal candidiasis almost all the time (up to 95%). Matinas did show their treatment was effective. But not as effective as the standard of care medicine. Well, duh!!! The standard of care in this case is hyper-effective!
Matinas’ treatment was developed for invasive, potentially lethal fungus infections, in immuno-compromised patients, for which there is no other treatment. Those are the patients they should have been testing on. That’s the population that the NIH is working with.
Testing this treatment in a study in simple vulvovaginal candidiasis, and against fluconazole, a very effective standard treatment, with very few side effects, is beyond stupid! It’s insane! You don’t run a comparison study that you are sure to lose! What were they thinking? This study was just setting them up for nominal failure comparing against a very effective existing treatment.
But the study didn’t fail. It was a moderate success. They demonstrated safety in humans, and they showed that the treatment was effective against a yeast infection. They are ready to go on to test it against its intended population.
Look, here were the actual results from the press release:
There were no serious adverse events reported in the study and the majority of adverse events occuring during treatment were mild in severity and unrelated to the study drug…MAT2203 demonstrated a clinical cure in 52% of patients at 200 mg/day and 55% of patients at 400 mg/day, compared to 75% of patients on fluconazole. In the mycology outcome, 36% of patients in the 200 mg arm and 32% in the 400 mg arm experienced eradication, compared to 84% of patients in the fluconazole arm. In the composite clinical cure score of signs and symptoms at Day 12, MAT2203 demonstrated an 81% improvement in clinical symptoms at 200 mg/day, 80% improvement at 400 mg/day, compared to 94% improvement in clinical symptoms for the patients on fluconazole.
What does that tell you? Their odd-ball delivery system actually works! With no bad side effects (so far). But amphotiericin just doesn’t work as well as fluconazole in this population. That’s was a pretty high bar to get over.
However, Seeking Alpha’s headline was Matinas Bio’s lead product candidate fails to match standard-of-care treatment in mid-stage yeast infection study, and I don’t blame them. The writer of the news article doesn’t have all the background about the company and the drug. He or she just has the study to go on. Probably most of the other news writers said the same thing, for the same reason.
Here’s what I think went wrong: MAT2203 was designed for those patients where mild medications like fluconazole don’t work and doctors have to use awful meds with terrible side-effects like intravenous amphotericin.
The only thing I can imagine is that they had a pie in the sky hope of getting approval as an alternate to fluconazole in this common indication. That would have given them a large population medication instead of a specialized one. They may have hoped that their system was good enough that they could get enough therapeutic dose of the stronger medicine amphotericin to the end cells to wipe out the candidiasis even better than fluconazole does, and without the awful side-effects that you get with IV amphotericin.
They were going for the home run. They haven’t got it THAT perfected yet. They just got a triple (substantial positive effects on the infection, without the bad side effects), but the way they set up the study, it looked like a failure, like a strike-out. They should have said at the beginning that they were only going for a single, and then they could have bragged about their triple, instead of having to explain it.
As far as Noah’s question of whether they have a viable platform? My answer is “Hell, Yes! An amazing platform!” As far as whether they have enough money to get them through, I don’t have a clue. As far as practical business intelligence, after that study I’m not at all sure.
I will keep my position small, even though the stock sold off without a good reason. This company seems to still have a long way to go before it will be out of the woods with a commercial product, even though it has a great platform, and a Qualified Infectious Disease Product with Fast Track status. They may run out of money and have to sell out cheap. Who knows?
Saul
For Knowledgebase for this board,
please go to Post #17774, 17775 and 17776.
We had to post it in three parts this time.
A link to the Knowledgebase is also at the top of the Announcements column
that is on the right side of every page on this board
