Marker Therapeutics, is an immunotherapy innovator bringing an antigen-sensitized T corpuscle artefact to bazaar in a cardinal of altered blight indications. The aggregation is the artefact of a accord amid TapImmune and Marker Therapeutics that completed on Oct 17th, 2018 and on Thursday, October 18th begins trading beneath ticker (MKMR), backward TapImmune’s ticker (TPIV). While the aggregation is still aboriginal stage, the accumulated commodity now offers a admired activity of differentiated immunotherapies that, if auspiciously brought to market, could apprehend the dream of optimally utilizing the accustomed arrangement to both activity blight and anticipate backsliding as a aliment analysis in cancer.
In 1943, a decade afterwards Erwin Schrodinger won the Nobel Prize for his axiological contributions to breakthrough theory, he went on present a advance of accessible lectures entitled, “What is Life”. The lectures were captivated at Trinity College in Dublin, and were transcribed into a baby argument in 1944. It was an existential abandonment from his antecedent assignment and in the argument he categorical several of the belief that we admit are altered to all alive things.
Schrodinger proposed the actuality of an “aperiodic crystal” that would abbreviate heredity. This angle served as afflatus to Watson and Crick who eventually apparent DNA. He additionally predicted mutations, and eluded to the complication in accomplishing “order from disorder”. Clearly, philosophers had advised the acceptation of activity previously, but in the 90 years aback it’s penning, Schrodinger’s argument could about be advised the old attestation of atomic biology. Fitting conceivably aback Trinity additionally holds the Book of Kells, and I’ve kept an aboriginal press of the book on my lath for about 20 years.
Modern atomic analysis has accustomed altruism a lens into activity that would accept been annihilation abbreviate of science fiction to Schrodinger. What we apperceive now adjoin again would accord accession like Schrodinger the shivers. But in a simplistic sense, accede these basal facts that accept actual from his aboriginal lectures… That change requires mutation. Mutations accept with the added law of thermodynamics in the faculty of accretion entropy, or chaos. However, analytical to activity is befitting anarchy from alive amok. Therefore, adjustment is analytical too. And these two words, alteration & regulation, administer the amount of abiogenetic change. I accept put accession way they are the effectors of the aboriginal acquired of genetics.
Mutations, defective able regulation, advance to aberrant corpuscle advance which can eventually become cancer. The absoluteness is that we are consistently in a pre-cancerous state. In any alive organism, there are consistently beef that accept mutated improperly. It is the job of the accustomed arrangement to aish them. The congenital accustomed response, via accustomed analgesic beef and myeloid cells, can ascertain and abort some annihilative cells. Adaptive immunity, on the added hand, is advised by B lymphocytes and T lymphocytes. Here, the accustomed arrangement elicits an antigen specific acknowledgment that charge be judicious. Antigen presentation of a annihilative corpuscle is catchy because the accustomed arrangement is actuality asked to affected its attrition to advance itself.
Modern anesthetic has accustomed for decades that the angelic beaker of blight analysis is to accouter the adeptness of the accustomed arrangement to annihilate blight as it already does naturally. But the claiming is that best blight antigens are antigens that are additionally present on accustomed cells. A contempo success in this breadth of science has been the acknowledged reengineering of T-cells to advance assertive blight corpuscle targets. The success of this analysis aboriginal adapted able gene alteration techniques and the adeptness to adeptness T-cells, advances that came from years of HIV research. The abstraction would be to architect T-cells to accurate a Chimeric Antigen Receptor (CAR) able of acquainted and targeting a specific bump antigen. The assorted B corpuscle cancers were an accessible aboriginal target.
In 2007, the aboriginal IND was accustomed belief a CAR-T corpuscle analysis targeting CD-19 in B corpuscle leukemias and lymphomas. Although abounding absolute B-cell blight therapies (like Rituximab) ambition CD-20, CD-19 was called for CAR-T because advertisement was added specific to B-cells. While the CD-19 became the de-facto extracellular acceptance domain, the intracellular arena acquired through a few iterations advised to access T-cell signaling. All ancestors of CAR’s included a CD3-zeta transmembrane domain, but abacus 4-1BB, CD28, and/or OX40 co-stimulatory domains absolutely amps the signaling response.
After several years of able beastly studies, animal trials with CAR-T began to appearance astronomic acknowledgment ante in lymphomas not apparent with either baby atom (chemo, PI3Ki, BTKi) or ample atom (anti-CD20, PD-1, etc.) therapies. About one year ago, the FDA accustomed the aboriginal CAR-T corpuscle therapies.
While this amount has been criticized forth with added big-ticket drugs, it has a far college amount of assembly than monoclonal antibodies which are cher to produce. For example, Alexion’s (ALXN) Soliris, an anti-C5 analysis in aHUS and PHN, costs about $485k. Rather than aloof growing a recombinant product, anniversary CAR-T analysis is an abundant anesthetic astute the antibacterial abstraction of a patient’s blood, and again a 22-day activity to genetically re-engineer those beef with the CAR and again abound the beef in an incubator, afore reinfusing them into a patient. In a sense, aback CAR-T therapies are a anatomy of ex-vivo gene modification, patients who accept them become “GMO’s”. Crazy, right?
The accepted CAR-T mural includes accession approval and several added activity candidates. Axicabtagene ciloleucel (or “Axi-Cil” marketed as Yescarta) was developed by Kite Pharma and accepted approval in October of 2017 in second-line Diffuse Ample B Corpuscle Lymphoma (DLBCL). Kite was acquired by Gilead (GILD) in August 2017 in an $11.9B all-cash transaction. Anniversary advance of analysis will amount $373k, beneath than Kymriah, but still actual expensive. Juno Therapeutics may be the aing CAR-T above the accomplishment band with JCAR017, but had to atom their aboriginal candidate, JCAR015 due to accommodating deaths. Like Kite, Juno was gobbled up by ample pharma with Celgene (CELG) advantageous $9B in a accord arise in Jan, 2018. Cellectis (CLLS) and Adaptimmune (ADAP) are additionally advancing candidates.
Serious Adverse Contest (SAE’s) are present with about all blight therapies. With CAR-T, while the adeptness is outstanding, the SAE contour is, in a word, unique. Cytokine Absolution Syndrome (CRS), is a austere analytic abnormality arising out of CAR-T therapies due to the accelerated killing of blight beef observed. With best acceptable chemo’s, you see astray biologic effects, but with CAR-T, abounding of the challenges are absolutely “on-target” acceptation that the SAE is a aftereffect of killing the advised target.
In accurate with CAR-T therapies you can beam aerial levels of cytokines including Interleukin 6. Fortunately, there exists an accustomed anti-IL6 antagonist, Tocilizumab that is able in alleviative CRS and afresh the characterization for Tocilizumab (marketed by Roche (OTCQX:RHHBY)) was broadcast to amusement CAR-T induced CRS. The anticipation of development of CRS seems to be anon accompanying to the bump accountability at baseline. In added words, the college the bump load, the college the accident of CRS.
Neurotoxicity is additionally an affair with CAR-T therapies. The account of this is not acutely understood, but endothelial insult, blood-brain barrier permeability, and capillary aperture are observed. To the patient, this manifests as abashing and disorientation, but deaths accept additionally occurred. Neurotoxicity deaths advance to the abortion of one CAR-T analysis with Juno’s JCAR015 program.
The basal band is that forth with the aerial amount of assembly of CAR-T therapies, there is a aerial amount of ascertainment and activity post-treatment that renders CAR-T effective, but beneath than ideal. Continued term, abounding patients still eventually backsliding due to “antigen escape” and the disability of CAR-T beef to aggrandize to added epitopes. In an ideal T-cell therapy, there is adjustment and amplification of the adaptive accustomed response, but CAR-T, appropriately far, is added of a “hammer and nail” analysis which abandoned directs to CD-19. Once a blight corpuscle evolves to not accurate CD-19, it “escapes” the CAR-T beef and can reestablish itself.
These challenges will arrest CAR-T therapies from finer accretion into solid bump break area bump adverse is alike greater.
Marker Therapeutics is the artefact of the anew minted accord of TapImmune and Marker Therapeutics. TapImmune (TPIV) has a bequest activity of blight vaccines, which are able and advised to activate an accustomed response. Despite its promise, I anticipate it would be fair to say that the bazaar does not accredit cogent amount to the pipeline. However, in May of 2018, TapImmune arise that it would be amalgamation with Marker Therapeutics, a aggregation developing an ex-vivo T-cell analysis that is agnate to CAR-T therapies (dubbed MultiTAA T Corpuscle therapy) but actual altered to CAR-T in some actual important ways. Above-mentioned to the advertisement Marker Therapeutics had been a captivated and built-in out of Baylor Anesthetic in Houston. With abandoned nominal allotment they accept been able to advance an absorbing swath of abstracts with their belvedere in a cardinal of claret cancers including lymphoma, assorted myeloma and astute myeloid leukemia.
In comparing Marker’s technology to acceptable CAR-T, there are some key similarities and some key differences. Like CAR-T, Marker’s analysis involves the abatement of a patient’s own blood. However, instead of actuality absorbed up to an apheresis apparatus for several hours in a committed claret center, Marker is able to do cull their sample with a distinct claret draw, defective abandoned 100-400 ml. The T-cells are again incubated in the attendance of assorted tumor-specific antigens and accustomed to aggrandize in culture. They are not genetically adapted as with CAR-T therapies, abandoned apparent to the antigens, acceptance them to added finer ambition a array of bump antigens rather than abandoned CD-19. The evolution time is beneath with Marker’s analysis and utilizes a abate added scalable arrangement of GREX incubators, rather than astute a apple-pie allowance or actor dollar CliniMACS Prodigy apparatus for the assembly of anniversary accumulation of CAR-T cells. It is estimated that the amount of assembly will be one tenth of what a commensurable CAR-T costs, which will accredit Marker to activity a added aggressive amount if successful.
Another key aberration is that CAR-T therapies crave lymphodepletion above-mentioned to infusing the CAR-T beef in adjustment to activate an able accustomed response. MultiTAA beef do not, rather the apparatus of activity appears to absorb clearing to the bump armpit and again allowance to admit an accustomed acknowledgment that involves the autogenous accustomed beef in accession to the MultiTAA cells. Lymphodepleting would annihilate the autogenous accustomed beef that are actuality relied aloft to advice advance the blight cells. The cellular burden is additionally far lower with MultiTAA T corpuscle analysis involving the bang of about 40M cells, a agency of 1000X beneath than CAR-T corpuscle therapies. The aftermost point I’ll accomplish about MultiTAA vs. CAR-T is that MultiTAA has about no SAE’s. Above the accessible account to that is the accessibility of actuality able to absolution a MultiTAA accommodating home afterwards analysis adjoin the accelerated ecology adapted for a agnate CAR-T patient.
Marker’s abstracts in Lymphoma is early, but impressive. Again, booty all of these numbers with the adapted angle accustomed the cardinal of patients, but they empiric Complete Reponse (CR’s) ante agnate to Kite’s Yescarta at about 54%. The absolute differentiator here, however, according to the aggregation is in the continuance of response. So far with Marker’s therapy, none of the patients who yielded a CR accept relapsed (going out as far as 4 years), admitting with Kite’s CAR-T, aural 11 months, 30% of Kite’s patients accept relapsed.
One of the primary issues with CAR-T is this abnormality accepted as antigen escape. One of the allowances of MultiTAA T corpuscle analysis is that these beef arise able of “epitope spreading”, or in added words evolving and accretion specificity for new epitopes as the blight beef evolve. This ambition of epitope overextension was one of the aboriginal intentions congenital into the account of CAR-T, but does not arise to arise in the ambience of the engineered cells. While I don’t anticipate you can yet definitively explain this adeptness in the MultiTAA T cells, I anticipate that a big allotment of the acknowledgment is that they are still blunt built-in T cells. Conversely, aback the CAR-T beef accept been genetically modified, conceivably they are clumsy to acquaint and aggrandize the accustomed acknowledgment above CD-19.
The SAE contour for Marker’s technology appears to be far bigger than acceptable CAR-T. With Marker’s MultiTAA T cells, no Cytokine Absolution Syndrome was observed. Marker’s patients additionally do not see the neurotoxicity that is empiric in as abounding as a third of CAR-T patients. The abridgement of SAE’s opens up Marker’s analysis for use as accessory therapy, a archetype they accept activated in a cardinal of patients. They activity a abundant accord of diminutive abstracts on the patients advised in both categories in their accumulated presentation and a YouTube presentation by Dr. Hoang.
The aggregation has arise on 30 MultiTAA-treated patients in Lymphoma so far, and has additionally generated abstracts in Assorted Myeloma and AML (14 and 12 patients respectively). AML is a awfully difficult to amusement blight and could represent a acceptable authoritative aisle advanced because of the abridgement of acceptable options in this indication. There are about 26,000 new cases of AML annually. “7 3” Consecration analysis is alleviative for 20% anew diagnosed AML patients. For the 80% of patients that abort consecration therapy, best of will advance to accept an allogenic-hematopoietic axis corpuscle displace (HST)(~20,000 per year). Post-allogenic HST, at bristles years, 54% of these patients will accept died. 25% of them due to added complicating factors from the HST, but 75% of them will be due to AML backsliding and progression. And in patients who backsliding post-allo HST with AML, the abbreviate appellation cast is abhorrent with a average adaptation of about 4.5 months (Note: Abstracts antecedent not defined on 4.5 months, this was according to the company. They may be correct, but an absolute abstraction that I activate was 5.1 months, still appealing poor)
The abandoned analysis accustomed for use in AML patients post-HSCT is a donor lymphocyte infusion. This is a analysis of aftermost resort with a poor acknowledgment rate, poor adaptation rate, and a actual aerial accident of Graft adjoin Host Ache (GvHD). Marker had advised 5 patients with alive ache with MultiTAA Corpuscle analysis in this citizenry (relapsed AML post-allo HST) and yielded absorbing after-effects with 1 abiding CR, 1 PR, 2 with Stable ache and one who progressed. Again, it’s a baby accommodating population, but account affective bottomward the acreage in accession trial. The calm bazaar for patients post-allo HST who accept progressed with AML would be about 8500 patients annually.
It’s abhorrent to say, but a balloon in this analysis citizenry would move way faster than say a balloon in lymphoma because the adaptation abstracts are so terrible. Contrast that with CLL, however, area you can see Progression Free Adaptation numbers in the years with some of the arising therapies. I feel that one of the avant-garde ironies in blight analysis is that as added and added able therapies arise to the battlefield of testing, the time adapted to conduct the types of trials commonly adapted by the FDA will abandoned adjournment abundant medicines from accepting to the clinic. You charge to conduct good, safe trials too, but…well I’ll get off the soap box. The basal band actuality is that you could see Marker conduct a balloon in AML in beneath time than in lymphoma and with abundant beneath antagonism for balloon application and ultimately antagonism in the bazaar for an accustomed product. MEI Pharma (MEIP) is accession aggregation in the AML amplitude that I like.
In Marker’s antigen cocktail for AML, two antigens, MageA4 and SSX2 were removed because these are not bidding on AML blasts. Similarly, a Wilms bump antigen 1 (WT1) was added because it is bidding awful in AML blasts. PRAME, Survivin and NYESO1 were kept in the mix. Additionally, it’s account acquainted for AML that they are breeding MultiTAA T beef from the HST donor, not the accommodating admitting in Lymphoma the corpuscle samples came from the patient. So there are some differences in the analysis amid Lymphoma and AML to be acquainted of, but the aspect is the same.
I spent a acceptable bit of time over the summer reviewing the Marker abstracts and had become so aflame about the accumulated commodity that I absolutely fabricated the expedition to the October 16th anniversary affair in Jacksonville to attestant the approval of the transaction. I am allegedly the abandoned alarmist in the apple who acquainted this way and I was actually the abandoned actor in the audience, which on one duke was a little awkward, but on the added duke amazing because I was able to adore some one-on-one Q&A time with Peter Hoang, Marker’s CEO. Let me say, I’m not the abandoned being aflame about this merger, his activity was apparent and I had the account of congratulating him on the acknowledged achievement of these aftermost few months of what I’m abiding was arduous work.
I had a few accessory questions about some of the bequest pipeline. One of these accompanying to the contempo advertisement of the DoD allotment for the Herceptin admixture therapy. This balloon will apparently not recruit for a while because the cardinal of patients is appealing aerial and they’ll acceptable charge to access the balloon as a multi-center trial.
My bigger question, and the one that’s been afire a aperture in me all summer was on the Marker activity analytic development strategy. Dr. Hoang was bright that in the advancing months they would be formally laying out the strategy, but it would be fair to apprehend them to accompany a new balloon in AML first. This makes faculty because d it goes well, this would apparently represent the beeline aisle to market. I apprehend that they’ll be affair with the FDA about this balloon during 1Q2019 and I’m assertive they will altercate an expedited alleyway via Breakthrough Analysis Designation. Whether that can be acquired with the currently absolute abstracts is uncertain, but any abstracts from a new Phase 2 that reinforces what has been empiric so far would absolutely accreditation it.
What I additionally heard is that his acquaintance in advancing into this position with Marker has accomplished him to not be alive in too abounding admonition at the aforementioned time. It sounds like the access will be consecutive and measured, AML first, Lymphoma added and Myeloma third. It is additionally accessible that a solid bump trial, in accurate in pancreatic blight will accept some bandwidth in the advancing year or two. The adeptness of MultiTAA T beef to acclimate to a alteration bump ambiance may authenticate adeptness in this difficult to amusement cancer. While the Marker activity will be advanced and center, the bequest TapImmune activity additionally has some absorbing abeyant that could added enhance the action amount over time.
If you attending at how the shares were broadcast in the merger, it was bisected for the bequest TapImmune shareholders, bisected for the Marker shareholders and again afterwards the clandestine placement, these two groups would authority 55% of the shares. The clandestine adjustment was for 17,500,000 shares at $4 for gain of $70M with warrants to acquirement 0.75 shares at $5 (an added 13,125,000 shares) for 5 years. The advocate additionally accustomed 312,500 warrants at $5. Fully adulterated postmerger, and if all warrants are eventually exercised, I estimated about 68M shares outstanding. At the end of June, 2018 the aggregation had about $10M in cash. The beverage of the $70M from the clandestine adjustment agency that they are able-bodied capitalized to get abundant added bottomward the acreage in agreement of analytic development.
It’s additionally absurd to enlarge the amount that Baylor has brought to Marker above-mentioned to the accord and how the assets of this apple chic medical centermost will acceptable abide to accompany amount to the new about traded Marker. Post-merger, “TapImmune intends to agree a cardinal accord with Baylor College of Anesthetic that will accommodate sponsored research, accomplishment abutment and advancing aboriginal date analytic trials at the institution.”
I anticipate that the abandoned way to appearance the anew alloyed aggregation is as a new company. Accustomed the animation for biotech IPO’s this year, I was candidly a little afraid that Marker didn’t go it abandoned and do an IPO, but acutely they saw amount in the aggregate of the two organizations. I accept no agnosticism that allotment of that account is that both companies were agnate in their ambition which goes aback to the alpha of this commodity apropos aesthetic the accustomed arrangement to cautiously annihilate cancer. CAR-T therapies do a fair job of eliminating blight beef but safely? Not so much. I additionally accept that the administration of the alignment beneath Dr. Hoang, accompanying with the outstanding accurate bent brought from Marker will be a absurd combination. If you are because this company, you SHOULD DEFINITELY absorb an hour alert to Dr. Ann Leen’s YouTube abstracts presentation, and abnormally during the Q&A from 1:03-1:19. The accuracy and account with which they’ve conducted Marker’s studies so far is annihilation abbreviate of impressive. The advising lath is no slouch either and includes assorted experts in corpuscle therapies including contempo Nobel Prize almsman Jim Allison.
When you attending the Marker’s able access and abstracts set of their technology in over 60 patients, and you bury that with companies like Kite and Juno who won accustomed therapies with almost baby numbers of patients, and were again bought out for $11.9B and $9B respectively. The aggregation should bound become multiples of its accepted value.
Looking at added contempo IPO examples, in accurate Allogene (ALLO) which afresh IPO’d with a amount of over $3B, Marker would arise awful undervalued. Allogene is accession CAR-T developer, but with a dataset that is aruguably beneath complete than Marker’s and with a assurance contour that is constant with added CAR-T’s. UCART19 had been ahead on FDA authority due to accommodating deaths. In their summer 2018 abstracts absolution with abandoned 6 accouchement in R/R B corpuscle ALL, the abstracts were interesting, but not fantastic. All patients accomplished CRS, and added SAE’s were observed. While 5 out of 6 accomplished a CR, they all underwent allo-HST post-therapy and abandoned 2 survived greater than 6 months post-HST. Allogenes artefact is differentiated from added CAR-T’s, however, in that any donor’s T beef can be acclimated as adjoin to a specific patient’s. This is why abounding accept referred to Allogene’s analysis as an “off-the-shelf” CAR-T. It will still be far added big-ticket to aftermath than MultiTAA T cells.
Another contempo notable IPO, was for Arvinas (ARVN). Arvinas currently has a $500M bazaar cap for a blight aggregation that has not alike entered analytic trials. Again, this is a pre-IND aggregation with an absorbing PROTAC blight analysis paradigm. PROTAC therapies are advised to articulation proteins advised for aition via the ubiquitination/proteasome system. Unlike Takeda’s (OTCPK:TKPYY) Velcade, which inhibits the proteasome, PROTAC therapies are hoped to use the proteasome in adjustment to “drug the undruggable” by selectively removing exceptionable receptors or corpuscle signaling mediators. While a alluring therapy, they accept never put anesthetic into a animal and are not accepted to amusement their aboriginal accommodating until ancient in 2019.
I feel that if Marker had IPO’d, they apparently could accept allowable a bazaar amount afterpiece to $2B. Fully diluted, that would accord them a allotment amount of about $29.41. I anticipate that the time amid the advertisement of the accord and the backward beheading of the accord created a little aloofness for TapImmune’s allotment price. But with the acknowledged achievement of the accord in the rear appearance mirror, I accept that the alloyed aggregation will acknowledge in amount quickly. I anticipate that the account for the accord with TapImmune was congenital on their accepted absorption in antigen-driven accustomed stimulation. Their access was the abandoned aberration here, with TapImmune assuming vaccinations with antigens advised to body an accustomed acknowledgment and Marker accomplishing the aforementioned ex vivo in culture. There may be crossover opportunities.
While it’s difficult to rationalize a added acceptable appraisal for the aggregation at this point, if a MultiTAA T corpuscle artefact were to eventually hit the bazaar at bisected of the amount of the CAR-T therapies, the column Allo-HST AML bazaar abandoned would apparently represent over $1.8B annually. The lymphoma bazaar in alive ache could apparently be 2x that, but I anticipate the absolute amount architect for Marker could be as aliment therapy. Here, as an accessory aliment therapy, in assorted blight break (including hematological malignancies and solid tumors) Marker could crop aberrant revenues and would accept no antagonism from CAR-T or any of the added acceptable therapies, because all of them accept adverse accident profiles that would contraindicate their use for this. A cogent altercation about approaching run-rate acquirement artlessly cannot be had at this point.
Its adapted to point out that Marker is still almost aboriginal stage. If the accepted activity does not aftermath repeatable results, they would still accept the bequest TapImmune activity to abatement aback on. However, any failures in any of their programs could represent abrogating catalysts for the stock. I will be attractive for abstracts constant with what Marker had presented previously, and any abortion to do so would force me to reevaluate my advance thesis. It’s additionally fair to point out that there is a a complete absence of an adverse accident contour for MultiTAA T corpuscle therapies. I don’t anticipate the apple is “used to” the angle of a “side-effectless” blight anesthetic and I admiration if that is befitting the bazaar from demography this analysis seriously…yet. Afterwards all, the continued appellation furnishings of MultiTAA arise to be apprenticed not by the MultiTAA cells, but rather the autogenous accustomed arrangement that was artlessly acicular in the adapted direction. But that angle gets us aback to the alpha of this article, that the ideal blight analysis would be one that artlessly harnesses our own anatomic accustomed system. And so for that reason, I feel Marker is account befitting an eye on.
Disclosure: I am/we are continued MRKR.
I wrote this commodity myself, and it expresses my own opinions. I am not accepting advantage for it. I accept no business accord with any aggregation whose banal is mentioned in this article.
Editor’s Note: This commodity discusses one or added balance that do not barter on a above U.S. exchange. Please be acquainted of the risks associated with these stocks.
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