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CM101 Phase II Clinical Plans
Exclusivity Protection and Documentation
It is clear that CM-101 offers the opportunity for significant reduction in tumor burden, and possible cure, of patients whose immunological competence is sufficient.  The mechanism of action (MOA) of CM-101 provides opportunities for optimal clinical responses in patients with agressively metastatic tumors having extensive neovascularization.  The clinical strategy and first possible oncology indications are numerous and open for active discussion.  Thus, the only clinical question with regard to market opportunity rests not on whether such an opportunity exists but the eventual size of that market and how long and how expensive the road to its achievement should be under proper management.  Patent protection and FDA extensions provides exclusivity through 2028-2031. Provisions in the Affordable Health Care Act provide additional exclusivity for biologics extending 12 years after FDA approval.
Progress on the path to NDA/NBA filing and FDA approval include: a) Phase I dose-ranging studies have been completed in over 24 patients as have preliminary non-GLP acute dose and multiple dose toxicity studies; b)  CMC (chemistry, manufacturing, controls) section components required for the NDA/NBA; c) pilot manufacturing of three lots; d) cGMP manufacturing of clinical trials materials; e) initial toxicology and pharmacology preclincal studies in 2 rodent and one non-rodent species; f) filing IND 4578 (to be re-opened, or re-filed) with the U.S. Food and Drug Administration (FDA).  Prior manufacturing operations were shut down, therefore replacement capability has now been negotiated at a contract manufacturing organization (CMO) with a proven background in GMP production of carbohydrate bulk drug substances for human and veterinary use.   The existent CMC section, and prior manufacturing batch records, provide basis for facile technology transfer to the CMO.  Thus, we view the next steps as:
Re-instituting manufacturing capacity within the framework of the existing CMC section;
Re-opening/re-filing an IND with the U.S. Food and Drug Administration;
Establishing a clinical regulatory strategy that includes evaluating cancer pathology to identify the most susceptible tumor subtype, patient population(s), orphan drug opportunities and most expeditious cost-effective route to NDA/NBA;
Initiating pilot Phase Ic/IIa/IIb iterative safety and dose-ranging efficacy studies potentially involving patients with a variety of cancer subtypes and stages; and,
Completing follow-on toxicology, immunology, metabolism and biodistribution animal studies as necessary to update the IND file for eventual approval as a biological product.
When these studies are completed, which we suggest could be accomplished in less than two years with a budget on the order of $5M, the product would be poised for a pivotal Phase III study leading to fast track and expedited review and approval in the ensuing two years at a cost of less than $10M.
The Product and The Markets
CM-101 is a subfraction of Group B streptococcus (“GBS”) polysaccharide that is toxic in newborn humans, rodents, canines and pigs, and consistently toxic in sheep.  The polysaccharide contains about 110 repeated units of three-dimensionally latticed polymannose and other sugars with terminal phosphate components necessary for activity (MW ≈ 300,000 daltons).  The polysaccharide/toxin has been shown to bind to a glycoprotein (identified as HP-59) situated on the endothelium of neonatal pulmonary vasculature.  This surface protein is not expressed in mature pulmonary endothelium.  Expression of a homologous protein (SP55) is found in neonatal pig pulmonary endothelium, sheep pulmonary endothelium, and neovascularization found in malignant tumors.  If there are no HP-59 endothelial receptor sites, the CM-101 polysaccharide is not bound and is presumably removed by renal filtration comparable to similar sized polydextrans used historically for volume replacement.  Studies in human neonates who have recovered from GBS infection have shown renal excretion of CM101 and serum levels calculated at 15- to 100-fold that of the proposed therapeutic dose indicating its wide safety profile.  CM101 has also been detected in serum samples from an adult with a cutaneous GBS infection at high levels but without respiratory symptoms.  Radiolabeling studies have demonstrated that CM101 is a bacterial product.
Allergic reactions to the CM-101 polysaccharide have not been clinically observed in animal studies or limited human studies.  Immunogenicity studies were conducted within the human Phase I study, where no immune reaction by subcutaneous injection was noted in any patient, some with more than 15 infusions of CM101, and one patient treated repeatedly at 7 and 18 months following the original trial.
This GBS exotoxin was initially discovered in the 1980s and sufficient preclinical work on the mechanism of action and activity against malignant neovasculature was undertaken in sheep, pig, and mouse models, to permit clinical investigation to be initiated in mid-1995.  Original patents on the chemical entity, CM-101, and its method of manufacture were issued in 1991.   Subsequently, a method patent on a method of purifying CM-101 was issued on August 17, 1999, with claims to purification using a hydrophobic interaction chromatographic resin.  A purified product claim to any CM-101 toxin, “wherein the toxin is at least approximately 60% pure,” or, if less pure, was diluted from such purity using a pharmaceutical carrier, was issued with a terminal disclaimer in 2000.  Thus, patent protection of pharmaceutical grade CM-101 is present through 2019 (U.S. Patent No. 6,136,789 or ’789 patent).   A 5 year extension to exclusivity from the Waxman-Hatch Act would bring this to 2024, and a 12 year extension after FDA approval under the Affordable Health Care Act, would bring exclusivity to 2029 if approved in 2017, for example, sixteen years from today.
Upon crosslinking several HP-59 sites on a pulmonary endothelial cell, the CM-101 toxin stimulates granulocyte margination, secretion of inflammatory cytokines, and a cell-mediated immune attack at the site of cross-linking.  This attack is apparently the etiology behind the neonatal respiratory disease associated with group B streptococcus and eventual death or disability of neonates with this disease.  At the point of endogenous attack, removal of the bacterial organism itself by antibiotic therapy has little effect on disease progression since the course of the disease is determined by the presence of CM101.
The lack of expression of the target endothelial glycoprotein by normal adult vascular endothelial and the recapitulation of expression of this puerperal glycoprotein in angiogenesis stimulated by malignant tumors offers the opportunity to stimulate an endogenous attack on the vascular tree supplying the malignant tumor in cancer patients with intact cell-mediated immune systems.
Dosing studies have been performed in sheep. A ten kg sheep has approximately 1010 pulmonary endothelial cells each containing many copies of the target glycoprotein.  A dose of 5 picomoles/kg of CM101 contains 3.3 x 1013 molecules of CM101.  Such a dose would saturate receptors in sufficient geographic proximity to permit cross-linking of two or more bound CM101 molecules by human antibody or cell-mediated immune mechanisms with consequent triggering of the immune response.
Clinical studies were initiated under an Investigational New Drug Application (“IND”)  # BB 4578 filed with the Center for Biologics Evaluation and Research (CBER).    After careful and thorough review by the U.S. Food and Drug Administration (“FDA”) in mid-1995, clinical studies were permitted to proceed.  The FDA carefully reviewed the manufacturing component and requested removal of a mouse monoclonal antibody purification step and some other more minor modifications.  The agency further requested completion of a formal subchronic toxicology study in 9 mice in which organs were recovered and evaluated histologically for toxicity by an experienced veterinary pathologist.  The agency accepted already performed toxicology studies in terms of an acute toxicology study in mice which failed to demonstrate an LD50 with generation of an LD10 only in lead sensitized animals as well as numerous published studies of use of the compound in mice, mice with human tumors, mice with mouse tumors, sheep, and neonatal pigs, all of which failed to detect any pathology unless the study involved use of an animal such as a sheep with a vasculature with a significant amount of HP59 glycoprotein binding sites.
Proof of concept studies in animal models had also demonstrated tumor reduction or effective tumor treatment in animals with tumor vasculature positive for SP55/HP59 such as mouse tumors and human Madison tumors transplanted into nude mice.
While the specific human cancer subtypes whose neovascularization provides the most opportunity for stimulation of an endogenous attack through use of CM-101 have yet to be identified, it is clear that CM-101 offers the opportunity for significant reduction in tumor burden, and possible cure, of patients whose immunological competence is sufficient.  Thus, and as will be re-stated after discussion of the existing clinical data, the clinical question with regard to market opportunity rests not on whether such an opportunity exists but the eventual size and how long and how expensive the road to its achievement should be under proper management.  The market size ultimately rests on definition of which tumors and patients are most responsive and whether response will be total or partial.
The Company
TumorEnd, LLC was formed in 2009 by Roger A Laine and Armand C Alciatore to bring the CM101 technology to market in veterinary and human uses.  A predecessor company (CarboMed, Inc.) was originally organized to commercialize the opportunity but ran into management and funding difficulties with eventual dissolution and return of the patented technology to Vanderbilt University.  The original CarboMed technology has now been licensed through an option from Vanderbilt to TumorEnd, LLC.  The ’789 patent was never licensed to CarboMed, Inc., and an exclusive option to license is held by TumorEnd, LLC. 
Patent Portfolio
The ’789 patent provides broad and lengthy exclusivity to the CM-101 technology for the foreseeable future.  In general, biological products are not subject to generic competition, however, there are frequent discussions in Congress about the wisdom of adding well-characterized biological products to the patent restoration and generic competition compromise enacted in 1986 for drug products.  The recent re-organization of CBER with the movement of all well-characterized or protein-derived drugs to CDER will likely trigger renewed consideration of generic applications for some biological compounds.  Any drug or biological product application for CM-101 , certainly, would be required to use the most purified form of CM-101 available that has activity.  Since this purified material is covered by patent protection, and 12 year exclusivity extensions under the Affordable Health Care Act, any possible generic competition is approximately two decades away.
Vanderbilt is assigned U.S. patent No. 6,136,789 which is exclusively licensed by them to TumorEnd, LLC.  This patent was issued as a divisional following the issuance of a patent on Dr. Hellerqvist’s improved process of purification of CM101 using hydrophobic interaction chromatography.  The composition of matter divisional was carved out by the U.S. Patent and Trademark Office with a terminal disclaimer of all exclusivity after August 17, 2019.  Claim 4 of the ’789 patent reads, in its entirety:
“A composition comprising a substantially pure group B beta-hemolytic streptococcus (GBS) toxin wherein the toxin is at least approximately 60% pure.”
The claim contains no limitation to the method of purification and, since was the first purification, would not incorporate that method.  There are other claims to pharmaceutical compositions that start with pure toxin.  Since the FDA will not approve a toxin which contains substantial impurities unless unavoidable, any approval of a comparable biological product subsequent to TumorEnd, LLC must infringe on this patent claim.  Finally, we would note that the patent term will be eligible for extension of up to five years pursuant to the provisions of the patent term extension provisions of Title 36, U.S. Code.  We would thus anticipate patent protection for exclusivity through approximately 2024, or in case of application of the Affordable Health Care Act provisions, to 2031 if approved near the 2019 date.
Controlling Patents 6,803,448  covering CM101 receptor HP59.   This patent was also not licensed to the previous company Carbomed, and has been exclusively licensed to TumorEnd, LLC.  This patent covers the HP59 receptor for the CM101 biologic, and therefore, with claims of activity based on binding to the receptor, is considered controlling in the patent portfolio.
•6,803,448 CM101 Receptor Jul. 21, 1999 Oct. 12, 2004 GBS Toxin Receptor.(HP59 peptide sequences) C.G. Hellerqvist and Changlin Fu. (Good to 2019 + 5 years exclusivity (2024) under Waxman/Hatch or + 12 years exclusivity after FDA approval under Obamacare. [i.e. if approved in 2015, exclusivity through 2027].
Relevant publication: Fu C, Bardhan S, Cetateanu ND, Wamil BD, WangY, Yan H-P, Carter CE, Shi E, Venkov C, Yakes FM, Page DL, Lloyd RS, Hellerqvist CG. Identification of a novel membrane protein HP59 with therapeutic potential as a target of tumor angiogenesis. Clin. Cancer Research 7:4182-4194 (2001). 
Pending Patents: In process. GBS Toxin Receptor Protein and DNA Sequences. C.G. Hellerqvist and C. Fu. U.S. Patent Application Serial No. 60/093,843. Total of 12 anticipated patents. Methods for Preventing or Attenuating Pathoangiogenic Conditions. C.G. Hellerqvist. U.S. C0779-2062. 
Current Pre-Clinical Data
Cellular in vitro studies have not shown acute cellular toxicity.  There are a large number of studies in mice and sheep although none were performed in accordance with the requirements of 21 C.F.R. Part 58 relating to good laboratory practices.  These studies demonstrate that administration of up to 40 mg/kg does not cause acute lethal toxicity (LD50> 40 mg/kg) unless mice are sensitized with pre-administration of lead.   Before initiation of the limited clinical study, the agency requested completion of a formal subchronic toxicology study in 9 mice in which organs were recovered and evaluated histologically for toxicity by an experienced veterinary pathologists.  This study was apparently filed to the now-closed IND.
In general, the FDA requires completion of both acute toxicity and subchronic toxicity studies in an animal species before initiation of a dose-ranging phase I study in humans.  Before initiation of more complex Phase II/III studies, FDA increases the dossier requirements for toxicological and pharmacological information.  In general, for biological products that mimic endogenous substances pharmacological studies of drug distribution, metabolism and excretion are difficult to perform.  The standard dossier requirement before drug approval generally includes the following studies performed under Good Laboratory Practices (see 21 C.F.R. Part 58)
Mutagenicity studies in cellular systems (Chinese hamster ovary cells, bacterial reverse mutation, rodent nucleated bone marrow micronucleus);  
Acute single-dose toxicity in at least two species of which one is non-rodent;
Subchronic multiple-dose toxicity in at least two species of which one is non-rodent with a total of six months exposure in one species;
Reproductive or teratogenicity studies: Segment I (male and female fertility) in rats; Segment II (implantation and pregnancy in rats and rabbits; and Segment III (teratogenicity, term fetal abnormalities) in rats and rabbits; and, for biotechnology products,
Immunogenicity studies by detection of antibody generation in rabbits or mice if the product is of biological origin. 
At this point, the agency has accepted preliminary acute toxicity and subchronic toxicity studies performed under non-GLP conditions.
Additionally, the agency prefers to see at least some attempt to evaluate metabolism in humans and confirm that the substance is metabolically degraded over time to constituent proteins, amino acids, sugars, etc.  The data on renal excretion in human patients with GBS infection may be sufficient.
Clinical Studies
In a preliminary study conducted under an IND, fifteen patients with untreatable metastatic cancer were exposed to CM-101 toxin in a dose escalation format.  Several patients had responses: three patients had unexpected local tumor regression.  Five patients had serious sequelae notwithstanding the benign nature of the drug in patients without tumors.  Three patients with pulmonary metastases had serious sequelae – transient respiratory distress or dyspnea requiring respiratory support in one.  Two other patients had serious hypotension of whom one also had supraventricular tachycardia.  Moderate toxicity included fever and chills in all and various other flu-like symptoms in between 5 and 9 patients.  All side effects were clinically manageable.  Patients were treated with 15 minute infusions gradually increasing from 7.5 to 37.5 μgram/kg of CM-101 with thrice weekly dosing (1 U/kg to 5 U/kg).   Patients with serious adverse events at a lower dose were not treated with higher doses.  The clinical responses of tumor regression (in addition to the responses of respiratory distress in patient with pulmonary metastases) suggest drug activity.  Severe pain at the site of the tumor occurred in three patients with tumor regression responses.
Lower levels of planned drug dosing were identified based on the likely prevalence of HP-59 sites in abnormal vasculature based on studies in sheep pulmonary vasculature  and the need for geographically possible cross-linking by antibody to two or more CM-101 bound to two or more HP-59 sites.  For dosing, we believe that an underlying assumption was made that the prevalence of HP-59 sites in tumors would mimic the prevalence in sheep.   Upper levels were chosen based on the likely availability of white cells to marginate to sites with cross-linked CM-101.  Margination on the order of 6,000 cells/mL occurs at a dose level of 37.5 μg/kg (5 U/kg) which represents the total body white cell count in the average healthy person.  This dosage was therefore viewed as above the maximum tolerable dose.  
The thrice weekly dosing schedule spaced with 2 weeks off was selected to permit recovery or restoration of a possible white cell response after the acute margination episode since not all cells are bound to sites but most likely respond to cytokine release.  Complete recovery was not seen in the thrice weekly schedule, especially when soluble E-selectin levels were assessed.  A dosing frequency of once weekly was also attempted in a further 9 patients with doses of 15 and 24.75 μg/kg (2 and 3.3 U/kg).   Clinical tumor responses were not observed at 3.3 U/kg and two patients developed deep venous thrombosis perhaps related to pelvic extension of prostate and small bowel carcinomas, respectively.  Cytokine responses were similarly attenuated on repeat dosing with this schedule.  The original QMWF schedule, off 2 weeks and repeated 4 times is targeted for further clinical work due to its efficacy.
Cytokine responses were measured.  There appears to have been a bell-shaped cytokine response with increases in TNF-α, IL-6, and IL-8 peaking at 50- to 500-fold baseline at doses of 3.3 U/kg (24.7 μg/kg).  IL-10 levels also increased but had the highest response at 5 U/kg.  Cytokine responses to 15 or 24.75 μg/kg were comparable in the second set of patients.
These studies have bracketed doses by toxicity at the high end and non-responsiveness at the low end and thus serves as a true Phase I dose-ranging study establishing the maximum tolerated and likely most efficacious dose.  However, the dosage and target cancer indication could benefit from refinement as was proposed in terms of dosing frequency.  Data on the prevalence and density of HP-59 receptors by tumor type, stage, CT density, location of metastasis, or other characteristic would be useful to assess the dosing and indication (patient eligibility) for a phase II study.  Additionally, a phase II study design could incorporate repeated dose regimens using a cytokine or white cell recovery or sustained response endpoint.  Alternatively, investigation into inflammatory reaction at the tumor site could be used to schedule repeated doses.  Finally, the maximum tolerated dose should be re-addressed in light of the fact that apparent toxicity may represent tumor response rather than an adverse effect.
FDA accepted rudimentary manufacturing controls in the initial IND which included manufacture in University of Maryland fermentation system directly from stored bacteria followed by purification and filtration in a university-laboratory and packaging at a Phase I quasi-GMP compliant facility associated with University of Kentucky, now a separate business called Coldstream Laboratories.  We have obtained quotations for complete cGMP manufacture from Benchmark Biosystems, Lincoln, NE.  Alternatively, we have a quotation from U Maryland for fermentation and bulk CM101 production from the same director of the fermentation facility who produced the first batch, and have contacted Coldstream regarding packaging.  Only small quantities of drug substance (~3g) are required to conduct the studies currently planned.  Duplication of the former manufacturing to produce additional clinical material for required pre-clinical studies and a pilot Phase II study would be helpful.   The preliminary clinical data and the recent movement of comparable products from CBER to CDER (where manufacturing flexibility is more evident) may permit manufacturing of a batch sufficient to complete preliminary studies.  We are not aware of any formal ICH-style stability studies., however, samples kept lyophilized for 10 years at room temperature were shown by Hellerqvists’ group to have identical activity as original.  Carbohydrates are particularly stable.
1. Resumption of studies will require re-opening IND 4578, and the amended IND is completed for submission including clinical plan. 
2. Resumption of studies will require drug supply.  We will contract for cGMP small scale manufacturing capacity and then refill this information with the FDA as part of the re-opened IND or a new IND.  While large scale contract manufacturing is possible, and will eventually be necessary before initiation of Phase III studies, such an effort can be both expensive and time consuming without additional benefit.
3. Preliminary pathological/laboratory studies with CM101 were conducted on a large cross section of tumor types (See Fu, et al. 2002), and all tumors were found to have HP59+ vasculature by monoclonal antibody tests. 
4. Once clinical supplies are available, we will initiate both stability studies and all necessary pre-clinical studies.  All such studies will be conducted in accordance with 21 CFR Part 58.
5. The next step is to initiate a Phase I/ pilot Phase II study to update the safety cohort, and in the Pilot Phase II, to evaluate tumor response in a well-defined population with defined entry criteria that establish eligibility based on tumor type, location, and stage.  We propose to initiate such a study with a variety of tumor types, locations or stages, based on pathological data noted above.  The study protocol would then evaluate responsiveness by dosing interval, dose, tumor type, location, and/or stage using objective measures of tumor destruction or inflammation, with the protocol automatically narrowing entry criteria based on most responsive subtypes or regimens.  The data analysis plan would, thus, contain several interim and iterative efficacy and safety analyses with eventual definition of the appropriate patient population for a Phase III confirmatory study.  
6. A clinical trial plan (available on request) has been written by Dr. David Gerber of University of Texas Southwestern Medical School Cancer Center, based on the amended IND which included acetaminophen to mitigate fever and chills and tumor site inflammatory pain.  Acetamenophen administered with CM101 was tested in sheep and caused no mitigation of the CM101 response.
Current Plans:  CM101 Cancer Therapeutics Clinical Trial
• Raise capital for Manufacturing, $1.5M First Step after which we can commence manufacturing and begin clinical trial.
• Commence meetings and paperwork for FDA approval of reopening IND 4578.   Amended IND completed, including Clinical Trial Plans.
• Phase Ic/II clinical trial ready to begin at Texas Southwestern Medical School.
• Funds for clinical trial have been identified, so phase II data can be collected on a selected indication.