Alan Joslyn, President and CEO

Oragenics (NYSE American: OGEN) is leveraging its synthetic biology platforms to address two significant unmet medical needs: oral mucositis (OM) and multi drug-resistant (MDR) bacterial infections.

According to the CDC, some 700,000 newly-diagnosed cancer patients are receiving chemotherapy and radiotherapy in the U.S., putting them at increased risk of developing OM, a serious and debilitating breakdown of the mucosal lining of the mouth.

“Patients will describe the pain as chewing on razorblades or barbed wire - they’re in a significant amount of pain. What we’re trying to do is prevent this from happening in the first place,” Alan Joslyn, Ph.D., president and CEO, says in an interview with BioTuesdays.

Mouth ulcers can take up to two weeks to heal, while the pain associated with OM can lead to the inability to eat and even drink, requiring that patients be hospitalized.

“Patients with severe OM are three-to-four times more likely to have an interruption in their chemotherapy regimen, and in head and neck cancer, patients are twice as likely to have an interruption in their radiation regimen. Both of these result in worse outcomes,” Dr. Joslyn points out.

Economic and Clinical Impact of Severe OM

“Because of the severity of patients’ ulcerations, they’ll likely require total parenteral nutrition, which is associated with an average nine-day hospital stay. As you can imagine, just the direct cost related to the hospitalization drives up the economic impact,” he adds.

Oragenics’ lead candidate, AG013, consists of genetically modified Lactococcus lactis, bacteria commonly found in dairy products and yogurt. The bacteria are modified to express human trefoil factor family 1 (hTFF1), a peptide naturally secreted in saliva that creates a protective mucosal barrier and promotes epithelial regrowth.

The hTTF1-expressing bacteria are produced in a large fermenter, rinsed, and freeze dried to produce AG013. “The cost of goods is extremely low for this technology, so it’s elegant and cost-effective at the same time,” Dr. Joslyn says.

The powder is mixed with a raspberry-flavored solution, which patients use to rinse their mouths after every meal. The bacteria stick to the lining of the mouth, and after producing hTTF1 for about two hours, the bacteria die a pre-programmed cell death.

AG013 in Action

Dr. Joslyn explains that when Oragenics inserted the hTTF1 gene into the genome of L. lactis, they removed a gene the bacteria require to make DNA. “We’ve placed a kill switch into these bacteria, so they will grow to the point they want to split into two bacteria but they’re unable to do so.”

AG013, which has been granted fast track designation by the FDA and orphan drug status in Europe, is currently in a Phase 2 trial in four countries. Oragenics expects to complete enrollment of 200 patients this fall, with topline data slated for early 2020.

“Right now, there’s one product out in the marketplace but it’s only indicated for patients receiving high dose chemotherapy before they receive a bone marrow transplant, so it’s a very narrow indication. And as an IV, it has very limited opportunity for use in the much broader chemotherapy outpatient setting. That’s where a product like ours will be used,” Dr. Joslyn contends.

While OM represents a significant unmet medical need and a potential global market that Dr. Joslyn estimates at nearly $1-billion, MDR infections remain one of public health’s biggest threats.

According to the CDC, more than 2.5 million people in the U.S. get an MDR infection every year, and some 37,000 die. MDR Clostridium difficile is considered an urgent threat, with 500,000 infections causing 29,000 deaths per year, a fatality rate that has increased four-fold since 2000. Moreover, 8% of C. difficile infections present with another MDR infection, making treatment even more difficult.

“A particular problem is that patients who develop recurrences of C. difficile infection are coming back on a relapse with a co-infection called vancomycin-resistant enterococcal infection, because vancomycin is one of the first-line treatments for C. difficile. This particular group of patients really is running out of treatment options,” he says.

Oragenics is addressing this challenge by leveraging lantibiotics - antibiotics produced by bacteria to control their own microbiome.

“Certain bacteria release tiny amounts of lantibiotics into their microbiome, which prevents other bacteria from encroaching on their space. The problem is if they make too much of this lantibiotic, it would kill the colony, so the bacteria have regulator genes that turn off production of the lantibiotic when the titer gets too high,” Dr. Joslyn explains.

To produce sufficient amounts of lantibiotics, Oragenics licensed a technology that disables this regulatory gene from a company,Intrexon, which is now collaborating with Oragenics on its AG013 program as well.

Oragenics then used this platform to create variants of a lantibiotic produced by Streptococcus mutans, and generated a library of more than 700 patent-protected, potential lantibiotics.

“We’re now able to manufacture OG716 at a 1,500-liter scale and are accumulating the material required for our two toxicology programs. We’ll then transition to cGMP manufacturing for Phase 1 clinical trials, at the current scale,” he says.

Oragenics is preparing to initiate preclinical toxicology studies of OG716 and expects to file an IND with the FDA in mid-2020.

“We have a number of tremendously innovative programs where we’re able to manipulate bacteria and use those bacteria in a cost-effective manner as therapeutics, and within approximately six-to-eight months we’ll be reporting results from a significant clinical trial,” Dr. Joslyn says.

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To connect with Oragenics, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.

Dr. Bill Williams, President and CEO

BriaCell Therapeutics (TSXV:BCT; OTCQB:BCTXF) has reported impressive early safety and efficacy data with its lead immunotherapies for the treatment of advanced breast cancer.

“Right now, there is no immunotherapy that works by itself against advanced breast cancer, an unmet medical need that was responsible for more than 40,000 deaths in the U.S. in each of 2017 and 2018,” Dr. Bill Williams, president and CEO, says in an interview with BioTuesdays.

Immunotherapy is a type of cancer treatment that marshals the ability of the body’s immune cells to destroy cancerous tumors, with the advantage of fewer side effects than chemotherapy.

BriaCell’s lead drug candidate, Bria-IMT, completed a Phase 1/2a clinical study in December, with “outstanding safety and efficacy data,” Dr. Williams contends.

Bria-IMT is now in a Phase 1/2a combination study with Merck’s (NYSE:MRK) checkpoint inhibitor, KEYTRUDA, and has shown “excellent safety and evidence of additive or synergistic activity,” he adds.

Dr. Williams says the company recently signed a clinical trial collaboration and supply agreement with Incyte (NASDAQ:INCY), which “will give us additional combination immunotherapies to try with Bria-IMT.”

BriaCell also is developing Bria-OTS, an off-the-shelf personalized immunotherapy, with patients matched to one or two of 15 HLA (human leukocyte antigen) alleles based on a quick diagnostic test performed on human saliva. HLA typing, for example, is used to match donor and recipient to ensure the success of the organ transplantation.

Personalized therapy without the need for personalized manufacturing

“We have seen several remarkable responses in late-stage breast cancer patients who match Bria-IMT at certain HLA alleles,” Dr. Williams says, adding that this “supports development of Bria-OTS and a related diagnostic test, BriaDX.”

Bria-IMT traces its roots to a breast cancer cell line called, SV-BR-1, developed by Dr. Charles Wiseman, a co-founder and inventor of most of the company’s intellectual property.

He conducted the first proof-of-concept study with SV-BR-1 between 1999 and 2003. The study, with 14 late-stage, treatment-refractory breast cancer patients, demonstrated a median overall survival of 12.1 months, about twice what he was expecting, and no severe drug-related adverse events.

According to Dr. Williams, SV-BR-1 was then genetically engineered to secrete granulocyte/macrophage-colony stimulating factor (GM-CSF), a monomeric glycoprotein which activates the immune system, effectively creating Bria-IMT.

Dr. Wiseman conducted a second proof-of-concept study with one ovarian cancer and three breast cancer patients between 2004 and 2006, using a combination of Bria-IMT; cyclophosphamide, a chemotherapy; and interferon alpha.

The study generated a median overall survival of 35 months, which was very impressive without serious side effects. Dr. Williams says one robust responder had a more than 90% tumor regression during treatment. When treatment halted, according to the FDA protocol, the patient relapsed, but then responded when treatment resumed.

“This patient was the only one matching a key HLA allele with Bria-IMT and she experienced tumor regression and complete remission at some metastatic sites,” Dr. Williams points out.

Dr. Williams, who joined BriaCell in late 2016, says Dr. Wiseman’s research funding ended after the second proof-of-concept study and little progress was made until the company was recapitalized during a reverse takeover earlier in the decade.

In 2017, the company reinitiated treatment with the Bria-IMT regimen in an FDA-approved clinical trial with 23 advanced breast cancer patients. “We confirmed Bria-IMT’s mechanism of action and achieved proof of concept,” Dr. Williams contends. “Tumor regression was seen in patients who matched Bria-IMT at HLA loci, confirming our main hypothesis.”

In the study, 21% of patients with one or more HLA matches had tumor shrinkage and 37% of patients had a biological response, which includes tumor shrinkage or lower circulating cancer-associated cells. In a subset of patients, with two or more HLA matches, 40% of patients had tumor shrinkage and 60% had a biological response.

“One patient in the study had previously failed seven rounds of chemotherapy and had 20 lung metastases. She also had two HLA matches and after she was treated with a Bria-IMT regimen, her lung tumors either disappeared or shrunk to tiny scars,” Dr. Williams notes.

In addition, Dr. Williams says BriaCell observed high levels of PD-L1 molecules on circulating cancer cells and cancer-associated cells in more than 90% of the patients. PD-L1 molecules block immune cells from attacking cancer cells. Checkpoint inhibitors, such as KEYTRUDA, are designed to neutralize PD-L1 induced immune suppression in cancer patients.

“That’s why we believe there is a strong rationale of combining Bria-IMT, which increases an immune system response, with checkpoint inhibitors, which are designed to decrease suppression of the immune system,” Dr. Williams suggests.

BriaCell is now in a Phase 1/2a study combining Bria-IMT and Merck’s checkpoint inhibitor, KEYTRUDA, in hopes of inducing a more potent anti-cancer response in advanced breast cancer patients.

At the 2019 American Association for Cancer Research annual meeting in April, BriaCell reported initial findings from the first six heavily pretreated “salvage” patients enrolled in the Bria-IMT and KEYTRUDA combination study. Early evidence suggests “rapid additive or synergistic anti-tumor activity, including examples of tumor reduction at multiple sites and disease stabilization,” he notes. The combination also was safe and well tolerated.

“While in earlier monotherapy studies, HLA matching between patients and Bria-IMT appeared to be important for the development of anti-cancer activity, we have seen some evidence suggesting that Bria-IMT in combination with KEYTRUDA may work for patients regardless of HLA matching,” Dr. Williams offers.

The company expects to have additional study data to report at the San Antonio Breast Cancer Symposium in December.

BriaCell also is advancing its combination thesis with additional compounds for advanced breast cancer under a clinical trial collaboration with Incyte. The companies hope to begin a Phase 1/2a study in the second half of 2019 with approximately 60 patients, and report safety and efficacy data by the end of 2020.

Incyte plans to provide compounds from its development portfolio, including INCMGA0012, an anti-PD-1 monoclonal antibody similar to KEYTRUDA, and Incyte’s lead cancer immunotherapy candidate, epacadostat, an IDO1 inhibitor, to be used in combination with Bria-IMT.

Hypothetical Mechanism of Targeted Immune Activation by Bria-IMT™ & Bria-OTS™ in Advanced Breast Cancer

Dr. Williams says the company also is developing Bria-OTS cell lines to express both GM-CSF and interferon-alpha along with patient-specific matching HLA types. “Cell lines will be pre-manufactured, expressing HLA alleles and matching more than 99% of the overall advanced breast cancer population.”

Using BriaDX’s companion diagnostic, he says the off-the-shelf alleles will be matched and selected for each patient prior to treatment. As a result, each patient would have a personalized mix and match of off-the-shelf alleles. “This has the potential to be personalized therapy without the need for personalized manufacturing.”

Dr. Williams explains that the mechanism of action of Bria-IMT/Bria-OTS involves the production of breast cancer antigens. Bria-IMT/Bria-OTS further boosts the immune response by secreting the GM-CSF protein. “Breast cancer antigens are taken up by dendritic cells and presented to CD4+ and CD8+ T-cells implicated in tumor destruction,” he suggests.

Bria-IMT/Bria-OTS also directly stimulates cancer-fighting CD4+ and CD8+ T-cells, further boosting the immune response, he adds. This unique mechanism sets Bria-IMT/Bria-OTS™ apart from similar immunotherapies. “Bria-IMT/Bria-OTS efficacy is enhanced when there is HLA matching of Bria-IMT/Bria-OTS with the patient. So, if the HLA type of a patient matches at least partially the HLA type of our cell line, we believe it is much more likely that the patient will experience a strong anti-tumor response.”

The company hopes to receive FDA authorization to begin dosing patients with Bria-OTS at the end of 2019, and expects to report initial safety and efficacy data by the end of 2020. “These results should allow us to segue into a combination study with Bria-OTS and a checkpoint inhibitor, as informed by our results with Bria-IMT combination therapy, at the end of 2020.”

“We anticipate that 2020 may be our value inflection point as we prepare for a registration study of Bria-IMT in combination with a checkpoint inhibitor,” Dr. Williams suggests.

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To connect with BriaCell, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.

Michael Swartz, President

MediXall Group (OTCQB:MDXL) has launched a new generation healthcare marketplace platform to address self-pay and high deductible consumers’ growing need for greater healthcare cost transparency and access to competitive pricing information.

“Our platform makes scheduling an appointment for specific healthcare services as simple and easy as booking a flight and hotel,” Michael Swartz, president, says in an interview with BioTuesdays.

“The online experience was designed to mirror e-commerce and online booking sites found in other markets: centered on providing consumers with ratings and reviews, transparent pricing, and comparative shopping,” he adds.

Last November, the company launched its MediXall.com platform in Florida, with plans to expand nationally. The company also inked a strategic partnership with CoreChoice, a leading specialty network for diagnostic radiology, including MRI, CT, PET, X-rays, ultrasounds and mammograms. The accord provides MediXall with access to more than 22,000 fully credited radiology providers and facilities throughout all 50 states.

“Once the existing network reaches its full dimension, the platform will include everything from dental to vision to cardiology, physical therapy, internal medicine and more,” he adds.

Mr. Swartz explains that with MediXall.com, consumers are able to search and compare most medical, dental and wellness services based on all-in cash price; location and distance to the provider; ratings and availability; and select the best value according to their personal preferences.

“In this era of rapidly increasing deductibles and healthcare costs, our cloud-based platform is designed to be transformational and disruptive to traditional methods of medical care and providing medical services to the consumer,” he contends.

To use MediXall.com, a user books a service on the website with a credit card, which locks in the price but is not charged until the service is provided. MediXall.com sends the payment to the physician or lab and, in return, the company receives an administration fee of $15 from the transaction.

“Through refinements of the pricing model, we have learned that we can make more than the $15 technology fee per appointment,” he adds.

According to Mr. Swartz, surveys have shown that patients want to obtain pricing information for various treatments from their doctors, but doctors previously haven’t had a tool to help patients save money.

As a result, the company recently launched the MediXall Patient Experience platform as a tool for physicians to share information about the cost and location of upcoming care options.

“This system empowers patients to take control of their healthcare by showing options personalized for each self-pay and underinsured patient, how much it will cost, and more,” Mr. Swartz points out. “Gone are the days of unsupported patient searches for the right specialist or lab that accepts their insurance.”

Mr. Swartz says MediXall.com’s plans for 2019 include ramping up MediXallRx, free tool that allows consumers to search and compare prescription drug prices and receive immediate savings of up
to 80% with their MediXallRx Savings Card at the cash register for both generic and brand prescription medications.

The card is accepted nationwide at more than 60,000 participating pharmacies, including Walgreens, CVS, Target, Walmart, and other national chains, as well as regional and local drugstores, he adds.

The company also has partnered with a national lab company and “negotiated pricing” in order to launch a laboratory testing services program. “This new program will provide a seamless ordering experience for physicians to search, compare, and order affordable pre-curated panels or design custom lab test orders for their patients,” Mr. Swartz contends.

With the recent appointment of Dr. Howard Braverman to its advisory board, MediXall is preparing for an expansion into eye care. Dr. Braverman is a former president of the American Optometric Association and was the national vision director for Humana’s Employer Group Segment.

Mr. Swartz says Dr. Braverman is assisting the company with the critical areas of identifying and pursuing key strategies to help facilitate MediXall’s rollout into the vision space.

MediXall also has entered initial negotiations that will facilitate adding additional in-demand medical and dental specialties on MediXall.com over the next three-to-six months.

MediXall.com’s growth strategy involves expanding from its current base of Florida to major cities that have strong coverage with the CoreChoice network, Mr. Swartz says.

“This would allow us to accelerate expansion and continue to increase our provider network with minimal effort and cost, focusing our resources on marketing to the consumer, and on technology development,” he adds.

Beyond Florida, the company expects to expand to Texas, concentrating on four regions: Dallas-Fort Worth, Houston, San Antonio, Austin and El Paso. The strategy also anticipates expanding by using a West-Southwest strategy, focusing on New Mexico, Arizona, Washington State, Colorado, Oregon, and Nevada, as well as high-density areas in Pennsylvania, New York, Massachusetts, Delaware, Illinois, Ohio and Indiana.

National Expansion Plan

“We are still in the early stages of learning how to bring new value to our customers through the intertwining of consumer technology and healthcare,” Mr. Swartz says. “Our goal remains to solidify and extend our brand and customer base. This requires sustained investment in systems and infrastructure to support outstanding convenience, selection, and service while we grow.”

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To connect with MediXall, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.

Gilles Gagnon, President and CEO

Ceapro (TSXV:CZO) is transitioning to a new business model - from a contract manufacturer to a biopharmaceutical company - to pursue multiple growth opportunities in nutraceuticals and pharmaceuticals.

“As part of our new product development, Ceapro will develop formulations potentially allowing delivery of bioactives through different modes of administration, including oral, topical, sub-lingual, and intranasal,” Gilles Gagnon, president and CEO, says in an interview with BioTuesdays.

“We have industry leading extraction manufacturing processes to produce high value active ingredients from natural plant based sources, with a focus on oats,” he adds. “Our two value-driving active ingredients - beta glucan and avenanthramides – are used in multiple brand-name cosmetics and personal care products, and form the revenue generating base business in our personal care business.”

These household brands include Aveeno, Jergens, Coppertone, Dove, Burt’s Bees, The Body Shop, Lubriderm, Nexcare, KY products and Neutrogena.

Mr. Gagnon explains that beta glucan is a water-soluble fiber found in the cell wall of oat kernels that is highly effective in stimulating collagen synthesis. He says beta glucan’s key benefits include skin restructuring and wound healing; replenishing and protecting skin’s moisture barrier; reducing fine lines and wrinkles to decrease visible signs of aging; and potential reduction of bad cholesterol (LDL) and/or heart disease risk.

“Ceapro was first company to demonstrate that beta glucan can be used as a delivery system because it can reach the dermal layer of skin,” he contends, referring to the layer of skin under the epidermis, which contains tough connective tissue.

Avenanthramides are a group of polyphenol compounds found exclusively in oats. According to Mr. Gagnon, they contain antihistamine and anti-inflammatory properties that provide relief for a host of skin conditions, such as eczema, chicken pox and insect bites.

Mr. Gagnon says that in cosmeceuticals, avenanthramides have demonstrated significant improvements in erythema symptoms in subjects with mild to moderate atopic dermatitis, or eczema. Johnson & Johnson, for example, has replaced cortisone with avenanthramides in one of its Aveeno line of skin care products, he adds.

“Ceapro is the only company in the world producing the only commercial natural avenanthramide product,” he contends, adding that avenanthramides also have potential benefits in controlling inflammation-based disorders.

Mr. Gagnon says Ceapro’s 2017 acquisition of the Juvente line of cosmeceuticals products was an “important step in our strategic market diversification business plan of moving closer to the customer.” Juvente utilizes Ceapro’s two active ingredients: beta glucan and avenanthramides.

“While we are targeting several markets with Juvente to bring energy back to aging skin; repair structural skin components, especially for burn victims; and provide long lasting hydration to decrease fine lines and wrinkles while improving skin health, the Juvente line of products will mostly be used for the development of topical/transdermal delivery systems using Ceapro’s proprietary new chemical complexes, leveraging our game changing PGX technology, Mr. Gagnon offers.

Ceapro’s initial foray into diversifying its business model includes developing a powder formulation of beta glucan plus an energy booster, co-enzyme Q10 (CoQ10), into a functional drink; a beta glucan formulation to reduce bad cholesterol (LDL) and/or the risk of heart disease; and an avenanthramide-based functional food to alleviate exercise-induced inflammation.

Mr. Gagnon says the company has demonstrated the first water-soluble formulation of CoQ10 using its pressurized gas expanded (PGX) technology, a novel spray drying technique for processing water-soluble biopolymers. “The platform can produce numerous morphologies of biopolymers, ranging from fine fibers to granular powder, which are highly water soluble and stable,” he points out.

The company has published results in peer-reviewed journals that confirmed the bioavailability of a water-soluble chemical complex of CoQ10 beta glucan, which differentiates itself from competing functional drinks. “All that remains is partnering, hopefully by the end of 2019 if we can get the right deal, to scale up production for sales,” he suggests.

Mr. Gagnon says it is well known that people who eat oatmeal can reduce their bad cholesterol. Using the company PGX technology, he says Ceapro has designed high and medium molecular weight formulations of beta glucan.

The first clinical study of the company’s potential cholesterol-lowering pill as an add-on therapy to cholesterol-lowering statins in subjects with hyperlipidemia now is recruiting patients at 11 sites in Canada as part of a collaboration with the Montreal Heart Institute. Mr. Gagnon explains that the study involves three sets of patients, with 66 treatment and 22 placebo subjects in each group, receiving three different doses of beta glucan.

The primary endpoint of the 18-to 24-month double blind, placebo-controlled study is the change in LDL-cholesterol after 12 weeks.

Ceapro and its collaborators at the University of Minnesota have demonstrated in bioavailability and bio-efficacy studies that low and high doses of avenanthramides can significantly reduce inflammation biomarkers in blood. Study results were presented at the 2018 American Society of Nutrition conference, with further data to be presented in a poster at the American Sports Medicine conference in Orlando in May 2019.

Mr. Gagnon points out that in addition to PGX, the company’s enabling technologies include an ethanol-based extraction manufacturing process that can produce commercial scale quantities of active ingredients, and a proprietary drying technology to produce commercial scale quantities of pharma grade tablets of phenolic-based compounds.

“Our strategy is focused on strengthening our base cosmeceuticals business and expanding into multiple growth markets,” he points out, adding that Ceapro’s enabling technologies have “broad utility in functional drinks, powders and pills.”

Pipeline

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To connect with Ceapro, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.