Ilan Danieli, Founder and CEO

Using a combination of advanced lab technologies, and a platform giving access to expert academic pathologists, Precipio (NASDAQ:PRPO) has staked out a unique position in its battle to prevent misdiagnosis of blood related cancers.

“Many studies have found that misdiagnoses can range between 2% in solid tumors and almost 30% in blood-related cancers,” Ilan Danieli, founder and CEO, says in an interview with BioTuesdays. “Misdiagnosis is a significant problem in cancer diagnosis and due to their complexity, blood-related cancers appear most prone to misdiagnosis.”

For example, he says there are some 100 different types of lymphoma and each one potentially could have a different treatment.

Unique Diagnostic Services delivered via specialized academic pathologists to eliminate diagnostic errors

“Our goal is to give physicians the correct diagnosis so patients receive the appropriate treatment, which would help save lives, as well as save insurers billions of dollars and pharma companies have access to accurate data.”

Precipio has partnered with the Department of Pathology at Yale University as well as with Harvard’s Dana-Farber Cancer Institute. Yale, for example, employs about 75 pathologists, Mr. Danieli says, noting that the company intends to have a network of pathologists across the country that covers every specialty in the blood cancer space.

“We span all aspects of the diagnostic process from proprietary triage algorithms that identify the correct disease state to proprietary in-lab technologies,” he contends. “And then we tap into pathologists at our academic partners to render a diagnosis and improve our accuracy.”

Mr. Danieli says Precipio has developed a hybrid pathology service and technology platform to reduce investor risk and increase returns. “The stability of our revenue-generating service business balances the cash needs of our technology investments,” he points out.

In addition, Precipio’s clinical laboratory in New Haven, Conn. acts as an incubator, enabling development of a portfolio of technologies, rather than a single technology. “We can develop from an idea to commercialization for about $100,000, which is a fraction of what most companies spend.”

Under its pathology services business, Precipio performs the technical lab work, which represents about 80% of reimbursement, while its academic pathology partners perform the professional interpretation work, representing about 20% of reimbursement.

“We are not aware of other laboratories pursuing a similar business model as Precipio’s, with its focus on services and products to aid in the misdiagnosis of blood cancers,” analyst Ben Haynor of Alliance Global Partners said in a June 2019 initiation report.

The strategy, along with an expanding sales force, seems to be working. Pathology case volume rose 39% in the second quarter of 2019, compared with the same quarter a year earlier; recurring ordering customers jumped 92% and the number of ordering customers was up 8% year-over-year.

“Emerging data suggests centralized pathology review in blood cancers should be conducted in clinical cases just as it is done in clinical trials and many large-scale and comprehensive biologic studies,” Mr. Haynor says.

Precipio is sponsoring a 1,000-patient study designed to independently evaluate the impact of academic pathology expertise on diagnostic accuracy and confirm its business model as a solution to the problem of misdiagnosis. The study should be complete later this year.

In 2018, the company released early data from the study, which showed a fourfold superiority of academic level diagnostic accuracy, compared with industry. The early data also showed that 73% of cases, which academic pathologists determined were previously misdiagnosed, had a definite or possible material impact on patient treatment plans.

Positive final data would go a long way in reimbursement discussions and lining up potential customers, Mr. Danieli adds.

In addition to its pathology services business, Precipio has developed two recently launched reagent products to improve the lab process following its 2017 merger with Transgenomic and its enabling technology for DNA liquid biopsies.

Mr. Danieli says the HemeScreen product enables cost-effective and rapid screening of four genes recommended in the guidelines by the National Comprehensive Cancer Network for patients with myeloproliferative neoplasms and myelodysplastic syndromes.

“Most labs batch these tests for cost reasons, leading to two-to-four week turnaround times, while with HemeScreen, laboratories can provide the same information in two-to-four days,” he points out.

The company also has developed IV-Cell, a proprietary media that enables culturing of all four hematopoietic cell lineages at once, compared with the existing dominant culture media, which requires the selection of only one cell lineage for culturing at a time.

Precipio recently announced a manufacturing agreement with Novamed for production of IV-Cell media for an initial term of three years. The accord would enable Precipio to provide cytogenetics labs in the U.S. and worldwide with IV-Cell media to meet their demand. The company also is in discussions with major labs about in-licensing IV-Cell.

Mr. Danieli figures the IV-Cell cytogenic media represents a market potential of $100-million a year, with the molecular HemeScreen media at $50-million a year.

AGP’s Mr. Haynor expects future launches will follow IV-Cell and HemeScreen, “targeting smaller markets of less than $100-million, where existing products leave something to be desired in terms of accuracy, ease-of-use, or turnaround time.”

In its pathology segment, the company is exploring expansion into renal and neurologic cancers because like blood cancers, “there is a high level of complexity in the diagnosis of those types of cancers as well, leading to misdiagnosis,” he points out.

The total U.S. cancer diagnostics market is expected to reach $50-billion in 2020, of which the blood-related cancer drug and diagnostics would account for some $6-billion. Renal and neurologic cancers each represent a market potential of $2-billion, he suggests.

“Our success is directly translated into saving patient lives, and that’s what motivates us to get out of bed every morning,” Mr. Danieli says. “We intent to make our products and services available to every patient worldwide. Nobody should be misdiagnosed with cancer in the 21st century.”

Market Opportunity

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Steve Lisi, Chairman and CEO

Beyond Air (NASDAQ:XAIR), formerly AIT Therapeutics, is developing a proprietary nitric oxide (NO) generator and delivery system that uses NO generated from ambient air, rather than bulky cylinders, and delivers precise amounts of NO to the lungs for the treatment of respiratory and other diseases.

“Our goal is to eliminate the use of cylinder-based NO systems currently used in hospitals around the world and potentially enter the home market to treat certain respiratory conditions,” Steve Lisi, chairman and CEO, says in an interview with BioTuesdays.

Beyond Air hopes to file for premarket approval with the FDA around the end of September 2019 for its cylinder-free NO generator and delivery system, the LungFit, to treat pulmonary hypertension (PH), or a narrowing of the pulmonary arteries in certain ventilated patients.

In January 2019, Beyond Air licensed commercial rights to LungFit PH to Circassia Pharmaceuticals (LSE:CIR) of London, a specialty pharmaceutical company focused on respiratory diseases, for the U.S. and China markets. Circassia plans a U.S. commercial launch in the second quarter of 2020.

Under the accord, Beyond Air is in line to receive $32.55-million in potential milestone payments, and royalties of 15% on net sales up to $100-million and 20% on net sales in excess of $100-million.

Beyond Air retains commercial rights to LungFit PH in Europe and expects to receive CE Mark for its device in the first half of 2020.

Mr. Lisi explains that LungFit PH is a portable system that utilizes electric voltage to produce precise quantities of NO from the nitrogen and oxygen in ambient air. And it uses a disposable filter to remove unwanted NO₂ produced during the chemical process.

“The system will not operate without our filter, thus this is our razor-razor blade business model as each filter has a 12-hour life, so you need two filters each day,” he adds.

Inhaled NO is a pulmonary vasodilator, which is approved in the U.S. for use as part of a regimen in the treatment of hypoxic respiratory failure associated with persistent pulmonary hypertension in infants. Outside of the U.S., inhaled NO also is used as part of the treatment of pulmonary hypertension associated with cardiac surgery.

Beyond Air has conducted more than 2,100 treatments with its LungFit platform in more than 85 patients in eight studies at NO concentrations of more than 150 parts per million (ppm), many times in excess of normal treatment level of 20 ppm for pulmonary hypertension in infants. Mr. Lisi says there have been no serious adverse events related to NO therapy.

Pulmonary hypertension is a life-threatening condition resulting from increased pulmonary vascular resistance and leading to decreased pulmonary blood flow. Beyond Air estimates the pulmonary hypertension market in U.S. hospitals has a sales potential of more than $300-million a year at peak sales, with the global market exceeding $600-million.

According to Mr. Lisi, inhaled NO causes smooth muscle relaxation, which increases blood flow to the lungs and decreases the workload on the right ventricle.

Currently, hospitals use two, 45-pound NO cylinders on a cart, plus a delivery system, weighing a total of about 175 pounds. “Our commercial generator, with a back-up system included, mounted on a cart would weigh 50 pounds. Plus, our system provides the hospital with the flexibility for use without a cart where the system would weigh just 20 pounds,” Mr. Lisi contends.

He suggests that hospitals would have a significant cost and logistics advantage with LungFit PH, avoiding burdensome cylinder inventory and storage requirements.

In addition, NO is supplied by LungFit PH as a hypoxic gas mixture and there are no purging procedures or additional safety measures needed to clear NO₂, a toxic gas, which is removed by the filter in the device.

“From a company standpoint, we don’t have any expenses associated with a manufacturing facility and we don’t have any logistics expenses delivering NO cylinders,” Mr. Lisi adds.

There are some 800 hospitals in the U.S. now using NO cylinders. However, there are more than 1,000 neonatal intensive care units in the U.S., according to the American Academy of Pediatrics and American Hospital Association.

“We expect to expand the current market by providing lower costs and ease of use, compared with cylinder systems,” Mr. Lisi contends.

Beyond Air has more than 20 issued patents and more than 10 patents pending across major global markets, which could run through 2037. The company’s IP covers its generator; breathing circuit; NO concentration, action in the body and dosing; the NO₂ filter and methods of use.

Beyond Air’s second indication is bronchiolitis, or acute lower respiratory infection, in early infancy. The company has completed two pilot studies in Israel with its LungFit BRO device, demonstrating a 24-hour reduction in the length of hospitalization, along with no serious adverse events.

“We treated babies in the pediatric unit, not in the NICU where NO cylinder systems are confined to,” Mr. Lisi says. “Discharging babies sooner has its obvious costs benefits for hospitals and insurers.”

Bronchiolitis is the most common reason for pediatric hospitalization in the U.S. and a leading cause of global child mortality. There are no drugs approved for bronchiolitis and the standard of care is oxygen and hydration. Beyond Air estimates the global market for bronchiolitis, where there is no competitor in the market, at more than $1.2-billion a year.

Mr. Lisi says the company wants to conduct a pivotal trial in the U.S. with LungFit BRO during the winter of 2020-2021. “Our goal would be to reduce the duration of bronchiolitis symptoms in infants and the length of hospitalization. The longer infants remain in hospital, the greater the risk for both hospital acquired infection and respiratory problems as they age.”

Studies have shown that infants with acute bronchiolitis can remain in hospital for three-to-four days.

Mr. Lisi says that eliminating high-pressure cylinders could make NO therapy accessible at home, where patients can self-administer. The LungFit plugs into any standard electrical outlet and requires a Beyond Air filter. After the mask is positioned on the face, patients only needs to press, go, he adds.

Beyond Air’s third indication is for severe lung infections, such as nontuberculous mycobacteria (NTM), with an initial target of NTM abscessus (MABSC), the most aggressive and difficult to treat form of NTM. The company plans to seek approval in NTM MAC (mycobacterium avium complex) following MABSC approval or potentially concurrently, pending further developments.

“NTM is an FDA disease of focus with limited [treatment] options. Patients can die within a few years from diagnosis,” Mr. Lisi points out.

In an earlier pilot study in Israel, with nine cystic fibrosis patients with refractory MABSC, the company’s NO formulation yielded positive safety and clinical results in measuring patients’ six-minute walk and FEV1, or the amount of air exhaled in one second.

Beyond Air hopes to begin a 12-week pilot study in the second quarter of 2020, where patients with NTM lung infections, excluding asthma, would self-administer NO therapy with the company’s LungFit NTM device at home at concentrations of up to 250 ppm. The company expects to release the study data around the end of 2020.

A pivotal study is slated to begin in the second half of 2021 and finish in the first half of 2023, leading to possible FDA approval and launch in 2024, Mr. Lisi suggests.

“Extensive in vitro data already exist supporting the direct killing effect of NO on MABSC,” he says, adding that NO therapy can target other severe, chronic and refractory infections, such as Pseudomonas aeruginosa, the most common pulmonary pathogen in patients with cystic fibrosis.

“Continuous exposure to NO at 200 ppm has been shown to kill 100% of P. aeruginosa bacteria in four-to-five hours.”

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Roger Aston, Executive Chairman

PharmAust (ASX:PAA) is gearing up to begin a pivotal Phase 2 study in Australia with its lead veterinary drug candidate, monepantel, for the treatment of lymphoma in canines, which if successful, could open the door to human use in a much larger market.

“We should have some results of the Phase 2 study in November or December this year and we’ll see where we go from there in terms of a human development program,” Roger Aston, executive chairman, says in an interview with BioTuesdays.

“If the canine study is successful, I don’t foresee any problem enticing a Big Pharma oncology company to license and develop monepantel for human use,” he adds. “A number of centers already have expressed an interest in looking at our compound as a treatment for cancer in humans based on the work we’ve done.”

Dr. Aston explains that monepantel is a repurposed drug already approved as an anti-parasitic in sheep by Elanco US Inc. PharmAust has patented monepantel as an anti-cancer drug and has an option agreement with Elanco for veterinary cancer applications.

Elanco (NYSE:ELAN), a leading global animal health company, recently outlined a new strategy to become a major player in the animal oncology space, which Dr. Aston says provides PharmAust with unique advantages moving monepantel forward. For example, PharmAust has reformulated pills with monepantel supplied by Elanco for its upcoming Phase 2 study.

According to Dr. Aston, many chemotherapy agents given to dogs are reformulated versions of the same agents that are given to humans. “The veterinary therapeutic market is dominated by repurposed drugs already approved for use in humans and/or animals.”

In addition, he points out that cancer studies in dogs are highly reflective of what a drug will do in humans. The reverse is also generally true. Repurposing of approved drugs potentially offers companies accelerated development and registration timelines.

Six million dogs are diagnosed with cancer in the U.S. each year and one-in-four will die of cancer. However, pets are living longer as owners are willing to pay $2,000-to-$5,000 for certain major treatments, contributing to a pet drug market of more than $10-billion in the U.S. in 2018.

Dr. Aston suggests that the annual U.S. cancer chemotherapy market alone in dogs is valued at $500-million to $600-million, if a safe drug exists with minimal side effects.

“But that figure only covers about 20% of dogs undergoing treatment. We believe our market potential for monepantel is much higher because owners more often than not do not wish to put their pets through a chemotherapy treatment regimen. We are targeting 100% of dogs needing treatment as monepantel has minimal side effects in canines,” he adds.

New oncology drugs for dogs represent an unmet need because of the significant side effects associated with chemotherapy. “Monepantel comparatively has little or no side effects,” Dr. Aston contends.

In 2017, PharmAust conducted a small pilot study in dogs with lymphoma that showed monepantel was effective at progression free survival (PFS). Of the seven dogs in the study, six showed statistical significance in PFS with an earlier formulation of the drug.

“We believe monepantel’s mode of action inhibits the mTOR pathway, which is connected to cell replication and quiescence in certain types of cancer,” he suggests.

Dr. Aston says the company performed an extensive reformulation program in 2018 and 2019 to develop a new, high-dose version of monepantel tablets, manufactured under GMP, which resulted in an improved pharmacokinetic profile. The program also improved the taste of monepantel, which was previously unpalatable, suggesting that dosing canines by their owners would be much less challenging.

PharmAust received approval from the NSW Department for Animal Care and Ethics Committee as well as the State of Victoria to begin its Phase 2 study with the newly formulated tablets.

Dr. Aston says the study should begin in August or September after PharmAust receives monepantel tablets from a manufacturer in the U.S. “We’ve given Elanco an option to license the veterinary oncology application for monepantel and we expect to present Elanco with an interim dossier in November or December.”

The 28-day Phase 2 open-label study is expected to first enroll up to 16 dogs. Anti-cancer efficacy is measured by achieving stable disease and PFS or regression of tumors. Preventing metastasis of the cancer also will be monitored. “We can cut the trial short if we see a profound effect and the longer we can suppress the tumor, the more commercial monepantel is,” he adds.

“Ultimately, we hope pet owners would put their companion animals on a maintenance treatment of monepantel and avoid the side effects of chemotherapy,” Dr. Aston says. “By putting the tumor into stasis, dogs would be able to build immunity to the tumor until their immune system is capable of removing it. The ultimate goal here is to improve quality of life.”

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Shawn Shirazi, CEO

Theralase Technologies (TSXV:TLT; OTCQB:TLTFF) has designed its Phase 2 clinical study in patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) based on FDA industry guidance issued in February 2018.

“The FDA confirmed that our protocol is aligned with the said guidance during our pre-IND conference call with the agency in June 2019 and if the trial is successful, it could support an application for marketing approval,” Shawn Shirazi, CEO of Theralase’s drug division, says in an interview with BioTuesdays.

“The FDA guidelines state that in Bacillus Calmette-Guérin(BCG)-unresponsive NMIBC, a single-arm clinical trial with complete response rate and duration of response as the primary endpoint can provide primary evidence of effectiveness to support a marketing application,” he adds.

“We also have the potential for fast track designation as we demonstrated a strong safety profile and obtained a strong efficacy signal in an earlier Phase 1b NMIBC study.” Two-of-three patients that received one therapeutic dose in the Phase 1b study had no clinical evidence of bladder cancer after 360 days.

Theralase began its Phase 2 study in April 2019. The company plans to enroll approximately 100 BCG-unresponsive NMIBC patients in a single-arm, open-label study at approximately 20 clinical study sites, beginning initially in Canada, before expanding to the U.S. in the fourth quarter of 2019.

Theralase’s Anti-Cancer Technology division focuses on light-activated photodynamic compounds, such as its lead drug, TLD-1433, and development of laser systems that activate TLD-1433 to target and destroy cancer cells.

Dr. Shirazi explains thatTLD-1433 is instilled into the bladder through a catheter, where it is absorbed preferentially by the bladder cancer cells.

TLD-1433 MECHANISM OF ACTION(18)

“Once TLD-1433 is absorbed by the cancer cells, it is light activated to produce powerful cytotoxins in the form of reactive oxygen species and singlet oxygen to destroy the cancer cell from within,” he adds.

In addition, he notes that pharmacokinetic studies have shown that TLD-1433 is removed from the body via urine (at nanograms per milliliter) within 24 hours and via plasma (at pictograms per milliliter) within 72 hours, so there is no photosensitivity issues presented to a patient. The procedure could eventually be performed as outpatient day surgery; however, this is not planned during the Phase 2 clinical study, Dr. Shirazi says.

The company’s IP includes 12 issued and 34 patents pending. Its U.S. composition of matter patent expires in June 2034. “Therefore, we have plenty of time to enjoy the fruits of its labor, if we are successful in commercializing this novel technology.”

There are some 240,000 new cases of bladder cancer in the U.S., Canada and certain European countries each year, of which 70% are classified as NMIBC. And 30% of these cases unfortunately become unresponsive to BCG standard of care within one year.

The standard of care for patients with high-grade NMIBC is intravesical BCG following trans urethral resection of the bladder tumor. However, there is an up to 80% rate of tumor recurrence and up to 50% disease progression within five years.

When patients fail to respond to current standard of care, clinical treatment guidelines call for a radical cystectomy, or surgical removal of the bladder and adjacent organs, which can significantly affect a patient’s quality of life, Dr. Shirazi points out.

“We are seeking regulatory approval for a drug/device combination as an alternative for patients who are unfit for cystectomy surgery or desire bladder-preserving therapies.”

During a pre-IND conference call in June this year, the FDA confirmed that the company’s Phase 2 protocol is in accordance with the agency’s guidelines. “This has the potential to make our Phase 2 study a pivotal study,” he suggests.

Theralase expects to enlist four clinical sites in Canada and up to 16 in the U.S. for the Phase 2 clinical study. Patients will be evaluated at a therapeutic dose of 0.70 mg/cm2. Unlike the Phase 1b study, where patients received one therapeutic procedure, patients in the Phase 2 study will receive two treatments at day zero and day 180.

The primary endpoint is complete response at any time post-initial treatment and duration of complete response at 360 days. Dr. Shirazi says complete response requires at least one of the following:

• Negative cystoscopy (no cancer in the bladder) and negative urine cytology (no cancer cells in the urine); or

• Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology; or

• Negative cystoscopy with malignant urine cytology if cancer is found in the upper tract or prostatic urethra and random bladder biopsies are negative.

The secondary outcome will measure safety by the incidence and severity of adverse events grade 4 or higher that do not resolve within 360 days post-initial treatment.

“This is well above anything we saw in the Phase 1b, as no adverse events were noted beyond grade 1 or 2 (mild or moderate) and of these, 95% were resolved completely within 180 days, with the remaining 5% deemed not study related by the principal investigator, as they were pre-existing indications,” he adds

Theralase is hoping to bring all of its clinical sites on board before the end of 2019 or early 2020. The company also hopes to enroll and treat all 100 patients during 2020 and follow them for 360 days in 2021. That could put the company in a position to file for marketing approval in the first half of 2022, if the study is successful.

“The Phase 2 is an open label study and if we see similar results to our Phase 1b study for efficacy on an interim basis, say, after the first 20 or 25 patients, we may have the opportunity to meet with the FDA and review the results, with a focus on obtaining accelerated approval,” Dr. Shirazi points out.

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