Kate Beebe, Titan's EVP and chief development officer

After receiving FDA approval last year for its Probuphine implant as a maintenance treatment for opioid addiction, Titan Pharmaceuticals (NASDAQ:TTNP) is employing its ProNeura drug delivery technology to develop an implant to treat Parkinson’s disease.

“The merits of continuous, non-fluctuating drug delivery of dopamine and dopamine agonists have shown to minimize side effects like dyskinesias in non-clinical and clinical studies,” Kate Beebe, EVP and chief development officer, says in an interview with BioTuesdays, referring to abnormal involuntary movements often associated with Parkinson’s.

The disease is characterized by the loss of dopamine, which alters activity in the brain region impacting movement and motor function and is treated with drugs designed to replace or mimic dopamine in the brain. After several years of treatment, however, these drugs can lose their benefit and trigger serious side effects in up to 80% of patients.

Parkinson’s affects approximately one million people in the U.S. and 10 million worldwide and the numbers are expected to double in the next few decades from an aging population. The disease is the 14th leading cause of death in the U.S., with an annual cost to American society of $14.4-billion.

There are about 60,000 new cases of Parkinson’s in the U.S. each year, leading to some 23,000 deaths. The exact cause and reason for disease progression is unknown and there is no cure.

April is Parkinson’s awareness month and the newly formed Parkinson’s Foundation, arising from a merger of the National Parkinson Foundation and Parkinson's Disease Foundation, is promoting various outreach programs to the Parkinson’s community.

Dr. Michael Okun, national medical director of the Parkinson’s Foundation

Among other things, the foundation is raising awareness of the disease by sponsoring Moving Day walks in various cities for patients and caregivers, to emphasize the importance of exercise in managing the symptoms of the disease.

The foundation has a vast nationwide network of Parkinson’s Centers of Excellence where movement disorder experts are available for consultations, as well as allied health professionals, about how to live with the disease and improve the quality of life for patients and caregivers.

Dr. Michael Okun, national medical director of the Parkinson’s Foundation, points out that Parkinson’s is not one disease, but rather a group of disorders with similar symptoms, without one underlying etiology.

“About 10% of cases arise from a single gene defect, leading many investigators to suggest that genes load the gun and the environment pulls the trigger.”

Dr. Okun, who also is Professor and chairman of neurology at the University of Florida, contends that Parkinson’s is the most complex disease in clinical medicine, with more than 20 motor and non-motor symptoms as well as dozens of pharmacologic, non-pharmacologic and surgical treatment options.

In addition, the disease is dynamic and the symptoms and treatments change over time. Common symptoms include tremors, stiffness and slowness as well as depression, anxiety, sleeping disorders and sexual dysfunction.

“We can treat Parkinson’s with behavioral approaches, such as physical and occupational therapy, dopamine replacement strategies, deep brain stimulation and various other therapies,” he suggests. And as researchers attempt to design new treatments, it’s important to keep in mind the non-motor symptoms that patients incur affect quality of life more than the motor symptoms.

“When you think about the disease, you need to think about three buckets of treatments,” he points out. “One bucket is meaningful symptomatic therapies to improve patients’ symptoms today. Another bucket is treatments to potentially slow disease progression. We’ve had 20 years of looking at slowing disease progression and not found a single therapy to place in this bucket yet. And the final bucket is a cure, which is furthest away but might be possible with several of the genetic causes of Parkinson’s.”

Titan’s ProNeura long-term drug delivery platform consists of an active pharmaceutical ingredient uniformly distributed throughout an ethylene vinyl acetate co-polymer matrix and blended and extruded into a match-sized device

According to Dr. Okun, an important focus in treatment today, where therapies are not “moving the needle enough” is walking, talking, thinking and improving the mood of patients.

And the next horizon of therapy, he suggests, is personalized medicine based on the specific profile of a patient’s symptoms or groups of symptoms. “Can we design a pharmacological or surgical or combination therapy to address the often very specific symptoms of an individual patient?” he asks.

Meanwhile, Titan’s Dr. Beebe says an implant device would benefit patients who do not need frequent change in doses of medication. “Not all patients need frequent dose changes, especially in the intermediate stages of the disease.”

Titan’s ProNeura long-term drug delivery platform consists of an active pharmaceutical ingredient uniformly distributed throughout an ethylene vinyl acetate co-polymer matrix and blended and extruded into a match-sized device.

A trained and certified health care provider inserts the implant subdermally in the inner side of the upper arm. Drug is released continuously into a patient's body through the process of dissolution, resulting in a stable level of medication in the blood and avoiding peaks and troughs of oral dosing.

Titan’s Parkinson’s implant contains the active ingredient, ropinirole, which is sold by GlaxoSmithKline as Requip, and has the potential to deliver continuous non-fluctuating levels of dopamine agonists for several months from a single treatment.

The company submitted an IND to the FDA in January and hopes to begin a Phase 1 pharmacokinetic study in mid-2017 to assess safety and tolerability over a three-month period.

The study will enroll Parkinson’s patients receiving adjunctive therapy with oral ropinirole and determine whether the ropinirole implant can replace the oral therapy.

TITAn's PRONEURA PRODUCT PIPELINE

James Oliviero, president and CEO

Checkpoint Therapeutics (OTCQX:CKPT) is taking an “aggressive path forward” with its clinical programs and expects to be in registration studies at the end of 2018 with its lead targeted anti-cancer agent, CK-101, and lead immuno-oncology (IO) agent, CK-301.

“Because these compounds have validated targets, we believe we can quickly establish safe dosages, with sufficient efficacy signals, to potentially move from early-stage studies into Phase 3 development before the end of 2018,” James Oliviero, president and CEO, says in an interview with BioTuesdays.

“We are developing each of our drug candidates initially as monotherapies and once safety and efficacy is established, we then can move to combination studies with our compounds to achieve leading-edge immune-enhanced activity,” he adds.

Mr. Oliviero explains that by using combinations of two IO agents or an IO agent plus a targeted therapy, “we hope to achieve higher response rates plus durable response rates potentially lasting years by engaging the immune system, particularly killer T-cells, to attack and kill cancer cells. This is where cancer therapy is going.”

“By owning all component drugs in a combination therapy in-house, we also can achieve pricing leverage below a combination therapy created by two different companies,” he adds.

Checkpoint also is collaborating with TG Therapeutics (NASDAQ:TGTX) to develop IO antibodies in combination with TG’s targeted therapies for blood-based tumors, such as non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.

“While we focus on solid tumors, TG will focus on hematological tumors and we’re eligible for milestones and royalties with their success,” Mr. Oliviero adds.

Checkpoint, which licensed its original technology in 2015 and went public in the fourth quarter last year, is a member of the Fortress Biotech (NASDAQ:FBIO) group of companies. Checkpoint hopes to up-list to NASDAQ this year.

checkpoint's strategy is to develop first-in-class or best-in-class combination treatments in targeted solid tumor cancers and liquid tumors in collaboration with tg therapeutics 

The company’s portfolio now includes two IO monoclonal antibodies and four targeted anti-cancer agents. Three of the six compounds are considered lead programs: CK-301, CK-302 and CK-101.

In its IO portfolio, Checkpoint plans to file an IND in mid-2017 for its anti-PD-L1 antibody, CK-301, and begin a Phase 1 study in the third quarter. It also plans to file an IND in the first half of 2018 for its anti-GITR antibody, CK-302.

Both compounds, which were licensed from the Dana-Farber Cancer Institute, are being developed for the treatment of multiple forms of solid tumor cancers.

According to Mr. Oliviero, an anti-PD-L1 antibody removes the ability of cancer cells to shield themselves from attack by the immune system’s killer T-cells, while an anti-GITR antibody heightens the activity of T-cells to attack cancer cells.

“It’s like taking the brakes off the immune system and then hitting the gas pedal,” he adds. “With the portfolio we have, there’s also the potential to combine three agents for even greater synergy.”

Mr. Oliviero also points out that unlike most other anti-PD-L1 agents, “our IO compound retains native features for potentially greater killing power.”

Checkpoint’s lead targeted anti-cancer agent is an EGFR inhibitor, CK-101, which is currently in the dose escalation portion of a Phase 1/2 trial for the treatment of patients with non-small cell lung cancer. Enrollment in the Phase 2 portion of the study is expected to begin in the second half this year.

Mr. Oliviero explains that CK-101 is a third-generation EGFR inhibitor similar to AstraZeneca’s Tagrisso, which has been approved by the FDA for lung cancer patients with the T790M mutation. AstraZeneca predicts peak sales of Tagrisso of $3-billion, a substantial market opportunity that can support additional entrants.

In mice, CK-101 showed strong activity against T790M mutated NSCLC with increasing dose

“We think CK-101 could be the next best alternative to Tagrisso, given potential safety advantages, which we will have to ultimately support in the clinic,” he adds.

The Phase 2 portion of the CK-101 trial will enroll about 60 lung cancer patients with the T790M mutation confirmed by a diagnostic to exclude non-responders. The protocol is similar to the initial Tagrisso trial, with the same primary endpoint of overall response rate.

“If we see sufficient response activity in the first quarter next year, we’ll begin submitting plans for a registration trial with the FDA and non-U.S. regulatory authorities, and hopefully commence a registration trial by the end of 2018,” Mr. Oliviero says. “The plan is to develop CK-101 as both a monotherapy and in combination with our synergistic IO agents.”

Lung cancer with the T790M mutation has an estimated annual incidence of 40,000 patients in the U.S., EU and Japan.

The company also plans to begin a Phase 1b study in the next 12 months with its PARP inhibitor, CK-102. It also plans to file an IND in the second half this year for CK-103, its small molecule inhibitor of the BET protein, BRD4. The company is targeting another IND in 2018 for its anti-CAIX monoclonal antibody for the treatment of renal cell carcinoma and other solid tumors.

According to Mr. Oliviero, the goal of targeted anti-cancer therapy is to “smart bomb” specific cancer pathways or driver mutations. “Our four targeted anti-cancer agents each have unique mechanisms of action for targeting cancer cells, which adds diversification and the potential for many combinations with the IO side of the portfolio.”

Wangzhi Li, an analyst with Ladenburg Thalmann, in an initiation report last month, said Checkpoint’s pipeline resembles that of Beigene (NASDAQ:BGNE), which has a market cap of $1.5-billion, and Tesaro (NASDAQ:TSRO), which has a market cap of $8-billion, in many ways, but at an earlier stage.

“We believe Checkpoint is currently under-recognized and presents an attractive investment opportunity tapping into the combination therapy trend for cancer treatment,” he added.

Dr. Li started Checkpoint with a “buy” rating and $20 price target. On Thursday, the stock closed at $12.50, giving the company a market cap of $218-million.

checkpoint therapeutics' pipeline

Maria Fardis, president and CEO

Lion Biotechnologies (NASDAQ:LBIO) is establishing a leading position in immuno-oncology through its tumor-infiltrating lymphocyte (TIL) technology to deliver personalized oncology therapies to patients with unmet medical needs.

“In an era of personalized medicine, our autologous cell therapy is as personalized as it gets,” president and CEO, Maria Fardis, says in an interview with BioTuesdays.

In the early stages of cancer, Dr. Fardis points out that white blood cells migrate to the tumor and launch an attack. However, the effect is usually short-lived because cancer adapts to evade immune detection and suppresses the body’s immune response.

“Our TIL technology is designed to overcome the immunosuppressive effects of cancer, while leveraging and enhancing the power of TILs to treat, and potentially cure solid tumors,” she contends.

Tumor-Infiltrating Lymphocyte (TIL) Therapy

Dr. Fardis explains that Lion’s technology is based on TILs isolated from a patient's tumor following resection. The cells are expanded to billions ex vivo, away from cancer's immune-suppressing effects.

The highly activated, potent TILs are then infused back into a patient, who has been preconditioned to remove all suppressive influences. Patients also receive one-to-six doses of interleukin-2 (IL-2) to help TILs multiply further, engraft and activate, to attack the tumor.

Unlike many cancer vaccines which target preselected tumor antigens, Dr. Fardis says Lion’s technology is based on a patient's own TILs, which naturally target antigens specific to those of a patient's tumor.

“Consistent response rates in treatment naïve and refractory melanoma patients who have failed other options, including checkpoint inhibitors, have been reported,” she adds.

Based on an adoptive cell therapy regimen developed by Dr. Steven Rosenberg, chief of surgery at the NCI, Lion’s TIL technology is currently in use as a physician-sponsored combination treatment for metastatic melanoma at NCI, MD Anderson Cancer Center and the H. Lee Moffitt Cancer & Research Institute.

Lion is also enrolling patients in a company-sponsored single regimen Phase 2 TIL study in refractory metastatic melanoma and is in startup for two Phase 2 trials in cervical and head and neck cancers.

In 2016, there were 76,380 new cases of melanoma, resulting in 10,130 deaths; in cervical cancer, 12,990 news cases and 4,120 deaths; and in head and neck cancer, 48,330 new cases and 9,570 deaths.

lion biotechnologies manufacturing process & logistics

Dr. Fardis says the company also has partnered with Karolinska University Hospital in Sweden to study a slightly different TIL technology. Phase 1 studies at Karolinska are scheduled to begin by end of 2017 in glioblastoma and pancreatic cancer.

A recent Phase 2 trial with 101 patients with metastatic melanoma conducted by Dr. Rosenberg at the NCI confirmed that TIL treatment was associated with high, durable objective response rates, including patients who were refractory to checkpoint inhibitors.

Specifically, the data demonstrated complete responses in 24% of patients, with 23 of 24 complete responders showing durability of 30-to-47 months. In addition, the overall response rate was 56% and overall survival was approximated 80% at 12 months.

Dr. Rosenberg’s NCI study also observed a complete response rate of 29% in 34 patients that had failed therapy with checkpoint inhibitors.

Dr. Fardis notes that toxicities in the study were largely associated with the known side effects of nonmyeloablative chemotherapy or total body irradiation and administration of a high dose IL-2. “We concluded from the data that there is no real benefit in patients receiving high amount of radiation as judged by response and overall survival.”

Recent data from a randomized Phase 2 trial in 101 patients with metastatic melanoma confirmed TIL treatment was associated with high, durable objective response rates, including patients that were refractory to checkpoint inhibitors

Dr. Rosenberg’s data with second-and third-line metastatic melanoma patients, or those heavily pretreated, demonstrated that 19 of 20 complete responders were still alive at seven years to more than 10 years after TIL treatment, without needing further therapy.

Lion is currently enrolling patients to assess the safety, efficacy and feasibility of an adoptive cell therapy based on an autologous TIL product, LN-144, followed by IL-2, in the treatment of patients with refractory metastatic melanoma.

The trial will include two additional cohorts of patients: one receiving fresh cells from the company’s existing manufacturing process and a second receiving frozen cells from a manufacturing process that has been shortened to approximately four weeks from six.

Dr. Fardis says Dr. Rosenberg at the NCI also studied an HPV-targeted TIL treatment with nine cervical cancer patients, with data showing one partial response, with a duration of response of three months, and two complete responses, who remained a complete response at the time that a manuscript was being published: one was at 15 months of follow up and one at 22 months.

Lion has initiated its own TIL Phase 2 trial in cervical cancer patients and another Phase 2 trial in head and neck cancer with its LN-145 drug candidate. Future studies in lung, bladder, breast and pancreatic cancers, and glioblastoma could be either company-sponsored or conducted through collaborations, she adds.

In terms of future R&D, Dr. Fardis says Lion is looking at selection of more specific TILs; whether lower cell numbers administered to a patient will generate a response; and further shortening the duration of TIL manufacturing. “Any of these would create new IP,” she adds.

In addition, Lion is looking at genetic engineering of TIL therapy to modulate certain additional biomarkers, and “what else we can give a patient pre-TIL and post-TIL treatment to help them get a response.”

Lion Biotechnologies Pipeline and Partners

Dr. Brent Norton, CEO and executive chairman 

Ortho Regenerative Technologies is developing a “sticky scaffold” biologic that has the potential to be best in class to repair symptomatic lesions in shoulder tendons, knee meniscus and articular cartilage.

“The timeline to market of our first product, Ortho-R, for rotator cuff tendon repair is short, with clear and manageable endpoints,” Dr. Brent Norton, executive chairman and CEO, says in an interview with BioTuesdays.

“With standard surgical repair of rotator cuff, there is a 50% failure rate within the first year,” he adds. “Clinical trials in this indication could have a follow-up as short as six months to a year against the comparative failure of operative repair.”

Dr. Norton explains that Ortho-R is a freeze-dried biopolymer that when mixed with a small amount of a patient’s platelet-rich plasma (PRP) forms a sticky scaffold in about five minutes and “fits seamlessly into current surgical procedures without any additional equipment required.” The powder biopolymer has a shelf life of three years at room temperature, he adds.

Dr. Norton notes that in preclinical models, the sticky scaffold has been shown to stabilize the PRP in an injury, impede its shrinkage and stick to the lesion surface. “We have demonstrated increased vascularization of tissues after two weeks, and later on, improvement of tissue repair and regeneration.”

Founded in 2015 to commercialize technology developed by Drs. Michael Buschmann and Caroline Hoemann at the Ecole Polytechnique in Montreal, Ortho RTi expects to begin trading soon on the Canadian Securities Exchange under the symbol, ORH.

In addition to shoulder rotator cuff repair, the company is developing technology for knee meniscus and articular cartilage repair, and other commonly injured joints, such as the elbow, ankle and hip.

In addition to shoulder rotator cuff repair, the company is developing technology for knee meniscus and articular cartilage repair, and other commonly injured joints, such as the elbow, ankle and hip

“Clinical trials for meniscus and cartilage repair require multi-year safety follow-up studies, which is why, as a way to build a small company, we selected the shorter rotator cuff repair route,” Dr. Norton points out.

The company received a U.S. patent last August for PRP/biopolymer compositions and has patents pending for additional compositions of matter and use. It also has a legal opinion affirming its freedom to operate without infringing any valid IP.

At the end of last month, Ortho RTi’s technology platform was front and center at the 2017 Orthopaedic Research Society annual meeting in San Diego. The company presented four key scientific studies validating Ortho-R’s ability to improve repair of three distinct joint tissues: rotator cuff tendons, meniscus and articular cartilage.

“This type of third-party scientific validation, where four of our studies were reviewed by external experts and selected for broad exposure at this, the most important event of its kind worldwide, is incredibly energizing," Dr. Norton points out.

According to Dr. Norton, the market for soft tissue injuries is growing at an average of 8% a year, driven in part by “weekend warriors.”

Some 25% of U.S. adults over the age of 40 will develop a rotator cuff tear, with aging. In addition, he says four million people in the U.S. with rotator cuff injuries are at risk for disability as 50% of rotator cuff tears progress in size in three years.

“There are approximately 600,000 rotator cuff surgeries performed each year, with 50% failing within six-to-12 months,” he adds.

In addition, Dr. Norton points to two million meniscal injuries annually, making up 16% of all orthopedic surgeries. “These first two indications represent a potential market of $1.75-billion,” he suggests.

Dr. Norton notes that in preclinical models, the sticky scaffold has been shown to stabilize the PRP in an injury, impede its shrinkage and stick to the lesion surface

Based on Ortho RTi’s tissue healing evidence in a rotator cuff large animal model at three months after surgery with Ortho-R and anchors, Dr. Norton says the tendon is mostly organized in bundles with small areas of tendon-like repair tissue, which is “what we see in a normal tendon.”

Histology at the tendon attachment site three months after surgery also indicates an abundant expression of glycosaminoglycan and remodeling, which is implicated in wound repair at the insertion site of Ortho-R, he adds. “This suggests that bone remodeling through endochondral ossification is still ongoing at the tendon and bone interface.”

The company has had a pre-IND meeting with the FDA and obtained feedback about its development plan and how it will be regulated as a biologic.

Later this year, Ortho RTi plans to release final preclinical data and move into a clinical rotator cuff pilot study in the first half of 2018 to measure safety and unexpected adverse events.

The company also plans to begin a registration trial in 2019 with about 200 patients at 15-to-25 clinical sites in the U.S. and Canada. Primary outcomes will be pain and function at six months following surgery. Health economic outcomes for payers also will be part of the study.

“There is strong R&D partnering and strategic interest from larger medical device companies in this space, which we hope to tap as we go forward,” Dr. Norton says.