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Clinical Trials

Breast cancer cells

Athenex’s lead drug candidate, an oral formulation of the chemotherapy paclitaxel, is intended to bring patients comparable, if not better, efficacy and fewer side effects than the intravenous version. But the company now faces questions about the drug’s safety in the wake of an FDA rejection.

Buffalo, New York-based Athenex announced the rejection of the cancer drug Monday. According to the company, the regulator recommended the biotech conduct a new clinical trial in metastatic breast cancer patients. The agency also suggested the company take steps to mitigate the drug’s toxicity.

Shares of Athenex fell sharply after the FDA rejection was announced, and closed Monday at $5.46 apiece, down nearly 55% from Friday’s closing stock price.

Paclitaxel, also known as Taxol, is a widely used chemotherapy for treating breast, ovarian, and lung cancers. Intravenous dosing of the drug can cause adverse reactions. To mitigate those effects, cancer patients are given steroids and antihistamines prior to dosing of the chemotherapy. Other side effects of intravenous paclitaxel include nerve damage, hair loss, and neutropenia, which is an abnormally low level of a type of white blood cell called neutrophils. Those side effects may reduce how much of a dose of the chemotherapy a patient can receive.

Athenex’s version of paclitaxel is given in combination with another drug, encequidar. According to the company, this compound blocks a protein in the intestinal wall that limits the absorption of chemotherapies. In results of a Phase 3 study testing Athenex’s oral paclitaxel in patients with metastatic breast cancer, the company reported its drug met the main goal of showing statistically significant improvement in the overall response rate compared against treatment with the IV version of the chemotherapy.

The company also reported that its drug can reach levels in the blood comparable to IV paclitaxel, and for a longer period of time. The company said in securities filings that this capability may translate to a better clinical response to the therapy. In the 402-patient Phase 3 study, Athenex observed a higher tumor response rate along with lower incidence and severity of nerve problems compared to IV paclitaxel.

Athenex said that the agency’s complete response letter cited the risk of an increase in problems related to neutropenia in the oral paclitaxel arm compared with the group treated with the IV formulation. The FDA also expressed concern about how the results of the study primary endpoint were evaluated under blinded independent central review, a group of independent physicians. According to Athenex, the FDA said there may have been “unmeasured bias and influence” on the review.

Speaking on a conference call, CEO Johnson Lau said the company was “surprised and extremely disappointed” by the FDA’s rejection. The neutropenia concerns cited are a known risk of paclitaxel, he said. Lau added that the review remained blinded, was conducted by independent radiologists, and the regulator had not issued any formal warnings flagging problems at the imaging lab.

The FDA’s recommendation that Athenex conduct another clinical trial specified that the study should include patients more representative of the U.S. population. Rudolf Kwan, the company’s chief medical officer, said on the call that none of the clinical trial sites were in the U.S. But he added that the company had discussed the clinical trial design with the regulator, and the single study, as proposed by the company, was understood to be sufficient to support approval if the results were positive.

Lau said that the company plans to request a meeting with the FDA to discuss the letter and clarify the scope of the new clinical trial needed to address the agency’s concerns.

“Whether it requires the whole study be done in U.S., we’ll have to clarify in the meeting,” Lau said.

Though Athenex has a pipeline of clinical-stage cancer therapies, company currently generates most of its revenue from the sales of generic injectable products. In 2020, it reported more than $105 million in product sales, a 73% increase over 2019 sales. In its financial report of fourth quarter 2020 and full-year results, Athenex attributed the revenue increase to growing sales of specialty pharmaceutical products used to treat hospitalized Covid-19 patients. As of Dec. 31, 2020, Athenex had $86.1 million in cash and $138.6 million in short-term investments.

Photo by American Cancer Society/Getty Images

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For decades, scientists have known that viruses can kill cancer cells. The challenge has been harnessing that power safely and effectively.

Buoyed by advances in immunotherapy and drug discovery, a new wave of researchers and companies is poised to make a run at that challenge over the next few years with a class of therapies known as oncolytic viruses.

“We’re just on the brink of some really exciting developments in our field,” said Charlotte Casebourne, CEO of Theolytics. Based in Oxford, England, the company hopes to move its lead oncolytic virus candidate into clinical trials over the next two to three years.

The field is based on a relatively simple premise. A virus is injected into tumor cells; the virus replicates and blows up – or lyses – the tumor cells; the immune system recognizes the remaining tumor cells and clears them out.

The premise was discovered decades ago in patients who came down with viruses alongside cancer. The viruses attacked the cancer but they also could harm patients.

Early research focused on attenuated viruses, which generally proved too weak to do much. Recent advances are solving that challenge while addressing new ones, such as preventing the immune system from turning on the virus.

“Right now, it’s about finding that Goldilocks, that perfect happy medium,” said Greg Delgoffe, a cancer immunologist and associate professor at the University of Pittsburgh.

The field got a shot in the arm in 2015 when Amgen won approval from the U.S. Food and Drug Administration for an oncolytic virus therapy called T-VEC. Based on a genetically modified herpes simplex virus and marketed as Imlygic, it is used to treat melanomas that cannot be surgically removed.

“We have this example which provides us with really nice clinical proof of concept that efficacy is possible with oncolytic viruses as a technical approach,” Casebourne said in a Zoom interview.

T-VEC, however, is injected directly into a tumor. Some of the newer therapies are designed to be injected intravenously, allowing them to move through the body to clear cancer.

Theolytics’ lead candidate is TheoAd281, an adenovirus-based therapy that targets ovarian cancer. Clinical trials will focus on its safety and efficacy as a monotherapy, delivered intravenously, before delving into its potential in combination with other therapies, Casebourne said.

The company was founded in 2017 by Casebourne and researchers Margaret Duffy, Kerry Fisher and Len Seymour. It raised $6.8 million in a Series A round in early 2021 led by Epidarex Capital and Taiho Ventures, with participation from existing investor Oxford Sciences Innovation.

In addition to Amgen’s approved therapy, the field has benefited from advances in drug discovery and gene sequencing, Casebourne noted. Theolytics uses a proprietary phenotypic platform to figure out which virus variants might be effective against particular tumors, Casebourne said. The platform speeds up the discovery process to between 12 and 18 months, she added.

Valo Therapeutics also is banking on a platform approach. Its platform incorporates peptides to create oncolytic viruses that do not linger in the body after they turn the immune system against tumor cells. Its lead candidate, PeptiCRAd 1, is expected to enter phase 1 trials this year, most likely for treating melanoma and non-small cell lung cancer, according to Paul Higham, CEO of Valo, which is based in Oxford, England.

The use of peptides is based on research by Vincenzo Cerullo, a professor and head of the drug research program at Helsinki University in Finland.

“Because it’s actually a simple process to attach peptides on the surface of the oncolytic virus, we can be extremely flexible in terms of what we attach to the viruses,” Higham said. “We can select all different kinds of peptides to stimulate all different kinds of immune responses.”

Different tumors may require different peptides, he said. “The most effective therapies in the future are going to be those that are most specific to the patient being treated, and our platform really allows to do that.”

Another contender in the space is CG Oncology, based in Irvine, California. In December, the company raised $47 million in a Series D round led by Kissei Pharmaceutical Co. Ltd. CG’s main oncolytic virus candidate, CG0070, is being examined in several clinical trials.

A phase 3 trial is testing the candidate as monotherapy for a form of bladder cancer. A phase 2 trial is studying CG0070 for the same indication but in combination with Merck’s Keytruda, a checkpoint inhibitor. The candidate is injected directly into the tumor.

Checkpoint inhibitors release the brakes on the immune system while the oncolytic virus strengthens the immune response, said Arthur Kuan, CG’s CEO. “I think oncolytic viruses will continue to emerge as one of the best combination partners with checkpoint inhibitors.”

The company is planning to move into other cancers this year, Kuan said in a phone interview. He and others expect that future oncologists will have a range of viruses to choose from based on a range of factors, including the type and location of the cancer.

It may be years before therapies win approval, Kuan said. But he believes the oncolytic virus field is coming into its own.

“We’re definitely in a rising-tide environment with many catalysts coming up in the next 12 to 18 months,” he said.

The field’s challenges over the years have made investors somewhat leery, said Dr. Mark McCamish, CEO of San Diego-based IconOVir Bio.

For its part, IconOVir was able to overcome investor skepticism by explaining how the field has overcome some of its earlier challenges, McCamish said. Those challenges have included creating an oncolytic virus that could escape detection by the immune system and confer lasting immunity against a tumor. IconOVir Bio raised $77 million earlier this year in Series A funding to advance its platform for creating oncolytic virus therapies. The platform is based on more than a decade of research by company co-founder Clodagh O’Shea of the Salk Institute for Biological Sciences.

“It’s data-driven. It’s not just a story,” said McCamish, who previously led immune-oncology company Forty Seven before it was bought last year by Gilead Sciences.

IconOVir is hoping to start clinical trials of its lead candidate, IOV-1042, in the first half of 2022. Derived from the common cold virus, IOV-1042 has been shown in preclinical research to infect and kill a range of tumor cells, including head and neck, bladder, lung and breast.

“I think it’s an exciting field and an exciting time,” said McCamish. “And if the science comes to fruition, it’s a great opportunity.”

Photo: Main_sail, Getty Images

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After leading an investment in patient data firm Seqster in Feburary, Takeda is broadening its partnership with the company. The drugmaker reached an agreement with Seqster to use its platform for clinical trials and patient engagement.

Seqster pulls in information from patients’ electronic health records, genomic data and wearable data across different health systems. Its CEO, Ardy Arianpour, has described the company as the Mint.com of healthcare. The San Diego-based startup claims to have more than 3,000 healthcare providers using its services.

Through the extended partnership, Seqster will give Takeda access to the company’s decision support system and research platform. The goal is to reduce the time it takes to consent patients and bring in data during clinical trials, and improve patient engagement.

“By leveraging Seqster and extending Takeda’s external data and digital collaboration ecosystem, we will have better access to real-world evidence, integrating real-time into our workflows generating powerful data and insights for research and patient services,” Dr. Emir Roach, head of emerging technologies and digital partnerships for Takeda, said in a news release.

With in-person visits disrupted at the beginning of the pandemic, Covid-19 has accelerated drugmakers’ adoption of virtual clinical trials. Earlier this month, Takeda announced a five-year plan to become a “cloud first” company, striking partnerships with Amazon Web Services and Accenture.  As part of that plan, it launched a secure data sharing and clinical trial platform for the COVID R&D Alliance—a group of biopharma companies working to develop potential treatments for Covid-19.

“Our technology will help Takeda accelerate transforming clinical development in the post-COVID era, improving patient engagement and services, and streamlining safety and efficacy demonstration,” Arianpour said in a news release. “By serving as one of Takeda’s collaborators in their digital ecosystem, Seqster is positioned as a leading patient-centric technology to help patients in their healthcare journey.”

Photo credit: Gerasimov174, Getty Images

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