From Aha! moment to FDA approval: The fascinating story behind a new treatment for bladder cancer

Lorenzi, then a researcher at the National Cancer Institute, discovers that mutations in a particular gene are linked to cancer. Having one of the gene mutations may mean your body is more likely to allow cancer cells to grow.

Although these mutations were thought to be rare at the time, subsequent advances in DNA sequencing over the next decade would reveal that certain genetic alterations are linked to a variety of cancers, including bladder cancer.

Janssen enters into an exclusive worldwide license and collaboration agreement with Astex Therapeutics Ltd., an oncology drug development company, to develop and commercialize a drug specifically designed to inhibit the gene.

Tim Perera, at the time a Director and Research Fellow at Janssen, and Patrick Angibaud, Scientific Director and Fellow, Internal R&D Discovery, Janssen, co-lead the internal Janssen drug discovery program.

Lorenzi, now at Janssen, and his team have a goal: determine the investigational medication’s safety and efficacy as a cancer treatment in patients with the gene-driven disease.

In July, Janssen begins its Phase 1 clinical trials to determine just that, as well as the appropriate dosage for the treatment and which types of cancers the drug may be most effective for.

“We looked at a wide variety of tumors that had this gene mutation,” says Peter De Porre, Executive Director, Clinical Oncology, Janssen. The team was particularly focused on breast and lung cancer, but also looked at other cancers with the mutations, including bladder cancer.

Early on in the clinical trials, one of the Janssen clinical investigators races into Lorenzi’s office and shows him some exciting news on his phone: a picture of a recent full-body CT scan of a patient with metastatic bladder cancer.

“We saw some promising activity in the patient after two cycles of therapy,” Lorenzi recalls. “We thought this could be the sign we were looking for, just not in the cancer we were primarily focused on. We were thrilled, but also mystified.”

Once they did genetic testing of the tumor, they had clarity: “The patient harbored a gene alteration, which likely controlled the growth of the tumor,” Lorenzi explains.

After further research, the Janssen team pinpoints the specific gene mutations, and their frequency, that seem to respond most to the treatment. “We learned during the course of our studies that bladder cancer patients with specific types of alterations responded well to the drug,” says Ademi Santiago-Walker, Associate Director, Translational Research and Biomarker Lead, Janssen.

This was an especially exciting learning because, up until this time, these select mutations had traditionally been less responsive to many other treatments.

The Phase 2 trial begins to gauge the effectiveness and tolerability of the treatment in patients with previously treated metastatic or unresectable (meaning it can’t be cured via surgery) urothelial carcinoma.

“During our research, we also discovered an important biomarker—phosphate, a mineral found naturally in the body,” adds De Porre. “Patients who had a higher level of it had a better response to the treatment.” This later becomes an important factor in determining effective dosage, which, after much work, the researchers zero in on by the end of 2014.

“This class of agents has a very narrow therapeutic index—too low or too high of a dose won’t be effective and safe,” says Kiran Patel, Vice President Clinical Development, Solid Tumor Franchise, Janssen.

Janssen researchers begin work to come up with a screening test to help determine which patients are most appropriate for and would benefit from treatment.

“There are various alterations within this particular gene that we had to examine to see which ones would respond to treatment,” Patel explains. “As a result, it was challenging to identify and enroll patients with these alterations, and in parallel determine which patients could potentially benefit from treatment.”

Janssen scientists, led by Jayaprakash Karkera, Scientific Director, Janssen R&D, come up with a test that could be used as a companion diagnostic, which is a test that determines what type of patient would be appropriate for treatment.

“Patients sent a sample of their tumor (collected by their physician) to the lab, which used the companion diagnostic to screen for specific alterations,” Santiago-Walker explains. “If they were positive, they could potentially be enrolled in our trial.”

The FDA grants Breakthrough Therapy designation— a process that expedites the development and review process for drugs that show significant promise—for the treatment.

“This is based on data we had for 59 patients with metastatic cancer, all of whom had already failed one or more prior lines of treatment,” De Porre explains. “We found that 42% of people in this group were responders, which is very positive given the high unmet need in this population.”

Janssen releases its Phase 2 results at the American Society of Clinical Oncology (ASCO) annual meeting. The study, led by physicians Arlene Siefker-Radtke at the MD Anderson Cancer Center and Yohann Loriot at the Institut Gustave Roussy in France, looked at 99 patients with metastatic urothelial cancer who were given the treatment, and found a 40% overall response rate.

Janssen submits a new drug application to the FDA seeking approval for the treatment of metastatic urothelial cancer, to be used in conjunction with a companion diagnostic kit.

“This was groundbreaking for us on many levels—this was the first Janssen Oncology compound developed from discovery all the way to approval; our first drug using pharmacodynamically guided treatment dosing, which means a patient’s dose is adjusted based on their phosphate levels; and our first drug developed with a companion diagnostic,” Patel says.

The therapy is approved by the FDA as a treatment for urothelial cancer, making it now accessible to people who may benefit most.