In 2001, Dr. Ulrich Specks, a pulmonary specialist, had a patient with granulomatosis with polyangiitis (GPA) whose symptoms were not improving.¹ GPA is a rare but severe form of vasculitis, which is an inflammation of the blood vessels. That inflammation restricts blood flow and can lead to life-threatening organ damage. At the time, the standard treatment for the disease was a chemotherapy drug called cyclophosphamide (CYC), which was not FDA-approved to treat GPA but Dr. Specks’ patient couldn’t tolerate CYC. He knew that without treatment, patients with this disease had a mean survival that was measured in months—he needed to do something.

There was a scientific theory that B-cells might be involved in autoimmune disorders, such as GPA and microscopic polyangiitis (MPA), which are both forms of ANCA-associated vasculitis (AAV). B-cells are an integral part of the immune system that help signal the body to activate an autoimmune response. When those signals are misfiring, B-cells, along with other cells and factors, can induce damaging immune responses that can lead to illness.

Dr. Specks and a rheumatologist named Dr. John Stone proposed a study to the Immune Tolerance Network (ITN), a government-funded scientific body that supports studies with novel drug therapies. The proposed study would involve the use of Rituxan (rituximab) Indication and Important Safety Information, a medicine that was first FDA-approved in 1997 to treat certain types of Non-Hodgkin’s Lymphoma.

Rituxan is thought to bind to a protein that is found on the surface of cancerous and normal B-cells, depleting them and calming down the over-aggressive autoimmune activity. Providing additional therapeutic options to CYC was important for patients who couldn’t tolerate the current standard of care. Drs. Specks and Stone, along with the ITN group, approached Genentech to provide the medicine and partial funding for a trial that came to be known as the Rituxan in ANCA-Associated Vasculitis (RAVE) trial. Through this trial, Genentech would seek a new indication for a rare and life-threatening disease while embarking on one of the most unusual pathways to FDA approval.

“It was a great opportunity for us,” says Dr. Paul Brunetta, now Global Head of Anti-CD20 Immunology at Genentech. “It was two doctors at the absolute top of their game, with the support of the ITN, studying one of our drugs for the treatment of a rare and devastating disease.”

This was the first time immunologists at Genentech would collaborate on a cooperative group study proposed by non-oncology investigators intended to seek FDA approval. “It shifted the paradigm from the classic company-sponsored approach to a new pathway in immunology,” says Brunetta. He knew that the study would be an unusual source of scientific data for FDA filing…first, because the disease was rare (and therefore hard to find patients to enroll in a study), and second, because the standard of care treatment (CYC) was not approved by the FDA.

Since CYC wasn’t approved, the usual “non-inferiority trial” design—where a new medicine is tested against an FDA-approved medicine to see if it works well—wouldn’t work. Nor could they do a comparison-to-placebo study where participants were given placebo infusions instead of Rituxan. This wouldn’t be ethical since CYC was an effective therapy for an otherwise fatal disease. The path forward was laden with obstacles, but according to Brunetta, “we thought that with a rare disease and really sick patients, regulators might be open to a different approach.”

The challenge for the clinical trial team was to come up with a study design that would be plausible and acceptable to the FDA. Brunetta was convinced, given the expertise of the lead investigators, they could pull it off. “They were experienced in doing multi-center trials, and brought forward the idea of doing an active comparator trial with Rituxan versus CYC. The scientific rationale and the safety considerations were strong,” he said. The situation was unique in that the trial would be comparing two unapproved medicines, without placebo comparison, as there was not an approved standard of care.

Drs. Speck and Stone and the Genentech team met with the FDA to determine the best course of action for their clinical trial design. While many people believe the FDA only gets involved when a medical trial is completed, their staff members are often very involved earlier in the process helping groups design trials for promising medicines where there are unmet medical needs.

Dr. Jeffrey Siegel, who at the time was an FDA official and is now the Global Head of Rheumatology and Rare Diseases in immunology product development at Genentech, met with the primary investigators, Genentech and ITN. He looked at data from previous independent studies and agreed that a trial could benefit some patients.

“I was intrigued, because I was particularly focused on studies that could help patients in areas of unmet need,” says Siegel. “This program was singled out as something that the FDA should support from the point of view of public health.”

The question that remained for the investigators was how to design a comparative study against a standard of care that was not approved by the FDA. “There was no straightforward path ahead,” says Siegel of the FDA’s stance on the matter. But he proposed a solution that was elegant yet complex. They could start by looking at historical data about how people with GPA did before CYC therapy then prove that CYC therapy yielded better outcomes. From there, if they could prove that Rituxan was at least as effective as CYC, it would be a valid study. In other words, if CYC was effective, and Rituxan was as effective as CYC, then Rituxan must also be effective. The investigators knew that prior to CYC, the lifespan of GPA patients could be measured in months, based on a published study from 1958.² This cleared the way for the study that the investigators hoped would show the effectiveness of Rituxan in both GPA and MPA.

Because the disease is so rare–it affects only three out of every 100,000 people¹–It took some time to assemble the patients. “In rare diseases if you have no approved therapy, the results from a modest number of patients can sometimes be adequate statistically to show that the drug is efficacious,” says Siegel. Still, it took five years to get enough patients to complete enrollment in the study.

Patient enrollment wasn’t the only issue. The trial required a separate safety and efficacy assessor at each site, and to make sure that the study was blinded, all patients were required to wear a covering on their heads to hide whether or not they were losing hair from the chemotherapy-like side effects of CYC. Lastly, since Rituxan is an IV therapy, and CYC is an oral therapy, steps had to be taken to blind the way the drugs were administered to patients as well.

Understanding and cataloguing the drugs’ effects on the disease was also challenging. “It required a lot of work at the site level, and included a very complicated instrument that has to account for every organ system,” says Brunetta. “So, the order of complexity was really high. Given the severity of the disease for the patients, it was about as complicated as it gets.” After working all of that out, the investigators had 197 patients enrolled in the study, which compared 99 patients treated with Rituxan and glucocorticoids against 98 patients treated with CYC.³

Despite all of the obstacles they’d faced in designing the trial and getting patients enrolled, when it came time to look at the data, the investigators were thrilled to find Rituxan effective, and demonstrated non-inferiority to CYC – 64 percent of the patients in the Rituxan arm achieved complete remission versus 53 percent in the CYC arm. Safety endpoints were also evaluated in the trial. The most common adverse reactions greater than 15 percent were infections, nausea, diarrhea, headache, muscle spasms, anemia and peripheral edema (other important adverse reactions include infusion reactions). But that was only half the challenge; they still had to convince the FDA that the data were strong enough to consider for approval.³ Even though the FDA had collaborated in the trial design, the team was nervous in presenting the culmination of their multi-year endeavor. “Before we had our meeting with the FDA, we estimated that the likelihood of approval was less than 50 percent,” said Brunetta.

The team from Genentech, along with the primary investigators, met with the FDA, prepared to sift through all of their data and explain their statistical approaches. They’d spent a full day rehearsing their arguments before the meeting. But five minutes into their presentation, a senior FDA official interrupted them with the conclusion that the results would be just fine for filing, having determined that Rituxan was just as effective as CYC for patients with GPA.

Brunetta remembers walking on air as he left that meeting. “We took a risk on behalf of patients and achieved our goal. We had gotten good feedback from the FDA. There was still a lot more work to do, but it was really just a fantastic day to celebrate.”

Rituxan, in combination with glucocorticoids, was approved for the treatment of GPA and MPA Indication and Important Safety Information by the FDA in 2011. It is currently the only FDA-approved medicine for the treatment of these diseases. One of the advantages to having an approved treatment for these rare diseases, says Brunetta, is that the disease now receives more attention. Presenting the results of the RAVE trial made more people aware of GPA/MPA. “FDA approval was a big advance in the treatment and in the general awareness of this severe disease,” says Brunetta. The RAVE trial has now led to multiple studies and publications.

In 2012, the RAVE trial team received a Partnership In Progress award from the National Organization of Rare Diseases (NORD) which is given each year for pioneering achievements of individuals, organizations, and companies in public policy, patient advocacy, medical research, and product development for rare diseases.

For Brunetta, the RAVE trial “showed that we’re willing to think of alternative uses for our medicines, and that we have a very strong commitment to the study of rare diseases. We’re willing to take a risk to pursue alternative regulatory strategies. And when we’re successful, we’re dedicated to publishing and supporting a greater understanding of the disease.”

The trial also demonstrated the power of collaboration. He credits the FDA and the other investigators for their roles in the RAVE trial. “It was the highlight of my career,” Brunetta says. “These world class experts ran the trial, but we had a very important role to play in making sure we had the right package to maximize the chance of getting approval. It’s incredibly gratifying to know that many patients may benefit from our efforts.”

What it Treats

What is Rituxan?

Rituxan is a prescription medicine used to treat:

Adults with Rheumatoid arthritis (RA): with another prescription medicine called methotrexate, to reduce the signs and symptoms of moderate to severe active RA, after treatment with at least one other medicine called a tumor necrosis factor (TNF) antagonist has been used and did not work well enough.

People with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) ages 2 years and above: with glucocorticoids.

Adults with Pemphigus Vulgaris (PV): to treat moderate to severe PV.

RITUXAN is not indicated in children less than 2 years of age with GPA or MPA or in children with conditions other than GPA or MPA.

Important Safety Information

What is the most important information I should know about Rituxan?

Rituxan can cause serious side effects that can lead to death, including:

• Infusion-Related Reactions: Infusion-related reactions are very common side effects of Rituxan treatment. Serious infusion-related reactions can happen during your infusion or within 24 hours after your infusion of Rituxan. Your healthcare provider should give you medicines before your infusion of Rituxan to decrease your chance of having a severe infusion-related reaction
• Severe Skin and Mouth Reactions: Tell your healthcare provider or get medical help right away if you get any of these symptoms at any time during your treatment with Rituxan: painful sores or ulcers on your skin, lips, or in your mouth; blisters; peeling skin; rash; or pustules
• Hepatitis B Virus (HBV) Reactivation: If you have had hepatitis B or are a carrier of hepatitis B virus, receiving Rituxan could cause the virus to become an active infection again. Hepatitis B reactivation may cause serious liver problems, including liver failure and death. You should not receive Rituxan if you have active hepatitis B liver disease. Your healthcare provider will monitor you for hepatitis B infection during and for several months after you stop receiving Rituxan
• Progressive Multifocal Leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus that can happen in people who receive Rituxan. People with weakened immune systems can get PML. PML can result in death or severe disability. There is no known treatment, prevention, or cure for PML

Before receiving Rituxan, patients should tell their healthcare provider if they:

• have had a severe reaction to Rituxan or a rituximab product
• currently have or have a history of other medical conditions, especially heart disease
• have had a severe infection, currently have an infection, or have a weakened immune system
• have had a recent vaccination or are scheduled to receive vaccinations
• are pregnant or planning to become pregnant. Females who are able to become pregnant: the patient’s health care provider should do a pregnancy test to see if they are pregnant before starting Rituxan and should use effective birth control (contraception) during treatment with Rituxan and for 12 months after the last dose of Rituxan
• are breastfeeding or plan to breastfeed. Patients should not breastfeed during treatment and for 6 months after the last dose of Rituxan
• are taking any medications, including prescription and over-the-counter medicines, vitamins, and herbal supplements

What are the possible side effects of Rituxan?

Rituxan can cause serious and life‐threatening side effects, including:

• Tumor Lysis Syndrome (TLS): TLS is caused by the fast breakdown of cancer cells. TLS can cause you to have kidney failure and the need for dialysis treatment or may cause an abnormal heart rhythm. Tell your healthcare provider right away if you have any of the following signs or symptoms of TLS: nausea, vomiting, diarrhea, or lack of energy
• Serious Infections: Serious infections can happen during and after treatment with Rituxan and can lead to death. Rituxan can increase your risk of getting infections and can lower the ability of your immune system to fight infections. People with serious infections should not receive Rituxan
• Heart Problems: Rituxan may cause chest pain, irregular heartbeats, and heart attack. Your healthcare provider may monitor your heart during and after treatment with Rituxan if you have symptoms of heart problems or have a history of heart problems
• Kidney Problems: especially if you are receiving Rituxan for non–Hodgkin’s lymphoma (NHL). Your healthcare provider should do blood tests to check how well your kidneys are working
• Stomach and Serious Bowel Problems That Can Sometimes Lead to Death: Tell your healthcare provider right away if you have any stomach-area pain during treatment with Rituxan

What are common side effects during treatment with Rituxan?

The most common side effects of Rituxan include:

• infusion-related reactions
• infections (may include fever, chills)
• body aches
• tiredness
• nausea

In adults with GPA or MPA, the most common side effects of Rituxan also include:

• low white and red blood cells
• swelling
• diarrhea
• muscle spasms

Other side effects with Rituxan include:

• aching joints during or within hours of receiving an infusion
• more frequent upper respiratory tract infections

These are not all of the possible side effects with Rituxan.

Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at (800) FDA‐1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835‐2555.

Please see the Rituxan Prescribing Information and Medication Guide including Most Serious Side Effects for additional Important Side Effect Information.