Tysabri/JCV Antibodies | Diaceutics

Tysabri/JCV Antibodies


This case study shows how taking a proactive approach to risk stratification by means of a diagnostic test, even in the case of severe adverse events, can help rescue and reposition an otherwise highly effective drug. Using Tysabri as an example, the case study also shows that the diagnostic lifecycle can evolve depending on the changing testing requirements for a drug. It will help you understand:
  • That a rare but serious adverse event, only discovered after the approval of natalizumab (Tysabri), changed the commercial trajectory for this highly promising novel multiple sclerosis therapy
  • How Biogen Idec and Elan took a very proactive approach to identifying the key risk factor for this serious adverse event and to developing a commercially available risk test, aided by strategic diagnostic partners
  • How the development and launch of the novel JC virus (JCV) diagnostic test was set to help reposition Tysabri, gain market share and recover lost Tysabri value
  • How the diagnostic lifecycle may evolve depending on a change in testing  and any adjustments a drugowner has to make
Download this case study to learn more.

Table Of Contents

1: Case Summary2: Tysabri is a Monoclonal Antibody Drug Against Multiple Sclerosis and Crohn’s Disease3: High Hopes for Tysabri are Shattered Quickly 4: One Year After Voluntary Withdrawal, the EMEA and FDA Approved Market Reintroductions of Tysabri5: Black Box Warning Added to the Label at the 2006 Relaunch of Tysabri 6: Indication was Limited to Second or Third Line Use in Selected Patients Only7: Barriers to Tysabri Use were Enforced by Complex Prescription and Administration Procedures8: Tysabri Added a Crohn’s Disease Indication in 2008 but Safety Concerns Prevailed9: Biogen Idec and Elan Supported Research to Develop a Test Assay to Detect Pre-Treatment JCV Infection10: FDA Approved the Quest JCV Test in January 2012 to Identify Tysabri Patients at High Risk of PML 11: JCV Test was Thought to Identify Patients at High Risk of PML12: In the US, Biogen Idec Partnered Exclusively with Quest to Launch an FDA-Authorized PML Risk Test13: A Similar Partnership was Established with Unilabs to Provide PML Risk Testing Outside the US14: Biogen Idec/Elan Provide Stratify JCV Dx in the US Market for Free “Where Allowed”, Via Quest15: Biogen Idec/Elan Provide Central Dx Information and Ordering Platform for EU Access to Unilabs Service …16: …Directly Linking to Unilabs' Order Management Web Platform17: Introduction of the Risk Test Strengthened Biogen Idec/Elan’s Reputation with Patient Advocates18: FDA Changed the Prescribing Information for Tysabri In August 2012, Further Strengthening the Role of the Companion Diagnostic19: Biogen Idec and Elan Filed for First Line Indication in JCV-Negative MS Patients in January 201320: Label Change Due to Novel Dx Expected to Add US$1bn to Revised Tysabri Peak Year Revenues21: Dx May Help to Protect Tysabri's Market Share Against Imminent Novel MS Therapies...22: ...as PML Risk Due to JCV Infection is Not Specific to Tysabri, Other Drugs Face Similar Challenges23: JCV Test May Not Be Sufficient and More Monitoring May Be Necessary24: MRI Screening May Offer an Additional Diagnostic Approach to Detect JCV25: Key Messages

1: Case Summary

This case will help you understand:

That a rare but serious adverse event, only discovered after the approval of natalizumab (Tysabri), changed the commercial trajectory for this highly promising novel multiple sclerosis (MS) therapy.

How Biogen Idec and Elan took a very proactive approach to identifying the key risk factor for this serious adverse event and to developing a commercially available risk test, aided by strategic diagnostic partners.

How the development and launch of the novel JC virus (JCV) diagnostic test was set to help reposition Tysabri, gain market share and recover lost Tysabri value.

How the diagnostic lifecycle may evolve depending on the changing testing requirements for a drug, and what adjustments the drug owner has to make.
Key messages:

Even in the case of severe adverse events, risk stratification by means of a diagnostic test can help rescue and reposition an otherwise highly effective drug.

Taking a proactive approach to diagnostic development can help drug companies to maintain ownership of the drug's positioning and, at the same time, demonstrate their commitment to addressing unmet medical need.

Offering a 'full service testing package' around a specific, highly relevant diagnostic test, even at no cost to the patients and payers, has become a valuable means for drug companies to support the competitive positioning of their drug assets.

The JCV test started as a risk stratification diagnostic prior to initiating therapy then the FDA boosted frequency to every six months. New data show JCV testing may not be enough and that MRI screening may become the next sanctioned monitoring tool. This example illustrates that the testing requirements for a drug may evolve over time and may require constant monitoring of new diagnostic findings, as well as a proactive approach to diagnostic lifecycle management by the drug's owner.
Key actions:

Understand the diagnostic lifecycle and how it may evolve.

Take a proactive approach to diagnostic and drug positioning.

2: Tysabri is a Monoclonal Antibody Drug Against Multiple Sclerosis and Crohn’s Disease

INDICATIONS AND USAGE

 

TYSABRI is an integrin receptor antagonist indicated for treatment of:


Multiple Sclerosis (MS)
As monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. TYSABRI is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate MS therapy.


Crohn’s Disease (CD)
Inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α.

So What?

When first launched, Tysabri (natalizumab) was broadly considered the biggest breakthrough in MS treatment since the introduction of interferons in the 1990s.


“Tysabri represents a significant advance in MS treatment, offering real hope of delaying the progression of disability and reducing the frequency of relapses.” - Professor Gavin Giovannoni, The Royal London Hospital, 2004.

3: High Hopes for Tysabri are Shattered Quickly

May 25, 2004

  • Biogen Idec and Elan submit Biologics License Application to the FDA, based on one-year data.
Nov 23, 2004

  • Tysabri approved for treatment of MS.
Feb 18, 2005

  • Biogen Idec informs FDA about two severe adverse events: one confirmed fatal case and one possible case of progressive multifocal leukoencephalopathy (PML), a rare neurological complication, in patients receiving Tysabri for MS.
Feb 28, 2005

  • Biogen Idec and Elan voluntarily withdraw Tysabri from the market after three cases of PML were reported.

4: One Year After Voluntary Withdrawal, the EMEA and FDA Approved Market Reintroductions of Tysabri

Throughout 2005

  • Review of existing safety data for Tysabri by drug manufacturers and regulators.
April 2006

  • EMEA recommends reintroduction of Tysabri for restricted use in relapsing-remitting MS patients only.
July 2006

  • FDA approves reintroduction of Tysabri as monotherapy for relapsing MS, to slow the progression of disability and reduce the frequency of clinical relapse. Tysabri now has a revised label with enhanced safety warnings and in the US can only be administered under the TOUCH Prescribing Program.

5: Black Box Warning Added to the Label at the 2006 Relaunch of Tysabri

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

See full prescribing information for complete boxed warning
  • TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability (5.1)
  • Monitor patients, and withhold TYSABRI immediately at the first sign or symptom suggestive of PML (4, 5.1)
  • TYSABRI is available only through a special restricted distribution program called the TOUCH@ Prescribing Program and must be administered only to patients enrolled in this program (5.1, 5.2)
So What?

However, at the time of the relaunch no test was available yet to predict the risk of PML in individual patients.

6: Indication was Limited to Second or Third Line Use in Selected Patients Only

Recommendations
 
 
Because of the possibility that natalizumab therapy may be responsible for the increased risk of PML, it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. This recommendation is very similar to that of the FDA.
 
 
Similarly, because combination therapy with IFN and natalizumab may increase the risk of PML, it should not be used. There are also no data to support the use of natalizumab combined with other disease-modifying agents as compared to natalizumab alone. The use of natalizumab in combination with agents not inducing immune suppression should be reserved for properly controlled and monitored clinical trials.

7: Barriers to Tysabri Use were Enforced by Complex Prescription and Administration Procedures

So What?

Deliberately high access barriers severely impacted treated patient numbers and, consequently, Biogen IDEC/Elan's revenues from Tysabri.

8: Tysabri Added a Crohn’s Disease Indication in 2008 but Safety Concerns Prevailed

January 15, 2008

  • FDA approves Tysabri for treatment of moderate-to-severe Crohn’s Disease.
February 2011

  • As of this point, 102 cases of PML had been reported among 82,732 patients treated with Tysabri worldwide, as per the FDA, confirming a risk of occurrence of PML in a non-stratified population of approximately 1.2 in 1,000.

9: Biogen Idec and Elan Supported Research to Develop a Test Assay to Detect Pre-Treatment JCV Infection

 
 
August 27, 2010 — Researchers from Biogen Idec Inc and Elan Corporation Inc say they have developed an enzyme-linked immunosorbent assay (ELISA) that can detect JC virus (JCV) antibodies in serum and plasma. They hope that with further research the assay could be used to identify patients with multiple sclerosis (MS) at greatest risk of developing progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment (Tysabri) and help guide use of this immunosuppressive agent...
 
 
Notably, Dr. Gorelik and colleagues say, all 17 (100%) of the pre-PML samples available from natalizumab-treated patients who were eventually diagnosed as having PML were seropositive for anti-JCV antibodies. "If these numbers can be confirmed," Dr. Jung Henson said, "it means we can identify which patients have not been previously exposed to the JC virus and therefore can be treated with natalizumab without fear of developing PML. Those who are positive will make a more informed decision about the risks they face in taking natalizumab...

10: FDA Approved the Quest JCV Test in January 2012 to Identify Tysabri Patients at High Risk of PML

FDA Drug Safety Communication: New risk factor for PML associated with Tysabri.

 
 
ISSUE: FDA notified healthcare professionals that testing positive for anti-JC virus (JCV) antibodies has been identified as a risk factor for PML. PML is a rare but serious brain infection associated with use of Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) or Crohn's disease. A patient's anti-JCV antibody status may be determined using an anti-JCV antibody detection test that has been analytically and clinically validated, and has been ordered by a healthcare professional. The Stratify JCV Antibody ELISA test2 was cleared by FDA on January 20, 2012. Testing positive for anti-JCV antibodies means that a person has been exposed to JCV in the past…
 
 
RECOMMENDATION: The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more of the other known risk factors for PML. Patients with all three known risk factors have an estimated risk of PML of 11/1,000 users...

11: JCV Test was Thought to Identify Patients at High Risk of PML

Patients with all three known risk factors have an estimated risk of PML of 11/1,000 users.

The risk factors are:

  • The presence of anti-JCV antibodies.
  • Longer duration of Tysabri treatment, especially beyond 2 years.
  • Prior treatment with an immunosuppressant medication.

The drug label for Tysabri has been revised to reflect this updated information including a table estimating the rate of PML stratified by the three known risk factors:

Table: Estimated PML Incidence Stratified by Risk Factor

 Anti-JCV Antibody Positive*Anti-JCV Antibody Positive*
Tysabri ExposureNo Prior Immunosuppressant UsePrior Immunosuppressant Use
1-24 months<1/1,0002/1,000
25-48 months<4/1,00011/1,000

 

 

 

So What?

It was thought that in combination with clinical risk factors, the JCV test could identify patients at high risk of PML.

12: In the US, Biogen Idec Partnered Exclusively with Quest to Launch an FDA-Authorized PML Risk Test

Quest Diagnostics STRATIFY JCV™ first FDA market authorized antibody-based blood test to help stratify PML risk in Multiple Sclerosis patients.

 
Based on exclusive collaboration with Biogen Idec, the test is only available in the US through Quest Diagnostics' Focus Diagnostics lab.
 
 
MADISON, N.J., Jan. 20, 2012 /PRNewswire/ -- Quest Diagnostics (NYSE: DGX) …,today announced that the U.S. Food and Drug Administration (FDA) has granted a de novo classification petition to its STRATIFY JCV™ Antibody ELISA testing service. STRATIFY JCV is the first blood test to be FDA market authorized for the qualitative detection of antibodies to the polyomavirus JC virus (JCV) for stratifying risk for progressive multifocal leukoencephalopathy (PML), an infrequent but serious brain infection, in patients with multiple sclerosis (MS) receiving TYSABRI® (natalizumab), a highly effective therapy for relapsing forms of MS.

STRATIFY JCV was developed under an exclusive collaboration for the United States market with Biogen Idec (NASDAQ: BIIB), .... The test employs technology licensed from Biogen Idec, and is exclusively offered through Quest Diagnostics' Focus Diagnostics laboratory in the United States.

"STRATIFY JCV is a great example of the capacity of pharmaceutical and diagnostic companies to collaborate to bring important medical innovations to market," said Kathy P. Ordonez, senior vice president, discovery and development, Quest Diagnostics. "The test has demonstrated its value as a tool that enhances PML risk assessment, and marks a significant step forward in the personalization of clinical management of MS patients who may benefit from natalizumab.”

About STRATIFY JCV … The assay is for professional use only and is to be performed only at Focus Diagnostics' Reference Laboratory.

13: A Similar Partnership was Established with Unilabs to Provide PML Risk Testing Outside the US

Unilabs announces global strategic alliance in companion diagnostic testing with Biogen Idec for STRATIFY- JCV

 
 
Copenhagen, Denmark, July 6, 2011 –Unilabs has been selected by Biogen Idec to provide a companion diagnostic anti-JCV antibody assay test, called STRATIFY-JCV. The test is a highly sensitive two-step ELISA assay used to detect anti-JCV antibodies.

To support customers, ordering needs and volume of samples, Unilabs and Biogen Idec have also developed a closed web interface to allow neurologists to order sampling and shipping materials, register courier sample pick up details, and request language and format of analytical reports. Also, neurologists can seek sampling, shipping and medical support in five major languages through a multilingual call centre. The project is centralised to and managed by Unilabs in Copenhagen.

According to Yvonne Lech, Managing Director of Unilabs Denmark,“The experiences and the innovations created for this project can be applied in the future to create added customer value for future global Companion Diagnostic projects.”

14: Biogen Idec/Elan Provide Stratify JCV Dx in the US Market for Free “Where Allowed”, Via Quest

So What?

The test ordering process appears to be well managed but the need to send samples to a central laboratory may still create barriers to maximal Stratify JCV uptake.

15: Biogen Idec/Elan Provide Central Dx Information and Ordering Platform for EU Access to Unilabs Service …

16: …Directly Linking to Unilabs' Order Management Web Platform

17: Introduction of the Risk Test Strengthened Biogen Idec/Elan’s Reputation with Patient Advocates

 
 
“This label change marks an important advance in assisting people with MS and their physicians to make better-informed decisions concerning the challenges of balancing effectiveness with safety… We are encouraged by the proactive role that Biogen Idec and Elan are taking in addressing PML risk stratification.”
Dr. Nicholas LaRocca, Vice President Heath Care Delivery and Policy Research at the National MS Society

18: FDA Changed the Prescribing Information for Tysabri In August 2012, Further Strengthening the Role of the Companion Diagnostic

 
 
 
 
On August 15, 2012, the FDA required another change to the prescribing information, recommending that patients with a negative anti-JCV antibody test result should be retested every 6 months.
 
 

19: Biogen Idec and Elan Filed for First Line Indication in JCV-Negative MS Patients in January 2013

Biogen Idec and Elan Submit Applications for First-Line Use of TYSABRI in anti-JCV Antibody Negative Patients with MS
- Marketing Applications Supported by Risk Stratification Data -

WESTON, Mass. & DUBLIN--(BUSINESS WIRE)--Jan. 16, 2013-- Today Biogen Idec (NASDAQ: BIIB) and Elan Corporation, plc (NYSE: ELN) announced that they have submitted applications to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) requesting updates to the TYSABRI® (natalizumab) labels. The applications request an expanded indication that would include first-line use for people living with certain relapsing forms of multiple sclerosis (MS) who have tested negative for antibodies to the JC virus (JCV). A formal assessment of both applications is ongoing.

These submissions are supported by risk stratification data and a risk algorithm that enables physicians and individuals living with MS to make informed decisions when considering treatment with TYSABRI. If approved, a first-line label will allow all appropriate anti-JCV antibody negative patients to consider TYSABRI early in the course of treatment, regardless of the level of disease activity or prior treatment history. TYSABRI is a highly efficacious treatment that has been shown to slow disability progression by 42 – 54 percent and reduce annualized relapse rates by 68 percent.

So What?

If granted, first line indication would expand the eligible patient population from 10 to 12 per cent to over 40 per cent of all MS patients.

Investment in 'safety Dx' is likely to earn a substantial return on investment.

20: Label Change Due to Novel Dx Expected to Add US$1bn to Revised Tysabri Peak Year Revenues

Tysabri gets boost from label change, new diagnostic
 
 
Biogen Idec and Elan, which market Tysabri for multiple sclerosis, won approval to add new safety information to the drug's label that could boost sales by helping doctors avoid a serious adverse event.

The Stratify JCV Antibody ELISA test, when used with other clinical data from the patient, can help healthcare providers determine the risk for developing PML, the FDA said. The test is sold by Quest Diagnostics.

RBC Capital Markets analyst Michael Yee predicted that the label change could boost Tysabri's 2016 global revenue by about a billion dollars, to $2.5-$3 billion, a 50% increase from the analyst's prior forecast. … Yee wrote that the drug's foothold is firm, having gained 1,700 new patients in the fourth quarter, and that its popularity as a first-line treatment is growing.
Deborah Weinstein, Marc Iskowitz January 23, 2012.

21: Dx May Help to Protect Tysabri's Market Share Against Imminent Novel MS Therapies...

 
2005

  • Rebif (Approved)
  • Betaseron (Approved)
  • Copaxone (Approved)
  • Avonex (Approved)
  • Novantrone (Approved)
2006

  • Tysabri (Approved)
  • Generic Metoxantrone (Approved)
2010-2012

  • Aubagio (Approved)
  • Gilenya (Approved)
  • Ampyra (Approved)
2013

  • Tecfidera (Approved)
  • Campath (PIII)
  • Daclizumab (PIII)
  • Laquinimod (PIII)
  • Firategrast (PII)

22: ...as PML Risk Due to JCV Infection is Not Specific to Tysabri, Other Drugs Face Similar Challenges

Since immunodeficiency causes JCV to progress to PML, a confirmed JCV infection is a general contraindication to immunosuppressant drugs.

 

Boxed warnings related to PML / JCV infections have been added to the label of several widely used novel drugs that act as immunosuppressants:

  • Rituximab (Rituxan, co-marketed by Genentech BioOncology and Biogen Idec) - Boxed warning statement that JCV infection resulting in progressive multifocal leukoencephalopathy, and death, has been reported in patients treated with the drug.
  • Efalizumab (Raptiva, marketed in the US by Genentech, and marketed in Europe by Merck Serono) - Boxed warning statement that JCV, resulting in progressive multifocal leukoencephalopathy, developed in three patients who received efalizumab in clinical trials. The drug was pulled off the US market because of the association with PML on April 10, 2009.
  • Brentuximab Vedotin (Adcetris) - Boxed warning statement that PML: JCV infection resulting in PML and death can occur in patients receiving Adcetris.
So What?

There is an opportunity for Dx owners to expand the use of JCV testing to other commonly prescribed immunosuppressant drugs.

23: JCV Test May Not Be Sufficient and More Monitoring May Be Necessary

 
 
The relatively high percentage of patients who had viremia and were seronegative appears to be greater than the false negative rate identified previously.
 
 
To establish risk-stratification algorithms for PML in patients who receive potent immunomodulatory therapies, a single measurement of viral activity such as a test for antibodies to JC virus may be useful but not sufficient to assess risk.
So What?

As the June 2013 study suggests, a JCV test may not be sufficient.

Will MRI screening become the complement Dx to JCV testing in monitoring patients?

24: MRI Screening May Offer an Additional Diagnostic Approach to Detect JCV

Early Detection of PML With Natalizumab Improves Outcome
Megan Brooks
Mar 13, 2013
 
 
"We know that some physicians do use MRI screening in their practices to monitor multiple sclerosis [MS] patients receiving Tysabri, however we cannot recommend this practice at this time. We continue to collect additional data and support clinical studies in order to better understand the utility of MRI screening," Dr. Dong-Si added.
 
 
But Mary Rensel, MD, staff physician in the Cleveland Clinic Mellen Center, Ohio, told Medscape Medical News she feels this study helps "confirm that it is indeed important to monitor the patients on natalizumab with brain MRIs."

25: Key Messages

Key messages:

Even in the case of severe adverse events, risk stratification by means of a diagnostic test can help rescue and reposition an otherwise highly effective drug.

Taking a proactive approach to diagnostic development can help drug companies to maintain ownership of the drug's positioning and, at the same time, demonstrate their commitment to addressing unmet medical need.

Offering a 'full service testing package' around a specific, highly relevant diagnostic test, even at no cost to the patients and payers, has become a valuable way for drug companies to support the competitive positioning of their drug assets.

The JCV test started as a risk stratification diagnostic prior to initiating therapy then the FDA boosted frequency to every six months. New data show JCV testing may not be enough and that MRI screening may become the next sanctioned monitoring tool. This example illustrates that the testing requirements for a drug may evolve over time and may require constant monitoring of new diagnostic findings, as well as a proactive approach to diagnostic lifecycle management by the drug's owner.
Key actions:

Understand the diagnostic lifecycle and how it may evolve.

Take a proactive approach to diagnostic and drug positioning.

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