BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS AUGUST 27 , 2012 P AGE A7 OF 18 Strategy Containing Campath By Erin McCallister According to the National Cancer Institute (NCI), about Senior Writer 16,000 patients will be diagnosed with CLL in the U.S. this year. Sanofi and its Genzyme Corp. subsidiary are not comHowever, the cancer drug is only used first line in the 10% of pletely withdrawing alemtuzumab from the market, but they are patients with the 17p deletion, according to Brian Hill, an making it harder for doctors to use the drug for its approved use, oncologist in the department of hematologic oncology and blood chronic lymphocytic leukemia, and nearly impossible to use off disorders at the Cleveland Clinic. label for multiple sclerosis. He said Campath is used so narrowly because of its safety In its 1H12 earnings, Sanofi disclosed it would withdraw profile and its efficacy in this subgroup. alemtuzumab from the market for CLL. On Aug. 8, the European Campath’s label carries a boxed warning about the risk of Commission issued a decision to withdraw the marketing autho- cytopenias, infusion reactions and infections. In the Phase III trial rization for MabCampath in Europe. Withdrawal in the U.S., in 147 treatment-naïve patients, 97% reported grade 3 or 4 where the drug is sold under the name Campath, will be effective lymphopenia and 42% reported grade 3 or 4 neutropenia. Sept. 4. Additionally, 55% of patients experienced CMV viremia, and Going forward, Sanofi and Genzyme 16% of patients had CMV infections. About will to provide Campath free of charge to 10% of patients experience grade 3 or 4 “I wasn’t surprised that they oncologists for CLL and a handful of offpyrexia and/or chills associated with infulabel indications through a patient access sion of Campath. took it off the market. It is program, which has already started in According to Hill, standard of care being relaunched in a Europe. fludarabine typically produces only a 30% In a written statement, the pharma told response rate in CLL patients with the 17p different context, a different BioCentury it has decided “to focus on deletion. patient population and a bringing alemtuzumab forward for MS,” In a subgroup of treatment-naïve paand that restricting access will help pretients with 17p deletions in the Phase III different dose.” vent off-label use of the drug in this inditrial, Campath resulted in median procation. gression-free survival (PFS) of 10.7 vs. 2.2 Steven Krieger, Mount Sinai In June, Genzyme and Sanofi submitted months for control and response rates of Medical Center applications to FDA and EMA to market 64% for Campath and 20% for control. alemtuzumab for MS under the name According to Howard Ozer, chief of Lemtrada. hematology/oncology and interim director of the University of Oncologists contacted by BioCentury were disappointed by Illinois Cancer Center, Campath also is used in heavily the decision, but generally don’t believe it will negatively affect refractory patients. patients as long as the access program isn’t too onerous. “Patients who are completely refractory to other treatments Neurologists weren’t bothered by Genzyme’s decision and can benefit from Campath and doctors like having the drug believe blocking off-label use will prevent safety issues from available as an option. Loss of the drug would not be a good arising while the Lemtrada applications are under review. thing,” he said. Meanwhile, the move offers financial upside for holders of the According to Genzyme spokesperson Bo Piela, the company Genzyme CVR. Sanofi acquired the biotech in 2011 for about started informing U.S. doctors of the impending withdrawal of $20.1 billion plus a $14 contingent value right, $12 of which is Campath and the patient access plan in July and European tied to sales milestones for Lemtrada for MS. doctors earlier this month. Off-label use of Campath would be cheaper than Lemtrada, He said physicians in the U.S. and Europe will be able to which is likely to be priced competitively with other MS drugs. request Campath/MabCampath on a per patient basis. Physicians will need to complete a product request form indicating basic patient information, the intended use, the Cancer OK number of vials requested and agree to the terms and conditions Alemtuzumab is a humanized mAb against CD52. The mAb of the program. “If the request falls outside of predefined criteria, physicians binds the target, which is present on the surface of B and T lymphocytes, and causes the cells to undergo antibody-depen- may also be asked to complete a medical review form to document the clinical rationale for the intended treatment,” Piela dent cell-mediated lysis and die. For CLL, which is associated with an increase in B lympho- said. He added the program also will make the drug available for cytes, alemtuzumab destroys the excess B cells. In MS, alemtuzumab is believed to exert its therapeutic effects certain off-label malignancies for which conventional therapies by depleting T and B cells that may be responsible for cellular have failed, are unsuitable or unavailable. The drug will also be provided for hematopoietic stem cell damage. In 2001, alemtuzumab was approved in the U.S. and Europe transplant conditioning and solid organ transplant at institutions to treat B cell CLL in patients previously treated with alkylating that have documented protocols. Alemtuzumab will be available for MS patients only within the agents and who have failed fludarabine therapy. Campath was See next page approved as a first-line treatment in the U.S. in 2007. BioCentury, Strategy, from previous page THE BERNSTEIN R EPORT ON B IOB USINESS AUGUST 27 , 2012 P AGE A8 OF 18 neurology at Mount Sinai Medical Center, wasn’t surprised by Genzyme’s decision. clinical trial setting, Piela said. “I wasn’t surprised that they took it off While doctors said they were assuaged the market. It is being relaunched in a by Sanofi and Genzyme’s plan to provide different context, a different patient poputhe drug under the patient access prolation and a different dose,” he said. grams, some physicians are concerned Edward Fox, a neurologist at Central Til Menge, University Hospital that the additional work could deter use of Texas Neurology Consultants and a Dusseldorf Campath. PI in the Phase II trials for alemtuzumab for “Restricted access is always concernMS, believes that once the Phase III results ing and the addition of more paperwork can create a lag time,” are published in scientific journals, off-label use could have been said Javier Pinilla-Ibarz, a hematologic oncologist at H. Lee expected to increase. Moffitt Cancer Center & Research Institute. Nevertheless, “I think once data is published that spells out how alemtuzumab he said, “I don’t think lag times will prevent its use among the can be given in MS, the chance of off-label use goes up majority of clinicians.” dramatically. The concern is that the company and FDA have not Matthew Davids, an instructor and attending physician in the instituted any sort of risk management system,” he said. lymphoma group at Dana-Farber Cancer Center, noted that Krieger agreed. larger research institutes have more experience in dealing with “I think now that the Phase III trials and data are public and special access programs like the one Sanofi and Genzyme are as publications come out detailing the data, there will surely be proposing and may be more immune to any potential obstacles. an interest. But with the drug under FDA review that is not the Nonetheless, he also believes most doctors will still use the best time to experiment with it,” he said. drug. Krieger added: “This is the time to expectantly wait to see “I don’t think the paperwork burden will be huge. It is an what FDA rules and if they approve it, how the drug should be important drug for those patients in which it works, so motiva- monitored and how to achieve the best benefit to risk profile.” tion is on the clinician’s side to get patients the drug,” Davids Genzyme would not disclose whether the company has said. submitted or FDA has requested a REMS for Lemtrada. The company submitted its sBLA in June. Even if data are published, Til Menge, a neurologist at However, Thomas Elter, a physician in the department of Hematology and Oncology at the University of Cologne, University Hospital Dusseldorf, believes doctors will rehasn’t yet used MabCampath since the program started in main hesitant to use alemtuzumab off label because of the mAb’s safety. Europe. Elter said Genzyme told him it should take no more than two “Given the known safety profile of alemtuzumab, I think MS weeks to receive the drug, although Piela told BioCentury it doctors will be reluctant to use it off label,” he said. should take no more five days from when a request is submitted In the Phase III CARES-MS trial of 840 patients with relapsingremitting MS (RRMS) who relapsed while receiving beta interto when the drug is shipped to the physician. In any case, Elter estimated it takes physicians about 30 feron or Copaxone glatiramer acetate, about 16% of Lemtrada patients developed an autoimmune thyroid-related adverse event minutes to fill out the paperwork, which is too long for him. “Before, it took just seconds between when I would prescribe and about 1% developed immune thrombocytopenia. The rates of immune AEs were not reported for the active the drug and could have access to it. But now it will take just a half hour to fill out the paper work. I don’t have a half an hour, control arm of Rebif interferon beta-1a. Teva Pharmaceutical Industries Ltd. markets Copaxone. so to save my time I will look for an alternative,” he said. According to Elter, other options could include enrolling CLL Merck Serono S.A., a division of Merck KGaA, markets Rebif with Pfizer Inc. patients with the 17p deletion in a clinical trial. Piela said that Genzyme is “hoping to implement online forms in the future.” On Friday, the Arzneimittelkommission der deutschen Covering the CVR Arzteschaft (AkdA) released a statement calling Genzyme Campath is distributed in a 1-mL vial of 30 mg/mL. The and Sanofi’s decision purely commercial and said the volun- recommended dose for CLL is 30 mg/day three times per week tary withdrawal unnecessarily complicates cancer treatment. for 12 weeks. AkdA is the Drug Commission of the According to Genzyme, the annual Bundesarztekammer, the German treatment cost for Campath is about Medical Association. $60,000 per patient. Assuming one 12“It is an important drug for week course per year, the per dose price those patients in which it of Campath is about $1,666.67. Off label, off limits In the Phase III trials for Lemtrada, the works, so motivation is on While most MS doctors contacted by mAb was dosed at 12 mg per day on the the clinician’s side to get BioCentury haven’t used Campath off lafirst five days of the trial. The patients bel, they believe the decision to withdraw were dosed again a year later with 12 mg patients the drug.” was a good one and could prevent potenper day for three days for a total of 8 tial safety issues from arising while the doses. Matthew Davids, drug is under review. MS doctors using Campath off label Dana-Farber Cancer Center See next page Steven Krieger, assistant professor of “Given the known safety profile of alemtuzumab, I think MS doctors will be reluctant to use it off label.” BioCentury, THE BERNSTEIN R EPORT ON B IOB USINESS Strategy, from previous page AUGUST 27 , 2012 P AGE A9 OF 18 The next $10 includes payments of $3 if net sales of Lemtrada total $1.8 billion over four quarters, $4 for sales of $2.3 billion over four quarters and $3 for sales of $2.8 billion. according to the Lemtrada dosing schedule would only use 96 mg of the CLL drug over two years for a total treatment cost of $6,666.68. The off-label cost of Campath for MS is considerably lower than other MS drugs. For example, the average wholesale cost of Tysabri natalizumab is $4,576.37 for a 15-mL vial of 20 mg/mL. With a recommended dose of 300 mg every four weeks, the annual cost of Tysabri is about $59,375.81. Biogen Idec Inc. and Elan Corp. plc market Tysabri. If Genzyme and Sanofi plan to price Lemtrada competitively with other MS drugs, doctors could use Campath off label at a lower cost, which would be bad news for holders of the Genzyme CVRs. In 2011, Sanofi acquired Genzyme for about $20.1 billion plus the $14 CVR, $13 of which is tied to milestones for Lemtrada for MS (see BioCentury, Feb. 21, 2011). The first CVR milestone for Lemtrada is $1 for FDA approval. The next $2 Lemtrada milestone will trigger if net sales over four quarters exceed $400 million. COMPANIES AND INSTITUTIONS MENTIONED Biogen Idec Inc. (NASDAQ:BIIB), Weston, Mass. Bundesarztekammer, Berlin, Germany Central Texas Neurology Consultants, Round Rock, Texas Cleveland Clinic, Cleveland, Ohio Dana-Farber Cancer Center, Boston, Mass. Elan Corp. plc (NYSE:ELN), Dublin, Ireland Genzyme Corp., Cambridge, Mass. H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla. Merck KGaA (Xetra:MRK), Darmstadt, Germany Mount Sinai Medical Center, New York, N.Y. National Cancer Institute (NCI), Bethesda, Md. Pfizer Inc. (NYSE:PFE), New York, N.Y. Sanofi (Euronext:SAN; NYSE:SNY), Paris, France Teva Pharmaceutical Industries Ltd. (NYSE:TEVA), Petah Tikva, Israel University Hospital Dusseldorf, Dusseldorf, Germany University of Cologne, Cologne, Germany University of Illinois Cancer Center, Chicago, Ill. Featured links this week Links to the following documents reside online on the BioCentury on BioBusiness page of www.biocentury.com. Antibiotics NICE guidance on use of antibiotics to prevent and treat early onset neonatal infection. Stem cells U.S. Court of Appeals for the District of Columbia Circuit ruling that upheld a lower court’s 2011 dismissal of a suit claiming NIH violated a law prohibiting federal funds for research in which a human embryo is destroyed (see BioCentury Extra, Friday, Aug. 24). Venture tax CalPERS California Public Employees’ Retirement System (CalPERS) fiveyear strategic plan for meeting the retirement and health benefits needs of its members. European Commission public consultation seeking evidence of direct tax problems that arise when venture capital is invested across borders and possible solutions; comments are due Nov. 5. Product documentation Devices Registration for the Aug. 30 FDA workshop to discuss postapproval studies for class III devices regulated under PMA regulations (see BioCentury Extra, Monday, Aug. 20). IOM Institute of Medicine summary of a June workshop to discuss implementation of the Cures Acceleration Network (CAN), a program that will allow NIH to fund R&D at biopharma companies. JOBS Act SEC FAQ on research provisions in Title I of the Jumpstart Our Businesses Startups (JOBS) Act. NIH NIH policy to give extra scrutiny to grant applications from researchers who already receive $1 million or more per year under active NIH awards (see BioCentury Extra, Wednesday, Aug. 22). ‘It’s the BioCentury’TM — Avastin: NICE final guidance recommending against Avastin bevacizumab in combination with capecitabine for first-line treatment of metastatic breast cancer; from the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY). — Alimta: CHMP revised EPAR updating SPC to include anaphylactic shock as an adverse reaction for Alimta pemetrexed to treat pleural mesothelioma and non-small cell lung cancer (NSCLC); from Eli Lilly and Co. (NYSE:LLY). — Humira: Briefing documents for the Aug. 28 meeting of the Gastrointestinal Drugs Advisory Committee to discuss an sBLA for Humira adalimumab to treat moderately to severely active ulcerative colitis in adults who failed conventional therapies; from Abbott Laboratories (NYSE:ABT) and Eisai Co. Ltd. (Tokyo:4523; Osaka:4523) (see BioCentury Extra, Friday, Aug. 24). — Xgeva: NICE final appraisal determination (FAD) recommending the use of Xgeva denosumab to prevent skeletal-related events (SREs) in patients with bone metastases from breast cancer and from solid tumors other than breast and prostate cancer for whom zoledronic acid would be indicated; and against use in patients with hormone-refractory prostate cancer (HRPC); from Amgen Inc. (NASDAQ:AMGN).