DID - Sept. 12, 2008 Issue

Vol. 7 No. 179

MedWatch Warning: Rituxan Patient Dies of Viral Infection

The death of a patient taking Genentech and Biogen Idec’s rheumatoid arthritis treatment Rituxan has triggered an FDA MedWatch warning and label change for the drug.

The companies sent a letter to healthcare professionals about a rheumatoid arthritis patient who received Rituxan (rituximab) in a clinical study and was diagnosed with a viral infection approximately 18 months after the last dose of the drug, which led to progressive multifocal leukoencephalopathy (PML) and ultimately death. The drug was being tested in a long-term safety extension trial.

This was the first reported case of PML in a Rituxan-treated rheumatoid arthritis patient, the companies say, adding that the patient had developed oropharyngeal cancer, which was treated with platinum chemotherapy and radiation therapy, nine months before the patient was diagnosed with PML. The patient also had longstanding rheumatoid arthritis treated with immunosuppressants and a complex medical history.

The warning section of the Rituxan package already noted reports of PML in patients with hematologic malignancies and autoimmune diseases for which Rituxan is not approved, and it has now been updated to reflect the death of the patient who had PML.

“Physicians treating patients with Rituxan should consider PML in any patient presenting with new-onset neurologic manifestations,” the letter from the companies says. “Consultation with a neurologist, brain MRI and lumbar puncture should be considered as clinically indicated. In patients who develop PML, Rituxan should be discontinued and reductions or discontinuation in concomitant immunosuppressive therapy and appropriate treatment including antiviral therapy should be considered.”

The letter to healthcare professionals can be viewed at www.fda.gov/medwatch/safety/2008/rituxan_DHCP_Final%209411700.pdf. The updated label is available at www.fda.gov/medwatch/safety/2008/Rituxan_PI.pdf. — Martin Gidron


King Takes Higher Alpharma Bid to Shareholders

King Pharmaceuticals has taken its $1.6 billion offer to buy Alpharma directly to shareholders after three previous attempts to buy the company were rejected by Alpharma’s board of directors.

Brian Markison, King’s CEO, expresses disappointment in a letter to Alpharma about the rejection of his company’s previous offers, including the last bid of $33 a share. King is now offering to buy the company for $37 per share.

“We have determined it is necessary to take our enhanced offer directly to Alpharma stockholders in order to deliver significant value to them as expeditiously as possible,” Markison writes. King emphasizes that the transaction would create a diversified specialty pharmaceutical company with an expanded portfolio of pain-management products and a strengthened pipeline.

King has expressed its willingness to enter into an agreement with a go-shop provision that would allow Alpharma to solicit third-party offers during a mutually agreeable period of time, Markison writes. Alpharma’s board rejected this offer.

Markison’s remarks come roughly a month after King disclosed its bids for Alpharma. 

To ward off King’s offers, which the company regards as inadequate, Alpharma’s board adopted a short-term shareholders’ rights plan last week, Dean Mitchell, Alpharma’s president and CEO, says in a statement.

“Mindful of Alpharma’s current and future value creation opportunities and in light of King’s unsolicited and aggressive actions, we believe it is both prudent and appropriate to adopt this rights plan to ensure that the Alpharma Board has adequate time to consider the best approach to protect and enhance the interests of Alpharma’s shareholders,” Mitchell said last week. The plan is not intended to prevent a takeover that offers fair terms in the best interests of the company, he added (DID, Sept. 3). 

King says it is willing to commence a consent solicitation to replace the board of directors of Alpharma with its own nominees, and it expects the proposed merger could receive all necessary regulatory approvals and be completed by the end of the year.

In reaction to King’s latest offer, Alpharma’s board urged shareholders to take no action until the company has announced its position on the offer. The board will make a recommendation to Alpharma’s shareholders within 10 business days.

 “King communicated its revised proposal to Alpharma last week, and we invited them to enter into a process designed to ensure Alpharma shareholders receive full and fair value for their investment in our Company. We continue to welcome and encourage King’s participation in that process,” Mitchell says in a statement about the latest offer. 

Merger of Similar Pipelines

King recently outlined some of the potential benefits of the merger in a presentation at the Thomas Weisel Partners Healthcare Conference, according to an SEC filing.

Among the benefits are greater scale and commercialization capabilities, which could allow for the successful launch of such new pain products as Remoxy (oxycodone), Acurox (oxycodone HCl) and Embeda (morphine sulfate extended-release with sequestered naltrexone HCl).

The FDA recently granted priority review to King and Pain Therapeutic’s Remoxy NDA for a controlled-release, long-acting oral formulation for moderate-to-severe chronic pain. If it is approved, King will have worldwide responsibility for commercializing it (DID, Aug. 13).
Last week, the FDA granted priority review for Alpharma’s Embeda, an abuse-deterrent formulation of long-acting morphine. Alpharma withdrew the NDA earlier this year after technical issues with the data presentation prevented a complete evaluation by the FDA within the six-month, priority review period (DID, April 23).

King’s Acurox, a short-acting oxycodone formulation designed to deter common types of abuse, has completed Phase III clinical trials, and the company anticipates submitting the NDA to the FDA by the end of the year. In addition, Alpharma’s ketoprofen in Transfersome gel, a topical nonsteroidal anti-inflammatory drug product, entered Phase III trials in the second quarter of this year.

Other pain medicines are in early to mid-stage development, including T-62, which is scheduled to begin in Phase II trials later this year to treat neuropathic pain, according to King. — Elizabeth Jones


Grassley Adds University of Texas to Conflict-of-Interest Probe

Sen. Chuck Grassley (R-Iowa), who says he has sent conflict-of-interest inquiries to almost two dozen research universities, is asking the University of Texas System to give him the number of NIH grants it has received and a dollar amount for all NIH funding received from 2000–2007.

 Grassley’s Sept. 9 letter to Mark Yudof, chancellor of the university system, continues the lawmaker’s investigation into conflicts of interest between pharmaceutical companies and academic researchers conducting studies with NIH grants.

The university system’s health-related institutions include the University of Texas Southwestern (UTSW) Medical Center at Dallas and the University of Texas Medical Branch (UTMB) at Galveston. The University of Texas says this is the third letter it has received from Grassley regarding the matter. In response to a previous letter, the university system provided Grassley with financial disclosure reports from two physician researchers — Augustus John Rush of UTSW and Karen Wagner of UTMB.

“Institutions are required to manage a grantee’s conflicts of interest. But I am learning that this task is made difficult because physicians do not consistently report all the payments received from drug and device companies,” Grassley writes.

The university system told DID it will respond to the senator’s request and it does not think it has any legal liability. It also said it was too early to determine whether any disciplinary action is warranted and that it has no plans to revise its policies on reporting conflicts of interest. Rush now works for Duke University, the university system said.

Both Rush and Wagner had grants from NIH. Rush’s grant was to conduct a clinical intervention-training program that included “proper conduct of clinical intervention research, ethics, human subjects,” the letter says.

Wagner led NIH-financed studies on depression that involved Eli Lilly’s antidepressant Prozac (fluoxetine HCl) and GlaxoSmithKline’s (GSK) antidepressant Paxil (paroxetine HCl).

Grassley’s staff compared the disclosures with information regarding payments pharmaceutical companies made to the researchers and found discrepancies, the letter says.

For example, in 2001 Rush disclosed the receipt of $3,000 from Lilly for his work as an advisory board member. However, Lilly reported to Grassley that it paid Rush $17,802 for his services as a board member that year.

From 2000–2005, GSK reported that Wagner received $160,404 from the company, but she only reported the receipt of $600 in 2005. Wagner’s university, UTMB, did not require financial disclosures until 2002 despite federal requirements for reporting such conflicts with NIH-funded studies in 1995, the letter says.

In addition to the NIH grant information, Grassley asks the university system to report the status of its review of discrepancies and what action it will take.

The senator wants to know if the university system considers there is enough information to detect violations of guidelines covering clinical trials and reporting conflicts to institutional review boards.

“Please respond by naming each clinical trial for which the doctor was the principal investigator, along with confirmation that conflicts of interest were reported,” Grassley requests. He also wants information regarding how the university system ensured that each conflict of interest concerning an NIH grant was managed, reduced or eliminated.

Grassley is sponsoring S. 2029, the Physician Payments Sunshine Act, which would require pharmaceutical manufacturers to report all gifts and reimbursements to physicians (DID, Oct. 23, 2007). His letter to the University of Texas System can be accessed at www.fdanews.com/ext/files/09092008LettertoUniversityofTexasSystem.pdf. — Christopher Hollis 


Median Brain Cancer Survival Doubles in Vaccine Trials

Patients with a lethal form of brain cancer who received Northwest Biotherapeutics’ DCVax-Brain in Phase I and Phase I/II clinical trials had a median survival rate that was more than double the rate for people on the standard treatment.

The testing in glioblastoma multiforme patients began in 2000 and 2003, and long-term data shows that their median survival rate is 36.4 months compared with 14.6 months under the standard of care, which may include surgery, radiation and chemotherapy.

In addition, 84 percent of those who received the personalized vaccine have lived beyond the median survival point; 68 percent have lived more than two years; and 26 percent have lived more than four years. Some patients have survived as long as eight years.

The data also show that more than 80 percent of the patients who received DCVax-Brain showed a clinical response compared with typical response rates for cancer drugs — in the 20 percent to 25 percent range. Moreover, since Dec. 31, 2007, only one of the 19 remaining patients has experienced disease progression (after 59.5 months), and only one patient has died, at 37.8 months.

DCVax-Brain is created by using a patient’s own immune cells and training them in the laboratory to attack the biomarkers from that patient’s tumor cells, the company said. It is administered as an injection under the skin.

The vaccine is in a Phase II study that is double-blinded and placebo-controlled, unlike the previous trials in which “the patients knew what they were getting” and there was no placebo arm, company President and CEO Alton Boynton told DID. Patients are being enrolled at 11 sites across the U.S.

While it’s too early to estimate the cost of making the vaccine if it wins approval, Northwest Biotherapeutics conducts one 10-day manufacturing run per patient, producing enough material for 11 off-the-shelf treatments over a two- to five-year course of therapy, Boynton said. Other companies making similar personalized vaccines do a separate manufacturing run for each treatment, which can be more expensive, he added. — Martin Gidron


FDA Considers Making Supplier Audits Mandatory

The FDA may change its regulations on raw drug ingredients in the wake of the heparin contamination to make drug manufacturers conduct physical audits of materials suppliers, according to an agency director.

“I think it’s possible that the regulation will be changed,” Richard Friedman, director of CDER’s Division of Manufacturing and Product Quality, said this week at the 2008 Parenteral Drug Association-FDA Pharmaceutical Ingredient Supply Chain Conference in Washington, D.C.

When asked why 21 CFR 211 — the current good manufacturing practice (cGMP) regulations — did not explicitly require supplier audits and whether that would change, Friedman explained there is an expectation that companies use some sort of supplier audit program. Such programs also are recommended in the FDA’s guidance on quality systems, he said, which was finalized two years ago (DID, Oct. 2, 2006).

Friedman noted that quality system regulations (QSRs) for medical devices — which call for audits of suppliers — were written in the 1990s. By that time, management science had evolved from when the cGMPs were first promulgated.

In addition to making audits mandatory, the FDA group working on modernizing the GMP regulations is considering other changes.

The agency recently finalized a rule that makes limited modification to the regulations. These changes, according to the FDA, bring the rule in line with current FDA practices (DID, Sept. 8). Additional modifications are being discussed, Friedman said.

“The next step is to do things that are a little more ambitious,” he said. One of the changes being discussed includes requiring more frequent GMP reviews. “Shouldn’t you be continuously [conducting GMP process reviews] or at least in the near term looking at them?” Friedman asked.

The working group is looking at 211.180(e), which is more of a process analytical technology mindset, “and also looking at things like design and supplier controls, a little bit more quality assurance and protecting quality assurance units, which is in the QSRs,” he said.

“Those types of things are all being bantered about as possibilities in the GMP, and we’ve had great success when we listen to industry and talk to you about how you think it should be designed exactly — the 211s of the future,” he added.

The FDA also is developing guidance on pharmaceutical ingredient quality control and quality assurance, Friedman said. It might address physical attributes of drug substances, such as particle size, he said. — Christopher Hollis


Study: Candesartan Reduces Diabetic Eye Disease Progression

Takeda Pharmaceutical and AstraZeneca’s drug candesartan reduced progression of retinopathy in Type 2 diabetes patients, according to data from trials that did not meet primary endpoints.

In Type 2 diabetes patients with early signs of diabetic retinopathy, candesartan increased the probability of regression of this condition by 34 percent compared with placebo. Overall, the drug reduced the risk of progression of retinopathy in Type 2 diabetes patients by 13 percent compared with placebo.

The data come from three double-blind, randomized, placebo-controlled Phase III clinical trials known as DIRECT that collectively enrolled more than 5,231 patients at 309 sites in 30 countries. Patients were tracked for four to six years. The program did not meet its primary endpoints, including one related to kidney damage.

Additionally, in each of the three studies, levels of retinopathy over time showed a statistically significant change toward less deterioration and more improvement with candesartan than with placebo.

However, in Type 1 diabetic patients with retinopathy at baseline, there were no differences in progression of the eye disorder between the two treatment groups. There was “a strong trend in favor of treatment with candesartan in reducing the incidence of diabetic retinopathy in Type 1 diabetes patients, although [it was] not statistically significant,” Takeda says in a statement.

Results were presented at the European Association for the Study of Diabetes meeting in Rome.

A spokeswoman for the American Diabetes Association told DID that the group cannot endorse or comment on clinical trial results. — Martin Gidron


Novacea Will Not Develop Asentar After Hold Is Lifted

Novacea has no plans to develop its prostate cancer treatment Asentar despite the FDA’s release of a clinical hold on the drug’s IND application.

Novacea and its partner Schering-Plough halted the ASCENT-2 Phase III clinical trial of Asentar last November due to an unexplained imbalance in the number of deaths in the treatment and control arms. Schering-Plough returned all Asentar rights to Novacea in April.

Data from the trial showed median survival of 16.7 months for patients in the treatment arm, which included Asentar in combination with once-weekly Sanofi-Aventis’ Taxotere (docetaxel), compared with an 18.5-month median in the control arm.

The FDA says if future clinical studies are conducted with the drug, the consent forms should include a statement about the ASCENT-2 trial showing reduced survival for patients with androgen-independent prostate cancer (AIPC) given Asentar with chemotherapy. In addition, forms may not refer to survival benefits observed in earlier clinical trials involving Asentar to treat AIPC patients.

John Walker, Novacea’s chairman and CEO, says the company has no plans for the drug because it is pursuing a new direction with its proposed merger with Transcept Pharmaceuticals.

The companies announced last week they had entered into a merger agreement. The transaction is subject to regulatory approvals and is expected to close during the fourth quarter of the year or the first quarter of 2009, according to Novacea. If the merger is completed, Novacea will be renamed Transcept Pharmaceuticals. — Elizabeth Jones

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