PREMARKET HISTORY

Preclinical History

In June 2005, Genmab reported that in laboratory experiments, HuMax-CD20 appears to induce more effective killing of targets expressing low levels of CD20 than rituximab (Rituxan; Biogen Idec). When low levels of CD20 are present on tumor targets, rituximab does not appear effective in killing the tumor cells. HuMax-CD20, however, is effective when CD20 is expressed at both high and very low levels. A panel of cell lines expressing varying amounts of CD20 molecules per cell (4,500-135,000 molecules) was generated by retroviral transduction of CEM tumor cells. HuMax-CD20 appeared to be highly superior in the induction of complement-mediated lysis of cells for all CD20 expression levels, as compared to rituximab. HuMax-CD20 appeared to induce significant lysis of cells at the lowest CD20 expression level tested, whereas such cells seemed resistant to rituximab. Complete lysis was achieved by HuMax-CD20 at intermediate expression levels of CD20, whereas complete lysis with rituximab was not achieved.

Preclinical trials used biological assays to assess capacity of HuMab-CD20 constructs to bind to tumor targets. Assays were also used to characterize effects of these constructs on tumor cell signaling and on the mechanism of tumor cytotoxicity. SCID mice engrafted with human B-cell tumors were used to evaluate therapeutic capacity of the new antibodies in animal disease models. In these preclinical evaluations, the lead rituximab-like MAb was far more efficient in a number of mechanisms compared to rituximab, and also appears to kill tumor cells that are resistant to rituximab.

In preclinical testing, HuMax-CD20 effectively killed tumor cells from a number of cancer patients with B-cell CLL (B-CLL). In side-by-side testing of killing in whole blood, HuMax-CD20 killed up to 50% of the B-CLL tumors, compared to <5% for rituximab. In addition, HuMax-CD20 also effectively killed B-ALL cells from a cell line derived from a patient with B-cell ALL. In side by side testing in whole blood, HuMax-CD20 killed up to 100% of B-ALL cells compared to <10% for rituximab.

Despite improved efficacy of rituximab chemotherapy combination in treating diffuse large B-cell lymphoma (DLBCL), 30-40% of patients did not survive. Ofatumumab was compared to rituximab for inducing complement dependent cytotoxicity (CDC) of lymphoma cells derived from patients with chemotherapy-refractory DLBCL by researchers at the VU University Medical Center (Amsterdam, Netherlands), Genmab (Utrecht, Netherlands), and University Medical Center (Utrecht, Netherlands). Both antibodies induced CDC of all DLBCL samples tested, including cell lines SUDHL4, SUDHL5, HT, and lymphoma cells derived from 10 chemotherapy-refractory DLBCL patients. Ofatumumab induced CDC in 9/10 DLBCL tumor samples more effectively than rituximab. Ofatumumab had a lower lethal dose LD50 (0.1 2.8 g/ml) than rituximab (6.4 4.9 g/ml). Sensitivity of patient DLBCL cells to ofatumumab and rituximab-induced CDC negatively correlated with expression of complement defense molecule CD59, but not with expression of CD46, CD55 or apoptosis inhibitors Bcl-2 and XIAP. Ofatumumab-induced CDC was less sensitive to expression of these complement defense molecules, CD55 and Cd59, than rituximab-induced CDC. These results demonstrate the ofatumumab is the most effective CDC-inducing anti-CD20 treatment for chemotherapy-refractory DLBCL, especially in patients with high CD59 expression, and is a valuable therapy option for patients with chemotherapy-refractory DLBCL (Cillessen, SAGM, etal, ASH07, Abs. 2346).

Anti-CD20 treatment of patients with chronic lymphocytic leukemia (CLL) relies on complement-mediated cytotoxicity (CMC) and can lead to complement depletion because of large number of circulating CLL cells. Ofatumumab or rituxumab were tested in 4 CD20+ cell lines (ARH77, Daudi, Raji, and Z138) in vitro with 50% normal human serum added as complement source by researchers at the University of Virginia School of Medicine (Charlottesville, VA), Genmab, and University Medical Center (Utrecht, Netherlands). Both antibodies bound to targeted cells quickly (half life 1/2 < 2 min at 37C). Ofatumumab exhibited higher rates and efficacy in promoting C3b deposition and subsequent CMC than rituximab, evident as early as 3 minutes post treatment of Raji cells. More Raji cells were killed by ofatumumab in 3 minutes than by rituximab in 12 minutes. Similar differential CMC efficacies were detected in Z138 cells. Ofatumumab even killed 60-80% rituximab-resistant ARH77 cells in <15 minutes. The killing by either ofatumumab or rituximab was reduced when the number of Z138 or Raji target cells increased from 10^6 to 10^8 cells/ml because of exhaustion of complement in serum. Supplementation with normal human serum restored killing by providing adequate complement levels. These results suggest that at high cancer cell burden, supplementation with a complement source may enhance killing of CD20+ cells by ofatumumab (Taylor RP, etal, ASH07, Abs. 2352).

MARKET STATUS

Approved/Filed Indication

chronic lymphocytic leukemia (CLL) refractory to treatment with fludarabine and alemtuzumab

Clinical Aspects

In January 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use recommended conditional approval of Arzerra for the treatment for chronic lymphocytic leukemia (CLL) that is refractory to treatment with fludarabine and alemtuzumab. Under conditional marketing approval, the drug may be commercailized, but GlaxoSmithKline would be required to provide additional data to gain full approval. The status is renewable annually.

In October 2009, Arzerra (ofatumumab) received accelerated approval from the FDA for use in patients with chronic lymphocytic leukemia (CLL) that is refractory to treatment with fludarabine and alemtuzumab. The approval is based on results from the pivotal phase III clinical trial (protocol ID: Hx-CD20-406; NCT00349349) in which 42% of patients with CLL refractory to both fludarabine and alemtuzumab responded to treatment with Arzerra with a median duration of response of 6.5 months. The most common AE (>/=10%) seen were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common SAE seen were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Arzerra is anticipated to be available for prescription use in the coming weeks.

In June 2009, the FDA extended by 3 months its review of ofatumumab because it needs more time to review additional chemistry and manufacturing data submitted on June 5, 2009. A decision is now expected by October 31, 2009.

In May 2009, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 10 to 3 that Arzerra (ofatumumab) data are reasonably likely to predict clinical benefit for patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine (Fludara) and alemtuzumab (Campath/MabCampath). The advisory committee made its decision based on an interim analysis of a pivotal trial (protocol ID: Hx-CD20-406; NCT00349349) that was presented at ASH08 annual meeting and at ASCO09 (see below). An FDA staff report, released ahead of the ODAC meeting, had questioned the way response was analyzed and its side effects. In terms of AE, one severely ill patient died from progressive multifocal leukoencephalopathy (PML).

A planned interim analysis was performed to assess the clinical benefit in patients with CLL refractory to fludarabine and alemtuzumab (double-refractory), or refractory to fludarabine with bulky (>5 cm) lymphadenopathy, treated with ofatumumab in the international pivotal clinical trial (protocol ID: Hx-CD20-406; NCT00349349). At the time of the analysis, among the 138 treated patients (double refractory=59, other=79) 63% had Rai Stage III/IV disease at screening. The median number of prior therapies was 5. Patients with disease refractory to fludarabine with bulky lymphadenopathy were treated with 8 weekly then 4 monthly ofatumumab infusions, at a first dose of 300 mg, and subsequent 11 doses at 2000 mg. The trial’s primary endpoint is overall response rate (ORR), as assessed by an Independent Review Committee, over 24 weeks. ORR was 58% in the double refractory group and 47% in the bulky lymphadenopathy group, and median OS was 13.7 months (not reached) and 15.4 months, respectively. Resolution of disease symptoms, maintained for >/=2 months, was observed in a large proportion of patients, including those considered nonresponders by NCI-WG criteria. Improvements in hematologic values were also observed in some patients with abnormal baseline values, particularly in platelet counts. Sustained increases in median platelet counts from 65×10^9/L to over 100×10^9/L by week 8 were noted in patients with thrombocytopenia at baseline (n=73); a similar pattern of rapid improvement was observed in Hgb values from <11 g/dL to >11 g/dL. Ofatumumab as single agent achieves high ORR, and improves disease symptoms and hematologic parameters in heavily pretreated patients with in this setting (Kipps TJ, etal, ASCO09, Abs. 7043).

In February 2009, GlaxoSmithKline and Genmab submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) for Arzerra (ofatumumab) for the treatment of chronic lymphocytic leukemia (CLL). If approved, ofatumumab would be indicated for the treatment of patients with refractory CLL or who are not candidates for standard therapies.

In January 2009, GlaxoSmithKline (GSK) and Genmab submitted a BLA to the FDA for Arzerra (ofatumumab) to treat patients with refractory chronic lymphocytic leukemia (CLL). If approved, ofatumumab would be the first anti-CD20 monoclonal antibody (MAb) available for this patient population. The submission is based on the results of a multicenter (n=60), international, single arm, pivotal, phase III clinical trial (protocol ID: Hx-CD20-406; NCT00349349) that treated 138 patients with CLL with limited or no response to both fludarabine and alemtuzumab treatment and those with CLL refractory to fludarabine who were considered inappropriate candidates for alemtuzumab treatment because of bulky tumor masses (>5 cm) in the lymph nodes. The primary endpoint of the trial was assessment of response. The overall response rate seen in these patient groups treated with single agent ofatumumab was 58% for the fludarabine alemtuzumab refractory group (n=59) and 47% for the bulky fludarabine refractory group (n=79). The most common AE seen with ofatumumab were related to infusion reactions and infections. AE seen in at least 10% of patients included fever, cough, diarrhea, rash, low white blood cell counts, fatigue, pneumonia, anemia, shortness of breath and nausea. In clinical trials to date, infusion reactions that were serious yet manageable, occurred in 3% of patients. There was one case of fatal multifocal leukoencephalopathy (PML) and one case of tumor lysis syndrome (Osterborg A, etal, ASH08, Abs. 328).

Market Status

Approved (10/09) and launched (11/09) USA

Sales History

USA sales of Arzerra were ~DKK29 million (~ $5.5 million in 4Q09). Under the terms of the collaboration with GlaxoSmithKline (GSK), Genmab expects to receive a royalty payment of ~DKK6 million (~ $1.1 million).

Year

2009

US Sales

$5,500,000.00

Total Sales

$5,500,000.00

CLINICAL STATUS

Indication in Development

non-Hodgkin's lymphoma (NHL), B-cell, relapsed or refractory, low grade or follicular, CD20-positive

Latest Status

Phase I/II (begin 8/04, completed 8/05) USA, Europe (Denmark, Germany, the Netherlands, Poland, UK); phase III (begin 7/06, closed 10/08) USA, Europe (Czech Republic, Denmark, France, Germany, Italy, Netherlands, Poland, Sweden, Spain, UK)

Clinical History

Combination trials with other approved agents are in the Combination Trials module.

According to top-line results reported in August 2009, from a multicenter, international clinical trial (protocol ID: Hx-CD20-405; NCT00394836) with Arzerra (ofatumumab) in patients with rituximab (Rituxan)-refractory follicular non-Hodgkin's lymphoma (NHL), the overall response rate (ORR) was 10%, well below expectations. Patients enrolled in this trial had disease that failed to respond with at least a PR to rituximab in combination with chemotherapy, progressed while on rituximab, or had progressed following a response within 6 months of the last dose of rituximab. Patients were treated with one infusion of 300 mg of ofatumumab followed by 7 weekly infusions of 500 mg or 1000 mg. Disease status was assessed every 3 months until month 12, then every 6 months until month 24. Patients will be followed every 6 months thereafter until month 60. The protocol was amended in 2007 to discontinue enrollment in the 500 mg dosing allowing full recruitment at 1000 mg. The objective of the trial was to determine the efficacy and safety of ofatumumab in rituximab-refractory follicular NHL. The primary endpoint of the trial was objective response as measured over a 6-month period from start of treatment and assessed by an Independent endpoints Review Committee according to the standardized criteria for NHL. Secondary endpoints include duration of response and safety. A total of 116 patients were treated in the trial, including 30 patients treated with ofatumumab at a dose of 500 mg and 86 patients at a dose of 1000 mg. The patients in the trial had highly refractory disease; in 49% disease was refractory to the last chemotherapy treatment. Patients in the trial had been previously treated with a median of 4 regimens. The trial’s primary endpoint was objective response (International Working Group Criteria) over 6 months from the start of treatment in those treated with a dose of 1000 mg. The ORR in the 1000 mg treatment arm was 10%, including one CR and 8 PR and disease stabilized in 50% (43) of patients. The ORR among all patients treated irrespective of dose was 11%. The ORR among patients with disease refractory to prior rituximab monotherapy (n=27) was 22% while among those with disease refractory to rituximab in combination with chemotherapy was 7%, and among those with disease refractory to rituximab maintenance was 9%. The median duration of response in the 1000 mg treatment arm was 6 months and the progression free survival (PFS) was 6 months. There were no unexpected safety findings reported during treatment and within 30 days after last infusion. The most common AE (>10%) were rash, urticaria, pruritus, fatigue, nausea, pyrexia and cough. The disappointing response rate in this trial would require a larger phase III clinical trial for regulatory submission, and possibly one comparing the drug directly against rituximab.

In August 2008, Genmab reported that it plans to begin a phase II trial to examine the retreatment and maintenance treatment of refractory follicular non-Hodgkin's lymphoma (NHL) in patients who participated in the ongoing phase III NHL trial and whose disease progressed following at least 6 months objective response to or SD on ofatumumab. Eligible patients will be administered one infusion of ofatumumab at 300 mg followed by 7 once weekly infusions at 1000 mg. Maintenance treatment will consist of one 1000 mg infusion every two months for two years. Trial’s primary objective is to evaluate the safety of ofatumumab retreatment and maintenance treatment.

In August 2008, Genmab reported that it plans to initiate an open label phase I trial to be conducted in Japan in a maximum of 12 patients with relapsed/refractory follicular non-Hodgkin's lymphoma (NHL) and at least 1 patient with CLL. Patients will be divided into 2 cohorts of 3 or 6 patients each and treated with one infusion of ofatumumab of 300 mg followed by seven weekly infusions of 500 or 1000 mg. Safety at the 500 mg dose level of ofatumumab will be examined before progressing to the 1000 mg dose level. The primary objective of the trial is to evaluate the safety and tolerability of ofatumumab in Japanese patients with relapsed/refractory follicular NHL and CLL.

In September 2007, Genmab amended the design of an ongoing pivotal phase III clinical trial (protocol ID: Hx-CD20-405; NCT00394836) of ofatumumab (HuMax-CD20) in rituximab-refractory follicular non-Hodgkin's lymphoma (NHL) to a single arm trial that will now include approximately 86 patients. All patients are being treated with one infusion of ofatumumab (300 mg) followed by 7 weekly infusions of 1000 mg of ofatumumab. The original trial design included 162 patients, who would have been treated with infusions of 300 mg of ofatumumab followed by 7 weekly infusions of either 500 or 1000 mg of ofatumumab. This is the first trial of ofatumumab in patients with rituximab-refractory follicular lymphoma. In order to establish that ofatumumab is efficacious in this refractory setting, reducing the number of patients in the trial will help to expedite a result. The lower dose (500 mg) was dropped to reduce the total number of patients to be accrued and ensure that these very sick patients are treated with the maximum dose. Data from patients who were already treated with the 500 mg dose will be analyzed for safety and included in the secondary efficacy analysis, but will not be included in the primary efficacy analysis. This trial was closed as of October 2008 and should be completed by September 2013.

In July 2006, Genmab initiated a multicenter (n=67), international (USA=10), pivotal, double blind, randomized, 2-dose-arm, parallel group, phase III clinical trial (protocol ID: Hx-CD20-405; NCT00394836) with ofatumumab (Humax-Cd20) to treat patients with follicular non-Hodgkin's lymphoma (NHL) refractory to rituximab (Rituxan; Biogen Idec) administered in combination with chemotherapy or as maintenance therapy. This trial will include approximately 162 patients randomized into two dose groups. Patients in each dose group are treated with one infusion of HuMax-CD20 (300 mg) followed by 7 weekly infusions of either 500 mg or 1000 mg of HuMax-CD20. Disease status is assessed every 3 months until month 24. The objective of the trial is to determine the efficacy and safety of two dose regimens of HuMax-CD20. The trial’s primary endpoint is objective response as measured over a 6 month period from start of treatment assessed by an Independent Review Committee (IRC) according to the standardized NHL response criteria. The trial is being conducted in the USA and Europe (Czech Republic, Denmark, France, Germany, Italy, Netherlands, Poland, Sweden, Spain, UK) under Study Chairs, Anton Hagenbeek, MD, University of Amsterdam (AMC) in the Netherlands, and Myron Czuczman, MD, Roswell Park Cancer Institute (Buffalo, NY).

The first clinical use of ofatumumab in relapsed or refractory Grade I or II follicular non-Hodgkin’s lymphoma (NHL) was in a phase I/II clinical trial conducted in Europe. This open label, dose-escalation, multicenter, phase I/II clinical trial (protocol ID: Hx-CD20-001, NCT00092274) was initiated in August 2004 in patients with relapsed or refractory CD20+ follicular NHL. Up to 4 cohorts of 10 patients were treated with 4 weekly IV infusions of 300, 500, 700, or 1000 mg. Endpoints are AE, CT verified tumor response (central review) according to the Cheson criteria, B-cell depletion, time to next antilymphoma treatment, duration of response, Bcl2 conversion, and PK. A total of 40 patients have been treated. Median number of prior treatment regimens was 2. A total of 15 patients were previously treated with rituximab. Rapid, efficient, and sustained peripheral B-cell depletion was observed in all dose groups. No DLT has been reported. Only 8 short lasting episodes of Grade 3 CTC were observed. Hematological toxicity was low and confined to 6 events of Grade 1 neutropenia. No cases of thrombocytopenia were reported. No correlation between PK and response was found. Objective responses (CR, CRu, PR) have been elevated in 36 patients and were obtained in all 4 dose groups, including 4 CR + 1 CRu/8 (300 mg), 1 CR + 2 PR/9 (500 mg), 2 PR/10 (700 mg) and 1 CRu + 4 PR/9 (1000 mg). Objective responses were achieved in 8 of 14 (57%) evaluable patients previously treated with rituximab, including 3 CR, 1 Cru, and 4 PR. In total, there are 18 SD, and progression was observed in only 3. Preliminary analysis demonstrates a favorable safety profile and encouraging efficacy of HuMax-CD20 in patients with follicular NHL. Objective responses were achieved in all dose groups with response rates up to 63%, including a 57% response rate in patients previously treated with rituximab. Participating institutions include J. Radford University Medical Center (Utrecht, Netherlands), Vejle Hospital (Vejle, Denmark), Southampton General Hospital (Southampton, UK), KAS Herlev (Herlev, Denmark), MSCM Cancer Center (Warsaw, Poland), Klinika Hematologii Akademii Medycznej (Gdansk, Poland), University of Iowa, Medical University of Lodz (Lodz, Poland), Oddzial Chemioterapii Bialostocki (Bialystok, Poland), Universitätskliniken des Saarlandes (Germany), Universitätsklinikum Schleswig–Holstein (Kiel, Germany), University Hospital (Cologne, Germany), Erasmus Medical Center (Rotterdam, Netherlands), and Christie Hospital NHS Trust (Manchester, UKK) (Hagenbeek A, etal, ASH05, Abs. 4760). This trial was completed in August 2005. In this trial four cohorts of 10 patients each were treated with 4 weekly infusions of 300, 500, 700, or 1000 mg of ofatumumab. The median prior treatments for follicular NHL were 2 regimens and 13% of patients had elevated lactate dehydrogenase (LDH). No safety concerns or MTD was identified. Of a total of 274 AE reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria Grade 1 or 2; 8 related events were Grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median TTP for all patients was 8.8 months and for responders 32.6 months. Median duration of response was 29.9 months at a median follow-up of 9.2, and a maximum follow up of 38.6 months (Hagenbeek A, etal, Blood, 15 Jun 2008;111(12):5486-95; comment in Blood, 15 Sep 2008;112(6):2584-5; author reply 2585; a.hagenbeek@umcutrecht.nl).

In December 2005, Genmab presented additional positive results in the open label, nonrandomized, multicenter, dose-escalation, phase I/II clinical trial (protocol ID: Hx-CD20-001, NCT00092274) of HuMax-CD20 to treat patients with relapsed or refractory follicular NHL. The trial was designed for 40 patients divided into 4 dose cohorts to be treated with IV infusions of HuMax-CD20 at doses of 300, 500, 700, or 1000 mg once weekly for 4 weeks, and were followed for 12 months. A total of 37 patients were evaluable. Patients had relapsed or refractory follicular lymphoma, and were previously treated with a median of 2 treatment regimens, including possibility of rituximab. Objective response rates (ORR) at each dose level in this safety portion of the trial include 63% (300 mg), 33% (500 mg), 20% (700 mg), and 60% (1000 mg) for an ORR of 43%, according to Cheson criteria. Response rates include 5 CR, 2 unconfirmed CR (CRu), and 9 PR. A CRu meets and exceeds PR criteria. Responders include 1 additional patient compared to the data previously reported in June. The new responding patient had previously responded to rituximab. This increases the ORR in patients who previously responded to rituximab treatment to 64% (9 of 14 patients), including 3 CR, 1 Cru, and 5 PR. Median duration of response and median TTP in responding patients have not yet been reached after 12 months of follow up. Of 16 patients who responded to treatment, 12 have not progressed at the end of the follow-up period. HuMax-CD20 was well tolerated by the patients. No DLT were reported, and MTD was not reached.

A multicenter, international, open label, dose escalation phase I/II clinical trial (protocol ID: Hx-CD20-001, NCT00092274), initiated in September 2004, is administering HuMax-CD20 to patients with CD20 positive, Grade I/II, relapsed or refractory, follicular NHL. This trial will enroll 40 patients, with cohorts of 10 being administered IV infusions at doses of either 300, 500, 700, or 1000 mg once weekly for 4 weeks. Before infusion, patients are treated with oral acetaminophen and IV antihistamine, and IV glucocorticosteroids if adverse events of Grade 3 or higher develop. Patients are followed for 12 months. Trial endpoints include CT scan verified tumor response, B-cell depletion in peripheral blood and lymph nodes, time to next antilymphoma treatment, duration of response, BCL2 conversion, PK, and adverse event. Data presented is for the first 17 patients. In the 300 mg group, all 10 patients were treated with all 4 infusions. The 500 mg group enrolled 7 patients, of which 3 are treated with 4 infusions, 2 with 3 infusions, and 2 with 2 infusions. Median baseline B-cell count was 114 x 10^6 cells per L, decreasing to 8 x 10^6 1 week after the first infusion in 16 patients. Furthermore, in 6 of these patients, no B-cells were detected. B-cell counts measured for 10 patients 1 week after the 4th infusion revealed no detectable B-cells in 8 patients, while 2 others showed counts of 11 x 10^6 and 34 x 10^6. Moreover, B-cell counts were undetectable in 2 patients when taken 8 weeks after the 4th infusion. No DLT was reported with administration of 300 or 500 mg, with infusion related adverse events primarily occurring during first infusion of HuMax-CD20 and including pruritus, dyspnea, rigors/chills, nausea, hypotension, urticaria, fatigue, fever, and rash. In 15 of the 17 patients, 51 adverse events were reported, 9 of which were Grade 3, 16 Grade 2, and 26 Grade 1. Participating centers include University Medical Center (Utrecht, Netherlands), Vejle Hospital (Vejle, Denmark), MSCM Cancer Center (Warszawa, Poland), Klinika Hematologii (Gdansk, Poland) and University of Iowa (Iowa City, IA) (Hagenbeek A, etal, ASH04, Abs. 1400). Brian K Link, MD, of the University of Iowa, is the PI. As of December 2004, 11 patients are evaluable among the first 15 of 40 at the week 11 evaluation point. A clinical response was achieved in 55% of these patients, including a CR in 2, and an unconfirmed complete response (uCR) in 1, for a 27% CR rate. In the 300 mg dose group, 4 of 7 patients achieved a clinical response, including a CR in 2, and PR in 2, with 1 maintaining the CR at week 19. Moreover, 1 patient with a PR at week 11 achieved a uCR at week 19. In the 500 mg dose group, 2 of 4 patients achieved a clinical response, 1 with a PR and the other with a uCR. No DLT was reported with administration of HuMax-CD20 up to a dose of 1000 mg in the 40 patients thus treated. Grade 3 events considered related to HuMax-CD20 occurred in 4 patients (hypotension, dyspnea), as 1 patient in the 500 mg group was withdrawn during the first infusion because of Grade 3 dyspnea and laryngeal edema. Brief Grade 1 and 2 toxicity have been reported in 25 patients. As of August 2005, this trial has been completed.

In December 2003, Genmab filed an IND in the USA and a Clinical Trial Application (CTA) in England to initiate this phase I/II clinical trial.

Indication in Development

chronic lymphocytic leukemia (CLL), B-cell, relapsed or refractory

Latest Status

Phase I/II (begin 10/04, completed 3/05) USA, Europe (Czech Republic, Denmark, France, Italy, Netherlands, Poland, Spain, Sweden, UK); phase III (begin 6/06, ammended 1/08, closed 7/09) USA; BLA (filed 1/09) USA; MAA (filed 2/09) EU

Clinical History

Combination trials with other approved agents are in the Combination Trials module.

According to an interim analysis, the pivotal phase III clinical trial (protocol ID: Hx-CD20-406; NCT00349349) with ofatumumab (HuMax-CD20) in two groups of patients with chronic lymphocytic leukemia (CLL) with high unmet medical need met the primary endpoint in both populations and results from the secondary endpoints also support the primary endpoint. In the interim analysis, the activity of ofatumumab was evaluated in 138 of 154 patients; in half of these patients (n=59) CLL was refractory to both fludarabine and alemtuzumab treatment. The analysis also included a second group (n=79) with CLL refractory to fludarabine who were considered inappropriate candidates for alemtuzumab because of bulky tumor in the lymph nodes. The prognosis for these patients is poor. The overall response rate (ORR) to salvage therapy is approximately 20% with a median survival of 9 months. All patients in the trial were treated with 8 weekly infusions of ofatumumab, followed by 4 monthly infusions of ofatumumab; 300 mg of ofatumumab were administered in the first infusion and 2000 mg at each subsequent infusion; 54% of patients were treated with all 12 infusions and 90% with >8 infusions. Patients were premedicated with paracetamol, antihistamine and glucocorticoid. Disease status was assessed every 4 weeks until week 28 and then every 3 months until disease progression or month 24. The trial’s primary end point was ORR assessed by an Independent end points Review Committee (IRC) over a 24-week period. Secondary endpoints are duration of response, PFS, time-to-next CLL therapy, OS, and AE. An objective response rate of 51% (p<0.0001) consisting of 30 PR was achieved in the group of patients with CLL refractory to fludarabine and alemtuzumab. In the fludarabine refractory, alemtuzumab inappropriate patient group, an objective response rate of 44% (p<0.0001) was achieved, including 1 CR, and 34 PR. Additionally, disease stabilized in 39 and 43 patients, respectively. Median time to next CLL therapy was 9 months for the patients with doubly refractory disease and 8 months for the patients with bulky disease; clinical progression was typically attributed to worsening lymphadenopathy. The median OS was about 14 months and 15 months, respectively. Based upon a landmark analysis at week 12, response was significantly correlated with longer survival for both groups. Ofatumumab was generally well tolerated in this trial. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of patients in the doubly refractory disease group and 38% in the bulky disease group, which were Grade 3 (no Grade 4) in 7% and 3%, respectively (only 1 Grade 3 event was considered a serious AE). These AE generally subsided with subsequent infusions. The most common g|Grade 3 or 4 toxicities were infections (25% and 27%, respectively) and hematologic events including neutropenia (12% and 10%, respectively) and anemia (8% and 4%, respectively). Early death, within 8 weeks from start of treatment, occurred in 2 patients (3%) in the doubly refractory disease group (sepsis=1 and fungal pneumonia=1) and in 3 patients (4%) in the bulky disease group (progressive disease=1, sepsis=1, myocardial infarction =1). No patient tested developed antibodies to ofatumumab. Therefore, ofatumumab is effective in patients with double-refractory CLL or bulky fludarabine-refractory disease. The drug well tolerated with no unexpected toxicities. The encouraging single agent activity in patients with refractory CLL warrants further investigation of ofatumumab in earlier disease settings, in combination with other agents, as maintenance, and in other B-cell malignancies (Osterborg A, etal, ASH08, Abs. 328).

In December 2006, additional positive results were reported from the phase I/II clinical trial (protocol ID: Hx-CD20-402, NCT00093314) of ofatumumab to treat patients with relapsed or refractory chronic lymphocytic leukemia (CLL). In this trial 13 of 26 evaluable patients, treated at the highest dose level (2000 mg), responded for an objective response rate of 50% patients, including one nodular partial remission (nPR) confirmed by CT scan and another that qualified as nPR but the patient had residual lymphadenopathy revealed by CT. Responders include one additional patient compared to previously reported data. Median TTP in all patients treated at 2000 mg was approximately 16 weeks ranging from 15 to 23 weeks. In the patients responding to HuMax-CD20 treatment, TTP was 23 weeks ranging from 20 to 31 weeks. The median time to next anti-CLL treatment was 52 weeks. These survival endpoints correlated statistically to the patients' total exposure to HuMax-CD20 over time and to the clearance of the antibody. This open label, dose-escalation trial that enrolled 33 patients who had failed previous therapy, tested three dose levels; 3 patients at the first dose level were treated with an initial dose of 100 mg followed by 3 weekly doses of 500 mg; 3 patients at the second dose level were treated with a dose of 300 mg followed by 3 weekly doses of 1,000 mg; and 27 patients at the third level were treated with an initial dose of 500 mg followed by 3 weekly doses of 2,000 mg. MTD was not reached and none of the patients developed human anti human antibodies. Trial endpoints were B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, TTP, duration of response, time to next anti-CLL treatment, and PK. The total follow up period for this trial is 12 months from treatment start and the primary endpoint of the trial is objective response over the period from screening to week 19. Among the 27 patients treated with the highest dose, 13 (48%) reported infections and infestations, most frequently Grade 1 or 2 events of nasopharyngitis, gastroenteritis, sinusitis and upper respiratory tract infection without causal relation to ofatumumab. Pronounced reduction of the leukemic CD19+CD5+ cell counts were seen in all patients. AUC correlated significantly to both TTP and time to next anti-CLL therapy to which parameters the clearance (Cl) of ofatumumab correlated inversely. This analysis of data from the first trial of ofatumumab in patients with CLL indicates that a clinical benefit is associated with high exposure and low clearance (Coiffier B, etal, ASH06, Abs. 2842).

In June 2006, Genmab initiated a multicenter (n=60), international, single arm, pivotal, phase III clinical trial (protocol ID: Hx-CD20-406; NCT00349349) with HuMax-CD20 (ofatumumab) to treat patients with refractory B-cell chronic lymphocytic leukemia (CLL). HuMax-CD20 received 'fast track' designation from the FDA in December 2004 for this indication. Originally the trial was to include approximately 100 patients with B-CLL refractory to treatment with fludarabine and alemtuzumab or with fludarabine monotherapy and are intolerant to or ineligible for alemtuzumab. In January 2008, the trial was amended to enroll 252 patients. Patients are treated with 8 weekly infusions of HuMax-CD20, followed by 4 monthly infusions of HuMax-CD20. Patients are treated with 300 mg of HuMax-CD20 at the first infusion and 2,000 mg of HuMax-CD20 at each subsequent infusion. Disease status is being assessed every 4 weeks until week 28 and then every 3 months until disease progression or month 24. The objective of this trial is to evaluate the efficacy and safety of HuMax-CD20 and the primary endpoint is objective response over a 24 weeks period from start of treatment. Responses will be assessed by an Independent Review Committee (IRC) according to the National Cancer Institute Working Group guidelines. This trial is being conducted in the USA (n=12) and in Europe in the Czech Republic, Denmark, France, Italy, Netherlands, Poland, Spain, Sweden, and UK. Anders Österborg, MD, of the Karolinska Hospital (Stockholm, Sweden), and William Wierda, MD, of M. D. Anderson Cancer Center, are Study Chairs. This trial was closed in July 2009.

In an open label, dose-escalation, multicenter, phase I/II clinical trial (protocol ID: Hx-CD20-402, NCT00093314), 3 cohorts of 3 (A), 3 (B), and an extended cohort of 27 (C) patients with relapsed or refractory B-CLL are treated with 4 weekly IV infusions of HuMax-CD20 and followed for 12 months. The first infusion administered was 100 mg, 300 mg, and 500 mg in cohort A, B, and C. The following 3 infusions were of 500, 1000, and 2000 mg, respectively. Patients are premedicated with oral acetaminophen and IV antihistamine, and are treated with IV glucocorticoids before first and second infusions. Endpoints are B-cell depletion, adverse events, objective response according to the NCI working group guidelines for CLL, TTP, duration of response, time to next anti-CLL treatment, and PK. Biopsies and CT images are evaluated centrally. MTD has not been reached. Adverse events are predominantly observed on days of infusion, and as expected, most frequently symptoms of cytokine release include rash, increased sweating, fatigue, rigors, pyrexia, and headache. Up to 5 serious adverse events assessed as related to HuMax-CD20 treatment are reported, including hepatic cytolysis, herpes zoster, neutropenia (n=2), and 1 death from pneumonia at week 4. In cohorts A and B, markedly reduced CD19+CD5+ cell counts were observed in 3 of 6 patients 1 week after final treatment, and depletion was sustained in 1 of these patients. In cohort C, all patients experience pronounced CD19+CD5+ reduction. Lymphocyte counts are =4.0 x 109/L in 21 patients. At week 11, =50% reduction in product of diameters of lymph nodes is observed in 12 of 20 evaluable patients with enlarged lymph nodes. A response rate of 52% (11 of 21 evaluable patients in cohort C) is observed at week 11. There are 4 clinical CR (bone marrow and CT pending), 7 PR, 3 SD, and 7 PD. Preliminary analysis of data from the first 33 patients with CLL treated with HuMax-CD20 demonstrates significant depletion of CD19+CD5+ cells, a favorable safety profile, and an indication of clinical efficacy. An updated report for all patients at week 19 will be presented (Coiffier B, etal, ASH05, Abs. 448).

As of September 2005, treatment with HuMax-CD20 significantly reduced leukemia cells in patients with relapsed CLL in a nonrandomized, international, multicenter, dose-escalation, open label, phase I/II clinical trial (protocol ID: Hx-CD20-402, NCT00093314). In a preliminary analysis at week 11, a response rate of 52%, 12 of 23 evaluable patients, was observed in patients treated at the highest dose level of 2000 mg. This includes a CR rate of 22% (n=5; bone marrow and CT pending) and a PR rate of 30% (n=7). After the fourth and final treatment, all patients treated at the highest dose level experienced pronounced leukemia cell depletion. Markedly reduced leukemia cell counts were observed in 3 of 6 patients treated at the 500 and 1000 mg dose levels, and depletion was sustained in 1 of these patients. At week 11, 15 patients experienced a more than 50% reduction in size of enlarged lymph nodes. HuMax-CD20 was well tolerated by patients with CLL, and MTD was not reached. Investigators reported 5 serious adverse events assessed as potentially related to HuMax-CD20, including hepatic cytolysis, herpes zoster, neutropenia (n=2) and 1 death from pneumonia. The pneumonia event was reported 4 weeks after last treatment. The patient suffered from CLL for 10 years, and had history of 3 episodes of interstitial pneumonia in years up to enrollment. A total of 33 patients with CLL who failed previous therapy were enrolled enrolled. The trial has 3 dose levels. Up to 3 patients at the first dose level are treated at an initial dose of 100 mg followed by 3 weekly doses of 500 mg. At the second dose level, 3 patients are treated at a dose of 300 mg followed by 3 weekly doses of 1000 mg. At the third level, 27 patients are treated at an initial dose of 500 mg followed by 3 weekly doses of 2000 mg. The total follow-up period is 12 months from treatment start. Primary endpoint is objective response over the period from screening to week 19. For purposes of interim analysis, responses were analyzed by blood parameters, organ enlargement, clinical symptoms, and physical examination of lymph nodes. At week 19, responses will be confirmed using the NCI working group guidelines for CLL.

In March 2005, Genmab completed enrollment in the HuMax-CD20 open label , dose escalation, phase I/II clinical trial (protocol ID: Hx-CD20-402, NCT00093314) treating 33 patients with CLL. This trial has 3 dose cohorts. Up to 3 patients in the first dose cohort are administered an initial dose of 100 mg, followed by 3 weekly doses of 500 mg. In the second dose cohort, 3 patients are administered a dose of 300 mg, followed by 3 weekly doses of 1000 mg. In the third cohort, 27 patients are administered an initial dose of 500 mg, followed by 3 weekly doses of 2000 mg. Treatment is ongoing at the highest dose level. The first important milestone for this trial, safety of using HuMax-CD20 in these patients at the planned dose levels, was achieved because no side effects limiting continued recruitment of patients were observed. Total follow up period for this trial is 12 months from treatment start, and primary endpoint is objective response over the period from screening to week 19. HuMax-CD20 obtained a ‘fast track’ designation from the FDA in December 2004 for the CLL development program. This trial was completed in January 2007.

A dose comparison, international, open label phase I/II clinical trial (protocol ID: Hx-CD20-402, NCT00093314), initiated in October 2004, will determine safety and efficacy of HuMax-CD20 as treatment for patients with relapsed of refractory CLL. James Wooldrigde, MD, of the University of Iowa (Iowa City, IA) is the PI. Participating institutions include Centre Hospitalier Lyon Sud (Pierre-Benite Cedex, France); Centre Henri Becquerel (Rouen, France); KAS Herlev, Vejle Hospital, and Odense University Hospital, in Denmark; University of Amsterdam, the Netherlands; University of Iowa (Iowa City, IA); Klinika Hematologii (Bialystok, Poland); Klinika Hematologii i Transplantacji Szpiku (Katowice, Poland); Klinika Hematologii Akademii Medycznej (Gdansk, Poland); MSCMCC (Warsaw, Poland); and Medical University of Lodz, Poland. A total of 32 patients will be treated for 4 weeks. Initially, treatment will be at a HuMax-CD20 dose of either 100 mg, 300 mg, or 500 mg, followed by 3 weekly doses of 500 mg, 1000 mg, or 2000 mg. The highest dose group treated will be expanded to include a total of 26 patients in order to obtain more information about efficacy. Total follow up period is 12 months from treatment start, and primary endpoint of this trial is objective response over the period from screening to week 19. This trial was completed as of March 2005.

In December 2004, the FDA designated HuMax-CD20 as a 'fast track' product for patients with CLL who have failed fludarabine therapy.

In June 2004, the FDA accepted Genmab's IND application to initiate this phase I/II clinical trial.

Indication in Development

non-Hodgkin's lymphoma (NHL), diffuse, large, B-cell (DLBCL), relapsed

Latest Status

Phase II (begin 12/07, closed 7/09) USA, Europe (Belgium, Denmark, France, Italy, Romania, Spain, UK), Turkey

Clinical History

A multicenter (n=62), nonrandomized, open label, phase II clinical trial (protocol ID: GEN415; NCT00622388), was initiated in December 2007, in the USA and Europe (Belgium, Denmark, France, Italy, Romania, Spain, UK), and Turkey, under PI Bertrand Coiffier at the Centre Hospitalier Lyon Sud, Département d'Hématologie (Pierre-Bénite Cedex, France), to evaluate the safety and efficacy of ofatumumab in treating patients with relapsed, diffuse large B-cell lymphoma (DLBCL) ineligible for transplant or that relapsed after autologous transplant. According to the protocol, patients are administered 8 weekly IV infusion of ofatumumab, 1 at 300 mg and 7 at 1000 mg. Patients are assessed 4 weeks after the last treatment and then every 3 months for 24 months according to the revised response criteria for malignant lymphoma. After 24 months, patients will be followed until initiation of alternative DLBCL treatment or month 60. The primary objective is efficacy, and the primary endpoint is OR over 6 months. Secondary objectives are to determine safety and PK. The trial, to enroll about 75 patients, was reported closed in July 2009.

Indication in Development

non-Hodgkin's lymphoma (NHL), follicular, CD-20 positive, relapsed or refractory • chronic lymphocytic leukemia CLL), relapsed or refractory

Latest Status

Phase I (begin 9/08, closed 4/09) Japan

Clinical History

A multicenter (n=3), nonrandomized, open label, phase I clinical trial (protocol ID: OMB111148; NCT00742144) was initiated in September 2008, in Japan, to evaluate the safety and efficacy of ofatumumab in treating patients with relapsed or refractory CD20-positive, Grade I-IIIa follicular non-Hodgkin's lymphoma (NHL), or CD5, CD19, CD20 and CD23-positive relapsed or refractory chronic lymphocytic leukemia (CLL). The trial’s primary objective is to evaluate tolerability. Secondary objectives are to determine AE; obtain clinical laboratory tests; measure immunoglobin, and HAHA; determine the objective response rate, duration of response, and PFS; detect CD5, CD19, CD20, and CD23-positive cells and complement (CH50); and assess PK parameters. According to the protocol, patients are administered 8 weekly infusions of ofatumumab. The trial, to enroll about 12 patients, was closed in April 2009.

Indication in Development

chronic lymphocytic leukemia (CLL), retreatment and maintenance of responders

Latest Status

Phase II (begin 12/08, ongoing 8/10) USA, Europe (Czech Republic, France, Germany, Italy, Poland, and Sweden)

Clinical History

A multicenter (n=20), international open label, phase II clinical trial (protocol ID: GEN416; NCT00802737) was initiated in December 2008, in the USA and Europe (Czech Republic, France, Germany, Italy, Poland, and Sweden), to investigate the efficacy and safety of ofatumumab retreatment and maintenance in patients with chronic lymphocytic leukemia (CLL) who previously responded or had stable disease after treatment with ofatumumab in an ongoing trial. Study Chairs are William G Wierda, MD, PhD, at M.D. Anderson Cancer Center, and Anders Österborg, MD, PhD, at Karolinska Institutet (Stockholm, Sweden). Patients must have been treated with at least 8 prior ofatumumab infusions, must not have aggressive B-cell malignancies, and must not undergo treatment with any drug other than ofatumumab two weeks prior to treatment. The trial’s primary objective is to assess the proportion of objective responders. Secondary objectives are to determine the duration of response, PFS, time to next therapy, OS, reduction in tumor size, AEs, major infections, human antihuman antibodies (HAHA), and PK parameters. According to the protocol, patients are administered an infusion of ofatumumab (300 mg). One week later, patients are administered once weekly infusions of ofatumumab (2000 mg) for seven weeks. Patients are then treated with ofatumumab (2000 mg) once monthly for two years. This trial, to enroll about 25 patients, is to be completed in March 2016.

In August 2008, Genmab reported that it plans to initiate a phase II trial to examine the retreatment and maintenance treatment of refractory chronic lymphocytic leukemia (CLL) in patients who participated in the ongoing phase III CLL trial and had disease progression following at least an objective response or SD during a 24 week treatment period of ofatumumab. Eligible patients will be administered one infusion of ofatumumab at 300 mg followed by 7 once weekly infusions at 2000 mg. Maintenance treatment will consist of 24 once monthly infusions of 2000 mg of ofatumumab. The primary objective of this trial is to estimate the proportion of objective responses over 52 weeks.

Indication in Development

Waldenstrom's macroglobulinemia

Latest Status

Phase II (begin 1/09, ongoing 8/10) USA

Clinical History

A multicenter (n=6), nonrandomized, open label, phase II clinical trial (protocol ID: 110921; NCT00811733) was initiated in January 2009, in the USA, to evaluate the effectiveness of ofatumumab in patients with CD20+ Waldenstrom's macroglobulinemia. The trial’s primary objectives are to determine ORR, CBR, safety, tolerability, and PK. This trial is to enroll about 36 patients.

Product Comment

A multicenter, double blind, randomized, placebo-controlled, parallel group, phase III clinical trial (protocol ID: GEN411/OFA110634; IND12060; EudraCT number:2007-002951-18; NCT00603525) of ofatumumab investigating clinical efficacy in adults with active rheumatoid arthritis (RA) with an inadequate response to TNF-alpha antagonist therapy was initiated in November 2007 in Europe. A phase II clinical trial (protocol ID: NCT00291928) with HuMAx-CD20 in rheumatoid arthritis (RA) was completed in May 2007.

In addition to the treatment of NHL, MAb targeting CD20 may also treat illnesses such as Crohn’s disease, and Wegener’s granulomatosis, and autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS).

Market Opportunities

CLL cells are malignant B-cells with a low concentration of CD20 molecules on their surface. B-cells normally protect the body from invading pathogens by developing into plasma cells, which make antibodies. These antibodies directly inactivate pathogens or attach to pathogens to prepare them for destruction by other white blood cells. Patients with CLL not responding to current standard therapies, or with relapsed disease following prior treatments, are at risk for infections and death. Less than 25% of patients with CLL resistant to current treatments respond to available therapies. In the USA, about 90,000 people are living with CLL, with approximately 15,000 new cases expected in 2009. Based on 2007 worldwide estimates, leukemia (all types) accounted for more than 330,000 new cases and more than 245,000 deaths. CLL affects approximately 3.5 in 10,000 persons in the European Union.

DLBCL is a cancer of the B-lymphocytes representing 30% of NHL in adults and is the most common lymphoid malignancy in the western world. There are an estimated 63,000 new diagnoses made of DLBCL in the USA per year. The median age at diagnosis is about 65 years.

Follicular lymphoma is the second most common lymphoma in USA and Europe, accounting for 11% to 35% of all NHL. In 2006, the incidence of NHL in the USA is estimated at approximately 54,000 new cases per year, accounting for approximately 5% of all USA cancer deaths.

CLL is the most common leukemia in adults in the USA and most of Western Europe. As of 2006, annual incidence is estimated between 8,100 to 12,500 in the USA with 85%-95% of the cases being of B-cell origin. CLL is a subgroup of non-Hodgkin’s lymphoma (NHL), and together with small lymphocytic lymphoma (SLL) comprises 20% of all NHL cases.

Patent/Legal Issues

Ofatumumab was granted orphan medicinal product status (EU/3/08/581) by the European Commission in July 2008.

Current as of

August 31, 2010