Drug Evaluation

1 2 Ofatumumab, a second- 3 4 generation anti-CD20 monoclonal 5 6 antibody, for the treatment 7 1. Introduction 8 of lymphoproliferative and 9 2. Synthesis 10 3. Preclinical development autoimmune disorders 11 4. Clinical development † 12 Jorge Castillo , Cannon Milani & Daniel Mendez-Allwood 5. Adverse events and † 13 Brown University Warren Alpert Medical School, The Miriam Hospital, Division of Hematology and contraindications 14 Oncology, Providence, RI, USA 15 6. Conclusions Background: Lymphoproliferative and autoimmune disorders share monoclonal 16 7. Expert opinion dysregulation and survival advantage of B-lymphocytes. Thus, therapies 17 18 directed towards eliminating B-cells will play an important role as CD20 is 19 exclusively expressed in B-lymphocytes and its modulation by monoclonal 20 antibodies such as rituximab has improved outcomes in lymphoproliferative 21 and autoimmune disorders. Ofatumumab is a new, fully human anti-CD20 22 antibody and has been shown to be effective and safe, but its role in these 23 conditions is still unclear. Objectives: To describe the preclinical and clinical 24 data available on ofatumumab for the treatment of lymphoproliferative 25 and autoimmune disorders. Methods: An extensive search of published 26 articles and abstracts on preclinical and clinical studies with ofatumumab 27 was undertaken. Conclusions: Ofatumumab is a second-generation anti- 28 CD20 antibody that has been demonstrated to be safe and efficacious in 29 patients with lymphoproliferative and autoimmune disorders. Ofatumumab 30 is fully human, attaches to a newly identified epitope and shows lower off- 31 rates and improved complement-dependent cytotoxicity. Initial data present 32 ofatumumab as an attractive agent with lower rates of infusion-related 33 events than rituximab. Ongoing Phase III trials in patients with follicular 34 lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis are 35 ongoing, and Phase II trials in patients with aggressive lymphoma and multiple 36 sclerosis are also under development. 37 38 Keywords: autoimmune disorders, CD20, chronic lymphocytic leukemia, lymphoma, monoclonal 39 antibody, multiple sclerosis, non-Hodgkin’s lymphoma, ofatumumab, rheumatoid arthritis 40 41 Expert Opin. Investig. Drugs (2009) 18(4):1-10 42 43 1. Introduction 44 45 B-lymphocytes play an important role in the development of lymphoproliferative 46 and autoimmune disorders (LPDs and AIDs, respectively). Briefly, LPDs are 47 characterized by a monoclonal proliferation of malignant B- or T-lymphocytes, in 48 which a combination of increased proliferation, survival advantage and/or 49 decreased apoptosis can be observed [1]. In a similar fashion, AIDs are character- 50 ized by B-lymphocyte dysregulation, which translates into increased activation 51 and development of uncontrolled self-recognition properties [2]. Furthermore, 52 there is a bidirectional association between these disorders, since patients with 53 LPDs often present with AIDs (e.g, lymphoma patients can develop autoimmune 54 hemolytic anemia) [3] and patients who suffer from AIDs have an increased risk 55 of developing LPDs (e.g., the risk of developing lymphoma in patients with

10.1517/13543780902832679 © 2009 Informa UK Ltd ISSN 1354-3784 1 All rights reserved: reproduction in whole or in part not permitted Ofatumumab

56 systemic lupus erythematosus is 7 times higher than in the anti-TNFα failure in 2006 based on a Phase III study 111 57 general population) [4]. Based on this evidence, drugs directed showing that the combination of rituximab and MTX 112 58 towards eliminating the malignant or autoimmune clones of improved responses in comparison to MTX alone based on 113 59 B-lymphocytes, such as anti-CD20 monoclonal antibodies, American College of Rheumatology (ACR) and European 114 60 can be of great therapeutic value in these disorders. League Against Rheumatism (EULAR) response criteria [17]. 115 61 Non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic The dosing regimen for RA is different than those used to 116 62 leukemia (CLL) represent two distinct subcategories of treat lymphoma. For MS, multiple therapies are available, 117 63 malignant LPD, which originate from clonal proliferation of such as interferon, glatiramer acetate, mitoxantrone and natali- 118 64 malignant lymphocytes. NHL is the most predominant zumab, a humanized anti-CD74 MAb. The use of rituximab 119 65 adult hematologic malignancy in the USA with 66,000 in MS is limited to small trials but with hopeful results [18]. 120 66 anticipated cases in 2008 [5]; 85% of these cases will arise The premise of MAb activity centers upon modulating 121 67 from a malignant B-lymphocyte. The most common subtypes new functional receptors in malignant or autoimmune cells 122 68 are diffuse large B-cell (DLBCL) and follicular lymphoma to augment therapeutic efficacy. The actual mechanisms of 123 69 (FL). CLL, on the other hand, is the most prevalent LPD in action of MAb are unknown but, theoretically, their func- 124 70 the USA with 95,000 cases [6]. CLL is characterized by the tion is elicited by inducing complement-dependent cytotox- 125 71 accumulation of neoplastic CD5+/CD19+ B-lymphocytes. icity (CDC), antibody-dependent cellular cytotoxicity 126 72 Fifty per cent of cases will be largely asymptomatic and will (ADCC) and/or direct apoptosis [19]. Nonetheless, inherent 127 73 not need therapy. DLBCL is considered a curable disease; limitations arise with rituximab as resistance ensues in 128 74 but FL and CLL are incurable with current standard therapies. patients with low-grade NHL and CLL and responses are 129 75 AIDs comprise a constellation of conditions, such as rheu- less potent and shorter in duration [20,21]. Similarly, the effi- 130 76 matoid arthritis (RA) and multiple sclerosis (MS). RA has cacy of second-line therapy with rituximab is unclear in 131 77 an annual incidence of 30 cases per 100,000 population; DLBCL patients who failed rituximab as front-line ther- 132 78 more than a million Americans live with RA [7]. This condi- apy [10]. Moreover, rituximab has been linked to life-threat- 133 79 tion, which is characterized by the development of painful, ening infusion reactions, hepatitis B reactivation, tumor lysis 134 80 swollen joints and the presence of anticyclic citrullinated syndrome, severe mucocutaneous reactions and progressive 135 81 peptide antibodies, can be disabling and has a great impact multifocal encephalopathy [22,23]. Thus, it is paramount to 136 82 on quality of life and productivity as the joint damage discover and implement a new generation of MAb as a viable 137 83 becomes permanent with time, decreasing mobility. MS is treatment entity to achieve long-term remission while 138 84 the most common autoimmune demyelinating disease of the decreasing the rate of therapy-related adverse events. 139 85 central nervous system, affecting more than 300,000 people 140 86 in the USA [8]. It is twice as common in females as in 2. Synthesis 141 87 males, with a peak incidence at the age of 35 years but does 142 88 not affect lifespan substantially [9]. The most common form Ofatumumab (HuMax-CD20; GlaxoSmithKline, Collegeville, 143 89 of MS is relapsing-remitting MS (RRMS), characterized by PA, USA and Genmab, Copenhagen, Denmark) is an IgG1, 144 90 unpredictable relapses followed by either complete, partial fully human, second-generation anti-CD20 MAb with a 145 91 or no neurological recovery. molecular weight of approximately 150 kDa. Ofatumumab 146 92 In 1997, the advent of rituximab (Rituxan®, Genentech, was produced by immunizing HCo7 and KM mice with a 147 93 South San Francisco, CA, USA), a chimeric anti-CD20 murine cell line (NS/0) transfected with human heavy- and 148 94 monoclonal antibody (MAb), dramatically altered the foun- light-chain genes. The hybridoma was created by fusing 149 95 dation for the treatment of NHL. Rituximab is approved as B-cells from immunized mice and NS/0 cells. CD20-specific 150 96 both first-line treatment for aggressive and indolent subtypes IgG1-producing hybridomas were then sequenced and sub- 151 97 of NHL (DLBCL and FL, respectively), and for relapsed or cloned. Unique features to ofatumumab compared with 152 98 refractory, indolent or follicular, CD20-positive NHL. Clinical rituximab are a different binding site, prolonged release time 153 99 data reported by multiple investigators demonstrated from the target site and stronger CDC activity. Ofatumumab 154 100 increased response rates and prolonged survival times with is now under clinical development for indolent and aggressive 155 101 rituximab in combination with chemotherapy in patients NHL, CLL, RA and MS with promising results. 156 102 with DLBCL [10-12] and FL [13,14]. Similarly, the clinical 157 103 benefits of rituximab can be seen in patients with CLL 3. Preclinical development 158 104 when added to other chemotherapeutic agents or, to a lesser 159 105 degree, as single agent [15,16]. Of note, rituximab is not yet Elegant work from Teeling and colleagues [24] defined a series 160 106 approved by the FDA to treat CLL but it is the most com- of three fully human anti-CD20 MAbs (ofatumumab, 7B8 and 161 107 monly used MAb for this condition. The treatment for RA 11B8) with distinct characteristics. The first two were desig- 162 108 is based in nonspecific modulation of B-cells by corticoster- nated as type I anti-CD20 MAbs (rituximab-like), given their 163 109 oids, methotrexate (MTX) and anti-TNFα MAb. Rituximab ability of translocating and concentrating CD20 molecules 164 110 obtained FDA approval for the treatment of RA after into detergent-insoluble lipid rafts and inducing CDC. The 165

2 Expert Opin. Investig. Drugs (2009) 18(4) Castillo, Milani & Mendez-Allwood

166 MAb 11B8 was designated as type II (tositumomab-like) epitope to the cellular membrane plays a role in achieving 221 167 given its greater ability of eliciting ADCC and apoptosis. By stronger CDC activity. 222 168 separately using plasma and polymorphonuclear and mono- Beum and colleagues [26], using a spinning disk confocal 223 169 nuclear cells as ‘effector fractions’, ofatumumab was able to microscopic analysis, were able to demonstrate the structural 224 170 elicit cell killing when incubated with plasma alone in the changes different lymphoma cell lines undergo after opsoniza- 225 171 absence of effector cells, suggesting ofatumumab to be a tion with rituximab and ofatumumab in the presence of 226 172 strong CDC inducer. Furthermore, the CDC effect was complement. In Daudi cells, larger deposition of C3b was 227 173 blunted after heat-induced complement inactivation. The observed in the ofatumumab-opsonized cells followed by 228 174 addition of polymorphonuclear fraction mildly increased membrane ‘blebbing’. After addition of normal human 229 175 cell-killing rates but addition of mononuclear fraction did serum, thin protruding structures called ‘streamers’ were 230 176 not, suggesting ofatumumab is a weak ADCC inducer. As identified. Ofatumumab produced streamers in 114 s while 231 177 part of the same experiment, CLL tumor cells, which are they were seen after 418 s with rituximab. Membrane bleb- 232 178 relatively rituximab-resistant given their low CD20 expression, bing and streamer formation are directly associated with 233 179 were exposed to ofatumumab demonstrating cell-killing anti-CD20 MAb complement-induced cell death since addi- 234 180 properties with plasma alone; rituximab showed no activity. tion of EDTA, which chelates Mg++ and Ca++ and blocks 235 181 Confirming this finding, rituximab and ofatumumab were complement activation; and lack of C5 and C9 blunted 236 182 effective against SU-DHL4 cells, which are characterized by death of nucleated cells. In ARH77 cells, a rituximab-resis- 237 183 high CD20 expression but, after exposure to Raji cells, tant cell line with high levels of CD55 and CD59, C3b 238 184 which show low CD20 expression but increased expression deposition, membrane blebbing, streamers and cell killing 239 185 of complement regulatory proteins (i.e., CD55 and CD59), were observed with ofatumumab; rituximab was not able to 240 186 only ofatumumab demonstrated activity. In addition, ritux- promote CDC activity after several hours of incubation. 241 187 imab showed similar on-rates (maximal levels of binding in Even in CLL cells, ofatumumab showed a higher ability of 242 188 less than 15 min) but faster off-rates than ofatumumab in inducing streamer formation than rituximab, although the 243 189 Ramos and Daudi cell lines. By means of radiolabeled killing rate was similar for both MAbs owing probably to 244 190 immunoglobulin in DOHH cells, ofatumumab showed the small sample size. 245 191 70% binding after 3 h of incubation compared with approx- Recently, Bleeker and colleagues [27] published a series of 246 192 imately 30% binding of rituximab. After 6 h of exposure, experiments directed to evaluate in vivo the dose requirement 247 193 rituximab-induced CDC levels were lower than ofatumumab for activity of ofatumumab. Initially, using Daudi cells, EC50 248 194 (50% vs 90%, respectively) suggesting delayed off-rates were values for ADCC and CDC were 0.02 and 0.13 ug/ml, 249 195 associated with maintenance of the CDC activity. respectively and maximal levels of ADCC (51% cell lysis) 250 196 In a second study by Teeling and colleagues [25] rituximab were obtained with 50% target saturation while maximal 251 197 did not have activity unless there were at least 30,000 CD20 CDC levels (68% cell lysis) required full target saturation. 252 198 molecules per cell and did not achieve full cell lysis even in In vitro target saturation was achieved at levels of 5 ug/ml 253 199 cells with the highest expression of CD20. By contrast, and no further increase in CDC or ADCC was observed 254 200 ofatumumab began showing activity at CD20 concentra- with higher levels of ofatumumab. To validate these find- 255 201 tions of 4500 molecules per cell and achieved full lysis of ings, a xenograft model was constructed using female severe 256 202 any cell line expressing more than 60,000 molecules per cell. combined immunodeficient (SCID) mice, which were 257 203 Additionally, by using a new human anti-CD20 MAb, 2C6, injected with luciferase-transfected Daudi cells allowing 258 204 with faster dissociation rates than rituximab, it was demon- in vivo evaluation of tumor growth by bioluminescence. 259 205 strated that faster off-rates were not always associated to Ofatumumab was administered on day 5 after tumor induc- 260 206 weaker CDC activity since 2C6 was a stronger CDC inducer tion as a single dose of 0.5 mg/kg. Control mice developed 261 207 than rituximab. The group postulated that ofatumumab disease on day 13 and tumor continued growing until day 35; 262 208 induced stronger CDC by recognizing a different form of control mice developed clinical signs and were sacrificed. By 263 209 CD20 or a different epitope. Rituximab and other murine contrast, the ofatumumab-treated mice developed disease 264 210 anti-CD20 MAbs bind to an epitope that contains an ala- with a delay of 3 – 4 weeks. To assess for dose–effect rela- 265 211 nine residue in position 170 (A170) and a proline in posi- tionship, mice were treated with a 0.5-mg/kg single dose of 266 212 tion 172 (P172). By mutating these residues, binding of ofatumumab 5 days and 14 days after tumor induction. 267 213 rituximab to CD20 was effectively blocked but the muta- Mice treated 5 days after tumor induction maintained an 268 214 tions failed to block the binding of ofatumumab. Pepscan ofatumumab concentration of above 1 µg/ml throughout 269 215 epitope mapping and ELISA testing were used to assess the the experiment, while mice treated 14 days after tumor 270 216 reactivity of the different anti-CD20 MAbs against the induction started at similar levels and these levels declined 271 217 sequenced potential epitopes. As expected, rituximab bound to 0.1 – 0.2 µg/ml by the end of the experiment, indicating 272 218 to the A170/P172 epitope, but ofatumumab bound to pep- that tumor burden may play a role in ofatumumab plasma 273 219 tides located in the small extracellular loop, N-terminal from concentrations. Accelerated tumor growth was observed 274 220 A170/P172. It is likely that the greater proximity of the new when ofatumumab levels were below 0.4 µg/ml. 275

Expert Opin. Investig. Drugs (2009) 18(4) 3 Ofatumumab

276 To clarify further ofatumumab efficacy, cynomolgus depletion was observed in evaluable patients from all dose groups 331 277 monkeys were used as their CD20 molecule is similar to until approximately 20 weeks after final treatment, with a 332 278 humans with only one amino acid difference. Three different slow recovery measured to week 54 from initiation of treatment. 333 279 dosing regimens of ofatumumab were used (1.25, 6.25 and Interim data indicated a decrease in median baseline B-cell 334 280 12.5 mg/kg), given daily for 4 days. B-cell depletion from count from 114 × 106 cells/l to 8 × 106 cells/l in 16 available 335 281 peripheral blood was observed immediately after ofatumumab patients 1 week after the first infusion; B-cells were not 336 282 infusion. Initial B-cell recovery was seen at 29 and 56 days detectable in eight patients. Conversion to negative BCL-2 337 283 with low-dose and medium-/high-dose ofatumumab, respec- in peripheral blood was assessed in all dose groups with a 338 284 tively. Full B-cell recovery was seen after day 96 in the low-dose 65% conversion rate in evaluable patients across dose groups. 339 285 group and after 136 days in the medium-/high-dose groups. Based on Kaplan-Meier estimates, at a median follow-up of 340 286 Lymphatic depletion of B-cells was also achieved with ofatu- 9.2 months, the median time to progression for all patients 341 287 mumab as germinal center atrophy was observed in mandibular was 8.8 months, the median time to progression for responders 342 288 and mesenteric lymph nodes 2 weeks after the final dose. The was 32.6 months and the median duration of response was 343 289 authors concluded that ofatumumab concentrations of 50 ug/ml 29.9 months. Four patients who did not progress were being 344 290 were needed to induce full B-cell depletion and concentrations monitored at the time of publication; median time to next 345 291 of 5 – 10 µg/ml were sufficient to sustain activity. anti-lymphoma therapy was not reached by 12 months. 346 292 Ex vivo experiments showed ofatumumab was more In an ongoing Phase II, open-label, randomized clinical 347 293 effective than rituximab in eliciting CDC in DLCBL cell trial, 56 previously untreated patients with FL received 348 294 lines, SU-DHL4, SU-DHL5 and HT, and in cells from 10 ofatumumab combined with cyclophosphamide, doxorubi- 349 295 refractory DLBCL patients [28]; the lethal doses for ofatu- cin, vincristine and prednisone (CHOP; NCT00494780). 350 296 mumab and rituximab were 0.1 ± 2.8 and 6.4 ± 4.9 µg/dl, The two dose cohorts would receive 300 mg of ofatumumab 351 297 respectively. Furthermore, the effect of ofatumumab was less at the first infusion, followed by five infusions of either 500 352 298 sensitive to the expression of complement regulatory proteins, or 1000 mg of ofatumumab every 3 weeks, in combination 353 299 CD55 and CD59, than rituximab. with six cycles of CHOP. Patients would be monitored at 354 300 12 weeks following the final treatment, every 12 weeks until 355 301 4. Clinical development 2 years and then every 24 weeks until 5 years or initiation 356 302 of alternative treatment. The primary end point was objec- 357 303 4.1 Non-Hodgkin’s lymphoma tive response from the initiation of treatment until 12 weeks 358 304 4.1.1 Phase I/II after final treatment at 30 weeks. This trial is ongoing but 359 305 Hagenbeek and colleagues reported results on a Phase I/II not recruiting patients at the time of publication. 360 306 open-label, multicenter, dose-escalating clinical trial In a Phase II, open-label, non-randomized clinical trial, 361 307 (NCT00092274) of ofatumumab in 40 CD20-positive 75 patients with relapsed DLBCL who were not candidates 362 308 patients with relapsed or refractory FL [29-31]. Ofatumumab for stem cell transplantation will receive an initial 300-mg 363 309 was administered in four incremental doses of 300, 500, infusion followed by seven weekly 1000-mg infusions of 364 310 700 or 1000 mg i.v. once weekly for 4 weeks (n = 10 in ofatumumab (NCT00622388). Patients would be moni- 365 311 each cohort) and followed for 1 year. Before infusion, tored every 4 weeks after final treatment and every 12 weeks 366 312 patients received oral acetaminophen and intravenous anti- thereafter for 5 years or the initiation of an alternative treat- 367 313 histamine; in case of grade 3 or higher adverse events (AEs), ment. The primary end point was objective response rate at 368 314 i.v. glucocorticosteroids were administered. Of the 24 weeks after treatment initiation. At the time of this 369 315 40 patients, 15 had previous rituximab exposure either as publication, recruitment was still ongoing. 370 316 monotherapy or part of combination therapy and, of these, 371 317 4 were refractory to rituximab. All patients were evaluated for 4.1.2 Phase III 372 318 safety parameters and 37 were included for efficacy assessment. A multicenter, international Phase III study co-chaired by 373 319 By week 19, response rates of 63,33,20 and 50% were Drs Hagenbeek and Czuzman and sponsored by Genmab is 374 320 achieved in patients receiving 300, 500, 700 and 1000 mg, ongoing (NCT00394836) and will randomize 112 patients 375 321 respectively. From week 19 to week 26, one additional response with rituximab-refractory FL to an initial 300-mg infusion 376 322 was noted in a patient receiving 1000 mg. Five patients followed by seven weekly infusions of either 500 or 1000 mg 377 323 achieved complete response (CR), 2 unconfirmed CR (CRu) and of ofatumumab. The primary and secondary objectives are 378 324 9 partial response (PR); stable disease (SD) and progressive efficacy and safety, respectively. Disease status will be assessed 379 325 disease (PD) were observed in 18 and 3 patients, respectively. every 3 months to complete 24 months of follow-up. 380 326 In patients previously treated with rituximab, 64% responded 381 327 across dose groups, with three achieving CR, one CRu, five PR, 4.2 Chronic lymphocytic leukemia 382 328 four SD and one PD. Of the four patients who were rituximab- 4.2.1 Phase I/II 383 329 refractory, three responded to ofatumumab treatment (1 CR, In a Phase I/II, open-label, multicenter, dose-escalating clinical 384 330 1 CRu and 1 PR). Rapid, significant and sustained B-cell trial (NCT00093314), 33 patients with relapsed or refractory 385

4 Expert Opin. Investig. Drugs (2009) 18(4) Castillo, Milani & Mendez-Allwood

386 CLL were treated with once-weekly infusions of ofatumumab ofatumumab followed by four monthly infusions (dose 1: 441 387 for 4 weeks: three patients received an initial dose of 100 mg, 300 mg; doses 2 – 12: 2000 mg) [35]. DR CLL was defined by 442 388 followed by three doses of 500 mg; three received 300 mg failure to therapy with fludarabine and alemtuzumab. The pri- 443 389 and three doses of 1000 mg; and 27 received 500 mg and mary end point was ORR over a 24-week period. Overall sur- 444 390 three doses of 2000 mg [32-34]. Patients were previously vival (OS) and safety were also evaluated. The interim analysis 445 391 treated with fludarabine (n = 20), rituximab (n = 7) and included all 138 treated patients (59 DR and 79 BFR 446 392 alemtuzumab (n = 6) and 67% of the patients were stage B patients); 54% received all 12 infusions and 90% received 8 447 393 according to the Binet clinical staging scale. Patients received infusions. The ORR, based on independent review committee 448 394 oral acetaminophen, intravenous antihistamine and gluco- assessment, was 51% for the DR group and 44% for the BFR 449 395 corticosteroid before ofatumumab infusion and were fol- group; one patient had CR. Additionally, 39 of 51 DR patients 450 396 lowed up for 12 weeks. The overall objective response and 43 of 44 BFR patients had SD. Median time to next 451 397 (ORR) was 44%; in the high-dose group (approximately CLL therapy was 9 months for the DR group and 8 months 452 398 50% of evaluable patients; 1 withdrew from hepatic cytoly- for the BFR group. Clinical progression was usually demon- 453 399 sis), there was one nodular PR and 12 PRs and there was strated by worsening lymphadenopathy. The median OS was 454 400 one PR in the low-dose group. In the high-dose group, 62% about 14 months for the DR group and 15 months for the 455 401 (16 out of 26) responded to treatment on physical examina- BFR group. Based upon analysis at 12 weeks, response was 456 402 tion and peripheral blood examination 4 weeks after treat- significantly correlated with longer survival for both groups. 457 403 ment; three did not respond until week 7 or 11. The Finally, exploring the concept of maintenance therapy 458 404 duration of response varied; at week 19, nine patients still with ofatumumab, a Phase II trial (NCT00802737) will 459 405 had a response. Of those, seven had received previous ther- include patients who, after receiving eight weekly doses of 460 406 apy; two maintained response until week 27 and the remain- ofatumumab (first dose 300 mg/m2, then 2000 mg/m2), 461 407 ing patients had PD with a median progression-free survival have achieved at least SD. Patients will continue receiving 462 408 (PFS) of approximately 15 weeks and time to the next anti- ofatumumab at 2000 mg/m2 once monthly to complete 463 409 leukemic therapy was 1 year. Of seven anemic patients, six 2 years. Primary outcome is proportion of objective respond- 464 410 improved at the two higher doses and eight of nine throm- ers. Duration of response, PFS, time to next CLL therapy, 465 411 bocytopenic patients improved across all doses. In eight OS, reduction in tumor size, AEs, major infections, human 466 412 high-dose patients who responded, the median percentage of anti-human antibodies (HAHA) and pharmacokinetic 467 413 bone marrow lymphocytes was 78% and 50% before and parameters are secondary outcomes. 468 414 after treatment, respectively, with three who had less than 469 415 30% posttreatment but had a nodular growth pattern. There 4.2.2 Phase III 470 416 was a median 55% reduction in CD5+/CD19+ B-cells in the A Phase III trial (NCT00748189) has started recruiting 471 417 blood in patients receiving the high dose after the first infu- newly diagnosed CLL patients. Patients will be randomized 472 418 sion, which increased to a median of 97% after the fourth to chlorambucil alone at 10 mg/m2 p.o. for 7 days every 473 419 infusion; similar reductions with CD5+/CD20+ B-cells and 28 days or the combination of chlorambucil and ofatu- 474 420 normal B-cells were observed; these reductions were mostly mumab at 300 mg/m2 i.v. on day 1 followed by 1000 mg/m2 475 421 sustained until week 24. i.v. on day 8 and every 28 days thereafter. Primary outcome 476 422 In an ongoing Phase II, open-label, randomized, is PFS and secondary outcomes are ORR and OS. 477 423 parallel-group, combination clinical trial in patients with 478 424 B-cell CLL (NCT00410163), 56 patients will receive a 4.3 Rheumatoid arthritis 479 425 300-mg infusion of ofatumumab, followed by five infusions 4.3.1 Phase I/II 480 426 of 500 or 1000 mg with fludarabine and cyclophosphamide In 2005, a Phase I/II, randomized, double-blind, placebo- 481 427 every 4 weeks until six infusions have been administered. controlled study (NCT00291928) was conducted to evaluate 482 428 Patients will be assessed every 4 weeks until week 24, every the safety and efficacy in patients with active RA who have 483 429 12 weeks thereafter until disease progression or by 2 years. failed one treatment with one or more disease-modifying 484 430 Patients that had not progressed at this time would be antirheumatic drugs [36]. The study included 39 patients 485 431 monitored at 24-week intervals to complete 4 years. The and 33 received either two infusions of 300, 700 and 486 432 primary end point is CR rate from the initiation of treat- 1000 mg of ofatumumab or placebo, given 2 weeks apart. 487 433 ment to 12 weeks after therapy; secondary end points are Efficacy was assessed by the ACR score at week 24. In the 488 434 duration of response, time to next anti-CLL therapy, reduc- 300-mg dose group, 75% patients who received both doses 489 435 tion in tumor size and AEs. At the time of this publication, obtained ACR20. In both the 700- and 1000-mg dose 490 436 the study was ongoing but recruitment had stopped; the groups, 78% of patients who received both doses obtained 491 437 estimated completion date is 2012. ACR20. Results showed a 77% ACR20 response rate in 492 438 In an international, multicenter study (NCT00349349), patients who received two doses of ofatumumab. Patients 493 439 patients with double refractory (DR) and bulky fludarabine who only received one dose showed a 66% ACR20 response. 494 440 refractory (BFR) CLL, received eight weekly infusions of None of the patients receiving placebo achieved ACR20. 495

Expert Opin. Investig. Drugs (2009) 18(4) 5 Ofatumumab

496 The previous study was expanded into a Phase II trial 40 patients; administration of ofatumumab will occur in a 551 497 that included 200 additional patients randomized into four hospital-based unit. Part B will be a blinded, randomized, 552 498 treatment groups. In each group, 50 patients received two placebo-controlled study. On the basis of findings in part A 553 499 infusions of 300, 700, or 1000 mg of ofatumumab or pla- of the study, selected doses will be taken forward for admin- 554 500 cebo, given 2 weeks apart. Patients were followed for istration in part B. Administration of ofatumumab for part B 555 501 24 weeks to evaluate safety and efficacy and then every is planned to be conducted in an outpatient setting. 556 502 12 weeks until B-cell counts returned to baseline levels. In 557 503 the intention-to-treat analysis ACR20, ACR50 and ACR70 4.3.2 Phase III 558 504 responses were achieved by 46,24 and 6% of all patients At present, two Genmab-sponsored, Phase III, randomized, 559 505 receiving ofatumumab compared with 15,5 and 0% in the double-blind, placebo-controlled, parallel assignment clinical 560 506 placebo group. Evaluated by dose groups, an ACR20 trials comparing ofatumumab with placebo in RA patients 561 507 response was obtained by 41,49 and 46% of patients receiv- are ongoing. The primary end point for both would be 562 508 ing 300, 700 and 1000 mg of ofatumumab, respectively. An reduced clinical signs and symptoms of RA after a single 563 509 ACR50 response was obtained by 19,26 and 26% of patients course of ofatumumab, measured by an ACR20 response at 564 510 receiving the varying doses of ofatumumab, with 9,4 and 24 weeks; the secondary outcome of both trials would be 565 511 6% obtaining an ACR70 response. In the subgroup of safety and efficacy after repeated doses of ofatumumab in a 566 512 178 patients receiving concomitant stable doses of MTX, 120-week, open-label period. In one trial, 248 patients with 567 513 results across the three dose levels of ofatumumab studied an inadequate response to MTX will be randomized to a 568 514 showed that an ACR20 response was obtained by 42,56 and single course of two 700-mg doses of ofatumumab 2 weeks 569 515 50% of patients in the 300-, 700- and 1000-mg dose groups, apart or placebo, in addition to background MTX 570 516 respectively, compared with 16% in the placebo group. An (NCT00611455). In the second trial, 236 patients refrac- 571 517 ACR50 response was obtained by 21,26 and 26% of patients tory or with inadequate response to anti-TNFα therapy will 572 518 receiving the varying doses of ofatumumab, with 8,2 and 5% be randomized again to a single course of ofatumumab 573 519 obtaining an ACR70 response. The corresponding responses 700 mg or placebo (NCT00603525). 574 520 for the placebo group were 7% and 0%, respectively. Over- 575 521 all, 72% of patients treated with each ofatumumab dose 4.4 Multiple sclerosis 576 522 experienced at least a moderate EULAR response compared 4.4.1 Phase I/II 577 523 with 40% of patients receiving placebo at week 24. Patients In December 2007, a double-blind, randomized, placebo- 578 524 in this study will be part of another Phase II, nonrandom- controlled, multicenter, dose-finding trial of ofatumumab in 579 525 ized, open-label, active-control study that started in January RRMS patients was announced (NCT00640328). The first 580 526 2008 set to evaluate the long-term effectiveness of repeated patient in the study was treated in June 2008. The purpose 581 527 courses of ofatumumab (NCT00655824). of the trial is to investigate the safety and the dose response 582 528 Following a protocol amendment, 203 patients from the of three doses of ofatumumab compared with placebo. It is 583 529 total patient population were subject to efficacy measurements a two-part study. In Part A, 36 patients will be treated in 584 530 for a 48-week follow-up period [37]. Continuation of ongo- cohorts of increasing doses of ofatumumab of 100, 300 or 585 531 ing therapy with MTX and low-dose prednisolone was per- 700 mg. In Part B, 288 patients will be randomized to one 586 532 mitted. Patients on 700-mg and 1000-mg doses of of three ofatumumab dose groups or placebo and followed 587 533 ofatumumab maintained numerically higher ACR20 response for a 48-week treatment period. After week 24, patients on 588 534 rates than those on placebo at the end of follow-up. The an active dose will receive re-treatment with the same dose 589 535 percentage of patients with a good or moderate EULAR of ofatumumab or placebo. Patients in the placebo group 590 536 response was statistically significantly higher in the 700-mg will receive ofatumumab at the highest tolerated dose from 591 537 group compared with placebo at week 48 (70% vs 49%, Part A. The dose response will be determined on disease 592 538 respectively). Only two possibly/probably related AEs, cellulitis activity as measured by MRI scans of the brain at 8 and 593 539 and Clostridium colitis, were recorded from weeks 24 to 48 24 weeks. 594 540 across all active arms. 595 541 A two-part Phase I/II study to evaluate a subcutaneous 4.4.2 Phase III 596 542 route of administration of ofatumumab in RA patients, stable No Phase III data were available at the time of this publication. 597 543 on MTX, is underway (NCT00686868). Part A will charac- 598 544 terize the safety and tolerability of ofatumumab when 5. Adverse events and contraindications 599 545 administered subcutaneously. The primary end point is 600 546 safety and tolerability. Part B will characterize the pharma- In a Phase I/II trial evaluating safety and efficacy of ofatumumab 601 547 cokinetics/pharmacodynamics of subcutaneous dosing. in relapsed or refractory FL, no safety concerns or maximum 602 548 Patients in both parts are allowed to continue a stable dose tolerated dose were identified [31]. A total of 274 AEs 603 549 of MTX therapy. Part A will be a randomized, single-blind, were reported; 190 were judged related to ofatumumab, most 604 550 placebo-controlled, dose-range finding study of approximately occurring on the first infusion day with Common 605

6 Expert Opin. Investig. Drugs (2009) 18(4) Castillo, Milani & Mendez-Allwood

606 Terminology Criteria (CTC) grade 1 or 2. Eight related rituximab-resistant patients and comparing ofatumumab 661 607 events were grade 3. Treatment caused immediate and profound with rituximab in treatment-naive patients. 662 608 B-cell depletion. 663 609 In the NCT00349349 CLL trial, ofatumumab infusion-related 7. Expert opinion 664 610 adverse events on the first infusion day occurred in 46% of 665 611 patients in the DR group and 38% in the BFR group, The advent of anti-CD20 MAbs has changed the treatment 666 612 which were grade 3 in 7% and 3%, respectively. The subse- paradigm of LPDs and AIDs. Rituximab-containing regimens 667 613 quent infusions did not demonstrate the potency of the have improved response and survival rates in low-grade and 668 614 initial infusion reactions. The most common CTC grade 3 aggressive NHL and in CLL [10,13,38,39]. Patients with RA 669 615 or 4 toxicities were infections (25% in DR; 27% in BFR and MS have also responded to anti-CD20 MAb therapy 670 616 group) and hematologic events including neutropenia (12% and current practice is moving away from other harder-to- 671 617 in DR; 10% in BFR group) and anemia (8% in DR; 4% in manage immunosuppressants [36]. Despite this fact, ritux- 672 618 BFR group). Early death, defined as within 8 weeks from imab therapy is far from perfect; the infusion-related 673 619 start of treatment, occurred in two patients (3%) in the DR reactions are common, some of them are life-threatening, 674 620 group (sepsis, n = 1; fungal pneumonia, n = 1) and three and patients will ultimately develop resistance following 675 621 patients (4%) in the BFR group (PD, n = 1; sepsis, n = 1; repetitive exposure to rituximab [10,20,21]. 676 622 myocardial infarction, n = 1). None of the patients tested The CD20 antigen continues to be a great target for 677 623 developed human antibodies against ofatumumab. MAb therapy. CD20 is not shed in the bloodstream and is 678 624 During the early stages of the initial RA trial [36], two very specific to B-lymphocytes [40]. Although CD20 func- 679 625 patients experienced infusion-related serious AEs–one tion has not been definitively elucidated, its modulation by 680 626 anaphylactoid reaction and one urticaria–and one patient MAb induces ADCC, CDC and apoptosis in the malignant 681 627 had a CTC grade 3 bronchospasm. These were observed when or autoimmune cell [19]. Current research has shown that 682 628 using the 300-mg dose, so premedication with corticosteroids not all anti-CD20 MAbs are created equal. Ofatumumab 683 629 and a slower infusion rate were implemented before the use has specific characteristics that differentiate it from ritux- 684 630 of higher doses. After premedication in all active groups, three imab, starting from a different binding site and binding 685 631 CTC grade 2 events–one fatigue and two bronchospasms– properties to longer half-life and higher intensity of 686 632 were observed in the 700- and 1000-mg groups, but no CDC [24,25]. Ofatumumab is also a fully humanized MAb 687 633 serious AEs were reported. At the conclusion of the study, with a low immunogenic potential and, so far, formation of 688 634 the incidence of CTC remained the same but one serious human anti-human antibodies has not been observed 689 635 AE was reported. Most nonserious AEs were observed on in patients exposed to ofatumumab. All these features 690 636 the first infusion day, were grade 1 and 2 CTC events and allow shorter infusions with fewer infusion-related reactions 691 637 were reported in 87% of patients in the 300 mg group, than rituximab and make ofatumumab an attractive product 692 638 75% in the 700 mg group and 58% in the 1000 mg group, to be used in repetitive doses in the treatment of LPDs 693 639 compared with 20,33 and 0%, respectively, during the second and AIDs. Much like rituximab, infusion-related AEs have 694 640 infusion. In a recent study to evaluate the long-term effects been reported more commonly during the first infusion. 695 641 of two i.v. doses of 300, 700 and 1000 mg of ofatumumab Administration of corticosteroids should be routinely used 696 642 given 2 weeks apart in patients with RA, two serious AEs before ofatumumab infusions and the rate of infusion should 697 643 (cellulitis and clostridium colitis) were reported. Of note, be decreased according to a protocol similar to that used 698 644 only serious AEs were reported at 24 and 48 weeks [37]. with rituximab. 699 645 Ofatumumab has shown preclinical and clinical efficacy 700 646 6. Conclusions in different rituximab-resistant settings [41]. Ofatumumab 701 647 induced lysis in cell lines with low expression of CD20 and 702 648 Ofatumumab is a second-generation anti-CD20 MAb that also has shown efficacy in cases of NHL that are primarily 703 649 has been demonstrated to be safe and efficacious in treating resistant or refractory to rituximab and in cases of CLL, 704 650 patients with NHL, CLL, RA and MS. Ofatumumab is a which are characterized by inherently lower expression of 705 651 fully human MAb, attaches to a newly described epitope CD20 [25]. There are ongoing Phase III trials using ofatu- 706 652 and shows lower off-rates and improved CDC effect than mumab in low-grade NHL, CLL and RA. Of note, none of 707 653 rituximab. Initial clinical data present ofatumumab as an these trials is a head-to-head comparison against rituximab. 708 654 attractive agent with lower rates on infusion-related events There is a general agreement that rituximab therapy has 709 655 than rituximab. Ongoing Phase III trials in patients with potentially serious complications, but the clinical experience 710 656 FL, CLL and RA are ongoing and Phase II trials in patients has been positive so far; as more years of experience accumulate 711 657 with DLBCL and MS are also under development. Thus far, in favor of rituximab it could potentially be harder to introduce 712 658 ofatumumab has shown safety and efficacy as a single agent a new anti-CD20 MAb, even if it proves to be noninferior. 713 659 as well as in combination with chemotherapy. Future Other second-generation anti-CD20 MAbs are under 714 660 research should be directed towards using ofatumumab in development. Veltuzumab (Immunomedics, Inc.), a humanized 715

Expert Opin. Investig. Drugs (2009) 18(4) 7 Ofatumumab

716 anti-CD20 MAb with high CDC effect and slow off-rates, galiximab (Biogen Idec, Inc.), lumiliximab (Biogen Idec, 758 717 is undergoing Phase II studies in NHL, CLL, RA and Inc.) and epratuzumab (Immunomedics, Inc.)–anti-CD80, 759 718 idiopathic thrombocytopenic purpura. Veltuzumab has been anti-CD23 and anti-CD22 mAbs, respectively–should be 760 719 shown to be safe and efficacious at low doses using intrave- attempted. Ofatumumab alone or in combination with 761 720 nous and, more recently, subcutaneous formulations [42-44]. chemotherapy and/or bortezomib could also be of value in 762 721 Ocrelizumab (Biogen Idec, Inc., Genentech, Inc., Roche Waldenstrom’s macroglobulinemia (WM) and mantle cell 763 722 Holding AG and Chugai Pharmaceuticals Co. Ltd.), another lymphoma. A Phase II trial of ofatumumab in patients with 764 723 humanized anti-CD20 MAb, is undergoing Phase III trials WM will start in 2009 (NCT00811733). The concept of 765 724 in combination with MTX for the treatment of patients maintenance ofatumumab should also be studied in patients 766 725 with RA and lupus nephritis, and Phase II trials for systemic with indolent NHL and CLL even after maintenance 767 726 lupus erythematosus and hematological malignancies [45,46]. rituximab failure. It would be of interest to see if an 768 727 The success of ofatumumab in front-line settings will be effective B-cell suppression can be achieved with fewer 769 728 based on showing noninferiority to rituximab in achieving infusions of ofatumumab in this setting. Given that both 770 729 and sustaining clinical responses and improving survival. antibodies bind different epitopes in the CD20 antigen, 771 730 The Phase III NHL trial is comparing two different doses of maybe a combination of both CD-20 MAbs will induce 772 731 ofatumumab and the Phase III CLL trial is comparing ofa- more potent and longer responses, although the implications 773 732 tumumab versus the combination of ofatumumab and of such profound B-cell depletion are unknown. Finally, 774 733 chlorambucil. These trials will be unlikely to change the ofatumumab-based radioimmunotherapy could prove to be 775 734 current management of these disorders, although they can useful given the characteristics of the binding site and longer 776 735 prove the principle of ofatumumab benefit in these settings. binding affinity. 777 736 Future Phase III trials in the development of ofatumumab Ofatumumab as a novel anti-CD20 MAb has shown to 778 737 should evaluate combination with chemotherapy and/or be safe and effective, alone or in combination, in treating 779 738 other targeted therapies in comparison with what is consid- patients with indolent and aggressive NHL, CLL, RA and 780 739 ered standard of care, namely R-CHOP in DLBCL, R-CVP MS, but its role is not clearly defined. Probably, ofatu- 781 740 (rituximab, cyclophosphamide, vincristine and prednisone) mumab will have an important role in treating patients who 782 741 in FL and FCR (fludarabine, cyclophosphamide and ritux- cannot tolerate rituximab or have developed rituximab resis- 783 742 imab) in CLL patients. A Phase III trial comparing FC tance; but it is unclear how ofatumumab will compare to 784 743 against FC in combination with ofatumumab in CLL rituximab as a single agent or in combination with chemo- 785 744 patients will start recruiting patients this year therapy in front-line settings. The best way to answer these 786 745 (NCT00824265). The latter trial is of great interest since questions is through the careful design, planning, execution 787 746 recent Phase III trials evaluating the addition of rituximab to and analysis of significant randomized controlled trials. Since 788 747 FC in CLL patients have shown higher response rates and many of these patients will have an insidious clinical course, 789 748 prolonged PFS in front-line [38] and relapsed settings [39]. it is also necessary to improve our present understanding of 790 749 In relapsed and refractory settings, ofatumumab has a the malignant and autoimmune cell biology to personalize 791 750 great opportunity to show superiority to rituximab since and tailor therapies so that better response and longer survival 792 751 most of the patients will already be rituximab failures. In rates may be obtained without affecting significantly patients’ 793 752 DLBCL patients, the combination of ofatumumab and quality of life. 794 753 ICE (ifosfamide, carboplatin and etoposide) and DHAP 795 754 (dexamethasone, cytarabine and cisplatin) regimens should Declaration of interest 796 755 be studied. In FL and CLL patients, combinations with 797 756 bendamustine, immunomodulators such as thalidomide and The authors state no conflict of interest and have received 798 757 lenalidomide, and other monoclonal antibodies such as no payment in preparation of this manuscript. 799

8 Expert Opin. Investig. Drugs (2009) 18(4) Castillo, Milani & Mendez-Allwood

Bibliography previously untreated advanced follicular receiving rituximab. N Engl J Med lymphoma. J Clin Oncol 2008;26:4579-86 2001;344:68-9 1. Rui L, Goodnow CC. Lymphoma and the control of B cell growth and differentiation. 14. van Oers MH, Klasa R, Marcus RE, et al. 23. Matteucci P, Magni M, Di Nicola M, et al. Curr Mol Med 2006;6:291-308 Rituximab maintenance improves clinical Leukoencephalopathy and papovavirus outcome of relapsed/resistant follicular infection after treatment with 2. Groom J, Mackay F. B cells flying solo. non-Hodgkin lymphoma in patients both chemotherapy and anti-CD20 monoclonal Immunol Cell Biol 2008;86:40-6 with and without rituximab during antibody. Blood 2002;100:1104-5. 3. D’arena G, Cascavilla N. Chronic induction: results of a prospective 24. Teeling JL, French RR, Cragg MS, et al. lymphocytic leukemia-associated randomized phase 3 intergroup trial. Blood Characterization of new human CD20 autoimmune hemolytic anemia. 2006;108:3295-301 monoclonal antibodies with potent Leuk Lymphoma 2007;48:1072-80 15. Hainsworth JD, Litchy S, Barton JH, et al. cytolytic activity against non-Hodgkin 4. Zintzaras E, Voulgarelis M, Moutsopoulos Single-agent rituximab as first-line and lymphomas. Blood 2004;104:1793-800 HM. The risk of lymphoma development maintenance treatment for patients with 25. Teeling JL, Mackus WJ, Wiegman LJ, et al. in autoimmune diseases: a meta-analysis. chronic lymphocytic leukemia or small The biological activity of human CD20 Arch Intern Med 2005;165:2337-44 lymphocytic lymphoma: a phase II trial of monoclonal antibodies is linked to unique 5. Jemal A, Siegel R, Ward E, et al. Cancer the Minnie Pearl Cancer Research epitopes on CD20. J Immunol statistics, 2008. CA Cancer J Clin Network. J Clin Oncol 2003;21:1746-51 2006;177:362-71 2008;58:71-96 16. Byrd JC, Rai K, Peterson BL, et al. 26. Beum PV, Lindorfer MA, Beurskens F, 6. The Leukemia and Lymphoma Society. Addition of rituximab to fludarabine may et al. Complement activation on B Chronic lymphocytic leukemia. Available prolong progression-free survival and lymphocytes opsonized with rituximab or from: http://leukemia-lymphoma.org [Last overall survival in patients with previously ofatumumab produces substantial changes accessed 31 December 2008] untreated chronic lymphocytic leukemia: in membrane structure preceding cell lysis. 7. Helmick CG, Felson DT, Lawrence RC, an updated retrospective comparative J Immunol 2008;181:822-32 analysis of CALGB 9712 and CALGB et al. Estimates of the prevalence of arthritis 27. Bleeker WK, Munk ME, Mackus WJ, et al. 9011. Blood 2005;105:49-53 and other rheumatic conditions in the Estimation of dose requirements for United States. Part I. Arthritis Rheum 17. Cohen SB, Emery P, Greenwald MW, et al. sustained in vivo activity of a therapeutic 2008;58:15-25 Rituximab for rheumatoid arthritis human anti-CD20 antibody. Br J 8. Multiple Sclerosis Foundation. Available refractory to anti-tumor necrosis factor Haematol 2008;140:303-12 therapy: results of a multicenter, from: http://msfocus.org 28. Cillessen SAGM, Mackus WJM, randomized, double-blind, placebo- [Last accessed 31 December 2008] Castricum KCM, et al. Chemotherapy- controlled, phase III trial evaluating 9. Debouverie M, Pittion-Vouyovitch S, Louis S, refractory diffuse large B-cell lymphomas primary efficacy and safety at twenty-four et al. Natural history of multiple sclerosis in (DLBCL) are effectively killed by weeks. Arthritis Rheum 2006;54:2793-806 a population-based cohort. Eur J Neurol ofatumumab-induced complement- 2008;15:916-21 18. Hauser SL, Waubant E, Arnold DL, et al. mediated cytoxicity. Blood (ASH Annual B-cell depletion with rituximab in 10. Feugier P, Van Hoof A, Sebban C, et al. Meeting Abstracts) 2007;110:2346 relapsing-remitting multiple sclerosis. Long-term results of the R-CHOP study in 29. Hagenbeek A, Plesner T, Johnson P, et al. N Engl J Med 2008;358:676-88 the treatment of elderly patients with HuMax-CD20, a novel fully human diffuse large B-cell lymphoma: a study by 19. Castillo J, Winer E, Quesenberry P. Newer anti-CD20 monoclonal antibody: results of the Groupe d’Etude des Lymphomes de monoclonal antibodies for hematological a phase I/II trial in relapsed or refractory l’Adulte. J Clin Oncol 2005;23:4117-26 malignancies. Exp Hematol follicular non-Hodgkin’s lymphoma. Blood 2008;36:755-68 11. Habermann TM, Weller EA, Morrison VA, (ASH Annual Meeting Abstracts) et al. Rituximab-CHOP versus CHOP 20. Davis TA, Grillo-Lopez AJ, White CA, 2005;106:4760 alone or with maintenance rituximab in et al. Rituximab anti-CD20 monoclonal 30. Hagenbeek A, Plesner T, Walewski J, et al. older patients with diffuse large B-cell antibody therapy in non-Hodgkin’s HuMax-CD20 fully human monoclonal lymphoma. J Clin Oncol 2006;24:3121-7 lymphoma: safety and efficacy of antibody in follicular lymphoma. First re-treatment. J Clin Oncol 12. Pfreundschuh M, Trumper L, Osterborg A, human exposure: early results of an 2000;18:3135-43 et al. CHOP-like chemotherapy plus ongoing phase i/ii trial. Blood (ASH rituximab versus CHOP-like chemotherapy 21. Hainsworth JD, Meng C, Spigel DR, et al. Annual Meeting Abstracts) 2004;104:1400 alone in young patients with good- Long-term followup of patients with 31. Hagenbeek A, Gadeberg O, Johnson P, prognosis diffuse large-B-cell lymphoma: a follicular lymphoma (FL) treated with two et al. First clinical use of ofatumumab, a randomised controlled trial by the years of maintenance rituximab: response novel fully human anti-CD20 monoclonal MabThera International Trial (MInT) to rituximab retreatment at progression. antibody in relapsed or refractory follicular Group. Lancet Oncol 2006;7:379-91 ASH Annual Meeting Abstracts lymphoma: results of a phase 1/2 trial. 2006;108:4723 13. Marcus R, Imrie K, Solal-Celigny P, et al. Blood 2008;111:5486-95 Phase III study of R-CVP compared with 22. Dervite I, Hober D, Morel P. Acute 32. Coiffier B, Lepretre S, Pedersen LM, et al. cyclophosphamide, vincristine, and hepatitis B in a patient with antibodies to Safety and efficacy of ofatumumab, a fully prednisone alone in patients with hepatitis B surface antigen who was human monoclonal anti-CD20 antibody,

Expert Opin. Investig. Drugs (2009) 18(4) 9 Ofatumumab

in patients with relapsed or refractory B-cell Meeting, San Francisco, CA, USA, Antibody, IMMU-106 (hA20): phase I/II chronic lymphocytic leukemia: a phase 1-2 24 – 29 October 2008 results. Blood (ASH Annual Meeting study. Blood 2008;111:1094-100 38. Hallek M, Fingerle-Rowson G, Fink AM, Abstracts) 2006;108:2719 33. Coiffier B, Tilly H, Pedersen LM, et al. et al. Immunochemotherapy with 44. Liebman HA, Saleh MN, Abassi R, et al. HuMax CD20 fully human monoclonal fludarabine (F), cyclophosphamide (C), Low-dose humanized anti-CD20 antibody in chronic lymphocytic leukemia. and rituximab (R) (FCR) versus fludarabine monoclonal antibody (MAb), veltuzumab, Early results from an ongoing phase i/ii and cyclophosphamide (FC) improves in adult immune thrombocytopenic clinical trial. Blood (ASH Annual Meeting response rates and progression-free survival purpura (ITP): initial results of a phase i/ii Abstracts) 2005;106:448 (PFS) of previously untreated patients (pts) study. Blood (ASH Annual Meeting 34. Coiffier B, Tilly H, Pedersen LM, et al. with advanced chronic lymphocytic Abstracts) 2008;112:3412 Significant correlation between survival leukemia (CLL). Blood (ASH Annual 45. Hutas G. Ocrelizumab, a humanized endpoints and exposure to ofatumumab Meeting Abstracts) 2008;112:325 monoclonal antibody against CD20 for (HuMax-CD20) in chronic lymphocytic 39. Robak T, Moiseev SI, Dmoszynska A, et al. inflammatory disorders and B-cell leukemia. Blood (ASH Annual Meeting Rituximab, fludarabine, and malignancies. Curr Opin Investig Drugs Abstracts) 2006;108:2842 cyclophosphamide (R-FC) prolongs 2008;9:1206-15 35. Osterborg A, Kipps TJ, Mayer J, et al. progression free survival in relapsed or 46. Genovese MC, Kain JL, Lowenstein MB, Ofatumumab (HuMax-CD20), a novel refractory chronic lymphocytic leukemia et al. Ocrelizumab, a humanized CD20 monoclonal antibody, is an active (CLL) compared with FC alone: final anti-CD20 monoclonal antibody, in the treatment for patients with CLL refractory results from the international randomized treatment of patients with rheumatoid to both fludarabine and alemtuzumab or phase III REACH trial. Blood (ASH arthritis: a phase I/II randomized, blinded, bulky fludarabine-refractory disease: results Annual Meeting Abstracts) 2008;112:lba-1 placebo-controlled, dose-ranging study. from the planned interim analysis of an 40. Stashenko P, Nadler LM, Hardy R, et al. Arthritis Rheum 2008;58:2652-61 international pivotal trial. Blood (ASH Characterization of a human B Annual Meeting Abstracts) 2008;112:328 lymphocyte-specific antigen. J Immunol Affiliation 36. Ostergaard M, Baslund B, Rigby W, et al. 1980;125:1678-85 Jorge Castillo†1 MD, Cannon Milani1 MD & Ofatumumab, a human CD20 monoclonal 41. Robak T. Ofatumumab, a human Daniel Mendez-Allwood2 MD antibody, in the treatment of rheumatoid monoclonal antibody for lymphoid †Author for correspondence arthritis: early results from an ongoing, malignancies and autoimmune disorders. 1The Miriam Hospital, double-blind, randomized, placebo- Curr Opin Mol Ther 2008;10:294-309 Division of Hematology and Oncology, controlled clinical trial [abstract 2086]. 42. Morschhauser F, Leonard JP, Coiffier B, 164 Summit Ave, ACR/ARHP 2007 Annual Scientific et al. Initial safety and efficacy results of a Fain Building, Meeting, Boston, MA, USA, 6 - 11 second-generation humanized anti-CD20 Providence, RI 02906, USA November 2007 antibody, IMMU-106 (hA20), in Tel: +1 401 793 4645; Fax: +1 401 793 7132; 37. Ostergaard M, Baslund B, Rigby W, et al. non-Hodgkin’s lymphoma. Blood (ASH E-mail: [email protected] 2 Efficacy of ofatumumab in rheumatoid Annual Meeting Abstracts) 2005;106:2428 Boston University School of Medicine, Roger Williams Medical Center, arthritis (RA) patients with inadequate 43. Morschhauser F, Leonard JP, Fayad L, et al. response to one or more DMARDs: Department of Medicine, Rituximab-relapsing patients with Providence, RI, USA 48 weeks follow up [abstract 373]. non-Hodgkins lymphoma respond even at ACR/ARHP 2008 Annual Scientific lower doses of humanized anti-CD20

10 Expert Opin. Investig. Drugs (2009) 18(4)