Antibody Drug Conjugates Still Making Slow Progress

July 15, 2011 Therapeutic focus - Antibody drug conjugates still making slow progress

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The field of antibody drug conjugates has long held promise and is generating more and more excitement but, so far, has actually delivered little in terms of products on the market. As such, broad backing for Seattle Genetics’ Adcetris yesterday from FDA advisors is an encouraging sign for a new generation of compounds moving through the clinic (Panel backs Adcetris but keeps leash short, July 15, 2011).

Using an antibody to target a tumour and deliver radiotherapy or a cytotoxic agent is not a particularly new idea, but researchers have struggled to produce the sort of clinical outcomes many have predicted for this field. Behind Adcetris are a handful of promising agents, most notably T-DM1 from Roche and ImmunoGen, viewed as a follow-on product for Herceptin. But with most agents still only in mid-stage trials and earlier, it seems the field still has some way to travel to deliver on its promise (see tables below).

On the market

Two antibody-drug conjugates are on the US market – GlaxoSmithKline’s Bexxar and Spectrum Pharmaceuticals’ Zevalin. Both deliver radiotherapies and are used to treat blood cancers.

Neither has been a particular commercial success; Glaxo does not reveal sales of Bexaar and Zevalin has passed through several hands since it reached the market back in 2002.

Zevalin is a CD20 antibody combined with the Y-90 radioisotope that targets the CD20 antigen expressed on malignant B-cells associated with non-Hodgkin’s lymphoma. In Europe it is sold by Bayer, which also does not disclose sales.

Spectrum reported US revenue of $6m in the first quarter of the year, unchanged from the same period in 2010. The company plans to test the drug in aggressive lymphomas this year, in an attempt to broaden its label, and is also trying to remove a requirement for patients to undergo a bioscan before therapy, which it hopes will help drive uptake.

Wyeth's Mylotarg was the first conjugate to use a cytotoxic agent to reach the market, also to treat leukaemia. However the product's current owner Pfizer withdrew it from the US market last year due to severe side effects and questions over efficacy. In Europe, where it is sold by UCB, use is very limited.

Given this thin showing on the market, it is not surprising to see that as many conjugates have been ditched as remain in clinical development today. Count of Antibody Drug Conjugates

Status Product Count

Marketed 3

Filed 1

Phase III 3

Phase II 12

Phase I 25

Pre-clinical 36

Research projects 14

Total Active Pipeline 91

Abandoned - Phase III 4

Abandoned - Phase II 16

Abandoned - Phase I 23

Abandoned - Pre-clinical 25

Abandoned - Research 15 project

Total Abandoned Pipeline 83

Total ADCs 177

Adcetris certainly represents a new wave of these agents; the drug’s clear effectiveness and more tolerable side effect profile means the drug appears to have a much greater chance of commercial success – assuming the regulator follows the advice of its panel.

Behind Adcetris is a product that holds the most hopes for this field, T-DM1. The product conjugates Herceptin to a toxic chemotherapy agent and is in development for HER2 positive breast cancer. Although Roche failed to win accelerated approval for the product last year, data that has emerged since has raised hopes a confirmatory phase III trial, due to report in the middle of next year, will put the drug firmly back on the path to market (ImmunoGen buoyed by T-DM1 surprise, April 8, 2011).

The other two remaining phase III candidates are not building such huge hopes at this stage. Pfizer has a phase III trial ongoing with a product inherited from Wyeth, CMC-544, a conjugate of a CD22 targeting antibody and a cytotoxic calicheamicin compound, ozogamicin - the same cytotoxic agent used in Mylotarg. The trial is running in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma who are not candidates for intensive high-dose chemotherapy. CMC-544 is being evaluated in combination with Rituxan, versus Rituxan plus another active agent of the physician’s choosing.

The study only started this year, and final results are not due until 2014.

Active Biotech’s Anyara is in a phase II/III renal cell carcinoma study, which completed enrolling 526 patients in June 2009. The company expects to present results in the first half of next year; 384 deaths will trigger the final analysis – the drug is being studied in combination with interferon alpha, versus interferon alone, and the primary endpoint is overall survival.

The study is only going on in Europe, where the drug has orphan status. The agent is a fusion of two proteins, an antibody fragment which targets the 5T4 antigen, delivering what the company describes as a superantigen, estafenatox, to the tumour cells. This triggers the body’s immune system to attack the cancer, so in essence the product is an immunotherapy.

The choice of control group certainly raises questions about how Active will move forward with this compound, if results are positive. Oral kinase inhibitors like Sutent are considered standard of care for kidney cancer now, particularly in the US. Add to this the fact the study has no US component, Anyara’s potential in the world’s biggest drug market is questionable, even if the results are positive. Antibody Drug Conjugates - Marketed and Late Stage Pipeline

Pharmacological Status Product Generic Name Company Originator Class

Anti-CD20 MAb- ibritumomab Spectrum Marketed Zevalin yttrium 90 IDEC Pharmaceuticals tiuxetan Pharmaceuticals/Bayer conjugate

tositumomab; Anti-CD20 MAb- Dana-Farber Cancer Bexxar iodine I 131 iodine 131 GlaxoSmithKline Institute tositumomab conjugate

Anti-CD33 MAb- Mylotarg (EU gemtuzumab Fred Hutchinson Cancer calicheamicin Pfizer/UCB only) ozogamicin Research Center conjugate

Anti-CD30 MAb- Seattle brentuximab Filed Adcetris auristatin E Seattle Genetics Genetics/University of vedotin conjugate Miami

Anti-HER2 (ErbB- Trastuzumab- trastuzumab 2) MAb-DM1 Phase III Roche ImmunoGen/Genentech DM1 emtansine maytansinoid conjugate

Anti-5T4 MAb- naptumomab Anyara SEA/E-120 toxin Active Biotech Pharmacia estafenatox conjugate

Anti-CD22 MAb- inotuzumab CMC-544 calicheamicin Pfizer Celltech/Wyeth ozogamicin conjugate

Anti-CD56 MAb- lorvotuzumab Phase II huN901-DM1 DM1 maytansinoid ImmunoGen ImmunoGen mertansine conjugate

Anti-cancer MAb- Peregrine Cotara - iodine 131 Cancer Biologics Pharmaceuticals conjugate

Anti-GPNMB MAb- glembatumumab CDX-011 auristatin E Celldex Therapeutics CuraGen vedotin conjugate

moxetumomab Anti-CD22 MAb- National Cancer Institute CAT-8015 AstraZeneca pasudotox PE38 conjugate (NCI; USA)

yttrium Y-90 Anti-MUC1 MAb- IMMU-107 clivatuzumab yttrium 90 Immunomedics Immunomedics tetraxetan conjugate

yttrium Y-90 Anti-CD22 MAb- IMMU-102 epratuzumab yttrium 90 Immunomedics Immunomedics tetraxetan conjugate

Anti-CD74 MAb- Milatuzumab- - doxorubicin Immunomedics Farmitalia/Immunomedics Dox conjugate

Anti-CD138 MAb- BT-062 - DM1 maytansinoid Biotest Biotest/ImmunoGen conjugate

Anti-cancer MAb- Teleukin - Philogen Philogen IL-2 conjugate Anti-fibronectin L19-131I - MAb-iodine 131 Philogen Philogen conjugate

Anti-fibronectin L19- - MAb-IL-2 Philogen Philogen Interleukin 2 conjugate

Anti-fibronectin L19-TNF - MAb-TNF Philogen Philogen conjugate

Beyond these late stage-candidates and the field is a broader mix of conjugates, from radiotherapy to cytotoxic to immunotherapy.

ImmunoGen, a dominant player in the field, is running phase I/II trials with IMGN901 in small cell lung cancer and has numerous other candidates in earlier stage studies with a number of different partners. For example BT-062 is being developed under a collaboration between ImmunoGen and Biotest, in multiple myeloma. The antibody targets CD138 antigens, which are over-expressed in many multiple myelomas, and delivers a cytotoxic maytansinoid derivative.

The study is ongoing and results should be available early next year; ImmunoGen has opt in rights in the US.

Seattle Genetics also has a number of other agents in earlier stage trials and in collaborations with other parties. Celldex's CDX-011 uses its technology to link a GPNMB targeting antibody to the cytotoxic agent monomethyl auristatin E. Trials are ongoing in GPNMB-expressing advanced, refractory breast cancer, which includes the hard-to-treat triple negative disease.

The company hopes to fully recruit its 120-patient phase IIb study by the end of the year and the compound counts as one of the most advanced of the mid-stage conjugate pipeline.

Another agent that is attracting attention is Peregrine's Cotara, an antibody linked to a radioisotope which is administered as a single-infusion therapy directly into brain tumours. At Asco this year the company announced results from a phase II trial in patients with recurrent glioblastoma multiforme; median overall survival reached 8.8 months, whereas most patients can expect to live for only 6 months.

The company is in the process of talking to the FDA about the path forward for the product; hopes must be that the regulator will signal accelerated approval is possible.

Earlier efforts

Most other candidates in the list above are in earlier stages of development.

Immunomedics is working on a number of conjugates, both cytotoxic and radiolabelled. Milatuzumab is being trialled as both a naked antibody and a conjugate – a phase I/II trial of the antibody attached to doxorubicin is ongoing, in multiple myeloma. IMMU-107 is clivatuzumab labelled with Y-90, currently undergoing a phase I/II trial in pancreatic cancer, while IMMU102 is a combination of two antibodies, veltuzumab and epratuzumab, the latter attached to Y-90, being tested in aggressive non-Hodgkin’s lymphoma.

Philogen is working on a number of what it terms as immunoconjugates – Bayer recently returned rights to several products following a 12-year collaboration between the two companies, which derailed the Italian company's IPO plans this year.

A couple have just made it into mid-stage testing: For example L19-TNF is a fully-human vascular targeting immunocytokine, consisting of the anti-EDB human antibody L19, fused to human TNF, a strong pro- inflammatory cytokine. A phase I/II study in colorectal cancer is ongoing. L19-131 I is the radiolabeled version of the human vascular targeting antibody L19, in trials for both solid and haematological malignancies, while L19-IL2 consists of the human vascular targeting antibody L19 and human interleukin-2, in studies for melanoma.

Meanwhile one of the few big pharma names in the space, AstraZeneca, is running a phase I/II study of CAT- 8015, an anti-CD22 recombinant immunotoxin, in various blood cancers.

So beyond Adcetris and TDM-1, the conjugate pipeline is still looking decidely early stage and experimental. Hopes are high for both candidates and are growing for the technology more broadly - some commercial validation is still needed. More from Evaluate Vantage

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