Seattle Genetics’ SGN-40 – The big comeback

 

Seattle Genetics’ lead product is SGN-40, an antibody targeting CD40 which is a very common receptor expressed on various hematological malignancies such as non-Hodgkin lymphoma [NHL], chronic lymphoid leukemia [CLL] and Multiple myeloma [MM]. Surprisingly, CD40 is also expressed on solid tumors such as breast and ovarian cancers, which may broaden SGN-40’s spectrum of application. Although everybody is smiling at the moment, the company has undergone quite a rollercoaster with this candidate, lasting more than 8 years and involving 3 different names for the same antibody.

 

In June 1998, Seattle Genetics licensed an antibody that targets CD40 from the Swedish company, Mabtech. It received worldwide exclusive rights in return to milestone payments and royalties from future sales of the antibody, that was designated SGN-14. The company developed SGN-14 independently for exactly one year, at the end of which, in June 1999 it licensed SGN-14 to Genentech, who renamed SGN-14 with the “catchy” name PRO64553.

The deal with Genentech included $41.0 million in potential milestone payments and also provided for milestone payments of up to $20.0 million and future royalties on net sales of each additional product Genentech would license. In January 2002, the company announced that PRO64553 has entered Genentech’s clinical development portfolio with a clinical trial expected to start later in 2002. However, in October 2002 Genentech informed Seattle Genetics it abandoned plans to further develop the antibody. Seattle Genetics decided to independently develop the “abandoned” antibody, renaming it again to SGN-40 and launched 2 clinical trials in 2004.

The first phase I trial evaluated SGN-40 in multiple myeloma [MM] patients. This trial did not produce objective responses at doses up to 8 mg/kg, although some minor antitumor activities were observed.

The second phase I trial, which was reported in December 2006 was the turning point for SGN-40. The study evaluated SGN-40 among 31 heavily pre-treated non-Hodgkin’s lymphoma [NHL] patients. These patients had been treated with a variety of agents, including Rituxan, but their cancer eventually relapsed.

One patient had a complete response and 4 others had partial response, which implies an objective response rate of 16%, quite encouraging for a phase I dose escalation trial, where the first enrolled patients receive very low doses of the drug. Interestingly, of the five objective responses, 4 were in aggressive NHL, 3 of which were in Diffuse Large B-Cell Lymphomas (DLBCL) patients, the most common subtype of aggressive NHL.

Based on these findings and other pre-clinical results which implied SGN-40 might have synergies with conventional NHL treatments, Genentech decided to re-partner with Seattle Genetics for the development of SGN-40, however, this time, it cost Genentech much more than the previous deal. The impressive clinical results gave Seattle Genetics much better negotiation leverage, as it was clear to both sides that SGN-40 has a huge potential. The new agreement includes a $60 mil upfront payment, more than 800$M in potential milestones and double-digit escalating royalties of future sales of SGN-40. In addition, Genentech is obliged to finance all costs of R&D, manufacturing and commercialization related to SGN-40.

It is clear that Genentech has extremely high hopes for SGN-40 as an important candidate in its pipeline, with possible synergies with its current NHL antibody – Rituxan. The market for NHL is huge, with over 63,000 cases expected to be diagnosed in 2007 in the US alone, over 40% of which will be diagnosed with aggressive disease. Rituxan proved to be highly efficient in treating NHL as a single agent or in combination with chemotherapy.

It is also effective to a lesser degree in patients with relapsed NHL who had previously received Rituxan, but ultimately many patients relapse or become resistant to available treatments and are left without a viable option. Thus, new treatments are urgently needed in order to increase the efficacy of current treatments, extend disease-free intervals and serve as an additional option for relapsed patients.

Rituxan is the best selling monoclonal antibody in history (almost $4 billion in annual sales in 2006), largely due to its use in NHL and CLL. This success has made NHL and more specifically, Rituxan’s target, the CD20 receptor, a very attractive target for other companies who develop monoclonal antibodies.

Unfortunately for Genentech, it could not patent the actual targeting of CD20 by monoclonal antibodies in order to fend off competition. This is in contrast to the situation with Herceptin, where Genentech had patented Herceptin’s target (her2) in a way that no one can sell anti-her2 antibodies, without getting Genentech’s permission. The two primary anti-CD20 antibodies currently in development are Genamb’s ofatumumab and Immunomedics’ (IMMU) veltuzumab, both might have certain advantages over Rituxan.

In order to tighten its grip on the NHL market, Genentech is currently developing several antibodies for the treatment of NHL, one of which targets CD20 while 3 others (Avastin, Apomab and SGN-40) do not target CD20. These antibodies are currently evaluated in combination with Rituxan, and if proven effective, may help Genentech maintain its dominant position in the NHL market.

Genentech and Seattle Genetics are not wasting any time and already announced what seems to be an extremely broad and ambitious clinical program for such an early stage candidate. In addition to two ongoing clinical trials, the companies expect to have 4 additional clinical trials by the end of Q1 of 2008. Altogether, these trials encompass a wide spectrum of potential use, from early stage to relapsed disease and from indolent to aggressive NHL, as well as two multiple myeloma evaluations.

An ongoing phase II study, which was initiated by Seattle Genetics before the agreement with Genentech, evaluates SGN-40 as a single agent in DLBCL patients. Considering the promising activity SGN-40 showed in the phase I trial specifically in that subset of patients and the fact that DLBCL represent the most common type of aggressive NHL, this trial looked like the obvious next step. This trial has chances of showing very impressive results due to the homogenous patient population and the high dose utilized in this trial (8 mg/kg/week). The companies expect to have data from this study next year.

A second phase II trial will evaluate SGN-40 in combination with Rituxan and the chemotherapy regimen- ICE, following promising preclinical results of this combination. This trial will be a double blind, randomized, which means that it is aimed at showing that SGN-40 has an additive effect to standard therapy. Rituxan+ICE are often used as 2nd line therapy for DLBCL in order to enable patients to undergo bone marrow transplant, so the ultimate goal here is to ameliorate the success rate of this procedure.

A third phase I trial is planned to start already in 2007 in England. This trial will evaluate the combination of SGN-40 with Rituxan in non-aggressive (indolent) NHL patients.

A fourth trial will evaluate the combination of SGN-40 with Rituxan and Eli Lilly’s (LLY) Gemzar in DLBCL patients. Rituxan + Gemzar are often used to treat patients with relapsed disease who cannot tolerate Rituxan+ICE.

Since SGN-40 didn’t prove to be highly effective in MM patients as a single agent, the companies decided to combine it with 2 of the most dominant drugs in the MM market. An ongoing trial was initiated this month, evaluating SGN-40 and Celgene’s (CELG) Revlimid. A second trial, expected to be launched in Q108, will evaluate SGN-40 in combination with Millennium’s (MLNM) VELCADE.

Although outcomes of clinical trials are unpredictable, the promising results in highly pretreated NHL patients, the aggressive clinical program and the strong presence of Genentech substantially improve success rates of SGN-40 when compared to the average candidate in the same clinical stage. Even if SGN-40 is not eventually approved for the treatment of every indication for which it is being evaluated, Seattle Genetics is still looking at a constant flow of several tens of millions of $ worth of milestones payments from Genentech over the next several years. As previously stated, all the costs related to the SGN-40 clinical development are paid by Genentech so Seattle Genetics can safely allocate resources to other clinical programs, which will be discussed in the coming posts.

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