Seattle Genetics starts its voyage towards precisely targeted cancer therapy
The first drug candidates
Early on in its operations SGEN envisaged developing four different types of targeted antibody-therapy. Alongside ADC candidates, it looked to genetically engineer mAbs that could be used as single-agents and or in combination with chemotherapy. The company also wanted to create single-chain immunotoxins. This treatment consists of mAb fragments fused with toxin components. It is designed to kill cells by blocking protein production. The last kind of treatment was an antibody-directed enzyme prodrug therapy. This involved administering a mAb fused with an enzyme that could activate a potent anti-cancer drug (prodrug) which formed the second part of the treatment (A/R 2001, p.4).
By 2001 SGEN had three product candidates in clinical trials. This included SGN-15, the company’s lead ADC candidate, which was undergoing phase II trials. The drug was composed of the cytotoxic drug doxorubicin that was linked to a chimeric mAb (BR96). It was designed to target Lewis-y, an antigen commonly expressed on tumours in patients with breast, colon, prostrate, lung and ovarian cancer. In addition to SGN-15, the company was evaluating SGN-30, a genetically engineered mAb, and SGN-10, a single-chain immunotoxin, in phase I trials (A/R 2002, p.26).
Out of the three candidates SGN-10 fared least well. It was discontinued in October 2002. Three years later, in July 2005, SGEN also halted its work on SGN-15. This was despite the fact that the ADC drug had provided some promising results in phase II. The company took the decision to prioritise its resources on other candidates. This included SGN-40, the product with which it was collaborating with Genentech. The drug, a naked antibody, entered phase I trials in 2003 and phase II trials in 2006. Yet, results from these trials proved disappointing (see above) so SGEN decided to end its development of SGN-40 in October 2009 (A/R 2003, p.25; A/R 2005, p.10; A/R 2009 p.7). In the end, the company clinically tested two drugs that targeted CD40, one with more potency than the other. Results from the second drug, however, proved just as disappointing as the first (2).
Overall Siegall was phlegmatic about the failure of the anti-CD40 drugs. For him drug failures were an ‘important part of building a biopharmaceutical company, especially one working in oncology.’ The key was never to close a project without learning something (James). From Siegall’s perspective the difficulties SGEN experienced with its anti-CD40 drugs highlighted the complex nature of developing a targeted antibody treatment. As he points out, antibodies that target the same receptor are not all the same. Each interact with unique epitopes in different ways. An epitope refers to the specific site on an antigen that an antibody binds to. A single antigen usually has several different epitopes (figure 8). The interplay between the antibody and epitope is important because it affects how the antibody gets trafficked within a cell, moves and sends signals to other cells. Overall the process is very complicated and takes a lot of research to work out. Drug development is not only reliant on just looking at specific receptors on a tumour cell. It also involves understanding those on normal tissue cells that you do not want to target. Picking out an appropriate target for drug development is therefore not a random process. A great deal of work has to go on first at the preclinical stage to understand how an antibody will function with a target antigen and those found on other cells before it can advance into clinical development (Siegall).
Figure 8: Diagram of antibodies binding to different epitopes on an antigen (Credit: ME Glen, ‘Choosing a Method for Epitope Mapping’, Methods in Molecular Biology (1996) in Epitope Mapping Protocols. 03 Dec. 2008, https://en.wikibooks.org).
The journey towards the first drug breakthrough - brentuximab vedotin
By the time SGEN closed its SGN-40 programme it had been in operation for 12 years and it had accumulated a deficit of approximately US $396 million (A/R 2009, p.30). Fortunately, by then the company had begun to get favourable results for another product in its pipeline that had entered clinical trials (Wright). The drug, known as SGN-35 or brentuximab vedotin, was an ADC candidate. Later given the brand name Adcetris, the drug emerged out of Clay Siegall’s research into the CD30 antigen. First identified in 1982, CD30 is part of the tumour necrosis factor (TNF) receptor superfamily (Weyden).
Siegall developed a deep interest in CD30 early on because he could see that it was expressed on Hodgkin lymphoma (HL) and T-cell lymphoma cells. Both cancers originate in lymphocytes, white blood cells, and can spread to other parts of the body. Neither cancer was amenable to treatment with rituximab, the drug that was approved in 1997 for combating B-cell lymphoma. Indeed there were few effective and durable treatment options for such cancers. This was a particularly difficult problem in the case of HL. While the disease is highly curable, up to 10-15 percent of patients with early stage HL and about 40 percent of patients with advanced-stage disease will relapse after their initial treatment and face a high risk of relapsing again after responding to multi-agent chemotherapy and autologous stem cell transplantation (Boltzmann).
From talking to doctors and scientists in the field, Siegall quickly realised that CD30 could be a great target for a drug. It had the advantage that it was expressed on many hematologic malignancies, including Hodgkin lymphoma and some types of T-cell non-Hodgkin lymphoma, but was largely absent on normal tissues (A/R, 2002, p.5). Some preclinical studies carried out in the mid- to late 1990s already indicated that an anti-CD30 murine mAb could inhibit the growth of anaplastic large cell lymphoma (ALCL) tumours transplanted into mice (Tian, Pfeffer). ALCL is a rare type of NHL.
By September 1999 SGEN had taken out an exclusive license with the University of Miami in preparation for the development of products to target the CD30 antigen. This led to the creation of SGN-30, a chimeric mAb drug, that the company started clinically testing as a single-agent in 2002. The first trial, a single-dose phase I study was conducted in 13 patients with HL and ALCL. Encouragingly the drug was well tolerated and some patients experienced anti-tumour responses. A second multi-dose phase I/II trial undertaken between 2002 and 2003 with 24 patients was equally promising. By 2004 the FDA had granted SGN-30 orphan drug designation and SGEN had launched phase II trials to test out the drug in patients with HL and ALCL. Patients were accrued for the study from 40 cancer centres in the United States and Europe (A/R, 2003, p.7).
This was just the start of a series of trials. In December 2006 SGEN reported that while the drug was well-tolerated and demonstrated objective responses in patients with relapsed or refractory systemic ALCL and in patients with CD30-positive lymphoproliferative disorders, it was less effective in those with relapsed or refractory Hodgkin’s disease. Thereafter, the company launched three phase II trials with the National Cancer Institute (NCI) to evaluate the safety and efficacy of SGN-30 as a combination therapy. The trials looked at the effects of SGN-30 with different chemotherapy combinations (A/R, 2006, p.9). By 2006, however, SGEN had decided it would no longer sponsor any more trials with SGN-30 because the naked antibody had proven insufficiently active as a single-agent. Instead it was left to the NCI to conduct limited trials for which SGEN supplied the clinical material (A/R, 2007, pp.20, 41.)
SGEN switched its attention instead to working on SGN-35, which was an ADC product. Also known as brentuximab vedotin, the drug contained an anti-CD30 mAb that was attached to MMAE, a potent cell-killing drug, with a protease-cleavable linker. Preclinical studies indicated that brentuximab vedotin was both effective at targeting CD30 and delivering its cytotoxic payload. It also had localised bystander effects within tumours. Like SGN-30, brentuximab vedotin was given orphan drug designation from the FDA to treat both HL and T-cell lymphoma patients. The first phase I trials for the drug were launched in November 2006 with patients with relapsed or refractory CD30-expressing hematologic malignancies, including Hodgkin’s lymphoma. These were aimed at assessing the safety of the drug and its pharmacokinetics and pharmacodynamics and its side effects at different doses and dosing schedules (A/R 2006, p.10).
It did not take long to see that brentuximab vedotin could be a viable product. This happened as soon as the drug entered a phase I dose escalation trial, which was launched in 2008. Siegall remembers this kept happening over a period of several months. The next thing Siegall heard was that hematologist oncologists were fighting to get slots for their patients to participate in the trial. As Siegall puts it, ‘I’ve been part of the development of many different drugs and some drugs work incrementally and other drugs can work but maybe are too toxic, and some drugs have small effects, albeit the drug is safe. But Adcetris was relatively safe and had a large anti-tumour effect on patients. So we knew this was different’ (Siegall).
Just how valuable brentuximab vedotin could be for patients was soon reinforced by the pivotal phase II trial. Launched in February 2009, with special protocol assessment (SPA) by the FDA, the trial enrolled 102 patients with relapsed or refractory HL patients who had failed previous treatments. Siegall recalls the excitement when they unblinded the data in late 2009. This revealed that 75 percent of the patients in the trial had achieved an objective response as assessed by an independent central review (ICR). The result was well in excess of the team’s expectations. Moreover, the median duration of response was 29 weeks as assessed by the ICR and 47 weeks as assessed by the investigators. In addition, 34 percent of the patients had gone into complete remission. Tumour reductions had also been achieved in 94 percent of the patients. Everyone in the room was thrilled when the data was unblinded (Siegall), (A/R 2010, pp.3, 10, 43).
Some months later SGEN unblinded data from another one of its pivotal phase II trials of brentuximab vedotin among 58 patients with relapsed or refractory sALCL. This showed that 86 percent of the patients had achieved an objective response as assessed by the ICR. Fifty-three percent of the patients achieved a complete remission (A/R 2010, p.43). The median duration of the objective response was subsequently found to be 13.2 months overall and 26.3 months in patients who achieved complete remission (Pro).
FDA approval of Adcetris®
By February 2011, SGEN had sufficiently positive evidence for it to submit a Biologics License Application (BLA) to the FDA. It sought approval for Adcetris to be used as a treatment in patients with relapsed or refractory HL and relapsed or refractory sALCL. Both of these indications affect small patient populations. In 2009 the NCI calculated that there were only about 2.8 new cases of HL diagnosed out of 100,000 persons in the US. Similarly, the incidence for ALCL was also low. ALCL is a very rare type of NHL and one of the subtypes of T-cell lymphoma. According to the Lymphoma Research Foundation this disease makes up 1 percent of all cases of NHL and approximately 16 percent of those with T-cell lymphoma. While the incidence of T-cell lymphoma is largely unknown, the NCI estimated there were 20.9 new cases of NHL per 100,000 persons in the US in 2009 (NIH, Holland).
The actual number of patients for which SGEN was seeking to get the drug approved for was reduced by the fact that it was to be used in those who had either failed to respond to initial treatments or those who faced the return of the disease after initial treatment. Altogether this was a small number of patients. Yet, it reflected SGEN's strategy to first win FDA approval for relatively late-stage indications and then go after earlier-line indications for which there was a larger pool of patients. The same approach, for example, had been used by Idec and Genentech in their development of rituximab (Marks). SGEN's BLA application was supported by safety information from a total 357 patients who had received at least a single dose of brentuximab vedotin, 160 of whom had taken part in the phase II trials (Claro).
The BLA submission marked a significant milestone for SGEN. Importantly, it validated its ADC technology. Nonetheless, the company still faced major challenges. Firstly, it had no guarantee that the FDA would approve the drug. Secondly, even if approved, it did not know how it would be accepted by physicians, patients, third-party payers and other key decision-makers. In addition, its drug targeted a very small niche of patients. All of this was daunting given the company did not yet have another commercial product on the market and as of December 2010 had accumulated a deficit of $462 million (A/R 2010, pp.27, 44).
SGEN also faced an uphill task of making sure it would have enough quantities of the drug should it get approval. Up to this point the company had relied on third-party manufacturers and other third parties to produce the drug. Some idea of how much SGEN spent on development and contract manufacturing can be gauged from figure 9. In the case of brentuximab vedotin SGEN looked to Abbott Laboratories, which supplied the mAb used in the drug and AMRI and SAFC for the drug linker. It also had a manufacturing and supply agreement with Pierre Fabre Medicament Production, S.A.S. for the cGMP fill/finish manufacture of commercial quantities of brentuximab vedotin (A/R 2010, p.29).
On top of this SGEN needed to build up a sales and marketing operation in the event that the drug got approved. SGEN's executives calculated that they would need to invest in approximately 50 to 75 sales representatives to market Adcetris in the United States and Canada. All of this had to be done before knowing that the FDA would approve the drug. To market the drug elsewhere in the world it had the help of Millennium and its Takeda affiliates with whom it reached an agreement in December 2009 (A/R 2010, pp 4, 28).
Figure 9: SGEN's expenses on research, development and contract manufacturing and clinical trials (US $ millions) (Credit: A/Rs, 2004-2018).
One factor SGEN had in its favour was that the FDA had granted Adcetris fast track status in March 2009 for the treatment of patients with HL. In the end the approval took just six months to come through. This happened in August 2011. The drug was given accelerated approval for relapsed or refractory HL and relapsed sALCL. Adcetris was the second ever ADC drug to be licensed for market. It also soon gained approval in the European Union (October 2012) and Canada (February 2013). By the beginning of 2014 Adcetris had received marketing licenses for relapsed HL and relapsed sALCL in 39 countries (A/R 2013, p.7). These authorisations gave SGEN a solid basis on which to start investigating Adcetris for other indications.
Figure 10: Net sales of Adcetris® in US and Canada (US $ millions) (Credit: Data from Brad Loncar: Biotech Data, Adcetris sales over time, https://www.loncarblog.com/adcetris-net-sales).
By the time SGEN had won the FDA’s approval in 2011 it had spent approximately US $750 million on research & development. This included its investment in other drug candidates, five of which had fallen by the wayside along the way (13). Over the next few years SGEN continued to pour more money into brentuximab vedotin, as well as other drug candidates in the company pipeline. These efforts totalled US $2.3 billion for the years between 2012 and 2018. Continued development of brentuximab vedotin sought to evaluate the drug as a frontline therapy for HL and peripheral T-cell lymphoma (PTCL), also known as mature T-cell lymphoma (MTCL), including sALCL, as well as for other CD30 positive malignancies such as cutaneous T-cell lymphoma (CTCL) and diffuse large B-cell lymphoma (DBCL). Some of these trials were directed towards examining the drug in combination with other chemotherapies.
While SGEN received two labels for post-transplant HL and for cutaneous T-cell lymphoma, the focus was on frontline HL and PTCL. The first milestone was reached in March 2018 when the FDA licensed brentuximab vedotin as a frontline therapy for patients newly diagnosed with HL. It was to be administered together with other chemotherapies. In November 2018, the FDA also granted approval for the drug to be used, together with other chemotherapies, in patients with previously untreated sALCL or other CD30-expressing PTCLs including angioimmunoblastic T-cell lymphoma. This brought the total indications for which the FDA had approved drug to six. By February 2019 the drug had received marketing authorization in 72 countries and marketing authorizations were being pursued in multiple other countries (A/R 2018, p.1).
Adcetris has provided an important income source for SGEN, which has seen a steady rise in revenue from its sales of Adcetris (figure 10). In addition the company has received a number of royalty and milestone payments from Takeda which has managed to win marketing approval for Adcetris in multiple countries outside North America. Much of the money SGEN has gained from Adcetris is being reinvested in further clinical trials. As of February 2019 Adcetris was being evaluated in more than 70 ongoing clinical trials in CD30-expressing lymphomas (SGEN).
A second drug breakthrough - enfortumab vedotin
By 2019 it was becoming clear that Seattle Genetics could have a second drug breakthrough with enfortumab vedotin (ASG-22ME). This is an ADC drug that contains a mAb that targets Nectin-4, a cell surface protein that is expressed in multiple cancers including bladder, breast, lung and pancreatic cancers, that is linked to MMAE, a potent microtubule disrupting agent. It emerged out of an agreement that SGEN entered with Agensys, which was acquired by Astellas Pharma in January 2007, to jointly research, develop and commercialise ADC drugs incorporating fully human antibodies (A/R 2007, p.13; Siegall).
Enfortumab vedotin entered the first of a series of phase I trials for Nectin-4 positive solid tumours in July 2011 (A/R 2012, pp.11, 46). By October 2016 sufficient data had been collected from a phase 1, open-label, dose-escalation multi-centre trial to show that enfortumab vedotin could be a promising treatment for metastatic urothelial cancer, a type of cancer that affects the bladder, ureter and renal pelvis and can spread to nearby tissues and other areas of the body (A/R 2016, pp.3, 14). Encouraging results from this trial led to the FDA granting the drug breakthrough therapy designation in March 2018, a status that is designed to expedite the development and review of drugs intended to treat serious or life-threatening conditions.
The following year the two companies started a pivotal phase II trial with the drug for patients with locally advanced or metastatic urothelial cancer, which is largely bladder cancer, who have previously received a platinum-containing chemotherapy and a PD1 or PD-L1 inhibitor therapy and a phase 1b trial to evaluate in combination with checkpoint inhibitor (CPI) therapy in patients with first- or second-line locally advanced or metastatic urothelial cancer. By July 2018 the two companies had launched a global, randomised phase III trial with enfortumab vedotin in patients with locally advanced metastatic urothelial cancer who have been treated with a platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. Urothelial cancer comprises 90 per cent of all bladder cancers (SGEN A/R 2017, p.6). An additional phase Ib trial was launched to evaluate the drug in locally advanced metastatic urothelial cancer, including in newly diagnosed patients in combination with pembrolizumab and/or platinum chemotherapy. Half of the expenses of the trials were covered by Astellas. The other half were paid for by SGEN (A/R 2018, p.9).
In June 2019, results from the phase II trial were presented to the ASCO Annual Meeting. These demonstrated that enfortumab vedotin rapidly shrank tumours in most patients (A/R 2016, pp.3, 14). A month later the two companies announced submission of a BLA for accelerated approval to the US FDA. An additional phase Ib trial was launched to evaluate the drug in locally advanced metastatic urothelial cancer, including in newly diagnosed patients in combination with pembrolizumab and/or platinum chemotherapy. Half of the expenses of the trials were covered by Astellas. The other half were paid for by SGEN.
In December 2019 the US FDA granted accelerated approval to enfortumab vedotin (Padcev) for the treatment of adult patients with locally advanced or metastatic urothelial cancer who had failed to respond to standard treatment including chemotherapy and immunotherapy. The FDA made the approval based on results of a clinical trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who had previously been treated with PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Overall, 12 per cent of the patients in the trial experienced a complete remission of their cancer and 32 per cent experienced a partial shrinkage of their tumours. On average the patients response lasted 7.6 months. The drug is continuing to be trialled to assess its clinical benefit. This is importance as a number of side effects were recorded with the drug during the clinical trial. This included high blood sugar, damage to peripheral nerves (peripheral neuropathy), eye disorders, skin reactions and infusion site reactions. There was also concern about possible harm to an unborn baby. For this reason all women of reproductive age who take the drug are advised to take contraceptive precautions (FDA news).
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