< PreviousIMMUNOTHERAPY EXPOSÉ́ 10 Pharma Business International www.pbiforum.net immunotherapy to those that would best respond to it. This is far from the only exciting outcome in the research and development space to affect the future of immunotherapy. Danish biotech Genmab joined forces with Immatics Biotechnologies to discover and develop next-generation bispecific immunotherapies. And they’ve lined up multiple cancer indications in the crosshairs. The research collaboration sees Genmab combine its propriety technologies and the expertise it has accrued working with antibodies with Immatics’ Xpresident targets and T-cell receptor capabilities. The specifics of the agreement mean that Genmab receives an exclusive license to three proprietary targets from Immatics with an option to license up to two additional targets. Perhaps one of the most exciting developments over the last few years comes from researchers at the University of California, San Diego and the University of Minnesota. The team has developed an immunotherapy that, they say, uses immune cells cultured from stem cells to seek and destroy cancer cells. This method differs from the norm where cells are typically taken from patients, potentially creating a new way in which immunotherapies are undertaken. The scientists say that this new approach may lead to off-the-shelf stocks of cancer-killing cells. In their research, the team detail how the cells showed enhanced anti-tumour activity in mice with ovarian cancer seeded from human cancer cells. This type of immunotherapy is chimeric antigen receptor therapy – or CAR, for short. Basically, it bolsters the cancer killing power inherent in immune cells by reprogramming them to express CAR protein, which has been specifically engineered to bind only to cancer cells. Much of the research taking place, and indeed where much of the funding is directed, is CAR-T cell immunotherapy. This more typical approach uses genetically altered T cells grown from cells taken from patients. This new approach, however, uses natural killer cells obtained from human induced pluripotent stem cells instead of patient specific T cells. According to 08-11.qxp_Layout 1 10/08/2020 15:25 Page 3Pharma Business International 11 www.pbiforum.net IMMUNOTHERAPY EXPOSÉ́ senior study author Dan N Kaufman, a professor of at the University of California, San Diego natural killer cells are advantageous because they don’t have to be matched to a specific patient. So this development can shorten the times in which patients are made to wait and create a more universal and robust solution for all patients. Elsewhere, scientists have found that by supercharging the mutation rate in cancer cells, a powerful vaccine can be created that is able to boost the effectiveness of immunotherapy, researchers claimed. The scientists forced cancer cells in the lab to evolve much more rapidly than usual using a molecule called APOBEC3B, which is often used by tumours to drive rapid genetic change and drug resistance. They found that these highly mutated cancer cells could be used to create a vaccine for each individual cancer type, which amplified the effects of immunotherapy – and cured mice with a variety of otherwise treatment-resistant tumours. The international study – carried out by scientists at The Institute of Cancer Research (ICR), London, the Mayo Clinic in Rochester, US, and the University of Leeds – is the first to show that APOBEC3B’s role in driving cancer evolution can be used to create vaccines that can boost the immune response. The researchers want to take their new technique for creating personalised vaccines into the clinic as early as next year – starting with a trial in children with brain tumours. Immunotherapy is forecast to be the oncology treatment with the market reaching $115 billion by 2023, according to analysis from ReportsnReports. It’s therefore no surprise that major pharmaceutical companies continue to muscle in on the market, either to bolster their own oncology divisions or to break into new therapeutic areas. A recent example saw Gilead Sciences acquire a 49.9 per cent equity interest in Pionyr Immunotherapeutics, a privately held San Fran company developing first-in-class cancer immunotherapies. Although immunotherapies are, at present, predominantly used against cancer, the outbreak of COVID-19 has seen innovative companies develop immunotherapies with the potential of treating the coronavirus. © Shutterstock /CI Photos 08-11.qxp_Layout 1 10/08/2020 15:25 Page 4CLINICAL TESTING 12 Pharma Business International www.pbiforum.net The launch of a new pharmaceutical or medical product is a long road paved with exhaustive, often strenuous research and development. As one of the key stages, clinical trials are a proving ground where new therapies, treatments and medicines can be validated or discovered to be inefficient or just unfeasible on a commercial scale. In any outcome, they provide researchers, clinicians and scientists with valuable insight that will shape future research endeavours and the fate of new product launches. Clinical trials can court controversy, attracting unwanted media attention and causing a pharmaceutical company’s shares to plummet. Though patient deaths are part of the risk involved in clinical trials, it’s the way in which trials are handled that many take umbrage with. Most clinical trials fail, with their results never finding their way into peer- review journals or in the public arena where they can be picked apart and scrutinised. Little wonder there’s been more vocal calls for changing the way in which trials are organised and, crucially, how they are reported on, irrespective or their outcome. However, instigating this far-reaching sea change isn’t only difficult to introduce, but harder still to maintain. Diagnosing the issues with clinical trials Despite their necessity, especially in the wake of COVID-19, clinical trials are still beset by many challenges. However, digital technology is helping to change things. 14 Á 12-15.qxp_Layout 1 10/08/2020 15:26 Page 1Pharma Business International 13 www.pbiforum.net CLINICAL TESTING © Shutterstock /sfam_photo 12-15.qxp_Layout 1 10/08/2020 15:26 Page 2CLINICAL TESTING 14 Pharma Business International www.pbiforum.net Trials are beholden to patients or the public to generate results from which new medicines live and die. The trouble is, it’s participants themselves that can leave researchers with a headache. Clinical trials are a multi-phase process. In most cases, a new drug or treatment will first be tested on a small number of volunteers, with any results being monitored and poured over before it is then tested on hundreds – perhaps even thousands – of volunteers. The bigger the pool of volunteers, however, the likelier the chance that some of them will drop out. It’s an issue that researchers must deal with during any trial and is of particular aggravation during cases where results need to be monitored over time. The average dropout rate of clinical trials comes in at around thirty per cent, which is bad enough before it’s considered that this causes eighty per cent of trials to not finish on time. Given trials are often expensive and difficult to organise and maintain, setbacks such as these can skew data, affect results and eat into funding (which is often limited and not forthcoming). Though there are very valid reasons why participants would need to drop out of a trial, such as individuals having poor – but not critical – reactions to the drug being tested and thus needing to be taken off the roster. But the biggest reason for dropouts is down to poor patient engagement between the pharmaceutical company, or the research team in charge of the trial, and the volunteers. This can be down to several reasons, such as a lack of feedback, or difficulty in allowing people to understand or follow study protocols or even a case of simple motivation. There are so many do’s and don’ts for people in these trials to adhere to, that poorly provided material and lists on what they can and 12-15.qxp_Layout 1 10/08/2020 15:26 Page 3Pharma Business International 15 www.pbiforum.net CLINICAL TESTING © Shutterstock /wutzkohphoto cannot do are likely to frustrate and, therefore, cause them to drop out. There’s no excuse for this in the digital age, however, with apps and social media at a company’s disposal to interact with patients at a moment’ notice. But they’re simply not being utilised. Pharma’s reticence in adopting social media is no secret, though companies are coming around and finding that engaging with consumers and patients via social media is having a meaningful impact. Applying this same approach to clinical trials could create a more harmonious and informed relationship between companies and participants which, in turn, should help to curtail dropouts. Another issue among participates is adherence to the rules of the study. This could be failing to take a set amount of medicine during set times of the day. Given patients can often struggle with medicine adherence at the best of times, they can perhaps be forgiven for slip-ups during clinical trials. Again, digital technologies are helping. There’s a slew of apps designed specifically to help patients take the right amount of medicine on time, which can be utilised for trials. Indeed, companies may wish to create their own app for exactly this purpose and, in doing so, have another set of data to collate. Clinical trials are a time-consuming and costly endeavour but a critical stage in the life of any new medicine, treatment and therapy. Despite this importance, they are beset by setbacks and challenges. Adherence and engagement are two of the biggest issues, but digital technology is helping to create a more transparent and efficient environment in which clinical trials can flourish. With the pressing need for COVID-19 treatments, the pandemic could well serve as a catalyst to transform the way in which clinical trials are undertaken and run. 12-15.qxp_Layout 1 10/08/2020 15:27 Page 4ANTIBODIES 16 Pharma Business International www.pbiforum.net 16-19.qxp_Layout 1 10/08/2020 15:28 Page 1Pharma Business International 17 www.pbiforum.net ANTIBODIES © Shutterstock /Mirror-Images Therapeutic antibody drugs, especially those based on monoclonal antibodies (mAbs), are amongst the best-selling drugs in the pharmaceutical market. Dozens of antibody drugs have been approved for a plethora of conditions, though development is increasingly focused on the treatment of cancer, as a targeted therapy. 2020 has seen a number of approvals for therapeutic mAbs, particularly in the US where (at time of writing) eptinezumab for migraine prevention (brand name Vyepti), isatuximab for multiple myeloma (brand name Sarclisa), teprotumumab for thyroid eye disease (brand name Tepezza), sacituzumab govitecan for triple-negative breast cancer (brand name Trodelvy), inebilizumab for euromyelitis optica and neuromyelitis optica spectrum disorders (brand name Uplizna), and tafasitamab for diffuse large B-cell lymphoma (brand name Monjuvi), have been granted first approvals. In the EU 2020 approvals include polatuzumab vedotin for diffuse large B-cell lymphoma (brand name Polivy), brolucizumab for macular degeneration (brand name BEOVU) and isatuximab. A further eighteen therapeutic mAbs are in regulatory review in the EU and US. Tafasitamab’s US Food and Drug Administration approval is the most recent, in combination with lenalidomide (aka Revlimid). It provides an alternative to CAR-T therapies to treat cancer. The approval comes for adults whose diffuse large B- cell lymphoma has relapsed or failed to respond to a prior treatment. The first line of treatment for diffuse large B-cell lymphoma is Rituxan and chemotherapy. If these do not work, high doses of chemotherapy and a stem cell transplant are recommended. This, however, is not suitable for all patients, as not all qualify for stem cell transplants, and the procedure itself is of course risky. The approval brings a new second-line treatment option and is based on an open-label phase II study of eighty-one patients. The study showed a fifty-five per cent overall response rate, including a disappearance of signs of the cancer in thirty-seven per cent of patients. A phase III study is underway. A predominant class 18 Á Expanding treatment options for a variety of conditions, drugs based on antibodies are a mainstay in medicine. 16-19.qxp_Layout 1 10/08/2020 15:28 Page 2ANTIBODIES © Shutterstock /Lightspring 18 Pharma Business International www.pbiforum.net 16-19.qxp_Layout 1 10/08/2020 15:28 Page 3Pharma Business International 19 www.pbiforum.net ANTIBODIES The pharmaceutical industry’s interest in discovering antibodies with therapeutic potential is high and development is wide ranging. This year has seen an antibody therapy show potential for reducing stroke related brain injury for example. XBiotech Inc announced that its drug candidate antibody that blocks interleukin-1 alpha (IL-1α) reduced brain damage after stroke in animals. Meanwhile a more recent promising therapy is under priority review by the US FDA for Ebola. REGN-EB3 is a treatment featuring three antibodies and has been found to reduce mortality rates. In another intriguing 2020 development, researchers from the University of Cambridge, University College London and Lund University have found a way to design an antibody that can identify the toxic particles that destroy healthy brain cells – a potential advance in the fight against Alzheimer’s disease. Their method is able to recognise these toxic particles, known as amyloid-beta oligomers, which are the hallmark of the disease, leading to hope that new diagnostic methods can be developed for Alzheimer’s disease and other forms of dementia. Wider moves in the antibody space have seen focus rise on bispecific antibodies as a class of targeted therapeutics designed to bind to two antigens at the same time. After years of challenges in their development, a plethora of validated platforms are now available, growing the commercial clinical pipeline. Most of the bispecific antibodies that have entered clinical study of late are being developed for cancer treatments. In a recent development, Janssen presented results from its Phase I CHRYSALIS study on amivantimab, a bispecific antibody for the treatment of non–small cell lung cancer with epidermal growth factor receptor Exon 20 insertion mutations. Amivantimab-treated patients achieved durable remissions. This came after receiving a breakthrough therapy designation in December for another bispecific antibody, teclistamab, for the potential treatment of multiple myeloma. Antibody-drug conjugates (ADCs) are also an expanding development area, combining the selectivity of antibodies with small molecule drug efficacy. Enabling precise and targeted applications, ADCs hold the advantages seen with antibodies, binding to a specific target, homing in on a protein on tumour cells, and the capabilities of a therapeutic payload. Hematology and oncology are where most ADCs in development are focused, with the targeted delivery of strong cytotoxic molecules into cancer cells a promising strategy. Just eight ADCs have successfully reached the market with many programmes impeded due to constraints with the format and toxic side- effects and limitations in the range of cancer patients who can be treated. While able to discriminate between healthy and diseased tissue, historically ADCs have displayed challenges for researchers. An issue with ADCs is that they can shed their toxic load while travelling to the site of a tumour, often due to a faulty linker. However researchers have unveiled more stable methods for attaching drugs to antibodies, next generation linkers, improving the treatment’s safety, with linker molecules refined to ensure toxins are only released when a drug is absorbed by a cancer cell. Novel technologies are also seeing further issues overcome, for instance technology from Spirea is offering high drug-to- antibody ratios (DAR), drug stability and design flexibility which enable the development of differentiated ADCs with improved efficacy and safety. Because the technology allows more drug to be loaded onto the targeting antibody whilst maintaining drug stability, payloads can also be customised to the target, enabling flexibility in payload potencies, creative drug combinations and novel modes of action to serve a wider patient group. Future developments are also seeing bispecific ADCs designed to increase selectivity and potency or deliver various types of payloads. The COVID-19 pandemic has shifted focus in antibody research. Opportunity has arisen in the development of anti-SARS-CoV-2 interventions. The majority of these involve mAbs. By the end of May, over fifteen organisations revealed intentions to begin clinical study of anti-SARS-CoV-2 molecules between June and December 2020. Several groups have now begun trials of mAbs designed to target and neutralise SARS-CoV-2. The primary hope for mAbs is that they could be a bridge until a vaccine becomes available, offering shorter term protection, or help treat those exposed to COVID-19 or those for whom vaccines would be less effective. Eli Lilly was amongst the first to begin clinical trials of mAbs, discovered by AbCellera Biologics and Shanghai Junshi Biosciences. In Lilly’s case, it is planning a clinical development program including a portfolio of monotherapy and combination antibody regimens (cocktails) in order to understand which provide the best efficacy and tolerability in patients. 16-19.qxp_Layout 1 10/08/2020 15:28 Page 4Next >