< PreviousTREATING FOOD ALLERGIES 30 Pharma Business International www.pbiforum.net Food allergies are often referred to as an epidemic. Causing serious suffering, constant fear of anaphylactic shock, and costing exorbitant amounts in healthcare bills each year, the number of people with food allergies is rising. While cures remain out of reach, oral immunotherapy is gaining traction in the treatment of food allergies. In this approach patients endure carefully monitored exposures to food allergens to reduce sensitivity and mitigate allergic responses. Oral immunotherapy does not come without its downsides of course, involving anxiety as a result of frequent contact with food allergens that hold the ability to trigger a deadly reaction. In addition it requires close supervision, does not work for everyone, is primarily a lifelong commitment (stopping treatment could see patients lose protection they have developed), and has been critiqued for not fixing the underlying issue, rather giving people the ability to eat a few nuts. One should not downplay the potential this has to change lives, though, providing an option arguably better than simply avoiding certain foods altogether. A key development for this treatment created new hope in those dealing with peanut allergies, one of the most common food allergies, in 2020 when the US Food and Drug Administration (FDA) approved Aimmune Therapeutics’ Palforzia to mitigate allergic reactions, including anaphylaxis, that may occur with accidental exposure to peanuts. It is the first and only FDA-approved treatment to help reduce the frequency and severity of allergic reaction to peanuts in children aged 4 to 17, as well as being the first approved therapy for Overcoming food allergies As the number of people with food allergies continues to grow, the need for novel treatments is clear. 32 Á 30-33.qxp_Layout 1 07/12/2020 10:55 Page 1Pharma Business International 31 www.pbiforum.net TREATING FOOD ALLERGIES © Shutterstock /Evan Lorne 30-33.qxp_Layout 1 07/12/2020 10:55 Page 2TREATING FOOD ALLERGIES 32 Pharma Business International www.pbiforum.net any food allergy. The powder is manufactured from peanuts and packaged in pull-apart colour-coded capsules for Dose Escalation and Up- Dosing, and in a sachet for maintenance treatment. The powder is mixed with a small amount of semisolid food - like yogurt - for the patient to consume. The approval of Palforzia followed the year- long Palisade trial, testing the treatment versus a placebo in 555 patients between four and fifty-five years old, with most of these children and adolescents. At the beginning of the trial participants could not tolerate 100mg or less of peanut protein. After a year of treatment sixty-seven per cent of patients could tolerate 600mg of peanut protein. Treatment with Palforzia consists of three phases: Initial Dose Escalation, Up- Dosing, and Maintenance. The Initial Dose Escalation phase is given on a single day. The Up-Dosing phase consists of eleven increasing dose levels and occurs over several months. During Up-Dosing, if the patient tolerates the first dose of an increased dose level, they may continue that dose level daily at home. After a patient completes all Up- Dosing levels, they may begin the daily maintenance dose. Emphasising confidence for Aimmune Therapeutics’ treatment, Nestlé Health Science (NHSc), aiming to create a global leader in food allergy prevention and treatment, recently completed the $2.6 billion acquisition of Aimmune Therapeutics, granting NHSc access to Palforzia. Aimmune’s pipeline also includes an egg allergy product (AR201), which is in Phase II trials, while the biopharma has completed its pre- investigational new drug application meeting with the FDA for a multi-tree nut allergy programme. 2020 also saw positive preclinical results published for Allergy Therapeutics’ peanut allergy vaccine candidate, paving the way for human trials. The study used a peanut allergy mouse model to demonstrate that the novel virus like particle (VLP) platform used in the vaccine candidate could offer an effective way to treat peanut allergies and prevent anaphylaxis. It provides the proof-of-concept for the generation of sustained immunity and protection through vaccination. The study showed that a single injection protected against systemic anaphylaxis - demonstrated via subsequent in vivo challenge, skin prick testing and oral challenge. In the study, mice were immunised with one of three vaccines containing either a mixture of allergens found in whole extract of roasted peanut or with one single, purified peanut allergen. Regardless of which vaccine was used, immunisation strongly reduced systemic and local allergic symptoms in vaccinated subjects 30-33.qxp_Layout 1 07/12/2020 10:55 Page 3Pharma Business International 33 www.pbiforum.net TREATING FOOD ALLERGIES and protected against anaphylaxis upon subsequent challenge with a whole peanut allergen mixture. Allergy Therapeutics’ subcutaneous recombinant vaccine candidate uses a formulation incorporating novel VLP-based technology, which enhances the body’s immune response by making the peanut allergen resemble an invading virus. The engineered, plant-based cucumber mosaic virus (CuMV) used in the vaccine is not able to replicate or infect humans and provides a platform to induce protective antibodies in a way more like traditional vaccination rather than current allergen-specific immunotherapy approaches. A patch is also in development, designed to deliver small and controlled amounts of peanut allergens through the skin to desensitise the immune system, though it faced hurdles in August when the FDA turned down the Viaskin Peanut patch from DBV Technologies for children between four and eleven years old, over concerns about the patch itself. The FDA noted that the patch’s design needed to be modified, focusing on site adhesion and how this affects the efficacy of the treatment. DBV Technologies will have to conduct a new human factor study and deliver supplementary clinical data and information on the chemistry and manufacturing of the patch. The FDA did not however raise any safety concerns. The patch previously won fast track and breakthrough labels from the FDA. A further step forward for food allergy treatments came with a recent study from Northwestern Medicine, indicating that BTK inhibitors could be taken proactively to prevent anaphylaxis, whatever the cause. BTK inhibitors work to block allergic reactions by inhibiting the BTK enzyme so the mast cells cannot be triggered by allergens and allergic antibody to release histamine and other allergic mediators. The study used three different BTK inhibitors, which blocked allergic reactions when tested on human mast cells in a test tube. The study also used one FDA-approved oral drug, which successfully reduced or prevented allergic reactions, including severe anaphylactic reactions in a new ‘humanised’ mouse model of anaphylaxis. The mouse’s organs contained transplanted human cells that, over several months, matured into human mast cells, the primary cells that react during allergic reactions. The findings could pave the way for future human clinical trials of such oral drugs to be used as a preventive treatment to avoid serious allergic reactions, said senior and corresponding author Dr. Bruce Bochner, the Samuel M. Feinberg Professor of Medicine at Northwestern University Feinberg School of Medicine. © Shutterstock /Albina Gavrilovic © Shutterstock /Rob Byron 30-33.qxp_Layout 1 07/12/2020 10:55 Page 4CLINICAL TRIALS 34 Pharma Business International www.pbiforum.net © Shutterstock /myboys.me 34-37.qxp_Layout 1 07/12/2020 10:55 Page 1Pharma Business International 35 www.pbiforum.net CLINICAL TRIALS Progress at an unprecedented pace The coronavirus pandemic has had a remarkable impact on clinical trials, both in terms of how treatments and vaccines have been rushed into trials at an unprecedented pace, and how it has hit, halted, and transformed clinical trials more widely. Outside of COVID- related studies, those concerning other treatments have seen severe delays, becoming less of a priority, and with the virus affecting the ability to carry out research, processes have had to be adapted, and face to face contact with participants minimised. A severe drop in recruitment was also highlighted at the start of the pandemic, alongside a reduced willingness for participants and staff to access clinical sites. Fortunately, many trials are recovering from the disruption. Though it has created problems for clinical trials, the pandemic has also spurred progress and change, impacting 36 Á Pharma Business International investigates recent developments in clinical trials for COVID-19 vaccines, as well as the impact the pandemic has had on trials. 34-37.qxp_Layout 1 07/12/2020 10:55 Page 2CLINICAL TRIALS 36 Pharma Business International www.pbiforum.net how trials are conducted. The intense research associated with COVID-19 for the rapid development of vaccines and treatments is set to be applied to accelerate future and current trials, illustrating just how quickly they can be set up - the UK RECOVERY Trial for example was set up in nine days. Of course it should be noted that much of the speed in development associated with coronavirus has come as a result of regulators being more flexible in response to the health crisis. Nevertheless, many innovative solutions have been employed to allow clinical trials to continue. Key has been the increased use of technology and virtual trials - the pandemic even forced the US Food and Drug Administration (FDA) to release guidelines. Easing participation in and expanding the reach of clinical trials, this holds the potential to speed up recruitment and improve participant retention. Since the outbreak of COVID-19, communication has primarily become virtual. Trial managers have made use of various platforms to have discussions with participants, trial management groups, independent oversight committees, sponsors and funders, and sites. Processes like informed consent and primary outcome data collection have also been moved online in many instances. As trials resume, requiring careful planning, there is the opportunity to investigate alternative approaches to conducting and designing them moving forward to boost efficiencies and cut costs. Progress meanwhile continues at breakneck speed for COVID-19 vaccines, with myriad trials underway. Taking just ten months to move from concept to reality, Pfizer and BioNTech’s mRNA vaccine - given as two injections, twenty- one days apart - was recently granted approval for use by Britain’s Medicines and Healthcare products Regulatory Agency (MHRA), following a worldwide Phase 3 trial involving over 43,000 people. The MHRA’s decision is based on a rolling submission, including data from the Phase 3 clinical study, which demonstrated a vaccine efficacy rate of ninety-five per cent. Efficacy was consistent across age, gender, race, and ethnicity demographics, with an observed efficacy in adults aged sixty-five and over of more than ninety-four per cent. In the trial, BNT162b2 was generally well tolerated with no serious side effects. Ten severe cases of COVID-19 were observed in the trial, with nine of the cases occurring in the placebo group and one in the BNT162b2 vaccinated group. Also advancing, two of three planned late-stage efficacy trials for Novavax’s vaccine (NVX-CoV2373) - a stable, prefusion protein antigen derived from the genetic sequence of the SARS-CoV-2 coronavirus spike (S) protein and adjuvanted with Novavax’s proprietary Matrix-M TM - are fully enrolled, and more than 20,000 participants have been dosed. In the UK Novavax has completed enrolment of 15,000 participants in a Phase 3 clinical trial to determine efficacy and safety of NVX- CoV2373 after the UK Vaccines Taskforce and National Institute for Health Research assisted in the rapid recruitment and enrolment of volunteers. Interim data are anticipated as soon as early first quarter 2021. Simultaneously a Phase 2b trial taking place in South Africa to evaluate safety and provide an early indication of efficacy is now fully enrolled. 4,422 volunteers are taking part in the trial, which includes 245 medically stable, HIV-positive participants. This trial is expected to increase the body of efficacy data of NVX-CoV2373 in racially and geographically diverse populations as well as in older adults. Moreover (at the time of writing) Novavax is due to begin its Phase 3 clinical trial in the United States and Mexico. The AstraZeneca Oxford coronavirus vaccine, AZD1222, meanwhile - which uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein - is moving forwards, with clinical trials resuming after “a standard review process triggered a voluntary pause to vaccination across all global trials on 6 September to allow review of safety data by an independent committee.” AZD1222 has since been shown to be effective in preventing COVID-19 following an interim analysis of clinical trials in the UK and Brazil, with one of the dosing regimens around ninety per cent effective. No hospitalisations or severe cases of the 34-37.qxp_Layout 1 07/12/2020 10:55 Page 3Pharma Business International 37 www.pbiforum.net CLINICAL TRIALS © Shutterstock /Microgen disease were reported in participants receiving the vaccine. Furthermore, Medicago and GSK have started Phase 2/3 clinical trials of a plant-derived vaccine candidate for COVID-19 to evaluate its efficacy, safety, and immunogenicity, based on positive Phase 1 results. The Coronavirus-Like Particle COVID-19 vaccine candidate (CoVLP) is composed of recombinant spike (S) glycoprotein expressed as virus-like particles (VLPs). Additionally a vaccine, mRNA-1273, developed by Moderna and the National Institute of Allergy and Infectious Diseases (NIAID), has been shown to be safe and effective at preventing symptomatic COVID-19 in adults after an independent data and safety monitoring board (DSMB) overseeing the Phase 3 trial of the vaccine reviewed trial data and shared its interim analysis with the trial oversight group. The DSMB reported that mRNA- 1273 was safe, well-tolerated and noted a vaccine efficacy rate of 94.5%. The vaccine combines Moderna’s mRNA delivery platform with the stabilized SARS-CoV-2 spike immunogen (S-2P) developed by NIAID scientists. A plethora of other trials are also underway. According to WHO, as of 2 December, fifty-one candidate vaccines are in clinical evaluation. Thirteen of these are in Clinical Stage Phase 3, four are in Phase 2, twelve are in Phase 1/2, and twenty-two are in Phase 1. 163 candidate vaccines are in preclinical evaluation. Concurrently, human challenge trials are beginning. 34-37.qxp_Layout 1 07/12/2020 10:56 Page 4FEATURES A cure for COVID-19? Collaboration RNAi therapies Licensing Delivery systems Digital therapeutics Next issue: Deadline - 3rd February 2020 REGULARS News Events M&A Round-up Eye on approvals Pharma BUSINESS INTERN ATION AL Visit us at www.pbiforum.net where you’ll find the latest news as it breaks – and why not subscribe to our newsletters so you can have the latest news emailed to your inbox, in between digital issues? @pbiforumwww.pbiforum.net company/po-business-international 38.qxp_Layout 1 07/12/2020 10:57 Page 1Next >