Therapeutic areas in focus
Helping the world prepare for future pandemics
Pharmafile speaks to
Yamin ‘Mo’ Khan, CEO of Open Orphan, guides us through the respiratory disease arena, and how the world of human challenge trials may help us to understand it better
How has the global respiratory disease market shifted in the last 10 years?
Yamin ‘Mo’ Khan:
Prior to COVID-19, I think it had basically mirrored most of the other therapeutic areas, as there had been growth in the field. COVID-19 has had a significant impact; at one point there were over 300 candidates in development to treat the disease. COVID-19 is such an outlier, and it changes the whole paradigm when it comes to respiratory disease, as well as the development of broader vaccines or antivirals.
On the other side, we have a lot of pressure on pricing as well. That’s one of the key factors that people in pharma and biotech are looking at, especially to see how they can speed up the process of drug development, to offer a lower price for marketing authorisation. That’s going to require more work. Everyone can appreciate and understand that the speed of these vaccines that came out against COVID-19 was amazing. People who are not in the industry don’t fully appreciate the speed at which the work was done.
Typically, it takes eight to twelve years to come up with a new product on the market. With COVID-19, the teamwork across the different kinds of groups internationally was amazing. From the discovery of the virus in Wuhan, different academics, sites, and pharma companies like Pfizer and Oxford- AstraZeneca, came together to expedite response to COVID-19. The regulatory bodies were happy to review the data on a rolling basis, which was not very common.
I think that part has been pretty amazing, and hopefully it goes some way towards putting together a blueprint for future epidemics and pandemics. I’m hoping that we will be better prepared next time. I think there was some criticism at the start – a lot of people talked about a potential pandemic and why we weren’t better prepared for this one.
What potential do human challenge studies have in helping us understand more about respiratory diseases?
When you want to run a challenge trial, you find healthy volunteers – usually young, healthy people. We will find around 160,000 unique volunteer leads this year to fill our studies. For our challenge studies, we offer a number of strains of influenza, RSV, coronavirus, malaria, and so on. There’s a long process of checking volunteer eligibility to participate in trials. For example, if you were a volunteer, we would do a serology test. We need to make sure that with an influenza challenge trial, you’ve not been exposed to that strain before, so you wouldn’t have antibodies for that. If you don’t have innate antibodies, you will get infected, but if you don’t get infected, you’re not really that useful to the trial. We do those kinds of screening processes, which means that we lose about 85% of the volunteers because they’re not suitable.
We would first give vaccines to the ones that are most suitable, and then two to four weeks later, we would challenge them with a live virus. Then we measure the signs and symptoms while they quarantine for ten days. These challenge drug trials have been done quite often in the past, but with the current pandemic, it has been brought to a higher
level. We are now seeing more and more emphasis on doing challenge trials. WHO, for example, has put forward new working guidelines on how challenge trials should be conducted. There have been discussions at the highest levels in the US, at the FDA, regarding challenge trials. We work with the MHRA here in the UK in getting every challenge trial approved. We also work with some of the key academics – for example, Imperial College London was involved in the COVID-19 trials that we ran. Remember, we know the exact point we inoculate a volunteer, and we know to the second when a patient gets infected.
As CEO of Open Orphan, are there any particular hopes and visions you have for the company in 2022, as well as for the respiratory disease space?
There’s no other company that has the breadth of challenge models we have. We have over nine challenge models and have done over 60 challenge studies, so it does put us in a unique situation. We also have a fantastic scientific team, with consultants from CMC through to clinical. With regards to respiratory, on a small scale, we started working on asthma, using HRV as an agent. We’ve developed a chronic obstructive pulmonary disease (COPD) model, but globally, we want to help the world to be better placed in fighting a future pandemic. We can’t just be doing trials on a day-to-day basis – we need to look at the long term and see what the key risks are for all of us as a global community.
As a company, developing new challenge trials all the time is something we invest in. We ran the first SARS-CoV-2 challenge trial, and the results of that were published in
in April. We are also working with some key academic leaders as well, to develop this model to make them better and faster. We were able to grow the company with the challenge agents and the new service portfolio, and are helping prepare for any future pandemics.
What are the main obstacles that arise in human challenge studies?
Recruitment: trying to find a sufficient number of healthy volunteers is a huge challenge. We have a large dedicated recruitment arm
called FluCamp, which advertises via social media and traditional press to recruit potential volunteers. These people are compensated when they go into quarantine, but I think that’s one of the key challenges. The other challenge is that for Phase I studies in respiratory using healthy volunteers, they require nurses and physicians with specialised skill sets. That’s different to the standard indication. When doing trials with respiratory disease patients, there’s more sampling and specialist procedures required. Doing multi-site trials in respiratory does increase the variability of data across the site. You avoid that in a challenge trial because this tends to be conducted at a single site. You have one site, one group of nurses, and one group of physicians, who do all the patient procedures and sampling. So there is less variability of data.
What is the potential of technology in human challenge studies?
Technology has changed, and will continue to change the way clinical trials are run. Let’s talk about patient-reported outcomes, when a patient is taking part in a clinical trial. With technology, you know in real time when data is being entered into the electronic diary. This increases the data integrity and the data quality. It also shortens the timelines for analysis, and gives the ability to collect more data. You have to ensure you only collect the data you really need. Technology enables you to get more data than otherwise possible in paper.
At Open Orphan, we run clinical trial challenge studies with wearables as well. We collect data on the patient 24/7. We analyse the correlation between the variable data
versus the signs and symptoms the patient is showing. When a patient is at home, you can continue to collect the data. We have more kinds of clinically-targeted wearable devices to collect this.
COVID-19 illuminated the need for safe treatments that manage the inflammatory responses to respiratory infections. What else did the pandemic highlight about respiratory diseases?
I think it highlighted the potential for new treatments. The use of high quality placebo trials to test treatments has been key. Even though we expedited the clinical development programmes for the COVID-19 vaccines, they’ve been shown to be safe and effective. Understanding the viral disease helps with regard to what treatments to test, and also deciding to target the underlying cause of disease, in the right population, at the right time, is key. For example, it was shown that dexamethasone is beneficial in more severe patients, but not so much in the mild-to-moderate COVID-19 disease. Identifying infection early on in at-risk groups was also important, of course. It did show that in a lot of cases, in the at-risk patient population, late treatments were frequently unsuccessful. With patients who are elderly or at risk, if they develop severe flu, it’s harder for them to recover.
At Open Orphan, we are now testing antivirals and immunomodulator treatments, as well as prophylactic drugs. We are currently using viral-induced studies in Africa, and hope to do more studies in COPD. I think those are some of the key findings.
Yamin ‘Mo’ Khan
is CEO at Open Orphan with over 25 years of experience in clinical research and the CRO industry. Mo previously worked as a Consultant assisting CROs to develop growth strategies, and also held a variety of senior roles at Pharm-Olam. In his time at Pharm-Olam Mo had leading roles in Clinical Operations, Project Management, Business Development and Executive Management functions.
Dose and deliver: How PMDIs are transforming asthma and COPD treatments
Chris Baron, Director of Business Development at Aptar Pharma, explores how pressurised metered-dose inhalers (pMDIs) are continuing to change the landscape of asthma and COPD care
Pharmafile: How do pMDIs aim to treat asthma and chronic obstructive pulmonary disease (COPD)?
From a pMDI perspective, it’s not a new technology; pMDIs have been used now for asthma and COPD for over 60 years. Even though they still look familiar in some aspects, the technologies within the pMDI container closure system and the drug/formulation are very different. It’s still using the same delivery methods of trying to treat asthma and COPD. The objective remains to deliver a repeatable and consistent dose to the lungs via aerosolisation of the aerosol, irrespective of the patients’ respiratory effort. There are always pros and cons of having a patient wanting or needing to inhale at a specific inspiratory flow rate depending on what type of delivery platform is being used. On a positive note, when you think of a pMDI, if it’s a traditional press-andbreathe, the fact that there is a propellant there which is expelling the drug means that even if the patient has very low respiratory efforts, or may be very old or very young, you can still deliver a formulation.
There are other ways – the perfect delivery system, from my perspective, would result in a lower respiratory effort where the patient would use a breathactuated pMDI. This would help reduce patient coordination errors but would add additional costs.
How do pMDIs compare to traditional treatments for asthma and COPD?
This has been the million-dollar question. When I first came into the business quite a few years ago, we were going through the transition from chlorofluorocarbons (CFC) to hydrofluoroalkane (HFA). In those days, it wasn’t global warming or climate change – it was the ozone depletion. People were saying: “Is it the end of the pMDI?” In those days, it was a transition which was mandatory – we had to reduce and then remove all CFC propellants, including those used in medical devices including pMDIs. This resulted in the development of formulations using new HFA propellants. These HFA propellants not only had a zero-ozone impact but they also reduced the actual global warming potential at that time by 300%. It was deemed a win-win for everybody.
At that time, they were thinking, “it’s going to be DPIs (Dry Powder Inhalers) that take over”. It certainly did not work out like that, and there are reasons for that. The most obvious one is that patients are used to using the pMDI because they are familiar with it. It gives a consistent dose and the patient experience is always the same when you use a pMDI, irrespective of the type of product you’re using. Whereas, if you use a dry powder technology platform, it’s more likely that you’re going to have a very different experience with so many different dry powder inhaler technologies. You have reservoir-type, blister-based, and capsule-based technologies that all offer a different patient experience. This means it’s not always easy to switch from one DPI technology to another DPI technology, and probably even more challenging to move from a pMDI to one of the DPIs.
The other thing you must consider if you’re taking a rescue medication, like salbutamol, is you could never use a capsule-based DPI. You don’t want to be playing with a capsule or putting that capsule into a device when you’re having an asthma attack. The other key difference is that the costing aspects of a pMDI per dose are significantly lower than any other technology platform. If you have a 200- dose pMDI, it’s much more cost sensitive to the industry versus single dose or multi dose DPIs. It’s very difficult to ever replace a pMDI for such rescue medication.
What are the issues with existing treatment options for COPD and asthma?
I think there’s an overuse of salbutamol. The challenge we have is that, when patients take medications, including controller medications for asthma & COPD, you may not feel any different for several days, then you begin to feel better, and that’s when many patients stop taking their controller medication. With rescue treatments, like salbutamol, delivered by a pMDI, you take the medication and you get an instantaneous hit. The patient
feels like it’s doing something, so they continue to take their rescue medication instead of their controller medication. The patient then becomes over-reliant on rescue treatment, as opposed to better managing their symptoms by using an appropriate controller medication. The net result is an over prescription of rescue medication. Perhaps this is maybe more of a communication issue between asthma nurses, physicians, and patients, i.e. not educating the patient enough to ensure that they need to continue with a controller medication. Even when they don’t feel that immediate hit or buzz, they need to continuously take the medication in line with the patient instruction leaflet. One could argue that if you are in control of your asthma, then you shouldn’t really need to use the rescue medication as frequently.
Another challenge for patients, when we think about the use of pMDIs in particular, some patients historically have co-ordination issues. When you use a conventional press-and-breathe pMDI, you should inhale and press, whilst still inhaling. Some patients may be very old or very young and sometimes patients struggle with coordination issues. To resolve this issue, you could incorporate a breath-actuated inhaler within the pMDI. You inhale through the actuator mouth-piece, which triggers the pMDI and delivers the medication, thus eliminating any coordination issues.
DPIs on the other hand are generally triggered by actually inhaling, which then delivers the dose from the device. This can be considered a pro but there are cons too. Some patients may not have a high enough respiratory effort to trigger the device and deliver the dose to the deep lungs.
The challenge then is cost, because the traditional pMDI is relatively inexpensive versus other technology platforms like DPIs and soft-mist inhalers. These new treatments could be used but it would just mean that the cost is more expensive.
Another key thing to mention is remaining doses. Many pMDIs on the marketplace today still don’t incorporate a dose counter. Even though it’s mandatory in the US and Australia, it’s still not mandatory in Europe, and that’s generally due to cost. If the patient knows how many doses are remaining, then they would know when to be in a position to go back to the physician and actually ensure that they’ve got their next prescription of medication, instead of having lots of pMDIs around the house, some half full, because the patient doesn’t know how many doses are left. The final unmet need with pMDIs is that you need to re-prime them if you do not use the pMDI for a period of time (one or two weeks). This means you have waste, and this is a sustainability issue. The other consideration is that most primeless valves are used in conjunction with a BAI (breath-actuated inhaler), which could offer benefits from both a sustainability and a patient compliance perspective. I’ve just returned from the 2022 Respiratory Drug Delivery Conference, during which there was a significant focus on tackling the sustainability aspects of pMDIs during the Conference. I think the above points are key to meeting those unmet needs.
How can we make them more sustainable?
If you can reduce the number of priming shots, then you’re going to have a more sustainable product, and as I mentioned earlier, using dose counters to confirm that the product is nearly empty. Many patients have products that they throw away, which are not empty. The other aspect is the link between digital health and connectivity. You could argue that it will be more expensive, but the patients who are not following their regime, and aren’t taking their medication every day, are the ones who end up in the hospital needing emergency care. From a life cycle assessment perspective, this has a significantly higher carbon footprint (more resources in hospitals through emergency equipment) than using a pMDI using existing propellants. If you can have something that is more controlled, and has better compliance and adherence, it will be more sustainable too. It may initially be more expensive for the device, but the final cost to the healthcare system
is more positive, and the burden on the healthcare system is eased. Once a patient requires rescue treatment in a hospital, this becomes very expensive.
From a pMDI perspective there is significant work ongoing to switch pMDIs using the current propellants which have relatively high carbon footprints versus other inhaler device technologies to new low GWP (global warming potential) propellants including P152a & HFO1234ze which have significantly lower carbon footprints.
What are your visions for the future of respiratory treatments?
I’ve presented at multiple conferences and written various papers looking at improving the sustainability with regards to low GWP propellants. The good news is that low GWP pMDIs are on the horizon, and we can look forward to a much more sustainable future. Several leading Big Pharmacos, including Chiesi, AstraZeneca, and GSK, have all made announcements regarding their new low GWP pMDI programmes.
I think we can have better waste collection centres for used devices and that could include pMDIs, SMIs (soft mist inhalers), and DPIs. We could use more sustainable and reusable resins within the inhaler devices, but this is not going to be a quick thing, because obviously such resins need to be approved to medical grade.
Several major actuator suppliers for pMDIs are looking to utilise such reusable medical grade materials, as and when such materials become available for medical use. It’ll just take time for those medical grades to come through and be approved accordingly.
With regards to improving patient experience, then using digital health solutions can make a real difference. Ensuring patient compliance and adherence is crucial, but this needs to be aligned with effective drugs and intuitive delivery devices which the patient will use. As stated previously, I think that, in the UK, there’s too much emphasis on rescue salbutamol medication and the overuse of salbutamol, whether that’s due to patients being prescribed too many rescue medications,
or simply not being in compliance with their m edication regimens.
T he other thing which I would love to see is t he patient coming first. The patient should a lways be the first thought of the physician, t he Pharmaceutical company and the device d eveloper. There are current examples w here, after being taught the environment i mpacts of a product, physicians and Health C are Institutions are provided financial i ncentives to switch a patient from a p MDI to what they’re perceiving is a more s ustainable technology. These arbitrary s witches may not be what is best in the l ong-term for the patient or the environment. Y ou are asking a patient to change from a p MDI, which they may be in control of, to a nother technology without really thinking i f this is going to benefit their health. I b elieve this is a dangerous precedence. A sustainable future is key, but the most s ustainable product will be the one which t he patient uses correctly and adheres to i t. In summary, patient preference should m atter as well.
I also think that dose counters should become mandatory in Europe, similar to in the US. Every pMDI should incorporate a dose counter or dose indicator. Why should we be lagging behind other countries purely due to a marginal increase in price? Patients who use products containing dose counters are more likely to be adherent and only replace the pMDI when the product is running out, thus reducing waste and reducing the cost/dose.
is Director of Business Development Pulmonary Category at Aptar Pharma. In his role, he is responsible for the global business development activities for Aptar Pharma’s inhalation drug delivery devices, as well as their respective services pertaining to the application fields of Asthma and COPD. With an Honors degree in Mechanical Engineering, Chris has gained over 28 years’ industry experience in the field of Inhalation Drug Delivery (IDD).