Life Cycle Management: An ‘Insider’s’ guide on how to make your drug last FOREVER $$$

A CASE STUDY

In the pharmaceutical and biotechnology industries, there is a critical point in dealing with your novel agent when it becomes vital to have a clear and cohesive strategy as to how to manage and optimize the life of said drug, agent or device! Namely, ahead of introduction to the market. So, just for fun, let’s do a step by step guide on how to make your drug last FOREVER – stay on the market, kick competitors’ butt(s) and thrive post patent despite or alongside generics.

Disclaimer: This is largely theoretical. Let’s be honest, if you had a drug that had successfully passed beyond Phase III into clinical trials and even post-introduction monitoring and analysis – you would use more than just this blog post to make decisions. This post is not approving every action it mentions, just acknowledging what is effective in the current climate. It does not claim that the pharma industry is without flaw and does not condone every action of the entire industry at large. But appreciate that with my background in this field, I find it interesting to talk about and explain to those who would like to read. 🙂

 

STEP 0: SWOT ANALYSIS + Disease Based Target Product Profile

This will allow you to recognize where exactly your drug fits into the market. Its positive and negative attributes as well as internal and external factors that will determine where and how marketing will and can be positioned.

Perhaps the drug has been approved for one therapeutic use but not yet another. Perhaps it has lesser adverse effects than existing drugs within the same class or a less favorable administration route. All of this will need to be taken into account before we even get started!

The best way to talk about this is with an example. This way, we can really dig deep. I found one example of a mock-up lifecycle management scheme that I drew up during my masters. Written in March 2017 – this is a great time to talk about it as I discussed a drug that was, at the time on the brink of release. So using this example – we can compare my suggestions to what really happened (thus far).

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The drug in question is Benralizumab, a respiratory biologic and monoclonal antibody for the treatment of eosinophilic asthma (as of now) and AstraZeneca’s answer to this rising drug class. AstraZeneca’s humanized murine IgG1k class respiratory monoclonal antibody, Benralizumab, is still not yet fully licensed; albeit in the very final stages; and as of 2018 had yet to conclude clinical trials in COPD.

All the existing drugs in this class, Mepolizumab, Reslizumab and Benralizumab, have a certain mode of action (i.e. They inhibit the action of IL-5 on target cells by binding to its receptor, IL- 5R, that consists of IL-5Rα and a common β chain, βc.). They all act to neutralize the IL-5 mediated eosinophilic inflammation response in the lungs to prevent the worsening of symptoms. They share a largely similar pharmacokinetic profile designed to maximize bioavailability by not relying on first pass metabolism.

Step 0 may not deserve a number, but it may be the most important of all! Sometimes one might have spent so much time in the lab, focusing on the product, eating, sleeping, dreaming it that it is hard to put the final product back into a broader context. And that is the beauty of the SWOT analysis and the dTPP in the process of trying to make your compound last FOREVER.

 

STEP 1: What is your USP?

Why would a doctor prescribe your drug over any other? Step 0 will have informed you quite well in this area. By knowing this, we have a better stab at working out how to KEEP things this way. In the case of Benralizumab, it held two differentiating factors from the other two, more established drugs on the market.

At the time, it was unsure whether the second would be realized; and indeed, this is still the case as of 2018. Firstly, Benralizumab has a different dosing schedule from the other two drugs being compared here: requiring a 30mg dose by subcutaneous injection with an accessorized pre- filled syringe every four weeks for the first three months, followed by the same dose every 8 weeks thereafter. Additionally, AstraZeneca was hopeful that it may equally be used in the treatment of severe Chronic Obstructive Pulmonary Disorder (COPD). After poor clinical results and the concession of defeat at the end of 2014, the drug was back in further trials with COPD patients in late 2017. It was announced in May 2018 that further trials in COPD patients were also unsuccessful.

 

STEP 2: Consider in-liscening deals or other agreements to get your drugs sold and distributed in more countries and regions more easily and thus reach more patients without having to jump through national drug regulation hoops one by one.   

Partnering with medium-sized pharmaceutical and biotechnology firms in different countries or regions and giving these either distribution rights, milestone payment rights, etc. can aid in spreading the drug more easily to new and untapped regions.

If you read my blog, you know that I feel very strongly about the potential of the developing world, middle-income nations in particular,  for the pharmaceutical industry.

Originally developed by Biowa, Benralizumab was the product of AstraZeneca’s in-licensing deal with BioWa, a subsidiary of the Japanese firm, Kyowa Hakko Kirin Co. Ltd. (Kyowa Hakko Kirin). As the biotechnology firm that initially developed Benralizumab, BioWa has milestone payment rights over the drug. Moreover, Kyowa Hakko Kirin holds marketing rights in Japan and other Asian countries.

In all other regions, Medimmune, AstraZeneca’s acquired biologics arm, holds marketing and distribution rights in all other regions. As is largely the trend in pharma, Medimmune was also initially a smaller biotechnology firm that was bought out by AstraZeneca.

Pro tip: If you are a smaller group with a great compound, an idea you LOVE and have got through preclinical trials or even a few Phase I trials successfully, SELL. It doesn’t matter how much you love your idea. You have no assurance of the outcomes of further trials and indeed, likely even of funding. Congrats, it is an amazing achievement if you have indeed got through the entire drug discovery process and successfully slightly beyond that threshold, too. Quit while you’re ahead. It’s not really quitting. It’s more like ‘Who wants to be a Millionaire’. Yeah, you COULD sacrifice your $500 000 for the promise of $5 000 000. But you could also leave with nothing. Just. Saying.

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STEP 3: Come in with a BANG: In other words, start trying to offset R&D costs from the word ‘Go’!

The graph below gives a good, basic illustration of the standard drug lifecycle curve from introduction to post-patent expiration and beyond.

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The period of introduction of a drug is generally one where profits are allocated to paying back VCs, angels and other investors in the R&D process. This is, after all, why they invested in the first place. So if the drug that they put their faith and money in reaches the market and begins to yield profits – the first step is to pay these investors back. Thus, coming in with a big bang, strong marketing plan and ethical informative sessions to physicians and researchers is vital. The aim here is to minimize the amount of time spent effectively burning money, rather than making it. We want to accelerate as healthily as possible into the growth period.

So here’s where I was wrong with my original case study. For the purposes of my paper in 2017, I made an assumption. Benralizumab would be AstraZeneca’s first biologic respiratory drug, and the firm expected it to be available on the UK market by August 2018. For the sake of this plan, from drug launch to patent expiry, I decided to assume that trials in severe COPD would be successful, and the drug would thus be available for use in both severe asthma and severe COPD. As of May 2018, the latest information that I could find in the public domain. Trials in COPD patients have yet to deem Benralizumab a candidate drug for this particular disease profile.

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So given the current circumstances, a good BANG entry plan for Benralizumab would be something like this. AstraZeneca will seek to maximize the benefit of the drug to patients whilst ensuring a healthy financial return on their investment thus far. This will include as mentioned before: balancing the high risk and cost of continued R&D, marketing, potential litigation, milestone payments, etc. A proposed lifecycle strategy would have begun in 2018 and assume that, like its predecessor, Nucala (Mepolizumab – Glaxosmithkline), Benralizumab, along with naming and branding, will be granted a 20 year patent life from the year of entry considering that a patent request has already been filed (including for the yet approved use in other diseases – i.e.COPD in this case).

Pro tip: File your patent request at the latest as soon as you are confident of the efficacy of the drug in late-stage CTs any particular area – even as trials are yet ongoing. Do not wait until after the drug has been fully approved. I feel yucky writing this. I’m sorry. But the theoretical ‘you’ – won’t be.

In the same vein, it is highly favourable to minimize the time between the start of the patent period and the introduction of the drug to the market. For obvious reasons. Having filed in 2017 with a plan to introduce the drug in August 2018 (UK), AstraZeneca indeed made this move. Aiming to allow only one year to elapse between these two crucial dates.

Just as a side point, according to an AstraZeneca’s spokesperson, the firm is embarking upon an era of major cost-cutting as it zeros in its focus on the areas of oncology, cardiovascular drugs and, of course, respiratory drugs. This, too, is an effective cost saving measure that applies almost exclusively to big pharma and not to medium pharma, small biotechs or university spin outs. I will discuss this in a future post and/or podcast.

 

STEP 3: Diversification during the early period of growth

Continued investment should be made in marketing within the regulatory framework of the concerned regions but with a pronounced focus on the aspects that differentiate your drug from others on the market. In the case of Benralizumab this would have (hopefully) been COPD. But for now, it may be its dosing schedule. Continue to sell on what sets your drug apart in its class. This is an action for 3 – 4 years down the line.

At the same time, the main target market – western Europe, for example, should take precedent. Procuring deals with financing bodies in these regions is the major focus. The secondary focus that will set your drug apart is continuing to invest in the markets where you have formed those partnerships we discussed in Step 2. This is where you diversify early.

In the case of AstraZeneca, I felt that this is the stage at which revised pricing structures should be announced, and negotiations should begin in the United States, United Kingdom and Europe via AZ’s Medimmune. Simultaneously, in Asia, Kyowa Hakko Kirin, having procured licensing in Japan, branch out into other major emerging pharmaceutical markets within Asia; particularly China, Indonesia, Thailand, India, the Philippines and Malaysia.

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Look at promising frontiers within the pharmaceutical industry at large when choosing deals and regions. Remember that if all went smoothly, your drug compound took approximately 8 – 12 years to reach introduction. And a further 3 to reach this stage. Assuming that your patent period will be 20 years; there is a lot of time in the maturity stage. During which the emerging market is simultaneously growing at an incredibly rapid pace. And in some cases; fiscal liberalism, still held International Monetary Fund (IMF) agreements and the pace of regulatory requirements and restrictions in line with economic and industrial growth are lagging somewhat behind the opportunity held. In other words, there are cases to be found where regulatory requirements on pharmaceutics are far less developed than the hoops you have had to jump through in other regions. This is certainly not true in all cases. This is not even the case in most cases. But there are enclaves. It’s not a good thing – but if you made it this far – you are clearly here to read the dirty. So there it is. Money making filth for free on a platter. I’m kidding. No, I’m not, You’ll never know.

The point is, promising frontiers for the pharmaceutical industry lie in nations with both a rising middle and wealthy class and thus the purchasing power to invest in novel treatments AND *bing bing bing* afford to become ‘brand loyal’; entirely independent of existing state healthcare structures and subsidies. Private health insurance. The golden star of the South. I am a South African. I don’t love this truth. But I can say it. If you are interested in this area: here’s a link to my “Challenges Facing the South African Pharmaceutical Industry” post.

So, without further a due, STEP 4.

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STEP 4: SURVIVE first. Then THRIVE.

The maturity phase is the most comfortable one of all. But one must walk before one can run. This is the period that we hope to start approximately 8 – 9 years down the line.

In the case of Benralizumab – the ‘first-in-class’ drug would theoretically be nearing patent expiration. The similarity of these two drugs means that this would affect Benralizumab. Remember, this is 2027. As Mepolizumab biosimilars enter the market, these will begin to serve as competition for Benralizumab – effectively shortening its functional patent life. It is at this point that Benralizumab, in its mature phase, can begin to increase investment in marketing once again, in the hopes of establishing loyalty due to its regimen as well as its adverse event profile.

Here’s the point: If your drug isn’t ‘first-in-class’, you want it to be ‘best-in-class’. Failing this. Grab for straws. ‘Cheapest’ is usually one of the last straws, unless you have the infrastructure to be both cheapest and making very good margins.

So what do you do as your drug matures? Make sure you are walking. Making actual profits. Money. Skirt the lines of the law whilst staying on the right side of it. Approach government bodies for big buys. Do your social responsibility wisely (do good, get noticed). Get notable patient advocate groups behind you. Entertain industry professionals and ‘Instagram celebrity doctors’ alongside local practitioners at the RAF, Graucho club and also a converted warehouse in the Meatpacking District. Make them feel comfortable but unusually ‘edgy’, let them read the research – provide it, and make them feel that they are on the elite edge of something groundbreaking. Just don’t give them complimentary company branded pens. That would be silly. And in most places illegal. YOU ARE A HUSTLER. Don’t sail off to St Tropez just yet. Okay, perhaps a few slopes at Courchevel are acceptable. But if you are willing to face the cold, be equally willing to drop by Davos in January too and shake hands with people who have by this point perhaps vaguely heard of your product but don’t know you. Get invited. You are no longer a reclusive scientist. The world, not the lab, is your playground now.

If you are in a phase where your competitor’s patent period is expiring – their biosimilars or generics entering the market are your competition now too. Make sure your foot is ever on the pedal. Your branding needs to be stronger than ever.  You will need it for the next step. YOU NEED A SONG. Or at least a colour scheme.

STEP 5: OH How quickly we have aged. DECLINE AND EXTENSION STRATEGY!

I assume that patent expiration is looming within 5 – 10 years at this point. And you are fast approaching the patent cliff. Don’t jump. Just hang in there. There are things we can do here.

I.e. Extension strategies. You want to find ways to effectively extend your patent in this period. One way to do this if applicable is to change the delivery mode, modify the device sufficiently or make subtle changes to the administration and formulation.

In the base of Benralizumab, long away in the 2030s. I felt that some changes could effectively extend patent life. Benralizumab is administered intravenously by subcutaneous injection, allowing the drug to enter the bloodstream directly. An alternative delivery route that is conducive to rapid perfusion into the bloodstream is by inhalation. (Remember, the idea was to bypass first pass metabolism so inhalation is a goodun’ – that said, I need to know more about the molecular composition)

This would allow the patient to inhale the drug and have a relatively rapid result. Moreover, asthmatic patients, in particular, are largely familiar and comfortable with this delivery route. Whilst it may require changes to the drugs formulation and potency to maximize bioavailability, in effect, this mode can extend patent life as this new formulation, and possibly even device can be patented individually as a therapy of its own. In this way, AZ may effectively be able to ‘turn back the clock’ on this particular drug.

After patent expiration, a drug does begin to decline in terms of sales volume. This is inevitable. Kind of like death. But this is where your strong branding comes in. As well as having targeted fancy pants patients and doctors all across the world as well as less informed ones, too. If you have established brand loyalty, many patients, depending on the disease or catchment age group as well as where the funding comes from (governments tend to switch more quickly to more affordable biosimilars and generics); those users will stay with you. And will use word of mouth to recommend your drug to patients who were well and are now dealing with the disease, in its period of decline. Revising your pricing structure for large buys (organizations, etc.) but only marginally for the retail market will help. You can never compete with the generics so don’t try to reduce the price on the retail market too much. Just hope that doctors will continue to prescribe your drug and that patients won’t ask if there is a generic version at the pharmacy counter.

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Pro tip: If you are a patient – DO ask if there is a generic at the pharmacy counter. A pharmacist will only bring you a drug that has the exact same molecular structure and effect – I can assure you. The name brand is not better. A compound is a compound is a compound. If you are reading this, however, you know that already. 😉

The bottom line is that nothing lasts forever. If you had a solid strategy in place, the drug has been lucrative during its lifetime and has also resulted in benefit to patients and the extension or amelioration of life and life quality. And at the end of the day, that achieves your goal and helps your consumer.

 

I usually say “Have a banging Friday”. But, as it is Wednesday. I will say “The end is nigh!

Cheers, peace and love,

– Christiana

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