Medicines for Malaria Venture At 20 Years: A Perfect Moment For New Innovation

MMV CEO David Reddy talks about the steps MMV is taking to support a new generation of malaria research leadership, promote more gender-sensitive malaria treatment and fast-track innovation on new malaria combination therapies. This follows a string of MMV successes over the past two decades in fostering new paediatric malaria treatments, new combination therapies to fight drug resistance and a breakthrough single-dose treatment, tafenoquine, for the relapsing form of malaria.

Health Policy Watch: You are celebrating the 20th anniversary of MMV’s creation. It was also one of the first non-profit “product development partnerships (PDP)” to be created, involving both industry and public sector actors in malaria R&D. How did MMV come about, and what gap has it filled in the R&D landscape?

David Reddy: MMV was formed in 1999, out of a WHA discussion with African leaders who were worried that there was more parasite resistance developing [to existing malaria drugs] and not enough R&D being done on new treatments, effectively there was a market failure.

It came out of the forward-thinking people in Industry and WHO, and incubated at the TDR, the Special Programme for Research and Training in Tropical Diseases.

Today we have a broad partner network, including some 26 pharma partners, both innovators and generic producers, as well as research and academic institutions, governments, international organizations, NGOs and non-profits, and clinical trial centres in endemic countries.

For the past two decades, MMV has been leading the development of new antimalarial treatments, supporting expansion of R&D capacity in malaria-endemic countries, and working to ensure access to antimalarial treatment by the world’s most neglected populations.

HP-Watch: We have heard you recently speak about how MMV had its roots in industry, while Drugs for Neglected Disease Initiative DNDi), had its roots in civil society activism – but you both have gotten to a similar place in your development. Can you talk a little more about that?

Reddy: Well, I compare it to the blue whale and the whale shark.  On the evolutionary tree, DNDI and MMV started from different places, but we are addressing the same underlying issues in the drug development ecosystem – market failure. In addition, we at MMV, we focus solely on malaria whereas DNDi’s remit is wider in terms of neglected tropical diseases.

Because of where we came from, we started from a strong R&D base; there were a lot of people from industry who became part of MMV.  So, I think we were positioned very well in terms of being able to get industry to contribute to the model.  Additionally, I have led teams [while at Roche] that had developed drugs with regulators, so I also know that mindset. And in fact, the regulators are quite agnostic about whether the innovation comes from industry or a non-profit group – the same rules apply.

HP-Watch: There has been a lot of discussion recently about the importance of insuring for wide access to treatments up front. When MMV engages with the private sector or others. What’s MMV’s approach on that, and how is it similar or different to others?

Reddy: In every agreement we have with our partners, we build in access and affordability clauses.  Those include two elements: a commitment to make the drug available and affordable in malaria-endemic countries.  We generally define what that means and in the context of affordability we have enforcement clauses, as well. If a partner doesn’t live up to those obligations, we can take action, such as moving manufacturing capacity across to another partner.

HP-Watch: Is there a motive for pharma to participate if the costs are kept low?

Reddy: Because of the sheer volume of the malaria drugs that need to be provided, [there is still an incentive]. It is a real challenge for other disease areas, where the populations are smaller. For some of our partners, the motive is corporate social responsibility. Others take a no-profit, no loss approach. Incentives such as the US FDA Priority Review Voucher programme can be important.  A partner can use a voucher (awarded upon approval of a new neglected disease treatment to get a rapid approval of another drug in a profitable disease area, where a six-month time to market advantage is worth a considerable amount of money.  And once the vouchers have been issued, they can also be transferred and sold. These kinds of benefits do help tip the balance of the pharma companies participating in this area.

HP-Watch:  Can you briefly summarize the 3-4 biggest breakthroughs you have experienced in drug development – up to the recent approval of the new drug tafenoquine – and their meaning for public health?

A health worker dispenses a child-friendly formulation of Coartem®, MMV’s first paediatric malaria treatment.

The first breakthrough was the product we co-developed with Novartis, that was a child-friendly version of their antimalarial drug, Coartem®, [the first artemisinin-combination therapy]. In less than ten years since launch, some 385 million courses of that treatment have been delivered.  This is a key success since most people who die from malaria are children under 5 years of age. And yet children are among the last to get [paediatric formulations of] medicines [due to the sensitivity of clinical trials involving children]. So, this was really important.”

Pyramax® (pyronaridine-artesunate), is another ACT – based on the drug pyrimidine, that has shown some nice activity in areas where resistance has been seen.

Testing for malaria (P. vivax) parasites in Brazil, the first malaria-endemic country to approve the first GSK and MMV co-developed treatment for relapsing malaria.

This is a particularly important development programme because we are working with a generic company, Shin Poong in South Korea, and they formed a joint team with us.  We were able to bring our knowledge of drug development and the malaria space to them and help bridge the gap between generic companies and innovators. So, it was a capacity development journey for them and for us it was useful in getting the product on the market.

Then, just last year, tafenoquine, which was developed in partnership with GSK and is a single dose cure for the relapsing form of malaria (caused by the Plasmodium vivax parasite), which in some patients can replace 14 days of treatment with the currently used drug. Tafenoquine was approved by the US FDA and Australian TGA. It has also just been approved by the Brazilian regulatory authorities.

 

A child receives injectable artesunate for severe malaria, a formulation that MMV is helping generic manufacturers produce.

In addition, we are supporting generic manufacturers to produce quality-assured variations of rectal artesunate and injectable artesunate, [for immediate treatment of severe malaria episodes]. This was massively important in terms of getting these products onto the WHO Pre-Qualification list, [which undertakes a stringent review and can be a pathway for approval by national regulatory agencies]. For the injectables alone, some 144 million vials have been shipped since 2011, and we estimate that has saved 950,000 more lives in comparison to the alternative treatment, injectable quinine – if people were even to receive that at all. For the suppositories, some 3.2 million have been shipped since 2017, and we estimate about 300,000 lives have been saved.

HP-Watch: What about malaria resistance… how serious a threat is that, where and what is MMV doing about it?

Reddy: There is resistance being seen with some of the ACTs – current first-line treatment for uncomplicated malaria. o\On that basis, we are developing, with Novartis, a new combination of novel compound ganaplacide with a new formulation lumefantrine. This is a non-artemisinin-based combination, which is what we need to be looking for, with a new mechanism of action against resistant parasite forms. It is in Phase 2b studies, and we are hoping it could be a one- or two-day therapy. That would provide a big benefit, in terms of its utility because one of the big challenges that we have seen with the ACTs [which have a 3-dose regimen] is that while people will take the first and second dose, there is a tendency for people to hold back on that last day of dosing, if they are feeling better, thinking that they can save the pill until the next child gets sick. And that fosters resistance.

Resistance is something that needs to be taken really, really seriously, we have seen it in each of the malaria drugs that have been developed, which is why using them in combination is so important.

So, we are trying to pursue an approach where multiple approaches for first-line therapy are available in every country, keeps the pressure on the parasite. Secondly, we are trying to develop new combinations with new mechanisms of action, like the Novartis project I just mentioned. Towards this end, there were 5 biological targets – ways we could hit the parasite – 20 years ago. Today there are 25 targets, and this can give rise to entirely new drugs; a number of them are already in clinical development.

Malaria parasite (blue-left) attaches to a human red blood cell (red-right)

We see the parasites being resistant to the drugs, we see the mosquitoes becoming resistant to the insecticides. We even see the parasites developing a form of resistance to the rapid tests that we use to identify them. In some of the tests, they had worked out a way to escape the test, by deleting a part of their genome that gave rise to a protein used by the rapid test to detect them. This multi-layered counter-offensive is something as a biologist that I have never seen.

The threat of resistance is compounded by other regional or global changes.  For instance, with climate change you get flooding, destruction of infrastructure that reverses the development progress that has been made. The other challenge is political instability, you can see that in the resurgence of malaria in Venezuela.

HP-Watch: The theme of malaria “eradication” has been much in the news, with some agencies saying it’s feasible and WHO saying that the elimination agenda first must get back on track. What’s your view?

Reddy: There were two reports on this topic that were launched a few months ago, one was by the Lancet Commission and one was by the WHO Strategic Advisory Group on Malaria Eradication (SAGEme).  Both effectively came to the same conclusion, which was that eradication should be our objective.  The WHO report [also] said that there is no biological impediment for why it cannot be achieved. But we will need new interventions.

I believe in the feasibility of eradication. What it requires is systematic elimination from countries and regions, as we have done it in Europe and North America. [It also requires a change in mindset], because many people have this inherent belief that the countries in Africa are locked into malaria.

Hans Rosling, in his book Factfulness said that countries in Africa have developed beyond most people’s understanding, at a strong pace. African countries are showing strong ownership of the concept of eradication and they are putting resources behind it. We have seen enormous progress in pushing back malaria, and a number of countries are on the cusp of elimination of malaria [as a public health risk]. But in other countries, we need to do more, including getting more real time data on what is working and what is not.  Groups such as USAID Presidents Malaria Initiative, the Global Fund and the Gates Foundation are really putting processes in in place to get better real time access to data that is needed. And part of it is up to us, to bring a new generation of medicines forward for prevention and treatment. We have made enormous progress; we have entirely new ways of attacking the parasite. Now it’s a matter of getting innovations through development and into the hands of clinics and patients.

HP-Watch: Some critics have accused the health sector of abandoning vector control, including environmentally-friendly measures such as better management of water resources and housing (e.g. screening) as modes of “treatment”, which can also reduce reliance on chemicals, and therefor vector resistance to chemical tools.

Reddy: I think vector control is being addressed from a different angle, the developmental angle.  We do see significant developmental progress and there will be a positive collateral effect on malaria. The Zero Malaria Starts with Me [a continent-wide campaign to eliminate malaria], begun by Senegal, is about communities; it is ensuring that trash is cleaned up, etc. I think the zero malaria starts with me is a good starting point.  But I agree that if we want to address malaria and really beat it, it is a belt and braces approach, we shouldn’t be throwing out any interventions without a thorough assessment.

HP-Watch: What about R&D costs, a subject in the news recently.  Do you have any assessment of the costs to bring a new or adapted drug to market?

MMV and partners have implemented a series of platforms to gather data to feed into a tool to allow unbiased prioritization of optimal drug combinations for further research.

Reddy: The overall costs for development of a malaria drug is about $US 100 million.  The fully loaded costs are probably in the region of $US 200 million. If we pay a dollar, the pharma pays a dollar plus in-kind contribution such as their facilities.  This is not including drug attrition. But since we have a strong system of pre-clinical assays, we can kill drugs pretty early.

Today, we have a strong network of SCID (severe combined immune deficiency) mice assays that allow you to test drug or drug combinations very quickly. [at a later stage] We can also run tests on healthy human volunteers infected with very small amounts of malaria parasites before it becomes clinical, you can treat them [with the experimental drug], and then you can treat them with the standard drugs, so that in a very, very controlled setting you can explore your drugs, are they going to work, and the likely dose you can use with patients. This keeps costs down and speeds things up.

HP-Watch: What challenges lie ahead, and do you see MMV continuing to address malaria only, or could there be other targets for your work?

Reddy: I think there is a real acknowledgement that it is not the current generation of leadership that will finish this job, and that includes me.  We need to be looking for that next generation of leadership and scientists. Much of that leadership is going to be coming from the malaria endemic countries.  So, our work on empowering needs to be rooted in the Malaria endemic countries.

MMV will be focusing on developing better treatments for pregnant women in the coming years

We will be looking more closely at groups such as pregnant women, who are disproportionately affected by malaria.  Yet in drug development programmes, pregnant women are classed as a vulnerable population, and therefore [in the traditional R&D mindset] you protect them from new drugs. [But that leads to us not having adequate drugs for women in pregnancy]. We are all realizing that we have been thinking about this in completely the wrong way, and so we need to see how we can get them included in studies so that they can benefit from new drugs earlier. We need to create a stronger programmatic stream [around malaria in women/pregnancy] if we are going to change things and move towards more equitable access.

Finally, new malaria combination drugs are going to become more and more important in order to avoid resistance.  So, we are launching a “malaria drug development catalyst” [initiative].  This is a unique way of bringing partners together at an earlier stage of development, to look at what drugs can be combined.

With out partners, we have already developed the technical tools, such as mouse assays and human volunteer studies, that allow us to perform tests in a consistent way. All partners can access the molecules, and the molecules can be put through the same assays, so that you can do an apples to apples comparison and see which molecules work best.

As with the assays, we want to create a common way of doing assessments and common agreements with the different companies and partners, so that it is easier for them to work with us and together. This is becoming very important now because we have a number of new drugs coming up through the pipeline. So, it is one of those perfect moments in time when everything comes together, and this is a way of formalizing and accelerating things.

 

This story is part of a series supported by MMV on malaria innovation.___________________________________

About David Reddy: Prior to joining MMV, in 2010, Reddy was a Vice President at Roche Pharmaceuticals, in Basel, Switzerland. With 20 years of management experience in the healthcare industry includes: successful leadership of drug development teams; licensing and alliance management; market analytics and business planning; product and disease area management; and interfacing with Governments, NGOs and patient advocacy groups in priority disease areas including HIV/AIDS and pandemic influenza. He has a doctorate in Cellular and Molecular Biology from the University of Auckland, New Zealand and completed a Post-Doctoral fellowship in molecular neurobiology at the Friedrich-Miescher Institute in Basel Switzerland.

 

Image Credits: Anna Wang/MMV, Novartis, Ben Moldenhauer/MMV, NIAID, NIH, MMV, Elizabeth Poll/MMV.