ABSTRACT
Introduction: Despite the great clinical need, the development of drugs for treating non-tuberculous mycobacteria lung disease (NTM-LD), partly from the scientific difficulty, but also because the eventual size and types of markets for commercially-developed drugs has been unclear.Areas Covered: Here, key questions regarding the markets for commercial NTM-LD drugs are discussed, together with potential solutions for resolving these questions.Expert Opinion: Many of these questions will become better resoled over time, but uncertainties will remain around likely competition and whether approval and reimbursement will be achieved for all NTM-LD or smaller subsections of the market. Additionally, both ‘push’ and ‘pull’ incentives should be considered by policymakers to ensure the NTM-LD market is successfully addressed.
1. Introduction
Developing drugs for non-tuberculous mycobacteria lung disease (NTM-LD) is technically difficult due to their intrinsic and acquired resistance, the complex multidrug regimens used, the poor correlation between in vitro antimicrobial activity and clinical response, and the lack of in vivo models mimicking human etiology [Citation1]. There are also significant differences between NTM species that exist in environmental reservoirs and the specialized pathogen Mycobacterium tuberculosis, that drive some profound differences in drug targets and susceptibilities, so we cannot rely just on drugs being developed for TB. However, significant efforts are being made to overcome these difficulties (such as by NIAID and FDA) so these technical issues should be overcome.
However, uncertainties around financial issues that drive for-profit drug development remain unresolved. On the upside, perceptions around Insmed’s launch of Arikayce® have been favorable, with their market capitalization in excess of $2 billion. Insmed also achieved typical orphan drug pricing, with wholesale acquisition costs (WAC) of $11,000 per month. As Arikayce® roll-out continues, many of the following factors should become more clear, but allocators of capital for NTM-LD drug development face uncertainties in financial projections, especially market size and likely competition. Because of these uncertainties, companies may delay early drug discovery, while venture or other funders of small and start-up companies may not make early-stage investments. These uncertainties are discussed, as is how to resolve these issues to come closer to true estimates of risk.
2. Prevalence vs. incidence?
As NTM-LD infections are non-reportable, estimating their numbers is difficult. Furthermore, most epidemiological NTM-LD studies only report prevalence, not incidence. Although studies comparing prevalence and incidence are rare, a Japanese study showed prevalence was 3.4 fold greater than incidence [Citation2], so market projections built upon incidence or prevalence will be different. For chronic incurable conditions, prevalence drives market size, while for acutely curable conditions incidence is key as it represents the yearly new pool of potential patients. NTM-LD does not fall easily into either category:cure (if achieved) can take several years, many patients are not cured and remain on treatment for variable periods, reinfection is common and a new paradigm of preventive therapy after cure is also developing. For these extended and repeat treatments however, prevalence may actually be more useful. Furthermore, the current ATS/IDSA guidelines are dated (although new ones are in preparation) and the clinical decision on whether to treat patients with positive cultures is difficult and complex. Because of these factors, prediction of patient numbers is difficult.
3. Approval for refractory vs. non-refractory disease?
Cases failing first-line therapy (oral macrolide, rifampin, and ethambutol) are termed refractory and have lowered probability of cure by further therapies. Although difficult to assess, Insmed estimates between 11% and 17% of the US, EU, and Japanese patient population have refractory disease. Therefore, potential market size is strongly dependent upon the indication(s) a drug will be approved and reimbursed for, whether just refractory or all NTM-LD, but the pharmaco-economic case for all NTM-LD needs making.
4. Cure vs. maintenance?
Most NTM-LD occurs in patients predisposed to infection by environmental NTM due to host factors (e.g. bronchiectasis) so reinfection is common: one-third of cured M. avium complex (MAC) patients had reinfection [Citation3] or recurrence [Citation4]. The paradigm of maintenance therapy (MT) after cure is still developing, but a recent study showed 75% of patients maintained sputum culture negativity over a median of 2.7 years [Citation5]. Further studies of recurrence/reinfection in patients with and without MT are needed, but approval in this indication could increase market size substantially.
5. Heterogeneity of organisms causing NTM-LD
Several different species cause NTM-LD, the two major groups being MAC and the M. abscessus complex (MABC) with the latter more resistant (e.g. to macrolides) than MAC and even harder to treat. Difficult MABC infections are notorious in Cystic Fibrosis (CF) and there could be significant value in developing compounds with activity against both MAC and MABC. Additionally, awareness and suspicion of the importance of other NTM species in causing disease are developing, and so treatments will likely be needed for these species.
6. Established NTM-LD competition
First-line therapy is frequently effective and broadly available generically, providing competition in non-refractory disease. Arikayce® may also exhibit potent activity in this, the largest sub-section of NTM-LD, and provide another layer of incumbent competition. Also, other approved anti-mycobacterial drugs being tested for NTM-LD (e.g. clofazimine or bedaquiline) [Citation6,Citation7] may prove successful, or repurposed agents with host-directed effects [Citation8] may be effective, generating further competition.
7. Emerging NTM-LD competition
The commercial success of Insmed generated much interest in the NTM-LD market, and there is both motive and capacity for much NTM-LD drug discovery. A recent search (google, terms NTM and pipeline) showed companies promoting NTM-LD pipelines at clinical and preclinical stages (e.g. AIT-SLI, BIOC-51, MAT-2501, Molgradex, RHB-204, and SPR-720) and other commercial entities are likely developing therapies less publicly. Since the success rate of anti-infective drug development is about 25% [Citation9], it is possible that several compounds could be approved. Finally, bacteriophage therapy in disseminated M. abscessus in CF [Citation10] may also become widespread. It is premature to predict which therapeutics may have favorable clinical efficacy, safety, and compliance profiles, but there is significant uncertainty about what the competition will be at launch and ongoing.
8. Patient access for clinical trials
Insmed’s regulatory pathway has been securing approval as add-on to standard therapy in refractory MAC disease first, followed by expansion into other organisms and indications. This seems a path that others will likely follow. However, Arikayce® is now approved for refractory MAC disease in the US, with other countries pending, and it is likely that refractory patients might accrue for studies of other agents only after failing combined standard therapy and Arikayce®. This could restrict eligible patient numbers for trials, and their more severe disease may make it more difficult to show efficacy and safety.
9. Anti-bronchiectasis and CFTR corrector competition
Since most NTM-LD occurs from infection of patients with predisposing factors, especially bronchiectasis and CF, the development of agents that cure or prevent deterioration of these predisposing factors could decrease NTM-LD market sizes. Several bronchiectasis programs are at preclinical and clinical stages (e.g. AZD9668, INS1007, MPH966, and POL6014). However, diagnosis of bronchiectasis is usually difficult and occurs relatively late in disease progression, so treatments might not be curative, rather delaying or preventing progression. As more CFTR correctors become available and are used earlier, the prevalence of NTM-LD in CF may also decrease, although this is only a small market subsection.
10. Biomarkers
Current microbiological endpoints (sputum culture) are difficult and noisy discrete variables limiting statistical analysis in clinical trials. They are also limited in their ability to support clinical therapy institution, and do not support monitoring of regimen efficacy during treatment. New biomarkers, based on host and/or mycobacterial factors could greatly benefit research and treatment.
11. Conclusion
Approval for curative treatment of all NTM-LD caused by MAC would lead to total incidence-based markets of about 20–30 K, 4–5 K and 35–45 K new patients per year for US, EU, and Japan, respectively. Assuming 1 year of treatment, total sales could be $2.5B–$4B, $0.3–$0.6B and $2.3B-$3B (using WAC of Arikayce® in US and 50% of that in EU/Japan). Approval for treatment of refractory disease leads to markets only 10–20% of this size. Maintenance therapy approval would lead to prevalence-based market sizes that are 3–4 fold larger than cure, but since it is likely to be intermittent, a lower WAC needs to be factored in to sales. Depending upon the competition at the launch of new therapies, some price erosion will occur, and competition between these therapies could decrease their individual market sizes, although best-in-class therapies should command premium market share and pricing. For example, achieving only 30% of total market for all NTM-LD cure and taking 50% discount on Arikayce® WAC, US and Japanese annual sales would still be $400M-$650M, and $400M-$500M, while having to support approval and sales in just two jurisdictions. The maintenance therapy market would be of a similar size.
12. Expert opinion
Much uncertainty in market size, indications (refractory vs. all cases, cure vs. maintenance) and established competition will be resolved by academic studies, and continued reporting from Insmed (assuming it remains publicly traded). However, a significant sized potential market is already reliably established (assuming that orphan drug pricing levels for Arikayce® continue). Therefore, this uncertainty should really not be viewed as a major impediment. The real uncertainties are likely competition at launch and afterward, and whether approval and reimbursement are for all disease, or only refractory. Since all disease approval is most likely for a very safe but potent compound, developers should be realistic and preferentially advance only compounds with these characteristics. In particular, efficacy and toxicity studies should use not only monotherapy, but in animal models treated with background therapy. This is because their likely indication is an add-on to background (and not as monotherapy) so significant additional potency and lack of toxicity in models treated with background therapy are essential. To gauge efficacy against emerging competition, continued development of animal models closely mimicking human NTM-LD would allow for preclinical head-to-head studies against other drugs. The progression of agents that target not only MAC but also CF-associated MABC should be strongly considered, and prioritizing agents with activity against more than just MAC and MABC would be useful. For example, activity against M. tuberculosis would be clinically useful, and could lead to a priority review voucher. Alternatively, prioritizing agents with activity against the ESKAPE pathogens causing multi-drug resistant infections for which a range of push/pull incentives is being developed could be considered. For policy makers, push incentives would help justify early-stage investments whilst these uncertainties are being clarified, and should be considered by organizations that operate in this space. Additionally, significant ‘pull’ incentives also need development to keep commercial entities engaged through expensive clinical stages and to approval and sales.
Declaration of interest
G Timmins is the CSO and Founder of SpinCeutica, a company who are involved in non-tuberculous mycobacteria-targeted (NTM) drug discovery. He also owns stock in this company. He is also an occasional scientific advisor for Avisa Pharma Inc. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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References
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