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Pharmavitae Analytics

  • Alnylam’s focus on RNAi therapeutics for rare genetic diseases pays off in the short term – Alnylam’s recently announced APOLLO Phase III success with its leading investigational RNAi drug, patisiran, met shareholders’ highest expectations, and bumped up the market value of the company’s extensive early to late-stage RNAi therapeutics portfolio by 52%, to $10.7bn.

  • Novel class of drugs – Alnylam’s breakthrough APOLLO Phase III data will attract more investment in innovative RNAi therapeutics.

  • Alnylam’s clinical breakthrough will not easily translate to long-term commercial success – Alnylam’s patisiran will face little competition for hATTR amyloidosis patients with polyneuropathy, but the complex nature of the orphan disease will make it difficult to find patients, leading to slow sales growth.

  • Pharmavitae Analytics’ poll of 50 neurologists based in the US and Europe indicates that neurologists who are familiar with the APOLLO data are overwhelmingly favorable about patisiran – 94% of neurologists who are currently treating hATTR amyloidosis patients with polyneuropathy said they would prescribe patisiran if it is approved.

 

Alnylam’s high stakes investment in RNAi therapeutics delivers a major short-term win for stakeholders, but long-term commercial success is still in question.

 

Analyst comment

Pharmavitae Analytics predicts that Alnylam’s patisiran for the treatment of hereditary transthyretin (TTR)-mediated (hATTR) amyloidosis patients with polyneuropathy will be the first RNAi interference (RNAi) therapeutic to launch in the US and Europe. Pharmavitae Analytics expects that the strong impact of Alnylam’s recently released topline APOLLO Phase III results for its leading RNAi drug on the market value of the company’s RNAi therapeutics pipeline will signal the potential of this new class to a wider audience of biopharmaceutical industry investors. However, Pharmavitae Analytics anticipates that commercialization of patisiran for this orphan disease will be particularly challenging, given the complicated nature of the condition and the physicians in numerous specialties that must be educated on its accurate diagnosis. Pharmavitae Analytics nevertheless expects that patisiran will reach blockbuster sales, and that the RNAi therapeutic will claim 80% of the hATTR amyloidosis with polyneuropathy market share.

 

 

Figure 1Patisiran's forecast ($m), 2016-26

 

figure1

 

Overview

 

 

On 20 September 2017, Alnylam Pharmaceuticals and Sanofi Genzyme announced positive topline results from the APOLLO Phase III trial of patisiran (Alnylam/Arbutus Biopharma/Ionis Pharmaceuticals/Sanofi) in hATTR amyloidosis patients with polyneuropathy (Alnylam, 2017a; Sanofi, 2017). Pharmavitae Analytics predicts that patisiran will be the first approved RNAi therapeutic in both the US and Europe, based on the strength of the APOLLO data.

 

 

The intravenously administered, TTR-targeting RNAi therapeutic met its primary and secondary endpoints in the APOLLO trial, demonstrating a highly statistically significant reduction in neuropathy progression, as measured by the modified neuropathy impairment score (mNIS+7), and improvement in quality of life, as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy, at 18 months compared with placebo, with a clean safety profile (Alnylam, 2017a; Sanofi, 2017). The impressive efficacy and reassuring safety data from the APOLLO study represent the first positive Phase III results for an RNAi therapeutic candidate.

 

 

Imminent approvals

 

Alnylam plans to file a New Drug Application (NDA) with the US Food and Drug Administration in late 2017, and a Marketing Authorization Application with the European Medicines Agency in early 2018 (Alnylam, 2017a; Sanofi, 2017). Pharmavitae Analytics predicts that patisiran will launch in the US in 2018 and in Europe in 2019. Sanofi will be the marketing partner for patisiran outside the US, Canada, and Western Europe (Alnylam, 2017a; Sanofi, 2017).

 

 

  • Lack of competition and pricing pressure – Pharmavitae Analytics predicts that the launch of patisiran for hATTR amyloidosis with polyneuropathy will benefit from the typical advantages associated with an approved drug in an orphan indication; little medium-term threat from competition and protection from pricing pressures in the US, albeit with coverage taking longer in Europe.
  • Alnylam’s M&A appeal – Alnylam’s extensive portfolio of RNAi therapeutics, with another six injectables in clinical development in the US (Figure 1), including two promising Phase II candidates – ALN-CC5 for paroxysmal nocturnal hemoglobinuria and givosiran for porphyria – presents an attractive potential M&A target. Alnylam is also a clinical development partner for the exciting Phase III RNAi drug inclisiran (The Medicines Company) for dyslipidemia/hypercholesterolemia, and for the promising Phase II RNAi therapeutic QPI-1002 (Quark Pharmaceuticals) for renal disease/renal failure.
  • As Alnylam’s shareholders are rewarded, Ionis feels the pinch – Although Ionis Pharmaceuticals is a development partner for patisiran, it is also in direct competition with Alnylam for potential hATTR amyloidosis with polyneuropathy market share, with its TTR-targeting antisense drug inotersen, which has demonstrated an inferior safety profile to patisiran. Ionis also plans to file an NDA in late 2017 (Ionis, 2017). The company’s stock dropped by 9% on the APOLLO data.
  • Investment in RNAi therapeutics – Pharmavitae Analytics predicts that the APOLLO results will substantially boost investment in the RNAi therapeutics class.

 

 

 

Figure 2Alnylam’s injectable RNAi therapeutics in clinical development in the US

 

figure2

 

 

Uncertain revenue

 

Pharmavitae Analytics predicts that the launch trajectory of patisiran for hATTR amyloidosis with polyneuropathy will depend on the education of physicians in multiple specialties on this rare condition (Alnylam, 2017b), and this new drug class. Pharmavitae Analytics anticipates that market penetration of patisiran will be high among correctly diagnosed patients, due to the lack of effective available treatments, but physicians’ poor awareness of the difficult to diagnose orphan disease will be a significant barrier. The different symptoms of hATTR amyloidosis with polyneuropathy can cause patients to see multiple specialists, including primary care physicians, gastroenterologists, urologists, and neurologists, and this process commonly takes four to five years to reach a diagnosis (Alnylam, 2017b).

 

 

Pharmavitae Analytics polled neurologists based in the US, France, Germany, Italy, Spain, and the UK on the APOLLO results, and found that out of 50 neurologists who are both familiar with the topline Phase III data and currently treat hATTR amyloidosis patients with polyneuropathy, 24 out of 25 (96%) neurologists based in the US and 23 out of 25 (92%) neurologists based in Europe would prescribe patisiran for hATTR amyloidosis patients with polyneuropathy if the RNAi drug is approved. Pharmavitae Analytics notes that this high acceptance rate is potentially biased by the fact that only neurologists who are both aware of the APOLLO data and currently treating hATTR amyloidosis patients with polyneuropathy responded to the survey question.

 

 

Reputation repair

 

Pharmavitae Analytics predicts that the APOLLO trial results will improve sentiment toward the RNAi therapeutics class after recent safety issues with Alnylam’s RNAi therapeutics clinical portfolio. Pharmavitae analytics expects that the APOLLO safety data will help to mitigate any remaining concerns from Alnylam’s discontinuation of its Phase III RNAi drug candidate revusiran for the treatment of hATTR amyloidosis with cardiomyopathy in October 2016 (Alnylam, 2016), and suspension of its Phase III RNAi therapeutic candidate fitusiran for the treatment of hemophilia A and B patients with and without inhibitors in September 2017 (Alnylam, 2017c).

 

 

Alnylam discontinued the ENDEAVOUR Phase III study of revusiran in hATTR amyloidosis with cardiomyopathy due to incidences of new onset or worsening peripheral neuropathy in the Phase II open-label extension study of revusiran, and subsequently uncovered an imbalance of mortality in the revusiran arm compared with placebo in the ENDEAVOUR study (Alnylam, 2016). Alnylam also suspended dosing in all ongoing fitusiran studies due to a fatal thrombotic event in a patient with hemophilia A without inhibitors in the Phase II open-label extension study of fitusiran (Alnylam, 2017c). Alnylam said that it aims to resume dosing of fitusiran as soon as possible, and potentially as early as late 2017, following further investigation of the safety finding, and upon agreement with regulatory authorities, with appropriate protocol amendments for enhanced safety monitoring (Alnylam, 2017c). The negative benefit-risk profile signals from these two drugs in Alnylam’s investigational RNAi therapeutics portfolio did however threaten market confidence in the novel drug class.

 

 

Bibliography

Alnylam (2016) Alnylam Pharmaceuticals Discontinues Revusiran Development. Available from: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=992320[Accessed 20 September 2017].

Alnylam (2017a) Alnylam and Sanofi Report Positive Topline Results from APOLLO Phase 3 Study of Patisiran in Hereditary ATTR (hATTR) Amyloidosis Patients with Polyneuropathy. Available from: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=1041081 [Accessed 20 September 2017].

Alnylam (2017b) Alnylam Pharmaceuticals Conference Call to Discuss Topline Results from APOLLO Phase 3 Study of Patisiran. Available from: http://investors.alnylam.com/eventdetail.cfm?EventID=185171 [Accessed 20 September 2017].

Alnylam (2017c) Alnylam Provides Pipeline Update on Fitusiran and Givosiran Investigational RNAi Therapeutic Programs. Available from: http://investors.alnylam.com/releasedetail.cfm?ReleaseID=1039464 [Accessed 20 September 2017].

Ionis (2017) Ionis to Independently Advance Inotersen and IONIS-FB-L Rx. Available from: http://ir.ionispharma.com/news-releases/news-release-details/ionis-independently-advance-inotersen-and-ionis-fb-l-rx [Accessed 20 September 2017].

Sanofi (2017) Sanofi and Alnylam Report Positive Topline Results from APOLLO Phase 3 Study of Patisiran in Hereditary ATTR (hATTR) Amyloidosis Patients with Polyneuropathy. Available from: http://news.genzyme.com/press-release/sanofi-and-alnylam-report-positive-topline-results-apollo-phase-3-study-patisiran-here [Accessed 20 September 2017].

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