Recent KOL feedback points to underserved market that is also shifting to overall prophylaxis; we project a consistent
role for Ruconest. Dr. Marc Riedl (Director, HAE Center of Excellence, UCSD) previously discussed the current landscape
of HAE and these are our takeaways. His view is that the treatment of HAE should shift more to prophylaxis treatment vs.
acute. Driving this is that most attacks are unpredictable and random with tremendous variability in attack frequency, and no
predictor available for attack severity. Further, he points to the belief that there is a global under-diagnosis of the disorder
(median diagnostic delay of 13.3 years compared to 1.7 years if no misdiagnosis). The convenience of administration, which we
believe Ruconest's new formulations focus on, should assist in procuring market share for home use. As a counter argument,
his early experience with Haegarda, while showing dramatic reductions in attacks, shows the need for dose increases, as well
as experiencing supply issues (i.e., needing 'shovel fulls' of plasma per patient), as we mentioned above. We believe that as the
treatment field evolves, especially with oral therapies and kallikrein inhibitors, Ruconest could still have a meaningful position
in the treatment landscape. To this end, even if the market were to shift away from C1 inhibitors, we believe that breakthrough
attacks would still be treated with C1 inhibitors, and Ruconest should be the drug of choice.
Competitive landscape evolving, but Ruconest remains differentiated. Few drugs are currently available for the treatment
of HAE in acute settings other than steroids, however, all of them display less than ideal safety profiles and lower efficacy
when compared to Ruconest. Cinryze and Berinert are isolated from blood plasma which increases risks associated with lower
purity plasma based pathogens and blood clots. Two other drugs, Firazyr and Kalbitor, have 97% injection site reactions and a
Black Box warning for anaphylaxis, respectively. In contrast, Ruconest has extremely high recombinant purity (>99.9%), very
low risk of allergic reaction, and no underlying plasma risk. In addition, all four leading competitors have lower responses at
four hours or less when compared to Ruconest and Firazyr and Kalbitor have shown higher rates of relapse or worsening of
symptoms (11-31%). More recently, newer drugs have been approved for prophylaxis and include: (1) Haegarda (CSL 830,
approved on June 23, 2017); and (2) Takhzyro (SHP643, lanadelumab), recently approved by the FDA (August 23, 2018) for
the treatment of HAE I and II in patients aged 12 years and older. However, both these drugs are associated with a higher risk
of side effects when compared to Ruconest: for Haegarda strong efficacy was observed only at very high doses (80 U/kg vs.
12-50 U/kg for the other drugs treating HAE) and side effects for both Haegarda and Takhzyro include injection site reactions,
upper respiratory infections, headache, rash, muscle pain, dizziness and diarrhea. Lastly, BCX7353 has recently been granted
Fast Track Designation by the FDA for the prevention of angioedema attacks in patients with HAE. Currently, two Phase 3
studies (APeX-2 and ApeX-S) are evaluating the long-term safety and dosage strengths of BCX7353 administered orally oncedaily
as a preventive treatment to reduce the frequency of attacks in patients with HAE. In addition, BCX7353 is being tested
in the ZENITH-1 Phase 2 in oral liquid formulation for the treatment of acute HAE.