• Prekallikrein MOA supported by compassionate use data, efficacy in similar targets
  • IONIS-PKK-LRx likely safe, could offer improved dosing over competitors
  • Success in HAE-1 and HAE-2 likely, but unclear in rarer subset HAE-nC1-INH

Ionis Pharmaceuticals’ Phase IIa IONIS-PKK-LRx (donidalorsen sodium) has a prekallikrein target that comparably competes with kallikrein inhibitors for prophylactic treatment of hereditary angioedema (HAE), experts said.

But unlike an analyst report suggesting donidalorsen sodium’s mechanism was advantageous over approved kallikrein inhibitors, experts said the two approaches would likely produce similar results and could not be compared directly based on existing data. Prekallikrein is the inactive precursor of kallikrein, which means targeting prekallikrein is likely to mirror the effects of impacting kallikrein in the bradykinin system that is implicated in HAE attacks, experts explained. Two kallikrein inhibitors–Takeda Pharmaceuticals’ monoclonal antibody Takhzyro (lanadelumab-fly) and BioCryst Pharmaceuticals’ small molecule Orladeyo (berotralstat)–received FDA approval in August 2018 and December 2020, respectively.

Nonetheless, strong efficacy and safety signals from previous compassionate use data, as well as the approved kallikrein inhibitors with a slightly downstream target, bolster confidence in donidalorsen sodium, they agreed. The 29-patient Phase IIa has a March study completion date.

Donidalorsen sodium could also offer some dosing advantages over the aforementioned kallikrein inhibitors, as patients may prefer its once-monthly subcutaneous injection to Orladeyo’s daily oral dosing requirement or Takhzyro’s twice-monthly injections, experts said. In 2020, Takhzyro had US sales of $751m. Orladeyo, approved last year, has estimated peak US sales of $269m in 2026, according to a GlobalData consensus.

While most experts did not have any major safety concerns, one cautioned that although existing safety data for the target is strong, there could still be potential long-term safety concerns given kallikrein’s role in vasodilation.

Also, since the prekallikrein and kallikrein system is not directly implicated in the subset of HAE patients with normal C1 inhibitor (HAE-nC1-INH), it is unclear whether the drug will be effective for that rare form of the disease, they said.

Ionis did not respond to a request for a comment. Ionis has a market cap of $7.64bn.

Prekallikrein MOA likely offers similar efficacy

In terms of efficacy, targeting prekallikrein should produce similar results to targeting kallikrein, which is the active form of prekallikrein in the bradykinin pathway, said Dr David Gailani, professor of Pathology, Microbiology and Immunology, Vanderbilt University Medical Centre, Nashville, Tennessee. Prekallikrein and factor XII (FXII) reciprocally convert each other into the active forms of kallikrein and FXIIa before kallikrein causes high-molecular weight kininogen (HK) to release the peptide bradykinin implicated in HAE, he explained. As a result, reducing the amount of prekallikrein will lower the amount of kallikrein, Gailani and Dr Danny Cohn, investigator and medical specialist, internal medicine, University of Amsterdam, the Netherlands, said.

The analyst report said the previous compassionate use data indicated directionally superior pharmacokinetics of donidalorsen sodium compared to these kallikrein competitors. However, Gailani said comparing reduction in plasma prekallikrein to lowered plasma kallikrein levels is a false equivalence. Instead, a greater reduction in prekallikrein is likely needed to achieve the same reduction in kallikrein, he explained. Nonetheless, the prekallikrein reduction in the compassionate use data supported the rationale for using donidalorsen sodium as an HAE treatment, said Cohn.

In a compassionate use study of donidalorsen sodium and its unconjugated form IONIS-PKKRx for two patients with bradykinin-mediated angioedema, both experienced a nadir of plasma prekallikrein of less than 10%, as well as fewer angioedema attacks during treatment (Cohn D.M., et al. NEJM, 24 September 2020, 383:1242-1247). In comparison, Takhzyro and Orladeyo were shown to reduce plasma kallikrein by 60% and 60–70%, respectively, at the approved doses (Banerhi A., et al. NEJM, 23 February 2017, 376:717-728; Aygoren-Pursun E., et al. NEJM, 26 July 2018, 379:352-362).

Because Orladeyo is dosed daily while the ongoing Phase IIa study calls for subcutaneous injections of donidalorsen sodium once every four weeks, the latter’s schedule could potentially increase adherence and add convenience for patients, Gailani said. However, dosing preferences are highly variable among HAE patients, some of whom have switched from Takhzyro, injected every two weeks, to Orladeyo for tolerability reasons, despite the former’s stronger efficacy, said Dr Anne Gompel, PhD, head of Gynaecology Endocrinology, Port Royal Cochin Hospital, Paris, France.

Phase IIa success benchmarks achievable

To achieve success in the Phase IIa and advance to a Phase III, Cohn expects to see at least a 50% reduction in the primary endpoint of time-normalised number of monthly HAE attacks relative to placebo. Though the ongoing trial has a double-blind design, Cohn said a noticeable variation in patient responses has been observed at his site. But even if donidalorsen sodium misses this target, both a higher dose or a more frequent dosing schedule can be evaluated, Cohn said.

For context, in a Phase III study, Orladeyo demonstrated a 44.2% decrease in time-normalised number of monthly HAE attacks, according to the drug’s FDA application. In a Phase III study, Takhzyro demonstrated an 87% relative reduction in time-normalised number of monthly HAE attacks relative to placebo, according to a November 2018 press release.

Because people can be naturally born kallikrein-deficient and have no known resulting complications, the strategy of inhibiting prekallikrein or kallikrein is thought to be very safe, Gailani said. The most common treatment-emergent adverse events (AEs) were injection site pain and injection site erythema in 41.7% and 9.5% of patients, respectively.

Although the existing safety data for donidalorsen sodium and kallikrein inhibitors is strong, long-term safety concerns remain given the role of kallikrein in vasodilation, particularly if a patient is subjected to a severe trauma, Gompel said. Because HAE is so rare, it is hard to get safety data required to feel completely comfortable with any new treatments, she added. HAE has an estimated prevalence of 1 in 50,000, equating to approximately 6,000 patients in the US, according to the 2020 Hereditary Angioedema Association Medical Advisory Board Guidelines.

MOA strong for common forms of HAE, uncertainty over rarer mutations

For patients with HAE type 1 (HAE-1) and type 2 (HAE-2), existing data and knowledge of prekallikrein’s role in the bradykinin pathway support the likely success of donidalorsen sodium in the ongoing Phase IIa, agreed Gailani and Cohn.

However, for the subset of patients with HAE-nC1-INH, a very rare form of the disease, it will be more of a “trial and error” approach with less supportive prior data, Cohn said. HAE-1 and HAE-2 are the common forms of the condition occurring in around 85% and 15% of patients, respectively, while HAE-nC1-INH is less than one percent.

In general, treatments for HAE-1 and HAE-2 in clinical practice also offered to patients with HAE-nC1-INH, but performing a trial in this patient group may be very challenging given the rarity of the condition, Cohn added.

In the Phase IIa, 29 patients were randomised into three groups: patients with HAE-1 or HAE-2 receiving either donidalorsen sodium or placebo, and patients with HAE-nC1-INH treated with donidalorsen sodium, according to ClinicalTrials.gov. Still, within this rare subset, it is plausible the prekallikrein target would be effective for patients whose HAE is caused in part by a mutation of factor XII (FXII), the plasma protein that reciprocally activates prekallikrein to produce kallikrein and FXIIa, Gailani said.

William Newton is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.