Phase 1 Trial Data Shows Givosiran Potential to Treat Acute Hepatic Porphyria

Once-monthly injections of givosiran can safely reduce the rate of recurrent porphyria attacks by effectively reducing disease-triggering neurotoxic compounds, data from a Phase 1 clinical trial suggests.

The trial findings were reported in a study, “Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria,” published at The New England Journal of Medicine.

“We are encouraged by the emerging safety and tolerability profile for givosiran, as well as the results of exploratory analyses suggesting favorable effects on porphyria attack rate and hemin use for acute attacks,” Akin Akinc, PhD, vice president and general manager of Givosiran program at Alnylam, said in a press release.

“With no treatment options currently approved for the prevention of porphyria attacks, we believe givosiran has the potential to make a meaningful difference in the lives of acute hepatic porphyria (AHP) patients,” he said.

Givosiran, formerly known as ALN-AS1, is an investigational RNA-based therapy developed by Alnylam Pharmaceuticals to inhibit the ALAS1 enzyme and prevent the accumulation of toxic molecules, such as aminolevulinic acid (ALA) and porphobilinogen (PBG), known to cause acute hepatic porphyria.

Acute attacks of hepatic porphyria can be life-threatening and usually are treated with hemin (marketed under the name Panhematin by Recordati Rare Diseases).

The Phase 1 trial (NCT02452372) was designed to evaluate the safety and activity of givosiran in patients with acute intermittent porphyria (AIP), one of the most common forms of AHP. The study was divided in three parts.

Part A and Part B included 23 patients who had not experienced porphyria attacks in the six months prior to the trial’s start. In Part A they were randomly assigned to receive a single subcutaneous (under the skin) injection of one of five tested ascending doses of givosiran — ranging between 0.035 and 2.5 mg per kilogram of body weight — or a placebo. In Part B they received two once-monthly injections of either 0.35 or 1.0 mg per kilogram of givosiran or placebo.

In the third part of the study 17 patients who had recurrent attacks randomly received injections of 2.5 or 5.0 mg per kilogram of the new agent or placebo, once monthly in a total of four injections, or two injections once quarterly.

Safety data demonstrated that the treatment, in general, was well-tolerated, with similar incidence of adverse reactions across the different groups of patients and with no clear relationship with givosiran dose.

The most common adverse side effects reported included nasopharyngitis (inflammation of the nasal cavities), abdominal pain, and diarrhea. Six patients who were treated with givosiran experienced serious side effects during the trial, which included a fatal case of hemorrhagic pancreatitis (pancreas inflammation) that was identified as being unlikely related to the treatment.

Other unrelated serious reactions reported were influenza infection, opioid bowel dysfunction, miscarriage, and abdominal pain. No serious side effects  were reported in the placebo group.

Assessment of the activity of givosiran revealed that all six patients who were treated with once-monthly injections had sustained reductions in ALAS1 gene levels, as well as lower ALA and PBG urine levels to near normal levels.

Further analysis showed that these metabolic changes were associated with a 79% lower mean annualized attack rate compared to patients treated with placebo. The mean annualized attack rate during the intervention period was also reduced by 56% compared to baseline among the patients who received givosiran, as compared to the 18% reduction in the placebo group.

Treatment with givosiran also significantly reduced annualized hemin use by 48% compared to patients treated with placebo.

“The Phase 1 results not only advance our understanding of the pathologic basis of AIP but they also signal hope to patients and their caregivers living with the tremendous burden of this disease and its current management,” said Eliane Sardh, MD, PhD. Sardh is a researcher at Karolinska Institutet, consultant at Karolinska University Hospital, and lead author of the study. “I look forward to continued evaluation of the safety and efficacy of givosiran in the ongoing OLE and Phase 3 studies.”

Patients who completed the Phase 1 study are eligible to continue treatment with givosiran in an open label Phase 1/2 extension (OLE) trial (NCT02949830). This new study will evaluate the long-term impact of monthly subcutaneous injections of givosiran up to a maximum period of 25 months.

Preliminary results of long-term treatment showed that givosiran could further stabilize the disease, with five of 12 treated patients having no porphyria attacks for a mean period of 7.4 months. These patients experienced a mean reduction of annualized attack rate of 93% and 94% in hemin use compared to placebo in the Phase 1 trial.

Alnylam is also assessing the potential of givosiran in the pivotal Phase 3 trial (NCT03338816), called ENVISION. The trial has enrolled 94 patients with acute hepatic porphyria across 36 sites in 18 countries. Top-line results from this study are expected to be announced soon.

The company recently initiated the process for submitting a new drug application (NDA) with the U.S. Food and Drug Administration for givosiran as treatment for acute hepatic porphyria. The request is expected to be supported by the Phase 1 and OLE trial data, as well as preliminary data from the ENVISION study, with addition of full clinical results in mid-2019.