Alnylam, the leading RNAi therapeutics company, announced today that the ENVISION Phase 3 study of givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria (AHP), met its primary efficacy endpoint and the majority of secondary endpoints. Specifically, givosiran met the primary endpoint of reduction in the annualized rate of composite porphyria attacks relative to placebo (p less than 0.00000001) and achieved statistically significant results for five of nine secondary endpoints (p less than 0.0001), with a safety and tolerability profile that the Company believes is encouraging, especially in this high unmet disease. Based on these results, the Company plans to complete its rolling submission of a New Drug Application (NDA) and file a Marketing Authorisation Application (MAA) in mid-2019.

“Patients living with AHP experience debilitating and sometimes life-threatening neurovisceral attacks as well as chronic disease manifestations which negatively impact their quality of life. We believe the ENVISION results demonstrate a robust therapeutic benefit of givosiran treatment on the debilitating aspects of this disease. Based on these results, we believe givosiran has the potential, if approved, to be a transformative medicine for AHP patients and their families,” said Akshay Vaishnaw, M.D., Ph.D., President, R&D at Alnylam. “We extend our profound thanks to all the patients, investigators, and study staff who participated in the ENVISION study.”

“These positive ENVISION results represent another landmark event in Alnylam’s pioneering efforts to advance RNAi therapeutics as a whole new class of medicines. Notably, givosiran is the first GalNAc-conjugate siRNA to achieve positive Phase 3 results, and the second example of Alnylam’s R&D strategy bearing fruit due to our focus on genetically validated targets for the advancement of potential high impact medicines,” said John Maraganore, Ph.D., CEO of Alnylam. “Assuming favorable regulatory review, we very much look forward to adding givosiran as the second product in our global commercialization efforts. Indeed, we believe today’s news brings us one important step closer to meeting our Alnylam 2020 goals of building a multi-product, global commercial company with a deep clinical pipeline for continued growth and a robust product engine for sustainable innovation.”

Givosiran has received Breakthrough Therapy and Prime designation by the FDA and EMA, respectively, and has Orphan Drug status in the U.S. and EU for the treatment of AHP. The Phase 1 results of givosiran were recently published in The New England Journal of Medicine¹. FullENVISION study results will be presented in an oral plenary session on Saturday, April 13 at EASL in Vienna, Austria. The ENVISION results have not yet been reviewed by regulatory authorities.

ENVISION Study Results

ENVISION, a randomized, double-blind, placebo-controlled trial, enrolled 94 patients with AHP (including 89 with genetically-confirmed acute intermittent porphyria [AIP], the most common subtype of AHP), at 36 study sites in 18 countries around the world, and is the largest ever interventional study conducted in AHP. Patients were randomized 1:1 to givosiran or placebo, with givosiran administered subcutaneously at 2.5 mg/kg monthly. The primary endpoint for the study was reduction relative to placebo in the annualized rate of composite porphyria attacks, defined as those requiring hospitalization, urgent healthcare visit, or hemin administration, in patients with AIP over six months.

At six months, givosiran met the primary endpoint in patients with AIP (p less than 0.00000001). All the components of the composite primary endpoint and all subgroup analyses for the primary endpoint favored givosiran. Secondary endpoints listed below also demonstrated statistically significant favorable differences in the givosiran arm compared to placebo (p less than 0.0001):

• Urinary ALA levels at three months in AIP patients;
• Urinary ALA levels at six months in AIP patients;
• Urinary PBG levels at six months in AIP patients;
• Annualized days of administered hemin doses in AIP patients; and
• Annualized attack rate in patients with AHP (including AIP).

The remaining four secondary endpoints did not meet the hierarchical threshold for significance and included: daily worst pain (p equal to 0.053), daily worst fatigue (p equal to 0.29), daily worst nausea (p equal to 0.25), and the physical component summary of the SF-12 health survey in AIP patients (p equal to 0.022).

Adverse events (AEs) were reported in 43/48 (89.6 percent) of givosiran and 37/46 (80.4 percent) of placebo patients and serious adverse events (SAEs) were reported in 10/48 (20.8 percent) of givosiran and 4/46 (8.7 percent) of placebo patients. There were no deaths in the study. One patient, described below, in the givosiran arm (2.1 percent) discontinued treatment due to an AE. AEs reported in greater than 10 percent of givosiran patients and seen more frequently compared to placebo were: nausea, injection site reactions, chronic kidney disease and fatigue; those reported in greater than 10 percent of placebo patients and seen more frequently than in givosiran-treated patients were headache, urinary tract infection, vomiting and pyrexia. The AEs of chronic kidney disease were reported in five givosiran-treated patients (10.4 percent) and no placebo patients; these events were all in patients with renal dysfunction at baseline and patients continued dosing throughout the study. Liver transaminase increases greater than three times upper limit of normal (ULN) were observed in 7/48 (14.6 percent) patients on givosiran and 1/46 (2.2 percent) patients on placebo; all had evidence of iron overload or liver disease at baseline. As previously reported and as noted above, one patient on givosiran discontinued treatment due to an increase in alanine aminotransferase (ALT) levels greater than 8 times ULN, a protocol-defined stopping rule; this elevation did not meet Hy’s Law and subsequently resolved. Peak ALT levels in the other six givosiran-treated patients ranged from 3.0-5.4 times ULN and were not accompanied by bilirubin increases. The patients were asymptomatic, and all events resolved with continued dosing (n=5) or after a brief pause in dosing (n=1).

Upon completion of dosing in the ENVISION double-blind period, all eligible patients (93/94 or 99 percent) enrolled in the ENVISION open-label extension (OLE) study, receiving monthly givosiran administration. In addition, patients continue dosing in the Phase 1/2 OLE study with over two years of exposure to givosiran.

Source: Alnylam

BiosanaPharma has received permission from the Australian Bellberry Human Research Ethics Committee HREC to start a phase I clinical trial of their first pipeline product. The trial consists of a bioequivalence double-blind, randomized, two-parallel-group phase I study of a humanized anti-immunoglobulin E monoclonal antibody ‘BP001’ as lyophilized powder formulation compared with the standard omalizumab (Xolair®) lyophilized powder formulation in healthy male volunteers. Prior to the submission of the Investigative Brochure to the HREC an extensive comparability exercise was performed between BP001 and Xolair®, indicating functional, binding and structural similarity between the two molecules. This extensive laboratory exercise was also sufficient for Biosana to obtain a waiver for preclinical studies in animal models from the EMA.

The Phase I trial is expected to be concluded and fully reported in Q4 2019.

Ard Tijsterman, CEO of BiosanaPharma: “We are extremely happy and proud that we’ve been able to develop our first biosimilar product, produced by our innovative ‘3C process’, the first fully continuous process to deliver a product entering phase I. We will start negotiations with potential marketing & sales partners now to perform phase III studies and secure future global distribution of the product.”

Omalizumab

Omalizumab is marketed by Roche/Genentech (USA) and Novartis (ROW) as Xolair® since 2006. It is used to treat moderate to severe allergic asthma and chronic idiopathic urticaria in patients aged 12 years and above in the US and the EU. Additionally, it is approved for paediatric patients aged 6 to 11 years in the EU. Xolair® is delivered via subcutaneous injections. Total sales for Xolair® in 2018 were US$ 2.9M with a consistent growth in both indications of 11-13% annually.  The US market accounted for roughly 2/3 of total Xolair® sales. The patent on Xolair® has expired in 2017 in the US and Europe (Novartis, 2016).

BiosanaPharma

BiosanaPharma is a Dutch/Australian biotechnology company with a disruptive approach to the manufacture and delivery of monoclonal antibody therapeutics (mAbs). BiosanaPharma’s “3C process” offers a 90% reduction in the cost of developing and manufacturing EMA/FDA quality mAbs. The 3C process is a fully-continuous, small footprint platform and produced BiosanaPharma’s first pipeline drug BP001, now approved to enter Phase I (see above).

BiosanaPharma is also developing a platform for oral delivery of biologicals, which has delivered successful preclinical results. The current pipeline consists of biosimilars and oral versions of blockbuster biologics.

Source: BiosanaPharma

BioMarin has announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion for the company’s Marketing Authorization Application (MAA) for Palynziq® (pegvaliase) Injection to reduce blood phenylalanine (Phe) concentrations in patients with phenylketonuria (PKU) aged 16 and older, who have inadequate blood Phe control (blood Phe levels greater than 600 micromol/L) despite prior management with available treatment options. In addition, the CHMP noted that the data collected in the Phase 3 trial and extension study was suggestive of an improvement in inattention and mood symptoms.

In May 2018, Palynziq, a PEGylated recombinant phenylalanine ammonia lyase enzyme, received regulatory approval from the U.S. Food and Drug Administration, making it the first approved enzyme substitution therapy to target the underlying cause of PKU by helping the body break down Phe. 

“For more than a decade, BioMarin has been committed to providing meaningful new treatment options for the PKU community.  Palynziq is the latest result of this commitment and represents the very first enzyme therapy for PKU; an important step forward in advancing the standard of care and in broadening available treatment options for PKU patients,” said Hank Fuchs, M.D., President Worldwide Research and Development at BioMarin. “We thank the CHMP for recognizing the potential of Palynziq to make a difference for patients living with PKU and are grateful to the PKU community for their continued support and participation in the clinical program.”

“People living with PKU have limited treatment options to manage their Phe levels. As a treating physician, I welcome the potential addition of a new option that could substantially lower Phe levels for more patients with this rare, genetic disease,” said Professor Francjan van Spronsen, Head of Metabolic Diseases at Beatrix Children’s Hospital, Center of Expertise for PKU and Tyrosinemia in The Netherlands. “This offers the potential to effectively control Phe levels in patients with PKU and allow for more normal nutritional intake.” 

The CHMP is a scientific committee composed of representatives from the 28-member states of the EU, and Iceland, Norway and Liechtenstein. The committee reviews medical product applications on their scientific and clinical merit and provides advice to the European Commission (EC), which has the authority to approve medicines for the EU. The EC, which typically adheres to the recommendation of the CHMP, is expected to make its final decision on Palynziq in Q2 2019. 

The CHMP based its opinion on the totality of data from the Palynziq clinical development program including a Phase 3 pivotal study, PRISM-2, which showed that a group of patients taking either 20 mg or 40 mg of Palynziq maintained mean blood Phe levels at 553.0 µmol/L and 566.3 µmol/L respectively, compared to their baseline in the randomized discontinuation trial (RDT) of 596.8 µmol/L and 410.9 µmol/L. The corresponding 20 mg and 40 mg placebo treated groups mean blood Phe levels increased to 1509.0 µmol/L and 1164 µmol/L compared to their RDT baselines of 563.9 µmol/L and 508.2 µmol/L respectively.The 8-week PRISM-2 double-blind, placebo-controlled, randomized drug discontinuation trial (RDT) consisted of 86 patients, who were randomized to either remain on Palynziq or receive matching placebo. 

The CHMP also considered data from an ongoing open-label extension study at 36 months, where patients being treated with Palynziq showed durability and an increase in participants reaching blood Phe thresholds of physiologically normal (≤120 µmol/L), as well as thresholds recommended in the U.S. (≤360 µmol/L) and the European Union (E.U.) (≤600 µmol/L).  At 36 months, 58% of the participants reached Phe levels of ≤120 µmol/L, 66% reached Phe levels of ≤360 µmol/L. and 72% reached Phe levels of ≤600 µmol/L.  These results were observed concurrent with a median increase in protein intake from intact food of 25g over baseline after 36 months on treatment. In addition, the CHMP noted that the data collected in the Phase 3 trial and extension study was suggestive of an improvement in inattention and mood symptoms as measured by the inattention subscale of the investigator-rated Attention Deficient Hyperactivity Disorder Rating Scale (ADHD-RS IV) and the Profile of Mood States (POMS) tool that was modified to be specific to PKU (PKU-POMS). 

PKU is a rare genetic disease that manifests at birth and results in a variety of cumulative toxic effects on the brain, and is marked by an inability to break down Phe, an amino acid that is found in all forms of protein. PKU affects approximately 50,000 diagnosed patients in the developed world, and in Europe, approximately 1 in every 10,000 newborn babies are affected by this disease.^[i] Approximately, 18,000 patients aged 16 and older are affected by PKU in Europe and the Middle East. Left untreated, high levels of Phe become toxic to the brain and may lead to serious neurological and neuropsychiatric-related issues, affecting the way a person thinks, feels, and acts. Due to the seriousness of these symptoms, in many countries, infants are screened at birth to ensure that they are diagnosed early and treated to avoid intellectual disability and other complications.

Phase 3 Study Design

The Phase 3 program consists of two studies.  PRISM-1 study was a Phase 3 open-label, randomized, multi-center study that enrolled 261 patients, and its primary objective was to characterize the safety and tolerability of Palynziq during induction, titration, and maintenance dosing. The secondary objective of the study was to evaluate blood Phe levels during induction, titration, and maintenance dosing to achieve a target dose of Palynziq 20mg/day or 40mg/day.

215 patients who completed PRISM-1 or PAL-003 (Phase 2 long term extension) enrolled into PRISM-2, which included a randomized, double-blind, placebo-controlled discontinuation study to evaluate the efficacy and safety of subcutaneous injections of Palynziq self-administered by adults with PKU, followed by an open-label extension.  The primary efficacy endpoint is change from the RDT baseline in blood Phe at eight weeks.

Patients who reached a target dose and achieved ≥20% decrease in blood Phe from PRISM-1 baseline were randomized into the RDT portion of the study to either continue their Palynziq dose or to start matching placebo.  Those participants not reaching a ≥20% reduction in blood Phe from PRISM-1 baseline did not match the inclusion criteria for the RDT and enrolled into the open label extension portion of the study.  In the open-label extension, physicians were allowed to modify dose based on blood Phe response using a range of doses from 10 mg/day to 60 mg/day.  Patients were evaluated for safety, changes in Phe levels and neurocognitive assessments focused on inattention and mood symptoms. 

Medical Guidelines Support Lifelong Therapy to Manage PKU

Medical guidelines in both the United States and Europe support the need for lifelong management of phenylalanine (Phe) levels in patients with phenylketonuria or PKU.  In Europe in 2017, The Lancet Diabetes & Endocrinology published shortened medical guidelines, and the Orphanet Journal of Rare Diseases published a full version of the Guidelines stating that untreated blood Phe concentrations greater than 600 μmol/l should be treated. Both publications can be accessed on the website of the European Society for Phenylketonuria (ESPKU). 

In the U.S., the American College of Medical Genetics and Genomics (ACMG) issued guidelines in 2014, which state that treatment of PKU should be initiated as early as possible and must be continued throughout adulthood and “lifelong,” with a goal of maintaining blood levels of Phe for all patients between 120-360 umol/L.  According to the guidelines “the primary goal of therapy is to lower blood Phe, and any interventions, including medications, or combination of therapies that help to achieve that goal in an individual, without other negative consequences, should be considered appropriate therapy.”

Source BioMarin