Dec 06, 2015 Press Release for Alnylam
Alnylam Reports that ALN-CC5 Achieves Up to 99 Percent Knockdown of Serum C5 and Up to 98 Percent Inhibition of Serum Hemolytic Activity with Durability Supportive of Once Monthly and Possibly Once Quarterly Subcutaneous Dose Regimen
Dec 06, 2015
- In Addition, Investigational ALN-CC5 Achieves Low Levels of Residual Serum C5 at or Below Levels of Free C5 Estimated from Reports with an Approved Anti-C5 Monoclonal Antibody -
- ALN-CC5 Shown to be Generally Well Tolerated with No Clinically Significant, Drug-Related Adverse Events to Date -
- Alnylam Remains on Track to Initiate Dosing in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) by Year's End and Guides for Initial Data in Mid-2016 -
- Management to Discuss Results at Upcoming R&D Day on
"We believe that these new ALN-CC5 results meet our goal of achieving
both inhibition of serum hemolytic activity at the 80% target level and
highly robust knockdown of serum C5 to residual levels at or below those
estimated - in separate studies -for free C5 at therapeutic doses of
eculizumab. We're also very pleased with the consistency and durability
of ALN-CC5 clinical activity, which we believe supports at least a once
monthly, and possibly a once quarterly subcutaneous dose regimen," said
"Significant progress has been made in the treatment of complement-mediated diseases, including PNH, but we continually strive for even further improvements for our patients. In this regard, I believe that a new medicine providing both a consistent level of inhibition of complement activity and infrequent subcutaneous dosing would be a welcome addition to the treatment landscape," said Peter Hillmen, MB ChB, F.R.C.P., F.R.C.Path., Ph.D., Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust, U.K. "I am encouraged by the data from this ongoing Phase 1/2 trial, and, in particular, the results showing very low residual levels of serum C5. If these results can be duplicated in patients with PNH, I believe ALN-CC5 has the potential to offer a novel therapeutic option for these patients."
New
data were presented in a poster at ASH, and include updated data
(N=20) from the single ascending dose (SAD) cohorts, as well as initial
data (N=12) from multiple ascending dose (MAD) cohorts. Safety data are
as of a cutoff date of
Alnylam and collaborators will discuss these new clinical results with
ALN-CC5 at the company's upcoming R&D Day, to be held on
Preliminary Phase 1/2 Study Clinical Activity Results
In the SAD cohorts (N=20), ALN-CC5 achieved potent and dose-dependent knockdown of serum C5 of up to 99 percent, with a mean maximum knockdown of 98 ± 0.3 percent (p less than 0.01 compared with placebo) in the top dose cohort. After a single dose, nadir levels of residual C5 as low as 1.1 microgram/milliliter (mcg/mL) were achieved. This level of residual C5 in healthy volunteers is at or below the levels of free C5 estimated for eculizumab at therapeutic drug concentrations in an earlier published study in patients with atypical hemolytic uremic syndrome (aHUS)1. Maximal effects on C5 knockdown were achieved starting on day 20, and lasted for several months. For example, an up to 97.8 percent knockdown of serum C5 was still maintained at day 98 after just a single dose of drug in the top dose cohort. The company believes that the durable and clamped nature of C5 knockdown supports a once monthly and possibly a once quarterly, fixed dose subcutaneous regimen.
In addition, single dose administration of ALN-CC5 was associated with potent, dose-dependent, and durable inhibition of complement activity. In particular, a single ALN-CC5 dose resulted in an up to 95 percent inhibition of complement alternative pathway (CAP) activity, an up to 97 percent inhibition of complement classical pathway (CCP) activity, and an up to 79 percent inhibition of serum hemolytic activity (mean maximum 74 ± 4.2 percent). In addition, as with C5 knockdown, the inhibitory effects of ALN-CC5 toward complement activity were found to be highly durable, lasting for several months after just a single dose.
In MAD cohorts (N=12) receiving five weekly doses of ALN-CC5, an up to 99 percent knockdown of serum C5 was achieved with a mean maximum knockdown of 98 ± 0.2 percent (p less than 0.01 compared with placebo) in the top dose cohort. Following ALN-CC5 administration, nadir levels of residual C5 as low as 0.6 mcg/mL were observed. Regarding effects on complement activity, multiple doses of ALN-CC5 resulted in an up to 97 percent inhibition of CAP activity, an up to 97 percent inhibition of CCP activity, and an up to 98 percent inhibition of serum hemolytic activity (mean maximum 84 ± 7.6 percent). These effects on complement activity were statistically significant (p less than 0.05 compared with placebo). The level of CAP inhibition achieved in these healthy volunteers is comparable to results seen in people with homozygous C5 deficiency2,3, which highlights the highly robust knockdown of serum C5 levels achieved with ALN-CC5. Furthermore, multiple dose administration of ALN-CC5 achieved the 80 percent target level of serum hemolytic activity inhibition previously correlated with LDH reductions in PNH patients4. Finally, after the last dose of ALN-CC5, C5 knockdown and inhibition of complement activity were highly durable, with effects lasting several months. For example, after five weekly doses in the 200 mg cohort, an up to 98.3 percent knockdown of serum C5 was maintained at day 112.
Preliminary Phase 1/2 Safety Results
All safety results remain blinded as to treatment allocation. Single and multiple weekly subcutaneous doses of ALN-CC5 or placebo were generally well tolerated with no clinically significant, drug-related adverse events (AEs) reported to date. There were no serious adverse events (SAEs), study discontinuations, or clinically significant laboratory findings. In Part A of the study, a total of 29 AEs were observed, all of them mild or moderate in severity, of which 3 were deemed possibly related to ALN-CC5 or placebo. Two patients experienced mild, transient injection site reactions (ISRs). In Part B of the study, a total of 30 AEs were observed, all of them mild or moderate in severity, of which 12 AEs were deemed possibly related to ALN-CC5 or placebo. Four subjects experienced mild, transient ISRs.
ALN-CC5 Phase 1/2 Study Design
The ongoing Phase 1/2 trial of ALN-CC5 is being conducted in three parts. Parts A and B are randomized (3:1, drug:placebo), double-blind, placebo-controlled, SAD and MAD studies, respectively, which will enroll up to a total of 60 healthy adult volunteers. These parts of the study are designed to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Additional objectives include clinical activity as measured by knockdown of serum C5 and levels of residual C5. In addition, additional objectives include measurement of effects on inhibition of serum complement activity, including measurements of CAP and CCP activity, and serum hemolytic activity. A total of 5 SAD cohorts were enrolled in the study, with fixed doses ranging from 50 to 900 mg. A total of 3 MAD cohorts have been enrolled in the study with fixed doses of 100, 200 or 400 mg, where subjects are receiving once weekly, subcutaneous doses of ALN-CC5 or placebo for 5 weeks. Part C is an open-label, multi-dose study in patients with PNH, to assess safety, tolerability, and clinical activity of ALN-CC5, administered for up to 13 weeks. This part of the study will include an exploratory evaluation of ALN-CC5 effects on levels of LDH, a measure of endogenous red blood cell hemolysis.
About ALN-CC5
ALN-CC5 is an investigational RNAi therapeutic targeting the C5
component of the complement pathway, currently in early stage clinical
development for the treatment of complement-mediated diseases. The
safety and efficacy of ALN-CC5 have not been evaluated by the
In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-CC5, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.
About RNAi
RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.
About
Alnylam is a biopharmaceutical company developing novel therapeutics
based on RNA interference, or RNAi. The company is leading the
translation of RNAi as a new class of innovative medicines. Alnylam's
pipeline of investigational RNAi therapeutics is focused in 3 Strategic
Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of
RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic
Disease, with a pipeline of RNAi therapeutics toward genetically
validated, liver-expressed disease targets for unmet needs in
cardiovascular and metabolic diseases; and Hepatic Infectious Disease,
with a pipeline of RNAi therapeutics that address the major global
health challenges of hepatic infectious diseases. In early 2015, Alnylam
launched its "Alnylam 2020" guidance for the advancement and
commercialization of RNAi therapeutics as a whole new class of
innovative medicines. Specifically, by the end of 2020, Alnylam expects
to achieve a company profile with 3 marketed products, 10 RNAi
therapeutic clinical programs - including 4 in late stages of
development - across its 3 STArs. The company's demonstrated commitment
to RNAi therapeutics has enabled it to form major alliances with leading
companies including
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including without limitation,
Alnylam's views with respect to the potential for RNAi therapeutics,
including ALN-CC5, expectations regarding the timing of clinical trials
with ALN-CC5 and the reporting of clinical data from these trials,
including the expected reporting of additional data from its ongoing
Phase 1/2 trial in mid-2016, its expectations regarding its STAr
pipeline growth strategy, and its plans regarding commercialization of
RNAi therapeutics, constitute forward-looking statements for the
purposes of the safe harbor provisions under
1 Lathia et al., 2014; ASCPT Annual Meeting; Abstract #387
2 Seelen et al., J Immunol Methods;296:187-198 (2005)
3 Cugno et al., J Thromb Haemost;12:1440-8 (2014)
4 Hill et al., Blood;106:2559-2565 (2005)
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