Pharma’s Cutting Edge

siRNA passes milestone

              Images courtesy of Alnylam

Researchers from Alnylam Pharmaceuticals, Roche Kulmbach, the Swiss Federal Institute of Technology, UT Southwestern Medical Center at Dallas, and MIT have collaborated on research published online yesterday in Nature (subscription req.) that demonstrates the efficacy and afety of systemically administered synthetic siRNA. 

Despite the hype that has followed siRNA for the last couple of years, accompanying the IPOs of SIRNA Therapeutics and Alnylam Pharmaceuticals, many unknowns remain about the feasibility of delivering systemic synthetic siRNA safely and effectively.  For siRNA proponents and their investors, one of the scariest unknowns was whether siRNA would suppress microRNAs.  microRNAs are ~22nt RNAs that regulate transcription and translation of proteins via a protein complex. known as RISC.   Unlike siRNA, which generally suppresses a single mRNA transcript, microRNAs each affect the regulation of more than one protein, providing a post-transcriptional mechanism for coordinated regulation of important cell growth and survival pathways. 

The concerns regarding siRNAs were brought to light last year, when it was discovered that systemic delivery of synthetic short hairpin RNAs (shRNAs, natural precursors to siRNA) disrupted microRNA synthesis, leading to frequent fatal toxicity.  The cause of toxicity was believed to be saturation of a protein needed for nuclear export of microRNA precursors.  Although it was believed that siRNAs would not cause the same saturation problem, it was not known for certain whether in vivo concentrations of siRNA sufficent to suppress mRNA by upwards of 80% would avoid similar microRNA disruption and its associated toxicity.  This latest work shows that siRNA administration leading to therapeutic effects is not associated with microRNA suppression or severe toxicity in mice.  Because these pathways are largely evolutionarily conserved, it’s expected that the findings will be transferable to humans, although no studies of systemic siRNA administration to humans have been conducted.  Non-human primates have been administered siRNA systemically, with promising results so far.

Bottom line is that this work was a necessary and important step in the progression of systemic siRNA therapy for humans.  Both Alnylam and Sirna (now a part of Merck) are testing synthetic siRNAs delivered locally into the airways and eyes, respectively.  Both also have siRNAs intended for systemic delivery in preclinical testing.  We can now be reasonably assured that both firms will eventually advance systemic siRNAs into the clinic.  Although the first clinical disease targets for systemic siRNA aren’t known for sure, decent bets for Alnylam are hypercholesterolemia and liver cancer, and for Merck are Hepatitis C and Type 2 diabetes.

As expected, the Senate voted by unanimous consent to send PDUFA 2007 (incorporating the Senate’s FDA Revitalization Act or FDARA) to the President for his signature.  The bill’s text can be found in the link in yesterday’s post.

PDUFA H.R. 3580 (2007)

In a 405-7 vote, the U.S. House passed legislation reauthorizing PDUFA.  The full-text link to the approved legislation is above.  Here are some highlights of the bill focused on amendments to laws affecting regulation of drugs (devices are also covered under the bill), which must now be passed by the Senate without further amendment (as early as this afternoon) and signed by the President before becoming law.

1. Fees: Total revenues from fees comparable to prior fees are set at $392.8M during FY 2008-2012, a 51% increase over FY 2007 expected revenues. In addition, fees are set aside specifically for drug safety, beginning at $25M for FY 2008, and progressively increasing to $65M by FY 2012.  Congress eliminated the orphan-drug exception to fee collection from companies with more than $50M in gross worldwide revenues for the preceding 12 months prior to the exemption request. Congress authorized collection of an advisory review fee for DTC ads submitted for advisory purposes to FDA prior to their public dissemination. The fee may not exceed $83,000 per advisory review and may not increaase more than 50% year over year. Total revenues from such fees are set at $6.25 M for FY 2008-2012.2. Drug Safety Surveillance: The expected scope and performance of drug safety surveillance supported by FDA is increased, with Congress explicitly authorizing use of “improved adverse-event data-collection systems…and improved analytical tools.”

3. Pediatric Research:  The Pediatric Research Equity Act and The Best Pharmaceuticals for Children Act are reauthorized with minor modifications.

4. FDA Modernization: The Reagan-Udall Foundation is authorized.  This non-profit foundation’s purpose is to advance FDA’s mission to modernize development of medicines, foods, and cosmetics, accelerate innovation, and enhance product safety.  The Office of The Chief Scientist is created to “oversee, coordinate, and ensure quality and regulatory focus of the intramural research programs…” of FDA.  Public-private partnerships between FDA and non-profit institutions to advance FDA’s Critical Path Intiative is established.

5. Conflicts of Interest: Waivers allowing financially conflicted experts to participate in advisory committee meetings are expected to to drop by 5% per year from the base year waiver percentage of 2007 (set as 100%) from 2008 through 2012, such that the percentage of meeting exceptions granted in 2012 will be 75% of that in 2007.

6. Clinical Trial Databases: The amount of information captured for the U.S. trial registry is significantly expanded to include more data pre-trial and links to results from trials, including results that are written in language comprehensible by lay audiences.  Result updates are to be made annually. HHS has three years after passage of PDUFA 2007 to implement this expansion fully.

7. Postmarket studies and surveillance:  Entire sections are added regarding postamarket studies and risk evaluation and mitigation strategies.  Probably the most important new addition is the requirement that sponsors respond to FDA notice of a postmarket safety issue with a supplemental label change.  FDA decides unilaterally when to make such notifications.  The sponsor’s proposed label change change is subject to review and discussions.  However, such discussions may last only 30 days following FDA notification, and within 15 days after conclusion of discussions, FDA may issue an order directing the labeling change. Within 5 days of this order, an appeal may be made using normal dispute resolution procedures.  Similar rules regulate notifications of a need for risk mitigation strategies.  Should sponsors fail to respond appropriately to FDA postmarket safety or risk mitigation notifications, drug products would no longer be qualified for sale in the U.S.

Congress has also authorized development of postmarket risk identification and analysis methods that includes linkages among multiple sources of data, with goals of at least 100,000,000 patients [under analysis] by 2012. FDA is authorized to seek public-private collaborations to improve its postmarket risk identification and analysis methods.

8.  Television and other DTC ads: FDA is given authority to require submissions of TV ads no later than 45 days before they are aired. FDA will establish standards in the next 30 months that will be used to determine whether a major statement relating to side effects or contraindications is presented appropriately. First-offense fines for false or misleading DTC ads are $250,000, with $500,000 per each subsequent violation.  A report on DTC ads and their benefits to subsets of the general population will be filed within 24 months of PDUFA 2007 passage.  A schedule for payments of fines, including fines for recurring violations, has been added to the enforcement rules.

9.  Citizens Petitions:  FDA may now deny a Citizen Petition whose primary purpose is to delay approval of an application and if it does not raise valid scientific or regulatory issues.  The 30-month exclusivity period for generics is extended if a Citizen Petition was filed against its approval and is denied.  The length of extension equals the time period between filing of the Petition and the Agency action on the Petition.  An annual report to Congress describing Petitions that resulted in delayed approvals of generics will be submitted.

10.  Postmarket drug safety information for patients and providers:  FDA must improve its procedures for internet-based dissemination of drug information to include a central clearinghouse of safety data and label information and enabling “patients, providers and drug sponsors to submit adverse event reports thrugh the Web site.” FDA will also establish an advisory committe on risk communication.

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There’s lots of well-intentioned stuff here, although one has to wonder how well some of the “wish list” items for FDA future operational improvements can be encouraged into action by legislation.  It seems to me as if  Congress is trying to substitute itself for effective FDA and HHS leadership, and that will never work.  Indeed, the best potential FDA leaders will be discouraged from taking the job if Congress is viewed as their micromanager.  That said, at least this Congress has made it known explicitly what it overwhelmingly believes are the top priorities for this Agency, and its hard to argue against their priorities.

PDUFA Reauthorization: Almost There

As Motley Fool and others are reporting, we can expect to see the 2007 bill reauthorizing the Precription Drug User Fee to emerge from conference committee this week, as FDA will give notices of layoffs to 2,000 employees on Sept. 21 without the legislation passing both houses and being signed into law by the president.  Conference committee sessions are closed to the public.  Congressional aides have been reporting that language providing a pathway for FDA approval of biosimilars aka biogenerics has been removed from consideration of the PDUFA legislation but could be debated as part of stand-alone legislation later this year.

I will report on the contents of the proposed PDUFA legislation as it is made public.  It’s fair to assume that morale and workflow are being disrupted within FDA while it awaits word on the bill.  It’s also fair to assume that such distractions are not good for sponsors. 

Obesity-associated improvements in metabolic profile through expansion of adipose tissue

Obesity is bad for you, right?  Not so quick.  It’s been known for decades that deficiencies of fat in unusual to rare syndromes known as lipodystrophies (aka lipoatrophic diabetes) can cause early-onset severe insulin resistance and eventually diabetes.  Based on these cases, clinical researchers surmised that fat isn’t necessarily bad for you–in fact you need some minimum amount of fat to have normal metabolism–and abnormal patterns of fat accumulation, such as an acquired loss of fat in subcutaneous tissues, can trigger insulin resistance and diabetes. 

Since those early clinical studies of lipoatrophic diabetes, many clinical and animal studies have demonstrated that the above is consistently true, and have recently led to a hypothesis that visceral fat (i.e. the fat surrounding internal organs, particularly in the abdomen) is harmful, whereas subcutaneous fat is not and may even help protect against diabetes.  The prevailing theory devised to account for the visceral/subcutaneous fat dichotomy is that triglyceride accumulation within subcutaneous fat serves as a kind of sink that shields vital organs from the sometimes harmful metabolic consequences of intracellular triglycerides (I say sometimes because elite athletes accumulate intracellular fat in muscle tissue without apparent harmful consequences).  In contrast, visceral fat accumulation leads to harmful metabolic consequences because venous drainage of visceral fat feeds fatty acids and glycerol to the liver, where they are reformed in hepatocytes into triglycerides.  Hepatic steatosis results, leading to insulin resistance.  For some unknown reason, says the lipotoxicity theory of diabetes, some people who consume an excess of energy relative to their energy expenditure, are able to accumulate visceral fat more effectively than subcutaneous fat and develop insulin resistance and beta cell failure (as a consequence of fat accumulation in the pancreas), leading to diabetes.  Aside from the “unknown reason” bit, it’s an elegant theory supported by a large body of observational and experimental data in multiple species, including humans.  What has been lacking, however, is an experimental model demonstrating that unconstrained subcutaneous fat expansion allows for development of obesity uncoupled from harmful metabolic consequences (i.e. insulin resistance, beta cell failure and diabetes).

In yesterday’s JCI (link above), Kim et al from Philpp Scherer’s group at UT Southwestern have published detailed descriprions of just such a model.  They created the unusual obesity model by breeding a transgenic mouse that constitutively overexpresses the hormone adiponectin onto an ob/ob mouse background.  The ob/ob mouse is a well described model of congenital leptin deficiency that results in morbid obesity and insulin-resistant diabetes.  Adiponectin is one of the hormones whose expression increases in response to PPAR gamma agonists, like the TZDs pioglitazone (Actos) and rosiglitazone (Avandia), drugs that increase fat mass, primarily subcutaneously, and that also improve insulin resistance.  As it turns out overexpressing adiponectin in leptin-deficient mice leads to diminished food intake (relative to body size) and diminished calorie expenditure (lower activity and lower body temperature) relative to leptin-deficiency alone.  It also leads to fat accumulation and even more weight gain, resulting in massively obese mice.  The balance of energy expenditure and fat accumulation without a change in fat clearance rate suggests enhanced efficiency of fat generation as an important mechanism for obesity in the mice.  Despite the weight gain and fat accumulation, the mice were protected from insulin resistance, beta cell failure and diabetes.  Furthermore, the triglyceride accumulation seen in the organs of leptin-deficient animals was absent in the transgenic animals, as was the associated inflammation (thought to be related to the lipotoxicity of intracellular fat).

Of interest clinically, the transgenic animals, including those bred on a WT background, also developed cardiomyopathy without fat accumulation in heart muscle.  As you’ll recall, as of August, the TZDs now have black-box warnings in their US labels regarding an increased risk of heart failure.  The animal finding suggests that adiponectin might be mechanistically related to the observed heart failure risk.  Keep in mind, though, that Kim et al also found that adiponectin feeds forward to enhance synthesis of PPAR gamma, so it’s not possible to make a TZD-adiponectin link to CHF based on these observations alone.

Although this model probably doesn’t offer any direct uses to drug hunters, it does offer an example of the rescue of a mouse model of obesity-related diabetes through fat accumulation.  In that regard, it serves two important purposes relevant to drug discovery.  First, it adds substantial weight to the lipotoxicity theory of type 2 diabetes, providing a basis for continued drug research in that area.  Many questions remain:  Is it possible to promote subcutaneous lipogenesis without simultaneously promoting morbid obesity?  Can these experimental findings be replicated by manipulating the downstream effectors of adiponectin action in fat; can it be done without promoting cardiomyopathy?  What exactly are the mediators of the toxic effects of triglycerides in liver, muscle and pancreas, and can they be safely interrupted?  Second it provides an animal-model benchmark for drugs intended to disrupt the obesity-diabetes link.  As it happens, the mark for prevention is set pretty high; the mice were completely protected against insulin resistance, beta cell dysfunction, and diabetes resulting from increased food intake.  Of course, the cure also further worsened their already morbid obesity, so there’s still lots of room for improvement. 

In some future post, I’ll discuss what has already been done and what might be done in the future to further test the lipotoxicity/fat deficiency model of diabetes in humans.