ORION-10 was the second of three 19-month Phase III clinical trials for inclusion for lowering cholesterol. Funded by sponsor The Medicines Company, a week after the sponsor announced the actual study data Novartis announced that it was paying $9.7 billion to buy the entire company—paying $85 per share in cash, representing a 41% premium to The Medicines Company 30-day volume-weighted average of $60.33. Both boards unanimously approved the acquisition. Novartis, in seeking to execute a strategy of volume to value with recent additions, puts more chips down in a bet for value-driven amount!

What is Going on?

Novartis, in its quest to build shareholder value, must continue to make bold bets on the shift from volume to value in the world of drug development. Novartis has made a number of moves into new value-driven specialties, such as gene therapy and radiopharmaceuticals, but for long term sustainable growth, they will need even more horsepower—meaning more volume in the form of sales. The Cardiovascular market reflects the epicenter of a health war—representing the number one driver of death in American, for example

Cardiovascular disease treatment drug development has been in somewhat of a drought. A range of innovative new drugs for high cholesterol and heart failure haven’t sold as well as forecast. The new medicines compete with a range of older, more established drugs—that happen to be much cheaper. Based on the social determinants of health, a patient’s economy can possibly associate with conditions such as weight and cardiovascular risk—price is a factor. Many that need such medication won’t be economic high-rollers—in fact, the target demographic represents the large working to middle classes who have seen their overall earning power decline over the past decades. Moreover, specialized physicians, such as cardiologists, often seek substantial evidence for long term benefits prior to writing prescriptions.

Novartis’ Ernesto represents an example. According to a recent Wall Street Journal by Denise Roland, the heart failure drug has fallen well short of its projected $5 billion now sitting at $1.2 billion nine months into the year;

the excitement from the acquired target centered on an investigational drug called inclisiran.

What is Inclisiran?

Known as ALN-PCSsc, or ALN-60212, the experimental drug for the treatment of Familial hypercholesterolemia (FH), a genetic disorder characterized by high cholesterol levels, very high levels of low-density lipoprotein (LDL or “bad cholesterol”), in the blood and early cardiovascular disease, is a small interfering RNA that inhibits translation of protein PCSK9The Medicines Company has been developing the company based on the securing of licensing rights from Alnylam Pharmaceuticals in 2013

ORION-10

The Phase III ORION-10 trial targeted up to 1561 patients. The Phase III, placebo-controlled, double-blind, randomized study in participants with ASCVD and elevated LDL-C despite the fact that maximum tolerated a dose of LDL-C lowering therapies to evaluate the efficacy, safety and tolerability of subcutaneous (SC) inclisiran injection(s). A multicenter study based in the United States, The Medicines Company used nearly 150 clinical research sites—they opted not to publish the identifications of the sites in Clinicaltrials.gov.

Results

By 2019, The Medicines Company announced positive results from a pivotal Phase III study (apparently all primary and secondary endpoints were met with efficacy consistent with Phase I and II studies. Consequently, The Medicines Company was preparing to file a New Drug Application (NDA) in Q4 2019 with the FDA and a similar submission in Europe in Q1 2020. Now Novartis will take on those duties.

Market Potential for Inclisiran

The market for drugs to lower LDL-cholesterol could expand or experience even more competition. After all, not long ago, Amgen launched Repatha, and Sanofi/Regeneron launched Praluent. Both part of a new class of drug known as PCSK9 inhibitors, they represented big potential as they proved highly effective in clinical trials—when in combination with generic statins evidencing the reduction of LDL-c below 50 mg/dL. However, they also came at extremely high price tags around $14,000 per annum for treatment. Health systems and payers were leery due to cost, and hence they established high thresholds for coverage.

Payer Problems

As a response, the commercial biopharma companies conducted billion-dollar cardiovascular outcome studies evidencing that this new class of therapy reduced heart attacks and strokes as compared to taking statins by themselves. Moreover, both Amgen and Sanofi/Regeneron severely cut prices—down to around $,5800—to win over payers and health systems. But the sales have disappointed: by 2018, Repatha hit $550 million, and Praluent hit $307 million—far under the potential as Pfizer’s Lipitor hit over $1 billion per month at the apex of its lifecycle.

Enter Inclisiran and the Differentiation

The Medicines Company long ago sought to out-innovate its competitors. Smaller biotech, it embraced a reputation for the flexible, agile, yet the quality-driven business of R&D. Inclisiran was different from the other two PCSK9 inhibitors in that it a siRNA-based molecule, hence inhibiting the expression of genes involved in the liver production of PCSK9—and in the process thereby blocking PCSK9 at the source. This was a fundamentally different approach than the other two, which targeted the PCSK9 protein directly.

Hence Inclisiran upon approval represents a differentiator that payers and patients may fully embrace: It need only be dosed twice a year, while Repatha is administered every two weeks. The Medicines Company did their cardiovascular homework—on the one hand, they would need to recoup significant R&D and clinical trial expenditures, and on the other hand they saw what happened to the PCSK9 inhibitors when it came to pricing and economics—they have all but not lived up to their potential. The Medicines Company’s inspiration is the revenues Pfizer’s Lipitor generated back in the day—why not price the drug for the cardiovascular patient masses? More powerful drugs will be needed, given the contributory factors such as the obesity crisis that will ensure cardiovascular drugs continue to sell.

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